OBJECTIVE: To examine the effects of caregiver and patient characteristics on caregivers' medical care use and cost. METHODS: One hundred forty-seven caregiver/patient dyads were followed annually for 6 years in three academic Alzheimer's disease centers in the United States. Logistic, negative binomial, and generalized linear mixed models were used to examine overall effects of caregiver/patient characteristics on caregivers' hospitalizations, doctor visits, outpatient tests and procedures, and prescription and over-the-counter medications. RESULTS: Patients' comorbid conditions and dependence were associated with increased health-care use and costs of caregivers. Increases in caregiver depressive symptoms are associated with increases in multiple domains of caregivers' health-care use and costs. DISCUSSION: Findings suggest expanding our focus on dementia patients to include family caregivers to obtain a fuller picture of effects of caregiving. Primary care providers should integrate caregivers' needs in health-care planning and delivery. Clinical interventions that treat patients and caregivers as a whole will likely achieve the greatest beneficial effects.

OBJECTIVE: Adherence to a Mediterranean-style diet (MeDi) may protect against clinical vascular events by reducing atherosclerosis, but data is limited. This is the first observational study of the association between MeDi adherence and carotid plaque thickness and area. METHODS: The study included 1374 participants of the population-based Northern Manhattan Study with diet assessed and carotid intima-media thickness (cIMT) and plaque measured using B-mode ultrasound (mean age 66 ± 9 years, 60% female, 60% Hispanic, 18% White, 19% Black). A MeDi adherence score (range = 0-9, 9 representing maximal adherence) was examined continuously and in quintiles (3/4/5/6-9 vs. 0-2). RESULTS: Mean cIMT = 0.9 ± 0.1 mm and 57% had plaque (median plaque thickness = 1.5 mm, 75th percentile = 2.2; median plaque area = 4.2 mm(2), 75th percentile = 15.8). There was no association between MeDi and cIMT or plaque presence. MeDi adherence was inversely associated with the 75th percentile of plaque thickness and median of plaque area in quantile regression analyses. These associations persisted after controlling for demographics, smoking, physical activity, and total energy consumption (effect of a 1-point increase in MeDi score on the 75th percentile of plaque thickness = -0.049 mm, p = 0.03; median of plaque area = -0.371 mm(2), p = 0.03), and when additionally controlling for vascular disease biomarkers, medication use, BMI, and previous cardiac disease. The protective associations appeared strongest for those with a MeDi score of 5 (4th quintile) vs. 0-2 (bottom quintile). Differential effects of a MeDi on plaque thickness and area across race/ethnic groups was suggested. CONCLUSIONS: Moderate and strict adherence to a MeDi may protect against a higher burden of carotid atherosclerotic plaque, which may mediate the protection against clinical vascular events. Efforts to improve adherence to a MeDi are critical to reducing the burden of atherosclerotic disease.

The aim of this paper was to investigate the association of three well-recognised dietary patterns with cognitive change over a 3-year period. Five hundred and twenty-seven healthy participants from the Australian Imaging, Biomarkers and Lifestyle study of ageing completed the Cancer Council of Victoria food frequency questionnaire at baseline and underwent a comprehensive neuropsychological assessment at baseline, 18 and 36 months follow-up. Individual neuropsychological test scores were used to construct composite scores for six cognitive domains and a global cognitive score. Based on self-reported consumption, scores for three dietary patterns, (1) Australian-style Mediterranean diet (AusMeDi), (2) western diet and (3) prudent diet were generated for each individual. Linear mixed model analyses were conducted to examine the relationship between diet scores and cognitive change in each cognitive domain and for the global score. Higher baseline adherence to the AusMeDi was associated with better performance in the executive function cognitive domain after 36 months in apolipoprotein E (APOE) ɛ4 allele carriers (P<0.01). Higher baseline western diet adherence was associated with greater cognitive decline after 36 months in the visuospatial cognitive domain in APOE ɛ4 allele non-carriers (P<0.01). All other results were not significant. Our findings in this well-characterised Australian cohort indicate that adherence to a healthy diet is important to reduce risk for cognitive decline, with the converse being true for the western diet. Executive function and visuospatial functioning appear to be particularly susceptible to the influence of diet.Molecular Psychiatry advance online publication, 29 July 2014; doi:10.1038/mp.2014.79.

Background: Accumulating epidemiological evidence from several populations supports the important role of the Mediterranean-type diet (MeDi) in reducing the risk for age-related diseases such as Alzheimer's disease (AD). However, the relevant literature is clearly deficient for most Mediterranean countries that more closely adhere to the originally described MeDi. Greece resides in the Mediterranean basin, and older generations traditionally adhere to a MeDi. Methods: We here present the design and the preliminary baseline characteristics of the Hellenic Longitudinal Investigation of Aging and Diet (HELIAD). The HELIAD is a population-based, multidisciplinary, collaborative study designed to estimate the prevalence and incidence of AD, other dementias, mild cognitive impairment, and other neuropsychiatric conditions of aging in the Greek population and to investigate associations between nutrition and cognitive dysfunction/age-related neuropsychiatric diseases in this Mediterranean population. The study also ascertains several demographic, medical, social, environmental, clinical, nutritional, and neuropsychological determinants and lifestyle activities. Results: In total, 1,050 participants of a random sample have already completed the initial evaluation. The subjects were, on average, 73.4 (SD = 6.0) years old, 60% of the sample were female, and most of the participants were poorly educated with an average of 5.41 (SD = 3.5) years of education. The performance on the neuropsychological tests was equivalent to the average scores of previous normative Greek samples. More than one third of the population under investigation was considered to be at high risk for malnutrition. Conclusions: The HELIAD may provide important data for expanding our knowledge regarding the prevalence, incidence, and risk factors of AD and several other neuropsychiatric diseases in the Mediterranean region. © 2014 S. Karger AG, Basel.

The active form vitamin D is a seco-steroid with multiple neurotrophic and neuroprotective functions in the central nervous system. Robust evidence from studies in animals suggests that vitamin D deficiency may impair brain physiological functioning causing anatomical and behavioral adverse effects. On the other hand, vitamin D has been found to be protective against biological processes associated with Alzheimer's disease and cognition, including amyloid-β deposition, inflammation, calcium homeostasis, and corticosteroid-induced perturbations in cortical areas and the hippocampus. Human studies that examined the relationship between vitamin D status and cognitive function have provided inconclusive results. The majority of cross-sectional and longitudinal studies suggest a potentially protective association, whereas results from clinical trials are mostly negative, or at best, controversial. We review these studies in humans, with particular emphasis on randomized and observational prospective ones.

BACKGROUND & AIMS: Evidence suggests that consuming light-to-moderate amounts of alcohol reduces the risk of dementia and is associated better cognitive function and less cardiovascular disease, relative to those consuming no or heavy alcohol. There are only minimal data on the association between alcohol and brain magnetic resonance imaging (MRI) markers. This study aimed to examine the association between alcohol and brain structure measured with MRI. METHODS: In this cross-sectional study, high-resolution structural MRI was collected on 589 multi-ethnic community residents of New York aged ≥65 with available alcohol intake assessments via a food frequency questionnaire. Total brain volume (TBV), white matter hyperintensity volume (WMHV), and presence of infarcts were derived from MRI scans with established methods. We examined the association of alcohol intake with these imaging markers using regression models adjusted for demographic, clinical, and vascular risk factors. RESULTS: Compared to non-drinking, light-to-moderate total alcohol (b = 0.007, p = 0.04) or wine (b = 0.008, p = 0.05) intake, but not beer or liquor intake, was associated with larger TBV. Further analysis showed a dose-response association between alcohol (p-trend = 0.03) or wine (p-trend = 0.006) and TBV. Overall, alcohol intake was not associated with WMHV or brain infarcts. CONCLUSIONS: Our study suggests that among older adults in the community, light-to-moderate alcohol intake, in particular wine, is associated with larger TBV. These findings suggest that light to moderate alcohol consumption is potentially beneficial for brain aging, but replication is needed.

BACKGROUND: The ability to predict the length of time to death and institutionalization has strong implications for Alzheimer's disease patients and caregivers, health policy, economics, and the design of intervention studies. OBJECTIVE: To develop and validate a prediction algorithm that uses data from a single visit to estimate time to important disease endpoints for individual Alzheimer's disease patients. METHOD: Two separate study cohorts (Predictors 1, N = 252; Predictors 2, N = 254), all initially with mild Alzheimer's disease, were followed for 10 years at three research centers with semiannual assessments that included cognition, functional capacity, and medical, psychiatric, and neurologic information. The prediction algorithm was based on a longitudinal Grade of Membership model developed using the complete series of semiannually-collected Predictors 1 data. The algorithm was validated on the Predictors 2 data using data only from the initial assessment to predict separate survival curves for three outcomes. RESULTS: For each of the three outcome measures, the predicted survival curves fell well within the 95% confidence intervals of the observed survival curves. Patients were also divided into quintiles for each endpoint to assess the calibration of the algorithm for extreme patient profiles. In all cases, the actual and predicted survival curves were statistically equivalent. Predictive accuracy was maintained even when key baseline variables were excluded, demonstrating the high resilience of the algorithm to missing data. CONCLUSION: The new prediction algorithm accurately predicts time to death, institutionalization, and need for full-time care in individual Alzheimer's disease patients; it can be readily adapted to predict other important disease endpoints. The algorithm will serve an unmet clinical, research, and public health need.

This review summarizes the findings and importance of 12 articles from research at Columbia University in New York City that were among the most cited in the literature between 2006 and 2011. The 12 articles summarized in this review made important contributions to the field of Alzheimer's disease in the last 5 years. Four of the articles established the Mediterranean diet as a food consumption pattern that may prevent Alzheimer's disease in addition to physical activity. Two of the articles advanced our knowledge of predictors of conversion from mild cognitive impairment to dementia. Four of the articles provided important knowledge of risk factors for the progression of Alzheimer's disease and its complications. Lastly, one of the articles laid the theoretical framework for the study of cognitive reserve, an important modifier of the manifestation of Alzheimer's disease. These studies have advanced our knowledge about risk factors, modifiers, and progression of late onset Alzheimer's disease

BACKGROUND: The behavioral and psychological symptoms associated with dementia (BPSD) can be burdensome to informal/family caregivers, negatively affecting mental health and expediting the institutionalization of patients. Because the dementia patient-caregiver relationship extends over long periods of time, it is useful to examine how BPSD impact caregiver depressive symptoms at varied stages of illness. The goal of this study was to assess the association of BPSD that occur during early stage dementia with subsequent caregiver depressive symptoms. METHODS: Patients were followed from the early stages of dementia every six months for up to 12 years or until death (n = 160). Caregiver symptoms were assessed on average 4.5 years following patient's early dementia behaviors. A generalized estimating equation (GEE) extension of the logistic regression model was used to determine the association between informal caregiver depressive symptoms and BPSD symptoms that occurred at the earliest stages dementia, including those persistent during the first year of dementia diagnosis. RESULTS: BPSD were common in early dementia. None of the individual symptoms observed during the first year of early stage dementia significantly impacted subsequent caregiver depressive symptoms. Only patient agitation/aggression was associated with subsequent caregiver depressive symptoms (OR = 1.76; 95% CI = 1.04-2.97) after controlling for concurrent BPSD, although not in fully adjusted models. CONCLUSIONS: Persistent agitation/aggression early in dementia diagnosis may be associated with subsequent depressive symptoms in caregivers. Future longitudinal analyses of the dementia caregiving relationship should continue to examine the negative impact of persistent agitation/aggression in the diagnosis of early stage dementia on caregivers.

OBJECTIVE: This meta-analysis aims to quantitatively synthesize all studies that examine the association between adherence to a Mediterranean diet and risk of stroke, depression, cognitive impairment, and Parkinson disease. METHODS: Potentially eligible publications were those providing effect estimates of relative risk (RR) for the association between Mediterranean diet and the aforementioned outcomes. Studies were sought in PubMed up to October 31, 2012. Maximally adjusted effect estimates were extracted; separate analyses were performed for high and moderate adherence. RESULTS: Twenty-two eligible studies were included (11 covered stroke, 9 covered depression, and 8 covered cognitive impairment; only 1 pertained to Parkinson's disease). High adherence to Mediterranean diet was consistently associated with reduced risk for stroke (RR = 0.71, 95% confidence interval [CI] = 0.57-0.89), depression (RR = 0.68, 95% CI = 0.54-0.86), and cognitive impairment (RR = 0.60, 95% CI = 0.43-0.83). Moderate adherence was similarly associated with reduced risk for depression and cognitive impairment, whereas the protective trend concerning stroke was only marginal. Subgroup analyses highlighted the protective actions of high adherence in terms of reduced risk for ischemic stroke, mild cognitive impairment, dementia, and particularly Alzheimer disease. Meta-regression analysis indicated that the protective effects of Mediterranean diet in stroke prevention seemed more sizeable among males. Concerning depression, the protective effects of high adherence seemed independent of age, whereas the favorable actions of moderate adherence seemed to fade away with more advanced age. INTERPRETATION: Adherence to a Mediterranean diet may contribute to the prevention of a series of brain diseases; this may be of special value given the aging of Western societies.

Poor oral health, including caries, tooth loss, and periodontitis, is ubiquitous worldwide, and is potentially treatable and preventable. Like adverse oral health conditions, Alzheimer disease and related disorders are also very common among aging populations. Established risk factors for Alzheimer disease include cerebrovascular disease and its vascular risk factors, many of which share associations with evidence of systemic inflammation also identified in periodontitis and other poor oral health states. In this review, we present epidemiologic evidence of links between poor oral health and both prevalent and incident cognitive impairment, and review plausible mechanisms linking these conditions, including evidence from compelling animal models. Considering that a large etiologic fraction of dementia remains unexplained, these studies argue for further multidisciplinary research between oral health conditions, including translational, epidemiologic, and possibly clinical treatment studies.

OBJECTIVES: To examine in an observational study (1) relationships between cholinesterase inhibitors (ChEI) and memantine use, and functional and cognitive end points and mortality in patients with Alzheimer's disease (AD); (2) relationships between other patient characteristics and these clinical end points; and (3) whether effects of the predictors change across time. METHODS: The authors conducted a multicenter, natural history study that included three university-based AD centers in the United States. A total of 201 patients diagnosed with probable AD with modified Mini-Mental State Examination (MMSE) scores ≥ 30 at study entry were monitored annually for 6 years. Discrete-time hazard analyses were used to examine relationships between ChEI and memantine use during the previous 6 months reported at each assessment, and time to cognitive (MMSE score ≤ 10) and functional (Blessed Dementia Rating Scale score ≥ 10) end points and mortality. Analyses controlled for clinical characteristics, including baseline cognition, function, and comorbid conditions, and presence of extrapyramidal signs and psychiatric symptoms at each assessment interval. Demographic characteristics included baseline age, sex, education, and living arrangement at each assessment interval. RESULTS: ChEI use was associated with delayed time in reaching the functional end point and death. Memantine use was associated with delayed time to death. Different patient characteristics were associated with different clinical end points. CONCLUSIONS: Results suggest long-term beneficial effects of ChEI and memantine use on patient outcomes. As for all observational cohort studies, observed relationships should not be interpreted as causal effects.

IMPORTANCE: Adherence to Mediterranean-type diet (MeDi) may delay onset of Alzheimer and Parkinson diseases. Whether adherence to MeDi affects time to phenoconversion in Huntington disease (HD), a highly penetrant, single-gene disorder, is unknown. OBJECTIVES: To determine if MeDi modifies the time to clinical onset of HD (phenoconversion) in premanifest carriers participating in Prospective Huntington at Risk Observational Study (PHAROS), and to examine the effects of body mass index and caloric intake on time to phenoconversion. DESIGN, SETTING, AND PARTICIPANTS: A prospective cohort study of 41 Huntington study group sites in the United States and Canada involving 1001 participants enrolled in PHAROS between July 1999 and January 2004 who were followed up every 9 months until 2010. A total of 211 participants aged 26 to 57 years had an expanded CAG repeat length (≥ 37). EXPOSURE: A semiquantitative food frequency questionnaire was administered 33 months after baseline. We calculated daily gram intake for dairy, meat, fruit, vegetables, legumes, cereals, fish, monounsaturated and saturated fatty acids, and alcohol and constructed MeDi scores (0-9); higher scores indicate higher adherence. Demographics, medical history, body mass index, and Unified Huntington's Disease Rating Scale (UHDRS) score were collected. MAIN OUTCOME AND MEASURE: Cox proportional hazards regression models to determine the association of MeDi and phenoconversion. RESULTS Age, sex, caloric intake, education status, and UHDRS motor scores did not differ among MeDi tertiles (0-3, 4-5, and 6-9). The highest body mass index was associated with the lowest adherence to MeDi. Thirty-one participants phenoconverted. In a model adjusted for age, CAG repeat length, and caloric intake, MeDi was not associated with phenoconversion (P for trend = 0.14 for tertile of MeDi, and P = .22 for continuous MeDi). When individual components of MeDi were analyzed, higher dairy consumption (hazard ratio, 2.36; 95% CI, 1.0-5.57; P = .05) and higher caloric intake (P = .04) were associated with risk of phenoconversion. CONCLUSIONS AND RELEVANCE: MeDi was not associated with phenoconversion; however, higher consumption of dairy products had a 2-fold increased risk and may be a surrogate for lower urate levels (associated with faster progression in manifest HD). Studies of diet and energy expenditure in premanifest HD may provide data for interventions to modify specific components of diet that may delay the onset of HD.

Populations of many countries are becoming increasingly overweight and obese, driven largely by excessive calorie intake and reduced physical activity; greater body mass is accompanied by epidemic levels of comorbid metabolic diseases. At the same time, individuals are living longer. The combination of aging and the increased prevalence of metabolic disease is associated with increases in aging-related comorbid diseases such as Alzheimer's disease, cerebrovascular dementia, and sarcopenia. Here, correlative and causal links between diseases of overnutrition and diseases of aging and cognition are explored.

Gait speed is associated with multiple adverse outcomes of aging. White matter hyperintensities (WMH) on magnetic resonance imaging (MRI) have been associated with gait speed, though few studies have examined changes in gait speed over time in population-based studies comprising participants from diverse cultural backgrounds. The purpose of this study was to examine the association between a decline in gait speed and total and regional WMH volumes in a community-based study of aging. Participants (n = 701) underwent gait-speed measurement via a 4-m walk test at the time of initial enrollment and MRI at a second time interval (mean 4.7 [SD = 0.5] years apart). Logistic regression was used to examine the association between large WMH volume and regional WMH volume with gait speed <0.5 m/s (abnormal speed), and a transition to abnormal gait speed. Analyses were adjusted for demographic and clinical factors. Large WMH volume was associated with abnormal gait speed and a transition to abnormal gait speed between the two visits, but not after adjustment for modifiable vascular disease risk factors. Increased frontal lobe WMH volume was associated with abnormal gait speed and transition to abnormal gait speed, but not in adjusted models. WMH are associated with slowing of gait over time. Prevention of WMH presents a potential strategy for the prevention of gait speed decline.

Objectives: A high body mass index (BMI) in middle-age or a decrease in BMI at late-age has been considered a predictor for the development of Alzheimer's disease (AD). However, little is known about the BMI change close to or after AD onset. Methods: BMI of participants from three cohorts, the Washington Heights and Inwood Columbia Aging Project (WHICAP; population-based) and the Predictors Study (clinic-based), and National Alzheimer's Coordinating Center (NACC; clinic-based) were analyzed longitudinally. We used generalized estimating equations to test whether there were significant changes of BMI over time, adjusting for age, sex, education, race, and research center. Stratification analyses were run to determine whether BMI changes depended on baseline BMI status. Results: BMI declined over time up to AD clinical onset, with an annual decrease of 0.21 (p=0.02) in WHICAP and 0.18 (p=0.04) kg/m2 in NACC. After clinical onset of AD, there was no significant decrease of BMI. BMI even increased (b=0.11, p=0.004) among prevalent AD participants in NACC. During the prodromal period, BMI decreased over time in overweight(BMI ≥25 and <30) WHICAP participants or obese (BMI≥30)NACC participants. After AD onset, BMI tended to increase in underweight/normal weight (BMI<25) patients and decrease in obese patients in all three cohorts, although the results were significant in NACC study only. Conclusions: Our study suggests that while BMI declines before the clinical AD onset, it levels off after clinical AD onset, and might even increase in prevalent AD. The pattern of BMI change may also depend on the initial BMI.

Stroke is one of the leading causes of long-term disability and mortality. Mounting evidence from observational studies suggests that among lifestyle factors, diet may be playing an important role for the prevention of stroke. Neuroimaging markers, particularly white matter hyperintensity (WMH) volume and brain infarcts (BI) are more sensitive measurements of cerebrovascular disease than clinical assessments. We reviewed published observational and clinical studies that evaluate the association between dietary factors and WMH and BI. The few existing studies examined only a handful individual nutrients or foods (dietary intake of alcohol, B vitamins, fish, choline, serum markers of antioxidants, and a few food groups, Mediterranean-style diet, and nutrient biomarker patterns. Findings from these studies are inconclusive either due to conflicting results from different studies or due to lack of replication. Further studies are necessary to replicate the existing findings. Many other foods or nutrients or dietary patterns may worth of investigation and longitudinal studies are needed.

OBJECTIVE: The behavioral and psychological symptoms associated with dementia (BPSD) are highly burdensome to caregivers. While BPSD consist of a wide variety of patient behaviors including depression, physical aggression, and paranoid delusions, it remains unclear whether specific symptoms have a differential impact on caregivers. The aims of this study were 1) to assess how individual BPSD, categorized based on how they may affect caregivers, impact depressive symptoms for dementia patient caregivers and 2) to test the pathways by which BPSD clusters impact caregiver depressive symptoms. DESIGN: Cross-sectional analysis of data from a longitudinal study of patients with Alzheimer disease and dementia with Lewy bodies. SETTING: Multiple U.S. dementia clinics. PARTICIPANTS: One hundred sixty patient-caregiver dyads. METHODS: Using multivariate generalized estimating equation logistic models, we analyzed the relationship between four BPSD clusters (patient depressive symptoms, accusatory/aggressive behaviors, nonthreatening psychotic symptoms, and difficult to manage behaviors) and caregiver depressive symptoms and assessed mediators of these relationships. RESULTS: Only the presence of patient depressive symptoms was associated with caregiver depression (odds ratio: 1.55; 95% confidence interval: 1.14-2.1). This relationship was mediated by caregiver report of both the symptom's impact on the patient and perceived burden to caregivers. CONCLUSION: Patient depressive symptoms may be the most important driver of the relationship between BPSD and caregiver depression. Research in this field should further test the effects of individual BPSD and also consider how symptoms may negatively impact caregivers by increasing burden and evoking empathy for the patient.

Many studies have shown that patients with Alzheimer's disease (AD) are at increased risk for developing seizures and epilepsy. However, reported prevalence and incidence of seizures and relationship of seizures to disease measures such as severity, outcome, and progression vary widely between studies. We performed a literature review of the available clinical and epidemiological data on the topic of seizures in patients with AD. We review seizure rates and types, risk factors for seizures, electroencephalogram (EEG) studies, and treatment responses. Finally, we consider limitations and methodological issues. There is considerable variability in the reported prevalence and incidence of seizures in patients with AD-with reported lifetime prevalence rates of 1.5-64%. More recent, prospective, and larger studies in general report lower rates. Some, but not all, studies have noted increased seizure risk with increasing dementia severity or with younger age of AD onset. Generalized convulsive seizures are the most commonly reported type, but often historical information is the only basis used to determine seizure type and the manifestation of seizures may be difficult to distinguish from other behaviors common in demented patients. EEG has infrequently been performed and reported. Data on treatment of seizures in AD are extremely limited. Similarly, the relationship between seizures and cognitive impairment in AD is unclear. We conclude that the literature on seizures and epilepsy in AD, including diagnosis, risk factors, and response to treatment suffers from methodological limitations and gaps.

THAP1 mutations have been shown to be the cause of DYT6. A number of different mutation types and locations in the THAP1 gene have been associated with a range of severity and dystonia phenotypes, but, as yet, it has been difficult to identify clear genotype phenotype patterns. Here, we screened the THAP1 gene in a further series of dystonia cases and evaluated the mutation pathogenicity in this series as well as previously reported mutations to investigate possible phenotype-genotype correlations. THAP1 mutations have been identified throughout the coding region of the gene, with the greatest concentration of variants localized to the THAP1 domain. In the additional cases analyzed here, a further two mutations were found. No obvious, indisputable genotype-phenotype correlation emerged from these data. However, we managed to find a correlation between the pathogenicity of mutations, distribution, and age of onset of dystonia. THAP1 mutations are an important cause of dystonia, but, as yet, no clear genotype-phenotype correlations have been identified. Greater mutation numbers in different populations will be important and mutation-specific functional studies will be essential to identify the pathogenicity of the various THAP1 mutations. © 2012 Movement Disorder Society.

BACKGROUND: Metabolic syndrome (MetS) is defined as a clustering of metabolic disorders: abdominal obesity, dyslipidemia, hypertension, and hyperglycemia. Although specific components of MetS have been associated with white matter hyperintensities (WMH), less is known about the association between MetS as a whole and WMH, especially in normal aging. We aimed to: (1) investigate this association in a cohort of healthy elderly individuals, and (2) examine the relationship between MetS and the regional distribution of WMH, to further understanding of the relationship between MetS and structural brain changes. METHODS: Analyses were carried out on 308 participants (48.1% men, age: 71.0 ± 3.9 years) from the French longitudinal ESPRIT (Enquête de Santé Psychologique--Risques, Incidence et Traitement) study, who were free of cerebrovascular disease cognitive and functional impairment. Logistic regression models were used to examine the cross-sectional association between MetS (defined using the National Cholesterol Education Program-Adult Treatment Panel III criteria) and (1) WMH volumes, and (2) WMH volumes according to their localization in insulofrontal and temporoparietal regions. RESULTS: After adjusting for potential confounders, participants with MetS had a twofold increased chance of presenting with high levels of WMH volume compared with those without (odds ratio [OR] = 2.74, 95% confidence interval [CI]: 1.25-6.03). MetS was specifically associated with an increase of temporoparietal WMH volumes, but no association was found between MetS and WMH localized in the insulofrontal region. CONCLUSION: Our findings suggest that effective management of MetS may reduce WMH accumulation in brain areas already vulnerable to the aging process.

BACKGROUND: Recent studies have demonstrated an association between a Mediterranean-type diet and Alzheimer's risk. We assessed the association between Mediterranean-type diet adherence and Parkinson's disease (PD) status. METHODS: Two hundred and fifty-seven PD participants and 198 controls completed the Willett semiquantitative questionnaire that quantifies diet during the past year. Scores were calculated using a 9-point scale; higher scores indicated greater adherence to the Mediterranean-type diet. Logistic regression models were used to assess the association between PD status and Mediterranean-type diet, adjusting for caloric intake, age, sex, education, and ethnicity. Adjusted linear regression models were used to examine the association between Mediterranean-type diet adherence and PD age at onset. RESULTS: Higher Mediterranean-type diet adherence was associated with reduced odds for PD after adjustment for all covariates (OR, 0.86; 95% CI, 0.77-0.97; P = .010). Lower Mediterranean-type diet score was associated with earlier PD age at onset (β = 1.09; P = .006). CONCLUSIONS: PD patients adhere less than controls to a Mediterranean-type diet. Dietary behavior may be associated with age at onset.

OBJECTIVE: The widely reported associations between various nutrients and cognition may occur through many biologic pathways including those of β-amyloid (Aβ). However, little is known about the possible associations of dietary factors with plasma Aβ40 or Aβ42. The aim of the current study was to evaluate the association between nutrient intake and plasma Aβ levels. METHODS: In this cross-sectional study, plasma Aβ40 and Aβ42 and dietary data were obtained from 1,219 cognitively healthy elderly (age >65 years), who were participants in a community-based multiethnic cohort. Information on dietary intake was obtained 1.2 years, on average, before Aβ assay. The associations of plasma Aβ40 and Aβ42 levels and dietary intake of 10 nutrients were examined using linear regression models, adjusted for age, gender, ethnicity, education, caloric intake, apolipoprotein E genotype, and recruitment wave. Nutrients examined included saturated fatty acid, monounsaturated fatty acid, ω-3 polyunsaturated fatty acid (PUFA), ω-6 PUFA, vitamin E, vitamin C, β-carotene, vitamin B(12), folate, and vitamin D. RESULTS: In unadjusted models that simultaneously included all nutrients, higher intake of ω-3 PUFA was associated with lower levels of Aβ40 (β = -24.7, p < 0.001) and lower levels of Aβ42 (β = -12.3, p < 0.001). In adjusted models, ω-3 PUFA remained a strong predictor of Aβ42 (β = -7.31, p = 0.02), whereas its association with Aβ40 was attenuated (β = -11.96, p = 0.06). Other nutrients were not associated with plasma Aβ levels. CONCLUSIONS: Our data suggest that higher dietary intake of ω-3 PUFA is associated with lower plasma levels of Aβ42, a profile linked with reduced risk of incident AD and slower cognitive decline in our cohort.

OBJECTIVE: To examine the association between a Mediterranean-style diet (MeDi) and brain magnetic resonance imaging white matter hyperintensity volume (WMHV). DESIGN: A cross-sectional analysis within a longitudinal population-based cohort study. A semiquantitative food frequency questionnaire was administered, and a score (range, 0-9) was calculated to reflect increasing similarity to the MeDi pattern. SETTING: The Northern Manhattan Study. PARTICIPANTS: A total of 1091 participants, of whom 966 had dietary information (mean age, 72 years; 59.3% women, 64.6% Hispanic, 15.6% white, and 17.5% black). MAIN OUTCOME MEASURES: The WMHV was measured by quantitative brain magnetic resonance imaging. Linear regression models were constructed to examine the association between the MeDi score and the log-transformed WMHV as a proportion of total cranial volume, controlling for sociodemographic and vascular risk factors. RESULTS: On the MeDi scale, 11.6% scored 0 to 2, 15.8% scored 3, 23.0% scored 4, 23.5% scored 5, and 26.1% scored 6 to 9. Each 1-point increase in MeDi score was associated with a lower log WMHV (β = -.04, P = .01). The only MeDi score component that was an independent predictor of WMHV was the ratio of monounsaturated to saturated fat (β = -.20, P = .001). CONCLUSIONS: A MeDi was associated with a lower WMHV burden, a marker of small vessel damage in the brain. However, white matter hyperintensities are etiologically heterogenous and can include neurodegeneration. Replication by other population-based studies is needed.

The Mediterranean diet (MeDi), due to its correlation with a low morbidity and mortality for many chronic diseases, has been widely recognised as a healthy eating model. We aimed to investigate, in a cross-sectional study, the association between adherence to a MeDi and risk for Alzheimer's disease (AD) and mild cognitive impairment (MCI) in a large, elderly, Australian cohort. Subjects in the Australian Imaging, Biomarkers and Lifestyle Study of Ageing cohort (723 healthy controls (HC), 98 MCI and 149 AD participants) completed the Cancer Council of Victoria Food Frequency Questionnaire. Adherence to the MeDi (0- to 9-point scale with higher scores indicating higher adherence) was the main predictor of AD and MCI status in multinominal logistic regression models that were adjusted for cohort age, sex, country of birth, education, apolipoprotein E genotype, total caloric intake, current smoking status, body mass index, history of diabetes, hypertension, angina, heart attack and stroke. There was a significant difference in adherence to the MeDi between HC and AD subjects (P < 0.001), and in adherence between HC and MCI subjects (P < 0.05). MeDi is associated with change in Mini-Mental State Examination score over an 18-month time period (P < 0.05) in HCs. We conclude that in this Australian cohort, AD and MCI participants had a lower adherence to the MeDi than HC participants.

Alzheimer disease (AD) and epilepsy are disorders commonly seen in the elderly. Many studies have shown that patients with AD are at increased risk for developing seizures and epilepsy. Whereas, patients with specific types of epilepsy, such as temporal lobe epilepsy (TLE), experience some degree of cognitive dysfunction, questions have been raised as to whether these disorders share some underlying pathophysiologic mechanisms or whether one is an epiphenomenon of the other. In this report, we review some of the available clinical and epidemiologic literature on various aspects of the topic of seizures in AD, including seizure rates and types, risk factors for seizures, electroencephalographic findings, treatment options, limitations, and methodological issues. Overall, multiple aspects of the literature on seizures and epilepsy in AD, including diagnosis, risk factors, the role of EEG in diagnosis, and the response to treatment are not clear and suffer from many methodological limitations and gaps.

OBJECTIVES: To examine the association between physical activity (PA) and Alzheimer disease (AD) course. BACKGROUND: PA has been related to lower risk for AD. Whether PA is associated with subsequent AD course has not been investigated. METHODS: In a population-based study of individuals aged 65 years and older in New York who were prospectively followed up with standard neurologic and neuropsychological evaluations (every ~1.5 years), 357 participants i) were nondemented at baseline and ii) were diagnosed with AD during follow-up (incident AD). PA (sum of participation in a variety of physical activities, weighted by the type of activity [light, moderate, and severe]) obtained 2.4 (standard deviation [SD], 1.9) years before incidence was the main predictor of mortality in Cox models and of cognitive decline in generalized estimating equation models that were adjusted for age, gender, ethnicity, education, comorbidities, and duration between PA evaluation and dementia onset. RESULTS: One hundred fifty incident AD cases (54%) died during the course of 5.2 (SD, 4.4) years of follow-up. When compared with incident AD cases who were physically inactive, those with some PA had lower mortality risk, whereas incident AD participants with much PA had an even lower risk. Additional adjustments for apolipoprotein genotype, smoking, comorbidity index, and cognitive performance did not change the associations. PA did not affect rates of cognitive or functional decline. CONCLUSION: Exercise may affect not only risk for AD but also subsequent disease duration: more PA is associated with prolonged survival in AD.

The coexistence of cerebral infarcts and Alzheimer's disease (AD) is common, but the influence of symptomatic cerebral infarcts on cognition is uncertain in AD. We hypothesize that symptomatic cerebral infarcts may provide an additive cognitive factor contributing to dementia in the AD population. We studied 1,001 clinically probable or possible AD patients in the Alzheimer Disease Research Center (ADRC) database. Linear regression was used to evaluate for an association between symptomatic cerebral infarcts and memory, language, executive function, abstract reasoning, and visuospatial performance, separately. Models were adjusted for covariates including age, gender, education, ethnicity, hypertension, diabetes mellitus, heart disease, clinical dementia rating, the presence of silent cerebral infarcts, and multiplicity or location of infarcts. Clinical history of stroke was present in 107 patients, radiological infarcts in 308 patients, and 68 patients with both were considered to have symptomatic infarcts. Adjusting for all covariates, AD patients with symptomatic infarcts had more impairment of executive function (P < 0.05). The influence of cerebral infarcts is neither general nor diffuse, and the presence of clinical history may have a more important influence on executive performance in AD.

OBJECTIVE: Cerebrovascular disease is 1 of the possible mechanisms of the previously reported relationship between Mediterranean-type diet (MeDi) and Alzheimer's disease (AD). We sought to investigate the association between MeDi and MRI infarcts. METHODS: High-resolution structural MRI was collected on 707 elderly 65 years or older community residents of New York with available dietary assessments administered an average of 5.8 years (3.22 standard deviations [SDs]) before the MRI. Participants were divided into 3 groups of adherence to MeDi (low, middle, and high tertiles). We examined the association of increasing adherence to MeDi with presence of infarcts on MRI. Models were run without adjustment, adjusted for basic demographic and clinical factors, and adjusted for vascular risk factors. RESULTS: A total of 222 participants had at least 1 infarct. In the unadjusted model, compared to the low adherence group, those in the moderate MeDi adherence group had a 22% reduced odds of having an infarct (odds ratio [OR], 0.78; 95% confidence interval [CI], 0.55-1.14), while participants in the highest MeDi adherence group had a 36% reduced odds (OR, 0.64; 95% CI, 0.42-0.97; p for trend = 0.04). In adjusted models, the association between MeDi adherence and MRI infarcts remained essentially unchanged. The association of high MeDi adherence with infarcts was comparable to that of hypertension (40% reduced probability), did not vary by infarct size or after excluding patients with dementia (n = 46) or clinical strokes (n = 86). There was no association between MeDi and white matter hyperintensities. INTERPRETATION: Higher adherence to the MeDi is associated with reduced cerebrovascular disease burden.

Much of the attention on diet and Alzheimer's disease (AD) or cognition among the elderly has focused on the role of single nutrients or foods, while available information on dietary pattern (DP) analysis, which better reflects the complexity of the diet, is sparse. In this review, we describe different patterning approaches and present studies performed to date that have assessed the associations between DPs and risk of AD or cognitive function in the elderly. Three patterning approaches have been most commonly used: (i) hypothesis-based that use dietary quality indexes or scores (e.g. Mediterranean pattern), (ii) data-driven that use factor or cluster analysis to derive DPs, (iii) reduced rank regression which combines characteristics of the former two approaches. Despite differences existing among the approaches, DPs characterized by higher intake of fruits, vegetables, fish, nuts and legumes, and lower intake of meats, high fat dairy, and sweets seemed to be associated with lower odds of cognitive deficits or reduced risk of AD. Overall, the inherent advantages as well as the existing evidence of DP analyses strongly suggest that this approach may be valuable in AD and aging research. Further studies are warranted, though, to confirm the findings in different population settings, to address some methodological issues, and possibly utilize the information for future clinical trial design.

It has been suggested that inflammation is involved in Alzheimer disease (AD) pathogenesis. The aim of this study is to evaluate the association between inflammatory aspects of diet and incident AD risk. About 2258 nondemented elderly (age ≥ 65) in New York who provided dietary information at baseline were followed-up prospectively for AD development. We examined the composite total Inflammation Factor Rating (tIFR), as a measure of inflammatory impact of foods, in relation with (i) serum level of high-sensitivity C-reactive protein (hsCRP) and (ii) risk of incident AD using Cox proportional hazard model. The tIFR was not associated with serum hsCRP level. After an average of 4.0 years of follow-up, 262 participants developed incident AD. The tIFR was not associated with AD risk: compared with the lowest tertile of tIFR (most proinflammatory), hazard ratios (95% confidence interval) for the highest tertile (most anti-inflammatory) was 0.97 (0.69-1.35) (P-for-trend=0.71), in the adjusted model. We conclude that tIFR might not be a biologically relevant measure of the inflammatory impact of the diet. In addition, although it remains possible that tIFR might be related with some other aspects of inflammation not captured by hsCRP, lack of association with AD risk suggests its limited clinical utility.

This study explores the longitudinal relationship between patient characteristics and use of 4 drug classes (antihypertensives, antidepressants, antipsychotics, and hormones) that showed significant changes in use rates over time in patients with Alzheimer disease. Patient/caregiver-reported prescription medication usage was categorized by drug class for 201 patients from the Predictors Study. Patient characteristics included use of cholinesterase inhibitors and/or memantine, function, cognition, living situation, baseline age, and sex. Assessment interval, year of study entry, and site were controlled for. Before adjusting for covariates, useage increased for antihypertensives (47.8% to 62.2%), antipsychotics (3.5% to 27.0%), and antidepressants (32.3% to 40.5%); use of hormones decreased (19.4% to 5.4%). After controlling for patient characteristics, effects of time on the use of antidepressants were no longer significant. Antihypertensive use was associated with poorer functioning, concurrent use of memantine, and older age. Antipsychotic use was associated with poorer functioning and poorer cognition. Antidepressant use was associated with younger age, poorer functioning, and concurrent use of cholinesterase inhibitors and memantine. Hormone use was associated with being female and younger age. Findings suggest accurate modeling of the Alzheimer disease treatment paradigm for certain subgroups of patients should include antihypertensives and antipsychotics in addition to cholinesterase inhibitors and memantine.

BACKGROUND: Osteonecrosis has been associated with the presence of white matter lesions. The objective of this study was to investigate the association between macro- and micro- vascular disease and white matter lesions. METHODS: Sixty-four patients with femoral head osteonecrosis were assessed during a cross sectional study in our university-based hospital. A vascular 'profile' was obtained for each patient and included measurement of plasma lipids, fundoscopic examination and common carotid artery triplex ultrasonography. All patients had brain MRI to assess for presence of white matter lesions. The two groups formed, with and without white matter lesions, were compared in order to define the association between white matter lesions and vascular disease. RESULTS: Patients without white matter lesions had more frequently corticosteroid induced osteonecrosis. There was no difference in the two groups with respect to intima media thickness and ApoB/ApoA1 ratio. Only one of our patients demonstrated retinopathy. CONCLUSIONS: There is no evidence of concurrent macro- and micro- vascular pathology in young patients with white matter lesions and femoral head osteonecrosis. Cortisone appears to have a 'protective' effect against occurrence of white matter lesions.

BACKGROUND: A dietary pattern common in regions near the Mediterranean appears to reduce risk of all-cause mortality and ischemic heart disease. Data on blacks and Hispanics in the United States are lacking, and to our knowledge only one study has examined a Mediterranean-style diet (MeDi) in relation to stroke. OBJECTIVE: In this study, we examined an MeDi in relation to vascular events. DESIGN: The Northern Manhattan Study is a population-based cohort to determine stroke incidence and risk factors (mean ± SD age of participants: 69 ± 10 y; 64% women; 55% Hispanic, 21% white, and 24% black). Diet was assessed at baseline by using a food-frequency questionnaire in 2568 participants. A higher score on a 0-9 scale represented increased adherence to an MeDi. The relation between the MeDi score and risk of ischemic stroke, myocardial infarction (MI), and vascular death was assessed with Cox models, with control for sociodemographic and vascular risk factors. RESULTS: The MeDi-score distribution was as follows: 0-2 (14%), 3 (17%), 4 (22%), 5 (22%), and 6-9 (25%). Over a mean follow-up of 9 y, 518 vascular events accrued (171 ischemic strokes, 133 MIs, and 314 vascular deaths). The MeDi score was inversely associated with risk of the composite outcome of ischemic stroke, MI, or vascular death (P-trend = 0.04) and with vascular death specifically (P-trend = 0.02). Moderate and high MeDi scores were marginally associated with decreased risk of MI. There was no association with ischemic stroke. CONCLUSIONS: Higher consumption of an MeDi was associated with decreased risk of vascular events. Results support the role of a diet rich in fruit, vegetables, whole grains, fish, and olive oil in the promotion of ideal cardiovascular health.

It has been suggested that inflammation is involved in Alzheimer disease (AD) pathogenesis. The aim of this study is to evaluate the association between inflammatory aspects of diet and incident AD risk. About 2258 nondemented elderly (age >/= 65) in New York who provided dietary information at baseline were followed-up prospectively for AD development. We examined the composite total Inflammation Factor Rating (tIFR), as a measure of inflammatory impact of foods, in relation with (i) serum level of high-sensitivity C-reactive protein (hsCRP) and (ii) risk of incident AD using Cox proportional hazard model. The tIFR was not associated with serum hsCRP level. After an average of 4.0 years of follow-up, 262 participants developed incident AD. The tIFR was not associated with AD risk: compared with the lowest tertile of tIFR (most proinflammatory), hazard ratios (95% confidence interval) for the highest tertile (most anti-inflammatory) was 0.97 (0.69-1.35) (P-for-trend=0.71), in the adjusted model. We conclude that tIFR might not be a biologically relevant measure of the inflammatory impact of the diet. In addition, although it remains possible that tIFR might be related with some other aspects of inflammation not captured by hsCRP, lack of association with AD risk suggests its limited clinical utility.

This study examined in detail patterns of cholinesterase inhibitors (ChEIs) and memantine use and explored the relationship between patient characteristics and such use. Patients with probable Alzheimer disease AD (n=201) were recruited from the Predictors Study in 3 academic AD centers and followed from early disease stages for up to 6 years. Random effects logistic regressions were used to examine effects of patient characteristics on ChEIs/memantine use over time. Independent variables included measures of function, cognition, comorbidities, the presence of extrapyramidal signs, psychotic symptoms, age, sex, and patient's living situation at each interval. Control variables included assessment interval, year of study entry, and site. During a 6-year study period, rate of ChEIs use decreased (80.6% to 73.0%) whereas memantine use increased (2.0% to 45.9%). Random effects logistic regression analyses showed that ChEI use was associated with better function, no psychotic symptoms, and younger age. Memantine use was associated with better function, poorer cognition, living at home, later assessment interval, and later year of study entry. Results suggest that high rate of ChEI use and increasing memantine use over time are consistent with current practice guidelines of initiation of ChEIs in mild-to-moderate AD patients and initiation of memantine in moderate-to-severe patients.

OBJECTIVE: To assess the association between food combination and Alzheimer disease (AD) risk. Because foods are not consumed in isolation, dietary pattern (DP) analysis of food combination, taking into account the interactions among food components, may offer methodological advantages. DESIGN: Prospective cohort study. SETTING: Northern Manhattan, New York, New York. PATIENTS OR OTHER PARTICIPANTS: Two thousand one hundred forty-eight community-based elderly subjects (aged > or = 65 years) without dementia in New York provided dietary information and were prospectively evaluated with the same standardized neurological and neuropsychological measures approximately every 1.5 years. Using reduced rank regression, we calculated DPs based on their ability to explain variation in 7 potentially AD-related nutrients: saturated fatty acids, monounsaturated fatty acids, omega-3 polyunsaturated fatty acids, omega-6 polyunsaturated fatty acids, vitamin E, vitamin B(12), and folate. The associations of reduced rank regression-derived DPs with AD risk were then examined using a Cox proportional hazards model. Main Outcome Measure Incident AD risk. RESULTS: Two hundred fifty-three subjects developed AD during a follow-up of 3.9 years. We identified a DP strongly associated with lower AD risk: compared with subjects in the lowest tertile of adherence to this pattern, the AD hazard ratio (95% confidence interval) for subjects in the highest DP tertile was 0.62 (0.43-0.89) after multivariable adjustment (P for trend = .01). This DP was characterized by higher intakes of salad dressing, nuts, fish, tomatoes, poultry, cruciferous vegetables, fruits, and dark and green leafy vegetables and a lower intake of high-fat dairy products, red meat, organ meat, and butter. CONCLUSION: Simultaneous consideration of previous knowledge regarding potentially AD-related nutrients and multiple food groups can aid in identifying food combinations that are associated with AD risk.

OBJECTIVES: To determine if plasma β-amyloid (Aβ) levels (1) can be linked to specific cognitive changes that constitute conversion to Alzheimer disease (AD) and (2) correspond to cognitive change independent of dementia. DESIGN: Longitudinal study including 3 visits during approximately 4¹/₂ years (2000-2006). SETTING: Northern Manhattan community. PARTICIPANTS: Eight hundred eighty individuals from a population-based and ethnically diverse sample who had 2 plasma Aβ measurements and were dementia free at the time of the first Aβ sample; 481 remained cognitively healthy, 329 were cognitively or functionally impaired but not demented at any point, and 70 developed AD. MAIN OUTCOME MEASURES: General estimating equations tested the association between plasma Aβ (baseline and change in values) and cognitive change (composite score and memory, language, and visuospatial indices). RESULTS: High baseline plasma Aβ42 (P = .01) and Aβ40 (P = .01) and decreasing/relatively stable Aβ42 (P = .01) values were associated with faster decline in multiple cognitive domains. In those who remained cognitively healthy, high baseline plasma Aβ42 (P = .01) and decreasing/relatively stable plasma Aβ42 (P = .01) was associated with faster cognitive decline, primarily in memory. CONCLUSIONS: The association between plasma Aβ and multiple aspects of cognition more clearly specifies the previously documented downward trajectory of plasma Aβ with AD onset. The predominant association with memory seen only in healthy elderly individuals also suggests that plasma Aβ is linked with even earlier neurologic changes that may or may not culminate in dementia.

We aimed to investigate the association between adherence to the Mediterranean diet (MeDi) and Alzheimer's disease (AD) risk in a prospective study. Specifically, we analyzed reduced inflammation and improved metabolic profile as a potential medium through which the MeDi reduced the risk of AD. During a 4-year follow-up, 118 incident AD cases were identified among the 1219 non-demented elderly (age ≥ 65) subjects who provided dietary information and blood samples at baseline. We used high-sensitivity C-reactive protein (hsCRP) as an index of systemic inflammation, and fasting insulin and adiponectin as indexes of metabolic profile. We investigated whether there was a change in the association between MeDi and incident AD risk when the biomarkers were introduced into multivariable adjusted COX models. Better adherence to MeDi was associated with lower level of hsCRP (p =0.003), but not fasting insulin or adiponectin. Better adherence to MeDi was significantly associated with lower risk for AD: compared to those in the lowest tertile of MeDi, subjects in the highest tertile had a 34% less risk of developing AD (p-for-trend =0.04). Introduction of the hsCRP, fasting insulin, adiponectin, or combinations of them into the COX model did not change the magnitude of the association between MeDi and incident AD. Ultimately, the favorable association between better adherence to MeDi and lower risk of AD did not seem to be mediated by hsCRP, fasting insulin, or adiponectin. Other aspects of inflammatory and metabolic pathways not captured by these biomarkers, or non-inflammatory or non-metabolic pathways, may be relevant to the MeDi-AD association.

BACKGROUND: Higher adherence to the Mediterranean diet (MeDi) may protect from Alzheimer disease (AD), but its association with mild cognitive impairment (MCI) has not been explored. OBJECTIVE: To investigate the association between the MeDi and MCI. DESIGN, SETTING, AND PATIENTS: In a multiethnic community study in New York, we used Cox proportional hazards to investigate the association between adherence to the MeDi (0-9 scale; higher scores indicate higher adherence) and (1) the incidence of MCI and (2) the progression from MCI to AD. All of the models were adjusted for cohort, age, sex, ethnicity, education, APOE genotype, caloric intake, body mass index, and duration between baseline dietary assessment and baseline diagnosis. MAIN OUTCOME MEASURES: Incidence of MCI and progression from MCI to AD. RESULTS: There were 1393 cognitively normal participants, 275 of whom developed MCI during a mean (SD) follow-up of 4.5 (2.7) years (range, 0.9-16.4 years). Compared with subjects in the lowest MeDi adherence tertile, subjects in the middle tertile had 17% less risk (hazard ratio [HR] = 0.83; 95% confidence interval [CI], 0.62-1.12; P = .24) of developing MCI and those in the highest tertile had 28% less risk (HR = 0.72; 95% CI, 0.52-1.00; P = .05) of developing MCI (trend HR = 0.85; 95% CI, 0.72-1.00; P for trend = .05). There were 482 subjects with MCI, 106 of whom developed AD during a mean (SD) follow-up of 4.3 (2.7) years (range, 1.0-13.8 years). Compared with subjects in the lowest MeDi adherence tertile, subjects in the middle tertile had 45% less risk (HR = 0.55; 95% CI, 0.34-0.90; P = .01) of developing AD and those in the highest tertile had 48% less risk (HR = 0.52; 95% CI, 0.30-0.91; P = .02) of developing AD (trend HR = 0.71; 95% CI, 0.53-0.95; P for trend = .02). CONCLUSIONS: Higher adherence to the MeDi is associated with a trend for reduced risk of developing MCI and with reduced risk of MCI conversion to AD.

BACKGROUND: Extrapyramidal signs (EPSs) are commonly accepted as a feature of Alzheimer disease (AD) and may influence both the profile of impairment and prognosis. OBJECTIVE: To examine rates of occurrence and risk factors for all types of EPSs and to describe the impact of EPSs over time on the clinical course of AD. DESIGN: Longitudinal study. SETTING: The Washington Heights Hamilton Heights Inwood Columbia Aging Project. Patients A total of 388 patients with incident AD (mean age, 79 years; 71.4% female). MAIN OUTCOME MEASURES: Extrapyramidal signs rated by means of a standardized portion of the Unified Parkinson's Disease Rating Scale; prevalence and incidence rates and cumulative risk for non-drug-induced EPSs; and rates of change in EPSs over time, taking into account potential covariates. RESULTS: Extrapyramidal signs were detected in 12.3% of patients at first evaluation and 22.6% at last evaluation. In a multivariate-adjusted generalized estimating equation model of change, total EPS score increased at an annual rate of 1.3%. Women (relative risk [RR], 1.57; P = .03), older patients (RR, 1.03; P = .02), and those with EPSs at baseline (RR, 2.07; P = .001) had greater rates of cognitive decline. CONCLUSIONS: Extrapyramidal signs occur frequently and progress significantly in AD. Patients with incident AD and concomitant EPSs have a greater rate of cognitive decline than do patients with incident AD but without EPSs.

BACKGROUND: Periodontitis is ubiquitous and associated with serological evidence of exposure to periodontal organisms, systemic inflammation and vascular disease. Dementia is a major public health problem likely related to a complex interaction between genetics and diseases associated with systemic inflammation, including diabetes, smoking and stroke. METHODS: To assess relationships between systemic exposure to periodontal pathogens and cognitive test outcomes, data were analysed from the Third National Health and Nutrition Examination Survey (NHANES-III), a nationally representative cross sectional observational study among older adults. We included 2355 participants >or=60 years who completed measures of cognition and Poryphyromonas gingivalis IgG. Using SUDAAN, logistic regression models examined the association of P gingivalis IgG with cognitive test performance. RESULTS: Poor immediate verbal memory (<5/9 points) was prevalent in 5.7% of patients, and 6.5% overall had impaired delayed recall (<4/9); 22.1% had difficulty with serial subtractions (<5/5 trials correct). Individuals with the highest P gingivalis IgG (>119 ELISA Units (EU)) were more likely to have poor delayed verbal recall (OR 2.89, 95% CI 1.14 to 7.29) and impaired subtraction (OR 1.95, 95% CI 1.22 to 3.11) than those with the lowest (

AIM: While clinical endpoints provide important information on the efficacy of treatment in controlled conditions, they often are not relevant to decision makers trying to gauge the potential economic impact or value of new treatments. Therefore, it is often necessary to translate changes in cognition, function or behavior into changes in cost or other measures, which can be problematic if not conducted in a transparent manner. The Dependence Scale (DS), which measures the level of assistance a patient requires due to AD-related deficits, may provide a useful measure of the impact of AD progression in a way that is relevant to patients, providers and payers, by linking clinical endpoints to estimates of cost effectiveness or value. The aim of this analysis was to test the association of the DS to clinical endpoints and AD-related costs. METHOD: The relationship between DS score and other endpoints was explored using the Predictors Study, a large, multi-center cohort of patients with probable AD followed annually for four years. Enrollment required a modified Mini-Mental State Examination (mMMS) score >or= 30, equivalent to a score of approximately >or= 16 on the MMSE. DS summated scores (range: 0- 15) were compared to measures of cognition (MMSE), function (Blessed Dementia Rating Scale, BDRS, 0-17), behavior, extrapyramidal symptoms (EPS), and psychotic symptoms (illusions, delusions or hallucinations). Also, estimates for total cost (sum of direct medical cost, direct non-medical cost, and cost of informal caregivers' time) were compared to DS scores. RESULTS: For the 172 patients in the analysis, mean baseline scores were: DS: 5.2 (SD: 2.0), MMSE: 23.0 (SD: 3.5), BDRS: 2.9 (SD: 1.3), EPS: 10.8%, behavior: 28.9% psychotic symptoms: 21.1%. After 4 years, mean scores were: DS: 8.9 (SD: 2.9), MMSE: 17.2 (SD: 4.7), BDRS: 5.2 (SD: 1.4), EPS: 37.5%, behavior: 60.0%, psychotic symptoms: 46.7%. At baseline, DS scores were significantly correlated with MMSE (r=-0.299, p < 0.01), BDRS (r=0.610, p < 0.01), behavior (r=.2633, p=0.0005), EPS (r=0.1910, p=0.0137) and psychotic symptoms (r=0.253, p < 0.01); and at 4-year follow-up, DS scores were significantly correlated with MMSE (r=-0.3705, p=0.017), BDRS (r=0.6982, p < 0.001). Correlations between DS and behavior (-0.0085, p=0.96), EPS (r=0.3824, p=0.0794), psychotic symptoms (r=0.130, ns) were not statistically significant at follow-up. DS scores were also significantly correlated with total costs at baseline (r=0.2615, p=0.0003) and follow-up (r=0.3359, p=0.0318). DISCUSSION: AD is associated with deficits in cognition, function and behavior, thus it is imperative that these constructs are assessed in trials of AD treatment. However, assessing multiple endpoints can lead to confusion for decision makers if treatments do not impact all endpoints similarly, especially if the measures are not used typically in practice. One potential method for translating these deficits into a more meaningful outcome would be to identify a separate construct, one that takes a broader view of the overall impact of the disease. Patient dependence, as measured by the DS, would appear to be a reasonable choice - it is associated with the three clinical endpoints, as well as measures of cost (medical and informal), thereby providing a bridge between measures of clinical efficacy and value in a single, transparent measure.

BACKGROUND: Vascular factors including medical history (heart disease, stroke, diabetes, and hypertension), smoking, and prediagnosis blood lipid measurements (cholesterol: total, high-density lipoprotein, low-density lipoprotein [LDL-C], and triglyceride concentrations) may be predictors for progression of Alzheimer disease (AD). OBJECTIVE: To determine whether prediagnosis vascular risk factors are associated with progression of AD. DESIGN: Inception cohort followed up longitudinally for a mean of 3.5 (up to 10.2) years. SETTING: Washington Heights/Inwood Columbia Aging Project, New York, New York. Patients One hundred fifty-six patients with incident AD (mean age at diagnosis, 83 years). Main Outcome Measure Change in a composite score of cognitive ability from diagnosis onward. RESULTS: In generalized estimating equation models (adjusted for age, race/ethnicity, and years of education), higher cholesterol (total cholesterol and LDL-C) concentrations and history of diabetes were associated with faster cognitive decline. Each 10-U increase in cholesterol and LDL-C was associated with a 0.10-SD decrease in cognitive score per year of follow-up (P < .001 for total cholesterol; P = .001 for LDL-C). High-density lipoprotein cholesterol and triglyceride concentrations were not associated with rate of decline. A history of diabetes was associated with an additional 0.05-SD decrease in cognitive score per year (P = .05). History of heart disease and stroke were associated with cognitive decline only in carriers of the apolipoprotein E epsilon4 (APOE-epsilon4) gene. In a final generalized estimating equation model that included high-density lipoprotein cholesterol and LDL-C concentrations and history of diabetes, only higher LDL-C was independently associated with faster cognitive decline. CONCLUSION: Higher prediagnosis total cholesterol and LDL-C concentrations and history of diabetes were associated with faster cognitive decline in patients with incident AD, which provides further evidence for the role of vascular risk factors in the course of AD.

CONTEXT: Higher adherence to a Mediterranean-type diet is linked to lower risk for mortality and chronic diseases, but its association with cognitive decline is unclear. OBJECTIVE: To investigate the association of a Mediterranean diet with change in cognitive performance and risk for dementia in elderly French persons. DESIGN, SETTING, AND PARTICIPANTS: Prospective cohort study of 1410 adults (> or = 65 years) from Bordeaux, France, included in the Three-City cohort in 2001-2002 and reexamined at least once over 5 years. Adherence to a Mediterranean diet (scored as 0 to 9) was computed from a food frequency questionnaire and 24-hour recall. MAIN OUTCOME MEASURES: Cognitive performance was assessed on 4 neuropsychological tests: the Mini-Mental State Examination (MMSE), Isaacs Set Test (IST), Benton Visual Retention Test (BVRT), and Free and Cued Selective Reminding Test (FCSRT). Incident cases of dementia (n = 99) were validated by an independent expert committee of neurologists. RESULTS: Adjusting for age, sex, education, marital status, energy intake, physical activity, depressive symptomatology, taking 5 medications/d or more, apolipoprotein E genotype, cardiovascular risk factors, and stroke, higher Mediterranean diet score was associated with fewer MMSE errors (beta = -0.006; 95% confidence interval [CI], -0.01 to -0.0003; P = .04 for 1 point of the Mediterranean diet score). Performance on the IST, BVRT, or FCSRT over time was not significantly associated with Mediterranean diet adherence. Greater adherence as a categorical variable (score 6-9) was not significantly associated with fewer MMSE errors and better FCSRT scores in the entire cohort, but among individuals who remained free from dementia over 5 years, the association for the highest compared with the lowest group was significant (adjusted for all factors, for MMSE: beta = -0.03; 95% CI, -0.05 to -0.001; P = .04; for FCSRT: beta = 0.21; 95% CI, 0.008 to 0.41; P =.04). Mediterranean diet adherence was not associated with the risk for incident dementia (fully adjusted model: hazard ratio, 1.12; 95% CI, 0.60 to 2.10; P = .72), although power to detect a difference was limited. CONCLUSIONS: Higher adherence to a Mediterranean diet was associated with slower MMSE cognitive decline but not consistently with other cognitive tests. Higher adherence was not associated with risk for incident dementia.

CONTEXT: Both higher adherence to a Mediterranean-type diet and more physical activity have been independently associated with lower Alzheimer disease (AD) risk but their combined association has not been investigated. OBJECTIVE: To investigate the combined association of diet and physical activity with AD risk. DESIGN, SETTING, AND PATIENTS: Prospective cohort study of 2 cohorts comprising 1880 community-dwelling elders without dementia living in New York, New York, with both diet and physical activity information available. Standardized neurological and neuropsychological measures were administered approximately every 1.5 years from 1992 through 2006. Adherence to a Mediterranean-type diet (scale of 0-9; trichotomized into low, middle, or high; and dichotomized into low or high) and physical activity (sum of weekly participation in various physical activities, weighted by the type of physical activity [light, moderate, vigorous]; trichotomized into no physical activity, some, or much; and dichotomized into low or high), separately and combined, were the main predictors in Cox models. Models were adjusted for cohort, age, sex, ethnicity, education, apolipoprotein E genotype, caloric intake, body mass index, smoking status, depression, leisure activities, a comorbidity index, and baseline Clinical Dementia Rating score. MAIN OUTCOME MEASURE: Time to incident AD. RESULTS: A total of 282 incident AD cases occurred during a mean (SD) of 5.4 (3.3) years of follow-up. When considered simultaneously, both Mediterranean-type diet adherence (compared with low diet score, hazard ratio [HR] for middle diet score was 0.98 [95% confidence interval {CI}, 0.72-1.33]; the HR for high diet score was 0.60 [95% CI, 0.42-0.87]; P = .008 for trend) and physical activity (compared with no physical activity, the HR for some physical activity was 0.75 [95% CI, 0.54-1.04]; the HR for much physical activity was 0.67 [95% CI, 0.47-0.95]; P = .03 for trend) were associated with lower AD risk. Compared with individuals neither adhering to the diet nor participating in physical activity (low diet score and no physical activity; absolute AD risk of 19%), those both adhering to the diet and participating in physical activity (high diet score and high physical activity) had a lower risk of AD (absolute risk, 12%; HR, 0.65 [95% CI, 0.44-0.96]; P = .03 for trend). CONCLUSION: In this study, both higher Mediterranean-type diet adherence and higher physical activity were independently associated with reduced risk for AD.

BACKGROUND: Transient symptoms in Alzheimer disease (AD) are frequent and include seizures, syncope, and episodes of inattention or confusion. The incidence of seizures in AD and predictors of which patients with AD might be more predisposed to them is based primarily on retrospective studies and is not well established. OBJECTIVE: To determine the incidence and predictors of new-onset unprovoked seizures. DESIGN: Prospective cohort study. SETTING: Three academic centers. Patients Four hundred fifty-three patients with probable AD observed prospectively from mild disease stages since 1992. Main Outcome Measure Informant interviews every 6 months included questions about whether the patient had a seizure (convulsion, fainting, or "funny" spell) and whether diagnosis or treatment for epilepsy or seizure was made. Two epileptologists independently retrospectively reviewed all available medical records for 52 patients with positive responses to either of these questions, and using a specific checklist form, events were diagnosed as to whether they were unprovoked seizures (intrarater concordance, kappa = 0.67). Diagnosis of unprovoked seizures constituted the event in survival analyses. Potential predictors included sex, age, race/ethnicity, educational achievement, duration of illness, baseline cognition and function, depression, medical comorbidities, and time-dependent use of cholinesterase inhibitors and neuroleptic agents, apolipoprotein E genotype, and previous electroencephalographic findings. RESULTS: Over the course of 3518 visit-assessments (per patient: mean, 7.8; maximum, 27), 7 patients (1.5%) developed seizures. Younger age was associated with higher risk (hazard ratio, 1.23; 95% confidence interval, 1.08-1.41; P = .003 for each additional year of age) of seizure incidence. No other predictor was significant. The overall incidence of seizures was low (418 per 100 000 person-years of observation) although significantly higher than expected for idiopathic unprovoked seizures in similar age ranges of the general population (hazard ratio, 8.06; 95% confidence interval, 3.23-16.61). CONCLUSIONS: Unprovoked seizures are uncommon in AD, but they do occur more frequently than in the general population. Younger age is a risk factor for seizures in AD.

Alzheimer disease (AD) is the most common type of dementia and will become increasingly prevalent with the growing elderly population. Despite established clinical diagnostic tools, the workup for dementia among primary caregivers can be complicated and specialist referral may not be readily available. A host of AD diagnostic tests has been proposed to aid in diagnosis, including functional neuroimaging such as positron emission tomography (PET). We review the basis for FDG-PET and PiB-PET, as well as available operating statistics. From this we advise scenarios for use of PET in primary settings and referral centers, approach to its interpretation, and outline a clinical prediction model based on findings.

To capture patterns of normal age-associated atrophy, we previously used a multivariate statistical approach applied to voxel based morphometry that identified age-associated gray and white matter covariance networks (Brickman et al. [2007]: Neurobiol Aging 28:284-295). The current study sought to examine the stability of these patterns by forward applying the identified networks to an independent sample of neurologically healthy younger and older adults. Forty-two younger and 35 older adults were imaged with standard high-resolution structural magnetic resonance imaging. Individual images were spatially normalized and segmented into gray and white matter. Covariance patterns that were previously identified with scaled subprofile model analyses were prospectively applied to the current sample to identify to what degree the age-associated patterns were manifested. Older individuals were also assessed with a modified version of the Mini Mental State Examination (mMMSE). Gray matter covariance pattern expression discriminated between younger and older participants with high optimal sensitivity (100%) and specificity (90.5%). While the two groups differed in the degree of white matter pattern expression (t (75) = 5.26, P < 0.001), classification based on white matter expression was relatively low (sensitivity = 80% and specificity = 61.9%). Among older adults, chronological age was significantly associated with increased gray matter pattern expression (r (32) = 0.591, P < 0.001) but not with performance on the mMMSE (r (31) = -0.314, P = 0.085). However, gray matter pattern expression was significantly associated with performance on the mMMSE (r (31) = -0.405, P = 0.024). The findings suggest that the previously derived age-associated covariance pattern for gray matter is reliable and may provide information that is more functionally meaningful than chronological age.

OBJECTIVE: To determine whether APOE epsilon 4 predicts rate of cognitive change in incident and prevalent Alzheimer disease (AD). METHODS: Individuals were recruited from two longitudinal cohort studies-the Washington Heights and Inwood Columbia Aging Project (WHICAP; population-based) and the Predictors Study (clinic-based)--and were followed for an average of 4 years. Three samples of participants diagnosed with AD, with diverse demographic characteristics and baseline cognitive functioning, were studied: 1) 199 (48%) of the incident WHICAP cases; 2) 215 (54%) of the prevalent WHICAP cases; and 3) 156 (71%) of the individuals diagnosed with AD in the Predictors Study. Generalized estimating equations were used to test whether rate of cognitive change, measured using a composite cognitive score in WHICAP and the Mini-Mental State Examination in Predictors, varied as a function of epsilon 4 status in each sample. RESULTS: The presence of at least one epsilon 4 allele was associated with faster cognitive decline in the incident population-based AD group (p = 0.01). Parallel results were produced for the two prevalent dementia samples only when adjusting for disease severity or excluding the most impaired participants from the analyses. CONCLUSION: APOE epsilon 4 may influence rate of cognitive decline most significantly in the earliest stages of Alzheimer disease.

BACKGROUND: The aim of this study was to investigate the effect of patient's age on the impact of typically proposed predictors of sustained virological response (SVR) in treatment-naïve, high-pretreatment viral load (>700.000 IU/ml), chronic hepatitis C (CHC) patients treated under real-life conditions in Greece. METHODS: We retrospectively analyzed 185 CHC patients (14.4% cirrhotics) who had been treated with weight-adjusted dosing (1.5 microg/kg per week) of pegylated interferon-a2b (PEG) plus genotype-based ribavirin (RIB) for 24 or 48 weeks of treatment, based on viral genotype. SVR was confirmed by undetectable serum HCV-RNA 6 months after the end of treatment. RESULTS: Overall, 68.5% of patients exhibited SVR and 31.5% were non-responders (non-SVRs). Among the non-SVRs, 71.4% were infected with HCV genotype-1. Importantly, 71.4% of genotype 4-infected treated patients exhibited SVR. In the multivariate analyses, only the early histological stage of liver disease (p=0.015) and the presence of genotype non-1 infection (p=0.003) were independent predictors of SVR. For patients younger than 35 years, none of the baseline parameters and neither viral genotype (p=0.284) nor the stage of liver disease (p=0.351) was an independent predictor of non-SVR, whereas for patients between 35 and 55, only the presence of genotype-1 infection independently predicted non-SVR (p=0.008). For older patients (>55 years), only the histological stage of liver disease (p=0.047) and not the viral genotype (p=0.275) independently predicted non-SVR. CONCLUSIONS: The impact of the typical predictors of SVR, such as viral genotype and liver histopathology, is modified according to patient's age in currently approved combination treatment.

OBJECTIVE: To assess combined antidepressant and cognitive enhancer treatment in elderly patients presenting with depression plus cognitive impairment. METHODS: Twenty-three elderly (>50 years old) depressed, cognitively impaired (DEP-CI) patients participated in a pilot study. We evaluated whether, after 8 weeks of open antidepressant treatment, donepezil HCl (Aricept) would afford added cognitive benefit compared to placebo in a randomized 12-week trial. A subsample continued in an 8-month extension phase of open treatment with donepezil. Neuropsychological testing (NPT) was performed and antidepressant response monitored at baseline and the 8, 20, and 52-week time points. RESULTS: At 8-weeks, the antidepressant response rate was 61% (14/23). Improvement in SRT immediate recall (SRT-IR; e.g. episodic verbal memory) was observed in responders compared to non-responders. During the 12-week, placebo-controlled, donepezil add-on trial, patients on donepezil showed further improvement in SRT-IR versus patients on placebo. In the open extension phase, patients who continued open donepezil treatment (n = 6) maintained improvement in memory and tended to show an advantage over patients who never received donepezil and were evaluated at the 52-week time point (n = 6). There were no observed significant donepezil effects on non-memory cognitive domains. CONCLUSION: These preliminary findings suggest that addition of a cholinesterase inhibitor (AChEI) following antidepressant medication treatment in elderly Dep-CI patients may improve cognition, and support the need for a confirmatory, larger randomized placebo-controlled trial.

Continuous arterial spin labeling (CASL) magnetic resonance imaging (MRI) was combined with multivariate analysis for detection of an Alzheimer's disease (AD)-related cerebral blood flow (CBF) covariance pattern. Whole-brain resting CBF maps were obtained using spin echo, echo planar imaging (SE-EPI) CASL in patients with mild AD (n=12, age=70.7+/-8.7 years, 7 males, modified Mini-Mental State Examination (mMMS)=38.7/57+/-11.1) and age-matched healthy controls (HC) (n=20; age=72.1+/-6.5 years, 8 males). A covariance pattern for which the mean expression was significantly higher (P<0.0005) in AD than in HC was identified containing posterior cingulate, superior temporal, parahippocampal, and fusiform gyri, as well as thalamus, insula, and hippocampus. The results from this analysis were supplemented with those from the more standard, region of interest (ROI) and voxelwise, univariate techniques. All ROIs (17/hemisphere) showed significant decrease in CBF in AD (P<0.001 for all ROIs, alphacorrected=0.05). The area under the ROC curve for discriminating AD versus HC was 0.97 and 0.94 for covariance pattern and gray matter ROI, respectively. Fewer areas of depressed CBF in AD were detected using voxelwise analysis (corrected, P<0.05). These areas were superior temporal, cingulate, middle temporal, fusiform gyri, as well as inferior parietal lobule and precuneus. When tested on extensive split-half analysis to map out the replicability of both multivariate and univariate approaches, the expression of the pattern from multivariate analysis was superior to that of the univariate.

BACKGROUND/AIMS: Alpha-1 antichymotrypsin (ACT), a serine proteinase inhibitor, has been implicated in vascular pathology. The TT genotype of the ACT signal peptide A/T polymorphism has been reported to confer susceptibility to primary intracerebral hemorrhage (PICH). We conducted a prospective study to test possible association of ACT signal peptide A/T polymorphism with PICH in a Greek cohort with enough power (80%) to detect a twofold increase in the odds ratio. METHODS: We prospectively recruited 147 patients with PICH. ACT signal peptide A/T genotypes were determined in patients and 206 healthy, age- and sex-matched control subjects from the neurology outpatient clinic using the polymerase chain reaction restriction fragment length polymorphism method. RESULTS: Our study did not show an association between ACT signal peptide A/T polymorphism and PICH. We also failed to find any influence on age at onset, the location and volume of PICH as well as on clinical severity at admission or 6-month outcome. CONCLUSION: Our data failed to confirm an association between ACT signal peptide A/T polymorphism and PICH. However, we cannot exclude the possibility that the TT genotype confers susceptibility at less than a twofold increase.

OBJECTIVE: To determine if baseline measurements of cerebral atrophy and severity of white matter hyperintensity (WMH) predict the rate of future cognitive decline in patients with Alzheimer disease (AD). DESIGN: Data were drawn from the Predictors Study, a longitudinal study that enrolls patients with mild AD and reassesses them every 6 months with use of the Columbia modified Mini-Mental State (mMMS) examination (score range, 0-57). Magnetic resonance images were analyzed to determine the severity of WMH, using the Scheltens scale, and the degree of atrophy, using the bicaudate ratio. Generalized estimating equations were used to determine whether severity of baseline magnetic resonance image measurements and their interaction predicted the rate of mMMS score decline at subsequent visits. SETTING: Three university-based AD centers in the United States. PARTICIPANTS: At baseline, 84 patients with AD from the Predictors Study received structural magnetic resonance imaging and were selected for analysis. They had a mean of 6 follow-up evaluations. Main Outcome Measure The mMMS score. RESULTS: Generalized estimating equation models demonstrated that the degree of baseline atrophy (beta = -0.316; P = .04), the severity of WMH (beta = -0.173; P = .03), and their interaction (beta = -6.061; P = .02) predicted the rate of decline in mMMS scores. CONCLUSIONS: Both degree of cerebral atrophy and severity of WMH are associated with the rapidity of cognitive decline in AD. Atrophy and WMH may have a synergistic effect on future decline in AD, such that patients with a high degree of both have a particularly precipitous cognitive course. These findings lend further support to the hypothesis that cerebrovascular pathological abnormalities contribute to the clinical syndrome of AD.

BACKGROUND: Although there has been much research devoted to understanding the predictors of nursing home placement (NHP) in Alzheimer's disease (AD) patients, there is currently a lack of research concerning the predictors of home health care. The objective of this study was to examine whether the Dependence Scale can predict home health aide (HHA) use. METHODS: The sample is drawn from the Predictors Study, a large, multicenter cohort of patients with probable AD, prospectively followed annually for up to 7 years in three university-based AD centers in the United States. Markov analyses (n=75) were used to calculate annual transition probabilities for the "new onset" of HHA use (instances where an HHA was absent at the previous visit, but present at the next visit) as a function of HHA presence at the preceding year's visit and dependence level at that preceding year's visit. RESULTS: The dependence level at the previous year's visit was a significant predictor of HHA use at the next year's visit. Three specific items of the Dependence Scale (needing household chores done for oneself, needing to be watched or kept company when awake, and needing to be escorted when outside) were significant predictors of the presence of an HHA. CONCLUSION: The Dependence Scale is a valuable tool for predicting HHA use in AD patients. Obtaining a better understanding of home health care in AD patients may help delay NHP and have a positive impact on the health and well-being of both the caregiver and the patient.

OBJECTIVE: To describe factors associated with survival in Alzheimer disease (AD) in a multiethnic, population-based longitudinal study. METHODS: AD cases were identified in the Washington Heights Inwood Columbia Aging Project, a longitudinal, community-based study of cognitive aging in Northern Manhattan. The sample comprised 323 participants who were initially dementia-free but developed AD during study follow-up (incident cases). Participants were followed for an average of 4.1 (up to 12.6) years. Possible factors associated with shorter lifespan were assessed using Cox proportional hazards models with attained age as the time to event (time from birth to death or last follow-up). In subanalyses, median postdiagnosis survival durations were estimated using postdiagnosis study follow-up as the timescale. RESULTS: The mortality rate was 10.7 per 100 person-years. Mortality rates were highest [corrected] among those diagnosed at older ages, and among non-Hispanic whites compared to [corrected] Hispanic [corrected] The median lifespan of the entire sample was 92.2 years (95% CI: 90.3, 94.1). In a multivariable-adjusted Cox model, history of diabetes and history of hypertension were independently associated with a shorter lifespan. No differences in lifespan were seen by race/ethnicity after multivariable adjustment. The median postdiagnosis survival duration was 3.7 years among non-Hispanic whites, 4.8 years among African Americans, and 7.6 years among Hispanics. CONCLUSION: Factors influencing survival in Alzheimer disease include race/ethnicity and comorbid diabetes and hypertension.

BACKGROUND: The objective of this study was to compare total costs of care and its major components for community-living patients with Alzheimer's disease (AD) or dementia with Lewy bodies (DLB). This cross-sectional analysis of baseline data from the Predictors II Study took place in three university-based AD centers in the U.S. METHODS: Community-living patients clinically diagnosed with probable AD (n = 170) or DLB (n = 25) with a modified Mini-Mental State examination (mMMS) score > or =30, equivalent to a score of approximately > or =16 on the Folstein Mini-Mental State Examination (MMSE), participated in this study. Patient and informant reported on patients' use of direct medical care, direct nonmedical care, and informal care. Patients' clinical and demographic characteristics included global cognitive status (measured by MMSE), functional capacity (measured by Blessed Dementia Rating Scale), psychotic symptoms, behavioral problems, depressive symptoms, extrapyramidal signs, comorbidities, age, and sex. Costs were compared by using covariate matching methods. RESULTS: Unadjusted total costs and direct medical costs were not significantly different between AD and DLB patients. Compared with AD patients, unadjusted indirect costs were significantly higher and unadjusted direct nonmedical costs were significantly lower among DLB patients. After adjusting for age, sex, cognitive and functional status, differences in all cost components between DLB and AD patients were no longer statistically significant. CONCLUSIONS: Apparent cost differences were largely attributed to differences in patients' cognitive and functional status. However, the small sample size for DLB patients might have limited power to detect statistically significant differences in costs of care between these groups.

OBJECTIVE: To determine whether beta-amyloid (Abeta) peptides segregated into distinct biochemical compartments would differentially correlate with clinical severity of Alzheimer disease (AD). DESIGN: Clinicopathologic correlation study. PARTICIPANTS: Twenty-seven patients from a longitudinal study of AD and 13 age- and sex-matched controls without a known history of cognitive impairment or dementia were included in this study. INTERVENTIONS: Temporal and cingulate neocortex were processed using a 4-step extraction, yielding biochemical fractions that are hypothesized to be enriched with proteins from distinct anatomical compartments: TRIS (extracellular soluble), Triton (intracellular soluble), sodium dodecyl sulfate (SDS) (membrane associated), and formic acid (extracellular insoluble). Levels of Abeta(40) and Abeta(42) were quantified in each biochemical compartment by enzyme-linked immunosorbent assay. RESULTS: The Abeta(42) level in all biochemical compartments was significantly elevated in patients with AD vs controls (P < .01). The Abeta(40) levels in the TRIS and formic acid fractions were elevated in patients with AD (temporal, P < .01; cingulate, P = .03); however, Triton and SDS Abeta(40) levels were similar in patients with AD and in controls. Functional impairment proximal to death correlated with Triton Abeta(42) (r = 0.48, P = .02) and SDS Abeta(42) (r = 0.41, P = .04) in the temporal cortex. Faster cognitive decline was associated with elevated temporal SDS Abeta(42) levels (P < .001), whereas slower decline was associated with elevated cingulate formic acid Abeta(42) and SDS Abeta(42) levels (P = .02 and P = .01, respectively). CONCLUSION: Intracellular and membrane-associated Abeta, especially Abeta(42) in the temporal neocortex, may be more closely related to AD symptoms than other measured Abeta species.

OBJECTIVES: To estimate incremental effects of patients' dependence and function on costs of care during the early stages of Alzheimer's disease (AD) and to compare strengths of their relationships with different cost components. DESIGN: Multicenter, cross-sectional, observational study. SETTING: Three university hospitals in the United States. PARTICIPANTS: One hundred seventy-nine community-living patients with probable AD, with modified Mini-Mental State Examination scores of 30 or higher. MEASUREMENTS: Patients' dependence was measured using the Dependence Scale (DS). Functional capacity was measured using the Blessed Dementia Rating Scale (BDRS). Total cost was measured by summing direct medical costs and informal costs. Direct medical costs included costs of hospitalization, outpatient treatment and procedures, assistive devices, and medications. Informal costs were estimated from time spent helping with basic and instrumental activities of daily living for up to three caregivers per patient using national average hourly earnings as wage rate. RESULTS: DS and BDRS were associated with higher total cost; a 1-point increase in DS was associated with a $1,832 increase in total cost, and a 1-point increase in BDRS was associated with a $3,333 increase. Examining component costs separately identified potential differences between DS and BDRS. A 1-point increase in BDRS was associated with a $1,406 increase in direct medical cost. A 1-point increase in DS was associated with a $1,690 increase in informal cost. CONCLUSION: Patients' dependence and function related differently to direct medical and informal cost, suggesting that measures of function and dependence provided unique information for explaining variations in cost of care for patients with AD, highlighting the value in measuring both constructs.

OBJECTIVES: To (1) compare home health and informal (unpaid) services utilization among patients with Alzheimer's disease (AD), (2) examine longitudinal changes in services use, and (3) estimate possible interdependence of home health and informal care utilization. METHODS: The sample is drawn from the Predictors Study, a large, multicenter cohort of patients with probable AD, prospectively followed annually for up to 7 years in three university-based AD centers. Bivariate probit models estimated the effects of patient characteristics on home health and informal care utilization. RESULTS: A large majority of the patients (80.6%) received informal care with a smaller proportion (18.6%) receiving home health services. Home health services utilization increased from 9.9% at baseline to 34.5% in year 4. Among users, number of days that services were provided in three-month recall increased from 21.9 to 56 days over time. Home health services utilization was significantly associated with function, depressive symptoms, being female, and not living with a spouse. Informal care utilization was significantly associated with cognition, function, comorbidities, and living with a spouse or child. CONCLUSIONS: Home health and informal care utilization relate differently to patient characteristics. Utilization of home health care or informal care was not influenced by utilization of the other.

BACKGROUND/AIMS: To examine the incremental effect of patients' dependence on others, on cost of medical and nonmedical care, and on informal caregiving hours over time. METHODS: Data are obtained from 172 patients from the Predictors Study, a large, multicenter cohort of patients with probable Alzheimer disease (AD) followed annually for 4 years in 3 University-based AD centers in the USA. Enrollment required a modified Mini-Mental State Examination score >or=30. We examined the effects of patient dependence (measured by the Dependence Scale, DS) and function (measured by the Blessed Dementia Rating Scale, BDRS) on medical care cost, nonmedical care cost, and informal caregiving time using random effects regression models. RESULTS: A one-point increase in DS score was associated with a 5.7% increase in medical cost, a 10.5% increase in nonmedical cost, and a 4.1% increase in caregiving time. A one-point increase in BDRS score was associated with a 7.6% increase in medical cost, a 3.9% increase in nonmedical cost and an 8.7% increase in caregiving time. CONCLUSIONS: Both functional impairment and patient dependence were associated with higher costs of care and caregiving time. Measures of functional impairment and patient dependence provide unique and incremental information on the overall impact of AD on patients and their caregivers.

Alzheimer's disease (AD) is increasing in prevalence. There are no known preventive or curative measures. There is evidence that oxidative stress, homo-cysteine-related vitamins, fats, and alcohol have a role in the pathogenesis of AD. Some epidemiologic studies suggest that higher dietary intake of antioxidants, vitamins B(6), B(12), and folate, unsaturated fatty acids, and fish are related to a lower risk of AD, but reports are inconsistent. Modest to moderate alcohol intake, particularly wine, may be related to a lower risk of AD. The Mediterranean diet may also be related to lower AD risk. However, randomized clinical trials of supplements of vitamins E, B(12), B(6), and folate have shown no cognitive benefit, and randomized trials for other nutrients or diets in AD are not available. The existing evidence does not support the recommendation of specific supplements, foods, or diets for the prevention of AD.

Because of the aging of the population, dementia has become a major public health problem. There has been growing evidence for a possible association between lipids and dementia. A large body of literature has demonstrated multiple hypothesized biologic links between lipids and neurodegenerative or other biologic pathways connected to dementing processes. However, the epidemiologic associations have been conflicting: dyslipidemia at middle age, but not in later life, seems to be associated with higher dementia risk in some but not all studies. Results from the Honolulu-Asia Aging Study reported by Saczynski et al. (Am J Epidemiol 2007;165:985-92) suggest that lipoprotein constituents, such as apolipoprotein A-I, a major component of the high density lipoprotein, may be more informative in enlightening the association between lipids and dementia. In this commentary, the epidemiology and biology of apolipoprotein A-I in relation to dementia is reviewed.

OBJECTIVE: To characterize deficits in nonverbal recognition memory and functional brain changes associated with these deficits in Alzheimer disease (AD). METHODS: Using O-15 PET, we studied 11 patients with AD and 17 cognitively intact elders during the combined encoding and retrieval periods of a nonverbal recognition task. Both task conditions involved recognition of line drawings of abstract shapes. In both conditions, subjects were first presented a list of shapes as study items, and then a list as test items, containing items from the study list and foils. In the titrated demand condition, the shape study list size (SLS) was adjusted prior to imaging so that each subject performed at approximately 75% recognition accuracy; difficulty during PET scanning in this condition was approximately matched across subjects. A control task was used in which SLS = 1 shape. RESULTS: During performance of the titrated demand condition, SLS averaged 4.55 (+/-1.86) shapes for patients with AD and 7.53 (+/-4.81) for healthy elderly subjects (p = 0.031). However, both groups of subjects were closely matched on performance in the titrated demand condition during PET scanning with 72.17% (+/-7.98%) correct for patients with AD and 72.25% (+/-7.03%) for elders (p = 0.979). PET results demonstrated that patients with AD showed greater mean differences between the titrated demand condition and control in areas including the left fusiform and inferior frontal regions (Brodmann areas 19 and 45). CONCLUSIONS: Relative fusiform and inferior frontal differences may reflect the Alzheimer disease (AD) patients' compensatory engagement of alternate brain regions. The strategy used by patients with AD is likely to be a general mechanism of compensation, rather than task-specific.

PURPOSE: To determine whether an acetylcholinesterase inhibitor, such as donepezil, would improve memory or other cognitive/psychological functions in epilepsy patients with subjective memory complaints. METHODS: Twenty-three epilepsy patients with subjective memory difficulty were randomized to either 3 months of donepezil (10 mg/day) or 3 months of placebo treatment, and then crossed over to the other treatment arm. Patients and physicians were blinded to treatment phase throughout data acquisition. Assessment of memory and other cognitive functions, subjective memory, mood, and self-rated quality of life (QOL) and social functioning was performed at baseline and following completion of both treatment phases. Seizure frequency and severity as well as treatment emergent adverse effects were also monitored. RESULTS: Donepezil treatment was not associated with improvement in memory or other cognitive functions, mood, social functioning or QOL. Comparable increases in self-rated memory functioning relative to baseline were evident during donepezil and placebo phases. Donepezil treatment was not associated with increased seizure frequency or severity. Similar to group results, analysis of change within individual patients as a function of treatment phase also showed neither significant benefit nor detriment associated with donepezil. CONCLUSION: This study found no benefit on memory or other cognitive/psychological functions in a heterogeneous group of epilepsy patients with subjective memory difficulty. Further investigation would be required to determine whether individual patients, or those with particular epilepsy syndromes, might benefit from donepezil or other acetylcholinesterase inhibitors, or if a higher dosage might be effective.

Cerebral white matter lesions (WML) are present in more than 50% of patients with osteonecrosis of the femoral head (ONFH). Paraoxonase 1 (PON1) gene product is a detoxifying and pesticide metabolizing enzyme. Genetic variants of the PON1 gene have been found to influence the occurrence and progression of WML. We examined whether two PON1 polymorphisms (M55L and R192Q) are associated with ONFH and influence the occurrence of WML. We studied 104 patients with ONFH and 113 healthy age- and sex-matched subjects. We used logistic regression models to examine associations and survival analyses (Cox proportional hazards models) to examine possible influence of alleles on age at onset of ONFH. We found no association of PON1 M55L alleles and genotypes with ONFH. The distribution of PON1 Q192R alleles (p = 0.001) and genotypes (QQ vs. QR/RR) (p = 0.004) were statistically different between controls and patients. Patients with QQ genotype had six times higher risk for WML at brain MRI (adjusted OR 5.95; 95% CI 1.30-27.03; p = 0.02). In Cox models, there was a significant association of allele Q with risk for ONFH indicating a possible dose effect (HR = 1.43; 95%CI = 1.04-1.97; p for trend = 0.03). We conclude that individuals with PON1 192QQ genotype may have increased risk for ONFH and WMLeOn.

BACKGROUND: We previously reported that the Mediterranean diet (MeDi) is related to lower risk for Alzheimer disease (AD). Whether MeDi is associated with subsequent AD course and outcomes has not been investigated. OBJECTIVES: To examine the association between MeDi and mortality in patients with AD. METHODS: A total of 192 community-based individuals in New York who were diagnosed with AD were prospectively followed every 1.5 years. Adherence to the MeDi (0- to 9-point scale with higher scores indicating higher adherence) was the main predictor of mortality in Cox models that were adjusted for period of recruitment, age, gender, ethnicity, education, APOE genotype, caloric intake, smoking, and body mass index. RESULTS: Eighty-five patients with AD (44%) died during the course of 4.4 (+/-3.6, 0.2 to 13.6) years of follow-up. In unadjusted models, higher adherence to MeDi was associated with lower mortality risk (for each additional MeDi point hazard ratio 0.79; 95% CI 0.69 to 0.91; p = 0.001). This result remained significant after controlling for all covariates (0.76; 0.65 to 0.89; p = 0.001). In adjusted models, as compared with AD patients at the lowest MeDi adherence tertile, those at the middle tertile had lower mortality risk (0.65; 0.38 to 1.09; 1.33 years' longer survival), whereas subjects at the highest tertile had an even lower risk (0.27; 0.10 to 0.69; 3.91 years' longer survival; p for trend = 0.003). CONCLUSION: Adherence to the Mediterranean diet (MeDi) may affect not only risk for Alzheimer disease (AD) but also subsequent disease course: Higher adherence to the MeDi is associated with lower mortality in AD. The gradual reduction in mortality risk for higher MeDi adherence tertiles suggests a possible dose-response effect.

BACKGROUND: Disruptive behavior is common in Alzheimer disease (AD). There are conflicting reports regarding its ability to predict cognitive decline, functional decline, institutionalization, and mortality. OBJECTIVE: To examine whether the presence of disruptive behavior has predictive value for important outcomes in AD. DESIGN: Using the Columbia University Scale for Psychopathology in Alzheimer Disease (administered every 6 months, for a total of 3438 visit-assessments and an average of 6.9 per patient), the presence of disruptive behavior (wandering, verbal outbursts, physical threats/violence, agitation/restlessness, and sundowning) was extracted and examined as a time-dependent predictor in Cox models. The models controlled for the recruitment cohort, recruitment center, informant status, sex, age, education, a comorbidity index, baseline cognitive and functional performance, and neuroleptic use. SETTING: Five university-based AD centers in the United States and Europe (Predictors Study). PARTICIPANTS: Four hundred ninety-seven patients with early-stage AD (mean Folstein Mini-Mental State Examination score, 20 of 30 at entry) who were recruited and who underwent semiannual follow-up for as long as 14 (mean, 4.4) years. MAIN OUTCOME MEASURES: Cognitive (Columbia Mini-Mental State Examination score, < or = 20 of 57 [approximate Folstein Mini-Mental State Examination score, < or = 10 of 30]) and functional (Blessed Dementia Rating Scale score, parts I and II, > or = 10) ratings, institutionalization equivalent index, and death. RESULTS: At least 1 disruptive behavioral symptom was noted in 48% of patients at baseline and in 83% at any evaluation. Their presence was associated with increased risks of cognitive decline (hazard ratio 1.45 [95% confidence interval (CI), 1.03-2.03]), functional decline (1.66 [95% CI, 1.17-2.36]), and institutionalization (1.47 [95% CI, 1.10-1.97]). Sundowning was associated with faster cognitive decline, wandering with faster functional decline and institutionalization, and agitation/restlessness with faster cognitive and functional decline. There was no association between disruptive behavior and mortality (hazard ratio, 0.94 [95% CI, 0.71-1.25]). CONCLUSION: Disruptive behavior is very common in AD and predicts cognitive decline, functional decline, and institutionalization but not mortality.

BACKGROUND: High rates of leisure activity have been associated with reduced risk of Alzheimer disease (AD). OBJECTIVE: To determine whether prediagnosis leisure activity modifies the rate of cognitive decline in patients with AD. DESIGN: Inception cohort followed up longitudinally for a mean of 5.3 years (up to 13.9 years). SETTING: Urban community. PARTICIPANTS: A total of 283 patients with incident AD (mean age, 79 years; 56.2% Hispanic and 31.1% African American). MAIN OUTCOME MEASURES: Change in a composite cognitive score from diagnosis on and during the entire study follow-up. RESULTS: In multivariate-adjusted generalized estimating equation models of postdiagnosis change (n = 133), each leisure activity was associated with an additional yearly decline of 0.005 of a z-score unit in cognitive score (P = .17). In models expanded to include cognitive change during study follow-up, including evaluations before and after diagnosis (n = 283), each activity was associated with an additional yearly decline of 0.005 of a z-score unit in cognitive score (P = .03). The association was strongest for intellectual activities. CONCLUSIONS: Greater participation in prediagnosis leisure activities, especially intellectual activities, was associated with faster cognitive decline, supporting the hypothesis that the disease course in AD may vary as a function of cognitive reserve.

BACKGROUND: Higher adherence to the Mediterranean diet (MeDi) has been related to lower Alzheimer's disease risk. Some dietary factors have been studied in patients with essential tremor (ET), but the MeDi's effect has not been investigated. METHODS: Adherence to the MeDi was calculated from a food frequency questionnaire administered in a case-control study of environmental epidemiology of ET in the New York Tri-State area. Logistic regression models were used to examine whether adherence to the MeDi predicted ET (vs. control) outcome. The models adjusted for age, gender, ethnicity, education, caloric intake, body mass index, smoking, ethanol consumption, coffee intake and blood harmane concentrations. RESULTS: 148 ET cases adhered less to MeDi (0-9 scale with higher scores indicating higher adherence) than 250 controls (mean 4.3 +/- 1.7 vs. 4.7 +/- 1.7; p = 0.03). Higher adherence to MeDi was associated with lower odds for ET [0.78 (0.61-0.99); p = 0.042]. As compared to subjects at the lowest MeDi adherence tertile, those at the middle tertile had lower ET odds [0.41 (0.16-1.05)], while subjects at the highest tertile had an even lower ET odds [0.29 (0.10-0.82); p for trend 0.021]. CONCLUSIONS: Compared to controls, ET cases adhered less to MeDi. The gradual reduction in ET odds with higher MeDi adherence tertiles suggests a possible dose-response effect. The mechanisms that underlie this association merit further study.

Temporoparietal and posterior cingulate metabolism deficits characterize patients with Alzheimer's disease (AD). A H(2)(15)O resting PET scan covariance pattern, derived by using multivariate techniques, was previously shown to discriminate 17 mild AD patients from 16 healthy controls. This AD covariance pattern revealed hypoperfusion in bilateral inferior parietal lobule and cingulate; and left middle frontal, inferior frontal, precentral, and supramarginal gyri. The AD pattern also revealed hyperperfusion in bilateral insula, lingual gyri, and cuneus; left fusiform and superior occipital gyri; and right parahippocampal gyrus and pulvinar. In an independent sample of 23 outpatients with mild cognitive impairment (MCI) followed at 6-month intervals, the AD pattern score was evaluated as a predictor of cognitive decline. In this MCI sample, an H2(15)O resting PET scan was carried out at baseline. Mean duration of follow-up was 48.8 (SD 15.5) months, during which time six of 23 MCI patients converted to AD. In generalized estimating equations (GEE) analyses, controlling for age, sex, education, and baseline neuropsychological scores, increased AD pattern score was associated with greater decline in each neuropsychological test score over time (Mini Mental State Exam, Selective Reminding Test delayed recall, Animal Naming, WAIS-R digit symbol; Ps<0.01-0.001). In summary, a resting PET covariance pattern previously reported to discriminate AD patients from control subjects was applied prospectively to an independent sample of MCI patients and found to predict cognitive decline. Independent replication in larger samples is needed before clinical application can be considered.

The alpha-synuclein Rep1 polymorphism was studied in patients and controls in an ethnic Greek population. There was an association of allele 2 with risk of Parkinson's disease (PD; adjusted odd ratio = 3.25; 95% CI = 1.80-5.87). Survival analyses (Cox proportional hazards models) were employed to explore the influence of genotypes on age at onset of PD. Age at onset of carriers of at least one Rep1 allele 2 was earlier (3.6 years) compared to noncarriers (adjusted hazard ratio = 2.21; 95% CI = 1.58-3.10). Kaplan-Meier analysis also supported a dosage effect of Rep1 allele 2 on age at onset. For Rep1 allele 1, there was neither association with risk of PD nor influence on age at onset. This is the first study showing an influence of Rep1 polymorphism on age at onset of PD.

OBJECTIVES: To estimate long-term trajectories of direct cost of caring for patients with Alzheimer disease (AD) and examine the effects of patients' characteristics on cost longitudinally. METHODS: The sample is drawn from the Predictors Study, a large, multicenter cohort of patients with probable AD, prospectively followed up annually for up to 7 years in three university-based AD centers in the United States. Random effects models estimated the effects of patients' clinical and sociodemographic characteristics on direct cost of care. Direct cost included cost associated with medical and nonmedical care. Clinical characteristics included cognitive status (measured by Mini-Mental State Examination), functional capacity (measured by Blessed Dementia Rating Scale [BDRS]), psychotic symptoms, behavioral problems, depressive symptoms, extrapyramidal signs, and comorbidities. The model also controlled for patients' sex, age, and living arrangements. RESULTS: Total direct cost increased from approximately 9,239 dollars per patient per year at baseline, when all patients were at the early stages of the disease, to 19,925 dollars by year 4. After controlling for other variables, a one-point increase in the BDRS score increased total direct cost by 7.7%. One more comorbid condition increased total direct cost by 14.3%. Total direct cost was 20.8% lower for patients living at home compared with those living in an institutional setting. CONCLUSIONS: Total direct cost of caring for patients with Alzheimer disease increased substantially over time. Much of the cost increases were explained by patients' clinical and demographic variables. Comorbidities and functional capacity were associated with higher direct cost over time.

We sought to study the presence of the receptor for advanced glycation endproducts (RAGE) and its ligands, advanced glycation endproducts (AGEs), S100/calgranulins and amphoterin (high mobility group box 1 protein; HMGB1), in the vitreous cavity and epiretinal membranes (ERMs) of eyes of patients with proliferative diabetic retinopathy (PDR) and proliferative vitreoretinopathy (PVR). Undiluted vitreous specimens were collected from 30 eyes of 30 patients undergoing pars plana vitrectomy for repair of retinal detachment (RD) secondary to PDR (n = 15) or PVR (n = 15). The vitreous samples obtained from 10 eyes undergoing macular hole repair were used as controls. Epiretinal membranes were obtained from eight eyes with PDR and from 10 eyes with PVR. The levels of AGEs in the vitreous were measured using ELISA. The vitreous levels of soluble RAGE (sRAGE), S100/calgranulins and amphoterin were measured using Western blot analyses. The localization of RAGE and its ligands in ERMs was determined with immunohistochemistry. The vitreous levels of sRAGE were significantly increased in both PDR and PVR (p < or = 0.05) compared to control vitreous. In both PDR and PVR, the vitreous levels of AGEs (p < or = 0.01), S100/calgranulins (p < or = 0.05), and amphoterin (p < or = 0.01) were also elevated compared to control eyes. Expression of RAGE was detected in six of eight ERMs from eyes with PDR and eight of 10 ERMs from eyes with PVR. Many cells expressing RAGE also expressed vimentin, suggesting a glial cell origin. Ligands for RAGE were also detected in ERMs, with AGEs detected in five eyes with PDR and eight eyes with PVR. Similarly, S100 and amphoterin ERM expression was observed in six eyes with PDR; these ligands were also expressed in ERMs from eyes with PVR (8 and 7 cases, respectively). We conclude that RAGE and its ligands are increased in the vitreous cavity of eyes with PDR and PVR and are present in ERMs of eyes with these proliferative retinal disorders. These findings suggest a role for the proinflammatory RAGE axis in the pathogenesis of proliferative retinal diseases.

BACKGROUND: Some (but not all) epidemiological studies have noted faster rates of progression in high education patients with Alzheimer's disease (AD), which has been attributed to harbouring/tolerating a higher pathological burden at the time of clinical dementia for subjects with higher education. We wanted to assess the relationship between education and rates of decline in AD. METHODS: During the course of a community based multiethnic prospective cohort study of individuals aged > or = 65 years living in New York, 312 patients were diagnosed with incident AD and were followed overall for 5.6 (up to 13.3) years. The subjects received an average of 3.7 (up to 9) neuropsychological assessments consisting of 12 individual tests. With the aid of a normative sample, a standardised composite cognitive score as well as individual cognitive domain scores were calculated. Generalised estimating equation models were used to examine the association between education and rates of cognitive decline. RESULTS: Composite cognitive performance declined by 9% of a standard deviation per year. Rates of decline before and after AD incidence were similar. For each additional year of education there was 0.3% standard deviation lower composite cognitive performance for each year of follow up. The association between higher education and faster decline was noted primarily in the executive speed (0.6%) and memory (0.5%) cognitive domains and was present over and above age, gender, ethnicity, differential baseline cognitive performance, depression, and vascular comorbidity. CONCLUSIONS: We conclude that higher education AD patients experience faster cognitive decline.

BACKGROUND: Cognitive impairment is increasingly recognized in patients with amyotrophic lateral sclerosis (ALS). Clinical and pathologic features overlap in frontotemporal lobar dementia and ALS. Demographics, respiratory status, bulbar site of onset, and disease severity are potential risk factors for cognitive impairment in ALS. OBJECTIVES: To further delineate the frequency, nature, and implications of cognitive impairment in ALS and to assess previously identified risk factors. DESIGN: Case-control and retrospective cohort study. SETTING: Academic referral center. PARTICIPANTS: Forty consecutive patients with ALS underwent baseline neurologic and neuropsychologic examinations. Cognitive test performance was compared in patients with ALS and matched controls. An exploratory analysis of the relationship between cognitive performance and ALS survival was performed. MAIN OUTCOME MEASURES: Neuropsychologic test performance, ALS severity, and survival. RESULTS: Twelve patients (30%) showed evidence of cognitive impairment, including 9 (23%) who met the neuropsychologic criteria for dementia. No statistically significant differences were found between demented and nondemented ALS groups regarding demographics, family history, site of onset, bulbar dysfunction, or ALS severity. Only 1 patient with dementia had bulbar-onset disease. An association was observed between increasing ALS severity and declining verbal fluency performance. Demented patients with ALS showed predominant impairment in free recall, executive function, and naming, with relative preservation of attention, psychomotor speed, and visuospatial function. No association was observed between cognition and survival, controlling for ALS severity. CONCLUSIONS: Nearly a third of the patients with ALS showed evidence of cognitive impairment in a pattern consistent with frontotemporal lobar dementia. Cognitive performance was not related to site of onset or survival.

We tested the hypothesis that age-related time production deficits are dopamine-mediated. The experiment was conducted double-blind, and with random assignment of 32 healthy aged and 32 healthy young participants to either inert placebo or levodopa (200 mg) groups. The procedure included training participants to produce two target time intervals (6 and 17 sec) in separate blocks, drug/placebo administration, a 1-hr delay, and then delayed free-recall time production retesting without feedback. Participants also performed a speeded choice reaction time (RT) task, as a control for potential dopaminergic and aging effects on attention and psychomotor speed. Results indicate that during retesting, aged participants show duration-dependent timing errors that are larger than those shown by the young participants. Levodopa administration yielded lengthened time production of both target intervals. The aging and levodopa effects did not interact. Also, aging slowed RT and increased RT variability, but levodopa had no effect on the RT. These results suggest that at this dosage and under these specific conditions, timing is dopamine-mediated but the effect of aging on time production is not. Moreover, the levodopa timing effect cannot be attributed to the effects of dopaminergic function on psychomotor speed.

OBJECTIVE: Previous research in Alzheimer's disease (AD) has focused on individual dietary components. There is converging evidence that composite dietary patterns such as the Mediterranean diet (MeDi) is related to lower risk for cardiovascular disease, several forms of cancer, and overall mortality. We sought to investigate the association between MeDi and risk for AD. METHODS: A total of 2,258 community-based nondemented individuals in New York were prospectively evaluated every 1.5 years. Adherence to the MeDi (zero- to nine-point scale with higher scores indicating higher adherence) was the main predictor in models that were adjusted for cohort, age, sex, ethnicity, education, apolipoprotein E genotype, caloric intake, smoking, medical comorbidity index, and body mass index. RESULTS: There were 262 incident AD cases during the course of 4 (+/-3.0; range, 0.2-13.9) years of follow-up. Higher adherence to the MeDi was associated with lower risk for AD (hazard ratio, 0.91; 95% confidence interval, 0.83-0.98; p=0.015). Compared with subjects in the lowest MeDi tertile, subjects in the middle MeDi tertile had a hazard ratio of 0.85 (95% confidence interval, 0.63-1.16) and those at the highest tertile had a hazard ratio of 0.60 (95% confidence interval, 0.42-0.87) for AD (p for trend=0.007). INTERPRETATION: We conclude that higher adherence to the MeDi is associated with a reduction in risk for AD.

Many studies have investigated APOE-related differences in cerebral structure, blood flow, metabolism, and activation in an attempt to detect early brain changes in subjects at risk for Alzheimer's disease (AD). Structural magnetic resonance imaging studies have produced conflicting results, with some failing to detect APOE-related differences and others suggesting that epsilon4 carriers have more pronounced atrophy, particularly at medial temporal structures. All functional imaging studies done during rest in middle-aged and elderly subjects have found decreased cerebral metabolism for epsilon4 carriers (mostly in areas that usually are affected by AD), and some have reported faster cerebral metabolic reductions over time. Areas with decreased resting cerebral perfusion and metabolism, in addition to other areas with increased perfusion, have been reported in young epsilon4 carriers. Imaging studies done during the performance of various cognitive tasks in middle-aged and elderly subjects, and a single study in young subjects, have produced mixed results with regionally nonspecific increased, decreased, or nondifferential APOE-related activations depending on the cognitive task used. APOE-related findings in imaging studies of nondemented subjects may be the result of incipient AD pathologic changes or of genetic heterogeneity in brain structure and function.

BACKGROUND: Few studies on cost of caring for patients with Alzheimer disease (AD) have simultaneously considered multiple dimensions of disease costs and detailed clinical characteristics. OBJECTIVE: To estimate empirically the incremental effects of patients' clinical characteristics on disease costs. METHODS: Data are derived from the baseline visit of 180 patients in the Predictors Study, a large, multicenter cohort of patients with probable AD followed from early stages of the disease. All patients initially lived at home, in retirement homes, or in assisted living facilities. Costs of direct medical care included hospitalizations, outpatient treatment and procedures, assistive devices, and medications. Costs of direct nonmedical care included home health aides, respite care, and adult day care. Indirect costs were measured by caregiving time. Patients' clinical characteristics included cognitive status, functional capacity, psychotic symptoms, behavioral problems, depressive symptoms, extrapyramidal signs, comorbidities, and duration of illness. RESULTS: A 1-point increase in the Blessed Dementia Rating Scale score was associated with a $1,411 increase in direct medical costs and a $2,718 increase in unpaid caregiving costs. Direct medical costs also were $3,777 higher among subjects with depressive symptoms than among those who were not depressed. CONCLUSIONS: Medical care costs and unpaid caregiving costs relate differently to patients' clinical characteristics. Poorer functional status is associated with higher medical care costs and unpaid caregiving costs. Interventions may be particularly useful if targeted in the areas of basic and instrumental activities of daily living.

OBJECTIVES: To assess the predictive value of neuropsychologic profiles, at diagnosis, for mortality in incident Alzheimer disease (AD). BACKGROUND: Rate of AD progression varies significantly across individuals for reasons that are not well understood. Several studies have linked rapid decline with disproportionately impaired executive functioning, presumably reflecting greater impairment of frontal networks. To the extent that differential neuropsychologic profiles reflect various neuropathologic presentations of AD, such profiles may inform survival estimates early in the disease. METHODS: Five neuropsychologic indices were used to characterize performance in 161 individuals at diagnosis of AD during a 15-year, longitudinal, primarily community-based study. RESULTS: Fifty-two percent of participants reached the mortality end point with a median survival of 5.52 years (95% confidence interval, 4.41-6.63). Cox proportional hazards analyses indicated that older age at diagnosis was associated with higher risk of mortality (risk ratios, 1.08; 95% confidence interval, 1.04-1.12) whereas Hispanic ethnicity predicted lower mortality [0.22 (0.09-0.55)]. Controlling for these 2 demographic variables, higher verbal fluency scores at diagnosis predicted lower mortality [0.69 (0.49-0.96)]. CONCLUSIONS: Disproportionate impairment of both category and letter fluency at the earliest stages of AD predicts mortality. The prognostic value of these tests may derive from their general psychometric properties, or may reflect the measures' sensitivity to an early or critical level of compromise to frontal networks.

Most estimates of the cost of informal caregiving in patients with Alzheimer's disease (AD) remain cross-sectional. Longitudinal estimates of informal caregiving hours and costs are less frequent and are from assessments covering only short periods of time. The objectives of this study were to estimate long-term trajectories of the use and cost of informal caregiving for patients with AD and the effects of patient characteristics on the use and cost of informal caregiving. The sample is drawn from the Predictors Study, a large, multicenter cohort of patients with probable AD, prospectively followed annually for up to 7 years in three university-based AD centers in the United States (n=170). Generalized linear mixed models were used to estimate the effects of patient characteristics on use and cost of informal caregiving. Patients' clinical characteristics included cognitive status (Mini-Mental State Examination), functional capacity (Blessed Dementia Rating Scale (BDRS)), comorbidities, psychotic symptoms, behavioral problems, depressive symptoms, and extrapyramidal signs. Results show that rates of informal care use and caregiving hours (and costs) increased substantially over time but were related differently to patients' characteristics. Use of informal care was significantly associated with worse cognition, worse function, and higher comorbidities. Conditional on receiving informal care, informal caregiving hours (and costs) were mainly associated with worse function. Each additional point on the BDRS increased informal caregiving costs 5.4%. Average annual informal cost was estimated at $25,381 per patient, increasing from $20,589 at baseline to $43,030 in Year 4.

BACKGROUND: Although dementia with Lewy bodies (DLB) may be one of most common forms of dementia, relatively little is known about its cognitive and functional course. OBJECTIVE: To compare change over time in general cognitive status, memory test performance, psychiatric symptoms, neurological signs, and functional abilities in patients with probable DLB and probable Alzheimer disease (AD). DESIGN: Twenty-eight patients who met diagnostic criteria for DLB were recruited into the study from 3 sites. Patients with AD (n = 55) were selected from a larger cohort and matched 2 to 1 to the patients with DLB on age and baseline global cognitive status. Patients were followed up at 6-month intervals for an average of 6.2 visits and assessed at each visit with tests of global cognitive functioning and verbal learning and memory and measures of psychiatric, neurological, and functional status. RESULTS: At the baseline evaluation, patients with DLB performed more poorly on a measure of constructional praxis and all measures of functional status. They also had more severe psychiatric symptoms and neurological signs than the AD group. Despite these initial differences, generalized estimating equations applied to regression analyses with repeated measures determined that the only difference between the 2 groups in change in cognitive test performance was on a measure of recognition memory; patients with AD declined, while patients with DLB remained relatively stable. Patients with DLB had relatively stable behavioral symptoms and visual illusions, whereas patients with AD had a significant increase in these symptoms over time. Neurological and functional changes over time were similar in the 2 groups. CONCLUSIONS: Both baseline and longitudinal differences between patients with DLB and patients with AD were noted; these have implications for clinical diagnosis and treatment.

OBJECTIVES: To examine the association between the Mediterranean diet (MeDi) and Alzheimer disease (AD) in a different AD population and to investigate possible mediation by vascular pathways. Design, Setting, Patients, and MAIN OUTCOME MEASURES: A case-control study nested within a community-based cohort in New York, NY. Adherence to the MeDi (0- to 9-point scale with higher scores indicating higher adherence) was the main predictor of AD status (194 patients with AD vs 1790 nondemented subjects) in logistic regression models that were adjusted for cohort, age, sex, ethnicity, education, apolipoprotein E genotype, caloric intake, smoking, medical comorbidity index, and body mass index (calculated as weight in kilograms divided by height in meters squared). We investigated whether there was attenuation of the association between MeDi and AD when vascular variables (stroke, diabetes mellitus, hypertension, heart disease, lipid levels) were simultaneously introduced in the models (which would constitute evidence of mediation). RESULTS: Higher adherence to the MeDi was associated with lower risk for AD (odds ratio, 0.76; 95% confidence interval, 0.67-0.87; P<.001). Compared with subjects in the lowest MeDi tertile, subjects in the middle MeDi tertile had an odds ratio of 0.47 (95% confidence interval, 0.29-0.76) and those at the highest tertile an odds ratio of 0.32 (95% confidence interval, 0.17-0.59) for AD (P for trend <.001). Introduction of the vascular variables in the model did not change the magnitude of the association. CONCLUSIONS: We note once more that higher adherence to the MeDi is associated with a reduced risk for AD. The association does not seem to be mediated by vascular comorbidity. This could be the result of either other biological mechanisms (oxidative or inflammatory) being implicated or measurement error of the vascular variables.

OBJECTIVES: To evaluate the alterations of serum procalcitonin (PCT) levels in patients with chronic hepatitis C during pegylated interferon-alpha (PEG-IFNa) plus ribavirin (RIB) treatment and to correlate them with clinical and virological outcomes. STUDY DESIGN: Fifty-two consecutive patients (29 males, age=41.2+/-14.7 years) with chronic HCV-related liver disease (six cirrhotics) were evaluated for PCT levels at baseline and during the treatment course (at week 12, 24, 48 and 72) with PEG-IFNa plus RIB. Sustained virological response (SVR) was confirmed by undetectable serum HCV-RNA at the end of treatment and again 6 months after completion of treatment. RESULTS: Two patients exhibited culture-proved bacterial infections during the treatment course. Thirty-six patients (69.2%) exhibit SVR and 16 (30.8%) were non-responders. Serum PCT levels remained within normal limits (0.1-0.5 ng/mL) in all treated patients throughout the follow-up period except those two who exhibited bacterial infections during the treatment course. Virological responders exhibited significant decline of serum PCT levels over time compared to non-responders (p<0.001), even when adjusted for multiple baseline parameters (p=0.037). CONCLUSION: Serum PCT levels decline in chronic hepatitis C patients during PEG-IFNa plus RIB treatment, especially in the sustained virological responder group, while they elevate only when bacterial infections complicate the treatment course.

In order to understand the brain networks that mediate cognitive reserve, we explored the relationship between subjects' network expression during the performance of a memory test and an index of cognitive reserve. Using H2(15)O positron emission tomography, we imaged 17 healthy older subjects and 20 young adults while they performed a serial recognition memory task for nonsense shapes under two conditions: low demand, with a unique shape presented in each study trial; and titrated demand, with a study list size adjusted so that each subject recognized shapes at 75% accuracy. A factor score that summarized years of education, and scores on the NART and the WAIS-R Vocabulary subtest was used as an index of cognitive reserve. The scaled subprofile model was used to identify a set of functionally connected regions (or topography) that changed in expression across the two task conditions and was differentially expressed by the young and elderly subjects. The regions most active in this topography consisted of right hippocampus, posterior insula, thalamus, and right and left operculum; we found concomitant deactivation in right lingual gyrus, inferior parietal lobe and association cortex, left posterior cingulate, and right and left calcarine cortex. Young subjects with higher cognitive reserve showed increased expression of the topography across the two task conditions. Because this topography, which is responsive to increased task demands, was differentially expressed as a function of reserve level, it may represent a neural manifestation of innate or acquired reserve. In contrast, older subjects with higher cognitive reserve showed decreased expression of the topography across tasks. This suggests some functional reorganization of the network used by the young subjects. Thus, for the old subjects this topography may represent an altered, compensatory network that is used to maintain function in the face of age-related physiological changes.

Little research has been conducted regarding age-related changes in nonverbal memory. Using positron emission tomography (PET), the authors studied 17 elderly volunteers and 20 young volunteers, during nonverbal recognition task performance, to examine differences in brain blood flow. The subjects were asked to recognize a study list size (SLS) of shapes that was adjusted so that each subject performed at approximately 75% accuracy. Positron emission tomography results showed that, relative to younger individuals, elderly subjects engaged different regions, including the insula, during recognition. Elderly subjects did not show the relationship between parahippocampal flow and SLS, which was observed in younger subjects. These differences suggest that age-related functional brain changes partly explain performance deficits.

OBJECTIVE: To investigate the association of (variable number tandem repeat) interleukin (IL) 1RN and (-511) IL-1B gene polymorphisms with brain hemorrhagic events after traumatic brain injury (TBI). METHODS: Data from brain CT, Glasgow Coma Scale (GCS) at admission, and 6-month Glasgow Outcome Scale (GOS) and modified Rankin Scale (mRS) were collected for 151 prospectively recruited patients with TBI. IL-1RN and IL-1B genotypes were determined using standard methods. Presence vs absence of any type of brain hemorrhage was the main outcome. Type of brain hemorrhage, GCS at admission, and 6-month GOS and mRS were secondary outcomes. Odd ratios (ORs) and corresponding 95% CI were calculated using logistic regression analyses. In adjusted models, the associations were controlled for age, gender, diffuse brain edema, volume of intracranial hematoma, neurosurgical intervention, and GCS at admission. p values less than 0.01 were considered significant. RESULTS: Compared with noncarriers, IL-1RN allele 2 carriers had higher odds of having cerebral hemorrhages after TBI (adjusted OR = 4.57; 95% CI = 1.67 to 12.96; p = 0.004). The associations for (-511) IL-1B polymorphism were not significant. CONCLUSION: There is an association between the presence of interleukin-1RN allele 2 and posttraumatic brain hemorrhage.

BACKGROUND: Associations between the APOE genotype and various medical conditions have been documented at a very young age. The association between the APOE genotype and cognitive performance varies at different ages. APOE related changes in brain activation have been recently reported for middle aged and elderly subjects. OBJECTIVE: To explore APOE related alterations during cognitive activation in a population of young adults. METHODS: Using H2(15)O positron emission tomography (PET), imaging was carried out in 20 healthy young adults (age 19 to 28 years; four epsilon4 carriers and 16 non-epsilon4 carriers) during a non-verbal memory task. Voxel-wise multiple regression analyses were undertaken, with the activation difference PET counts as the dependent variable and the APOE genotype as the independent variable. RESULTS: Brain regions were identified where epsilon4 carriers showed significantly lower or higher activation than non-carriers. CONCLUSIONS: The results suggest that APOE dependent modulation of cerebral flow may be present even at a young age. This may reflect an APOE related physiological heterogeneity which may or may not predispose to brain disease in the ensuing decades or, less likely, the effect of very early Alzheimer's disease related pathological changes.

BACKGROUND: Delusions and hallucinations are common in Alzheimer disease (AD) and there are conflicting reports regarding their ability to predict cognitive decline, functional decline, and institutionalization. According to all previous literature, they are not associated with mortality. OBJECTIVE: To examine whether the presence of delusions or hallucinations has predictive value for important outcomes in AD. DESIGN, SETTING, AND PARTICIPANTS: A total of 456 patients with AD at early stages (mean Folstein Mini-Mental State Examination [MMSE] score of 21 of 30 at entry) were recruited and followed up semiannually for up to 14 years (mean, 4.5 years) in 5 university-based AD centers in the United States and Europe. Using the Columbia University Scale for Psychopathology in AD (administered every 6 months, for a total of 3266 visit-assessments, average of 7.2 per patient), the presence of delusions and hallucinations was extracted and examined as time-dependent predictors in Cox models. The models controlled for cohort effect, recruitment center, informant status, sex, age, education, a comorbidity index, baseline cognitive and baseline functional performance, behavioral symptoms, and use of neuroleptics and cholinesterase inhibitors. MAIN OUTCOME MEASURES: Cognitive (Columbia MMSE score of < or =20/57 [approximate Folstein MMSE score of < or =10/30]), functional (Blessed Dementia Rating Scale [parts I and II] score of > or =10), institutionalization equivalent index, and death. RESULTS: During the full course of follow-up, 38% of patients reached the cognitive, 41% the functional, 54% the institutionalization, and 49% the mortality end point. Delusions were noted for 34% of patients at baseline and 70% at any evaluation. Their presence was associated with increased risk for cognitive (risk ratio [RR], 1.50; 95% confidence interval [CI], 1.07-2.08) and functional decline (RR, 1.41; 95% CI, 1.02-1.94). Hallucinations were present in 7% of patients at initial visit and in 33% at any visit. Their presence was associated with increased risk for cognitive decline (RR, 1.62; 95% CI, 1.06-2.47), functional decline (RR, 2.25; 95% CI, 1.54-2.27), institutionalization (RR, 1.60; 95% CI, 1.13-2.28), and death (RR, 1.49; 95% CI, 1.03-2.14). CONCLUSIONS: Delusions and hallucinations are very common in AD and predict cognitive and functional decline. Presence of hallucinations is also associated with institutionalization and mortality.

OBJECTIVE: To examine whether the presence of motor signs has predictive value for important outcomes in Alzheimer disease (AD). METHODS: A total of 533 patients with AD at early stages (mean Folstein Mini-Mental State Examination [MMSE] 21/30 at entry) were recruited and followed semiannually for up to 13.1 years (mean 3) in five University-based AD centers in the United States and European Union. Four outcomes, assessed every 6 months, were used in Cox models: cognitive endpoint (Columbia Mini-Mental State Examination < or = 20/57 [ approximately MMSE < or = 10/30]), functional endpoint (Blessed Dementia Rating Scale > or = 10), institutionalization equivalent index, and death. Using a standardized portion of the Unified PD Rating Scale (administered every 6 months for a total of 3,149 visit-assessments, average 5.9 per patient), the presence of motor signs, as well as of individual motor sign domains, was examined as time-dependent predictor. The models controlled for cohort, recruitment center, sex, age, education, a comorbidity index, and baseline cognitive and functional performance. RESULTS: A total of 39% of the patients reached the cognitive, 41% the functional, 54% the institutionalization, and 47% the mortality endpoint. Motor signs were noted for 14% of patients at baseline and for 45% at any evaluation. Their presence was associated with increased risk for cognitive decline (RR, 1.72; 95% CI, 1.24 to 2.38), functional decline (1.80 [1.33 to 2.45]), institutionalization (1.68 [1.26 to 2.25]), and death (1.38 [1.05 to 1.82]). Tremor was associated with increased risk for reaching the cognitive and bradykinesia for reaching the functional endpoints. Postural-gait abnormalities carried increased risk for institutionalization and mortality. Faster rates of motor sign accumulation were associated with increased risk for all outcomes. CONCLUSIONS: Motor signs predict cognitive and functional decline, institutionalization, and mortality in Alzheimer disease. Different motor sign domains predict different outcomes.

Memory loads exceeding the limited capacity of working memory (WM) have been shown to expand the prefrontal areas that participate in WM and have revealed substantial individual differences in performance. We used a delayed-match-to-sample (DMS) task in an event-related fMRI study to map the full extent of the expanded regional activations associated with supracapacity loads. A 6-letter study array was compared to arrays of 1 and 3 letters. The task comprised separate encoding, retention, and retrieval fMRI epochs. A brain-wide spatial covariance analysis was applied to the data of all task epochs to identify patterns of correlated regional activations whose expression increased monotonically across 3 memory-load levels on a subject-by-subject basis. Such load-related activation patterns were in all task phases. Of greatest interest is the activation pattern that was obtained during the maintenance phase: increasing activation with memory load was found not only in the lateral PFC (BA 9,44) but also in the parietal lobe (BA 7,40), anterior cingulate (BA 32), and cerebellum. Decreasing activation was found in the occipito-temporal lobe (BA 19,39) as well as the medial prefrontal cortex (BA 9,10). Subject increases in pattern expression from 1 to 6 items were positively correlated with the corresponding reaction time increases (p<0.05) and negatively correlated with NARTIQ (p<0.05), indicating that people who were faster in their responses and had higher NARTIQ had to increase their subject expression of the memory-load-related activation pattern less and were more efficient at the cognitive task. Our method thus not only reproduced findings of other WM studies but also addressed the issue of interactions between lateral PFC and other parts of the brain during the task, for the retention of the to-be-remembered information. The load-related activation patterns from encoding and retrieval phase and their relationship to behavior are also discussed.

BACKGROUND: In cognitively impaired patients without dementia, the utility of apolipoprotein E (APOE) genotyping is unclear. OBJECTIVE: To evaluate the predictive utility of the APOE epsilon4 genotype for conversion to probable Alzheimer disease (AD). DESIGN: Naturalistic, longitudinal study. SETTING: Memory disorders outpatient clinic. PATIENTS: A total of 136 patients with memory complaints were determined to have mild cognitive impairment and were evaluated every 6 months. Fifty-seven age- and sex-matched healthy controls were evaluated annually. MAIN OUTCOME MEASURES: Primary outcome measures included conversion to AD. Secondary outcome measures included change over time in Mini-Mental State Examination (MMSE) score and Selective Reminding Test (SRT) delayed recall score. RESULTS: The APOE epsilon4 allele was present in 25% of patients and 21% of healthy controls. During a mean +/- SD follow-up of 35.2 +/- 24.3 months, 35 of 136 patients converted to AD. APOE epsilon4 carrier status did not differ between converters (31%) and nonconverters to AD (23%, P = .3) and did not affect the time trend in MMSE or SRT scores in the entire sample. Four of 5 APOE epsilon4 homozygotes converted to AD compared with 7 of 29 heterozygotes (P = .02). In a Cox proportional hazards model stratified by age quartiles, after controlling for sex, education, MMSE score, and SRT delayed recall score, APOE epsilon4 increased the risk of AD in patients 70 to 85 years old (n = 57; risk ratio, 2.77; 95% confidence interval, 1.1-7.3; P = .03) but not in patients 55 to 69 years old (n = 79; P = .7). CONCLUSIONS: APOE epsilon4 carrier status was associated with conversion to AD in older outpatients after controlling for known demographic and clinical risk factors, and APOE epsilon4 homozygosity was associated with increased risk of conversion to AD. However, APOE epsilon4 carrier status by itself did not predict cognitive decline or conversion to AD, indicating that APOE genotyping in patients with mild cognitive impairment may have limited clinical applicability for prediction of outcome.

Laparoscopy has emerged as an important staging procedure for determining resectability of pancreatic cancer. However, a small fraction of patients with pancreatic cancer benefit from its use and therefore the routine application of laparoscopy remains controversial. We hypothesized that serum CA 19-9 levels may identify patients who will or will not benefit by laparoscopy. We retrospectively reviewed our database of 63 patients with pancreatic adenocarcinoma who underwent staging laparoscopy and correlated findings with CA 19-9 levels. Overall, laparoscopy identified metastatic disease in 12 patients (19%). None of those required any further operation. The resectability rate (patients who underwent resection after laparoscopy) was 73.5%. There was one false-negative laparoscopy (1.6%). Patients with higher CA 19-9 levels had significant higher odds of having metastasis identified by laparoscopy (odds ratio, 1.83; 95% confidence interval, 1.03-3.24; P = .04). There was no patient with CA 19-9 levels below 100 U/ml in whom metastatic disease was identified during laparoscopy: 18 patients (28.6%) with CA 19-9 levels below this cutoff point had negative laparoscopy and could have avoided the procedure had this cutoff been used for screening. This would have increased the laparoscopy yield to 26.7%. In patients with adenocarcinoma of the pancreas, low CA 19-9 levels predict low probability of metastatic disease; in those patients, laparoscopy can be spared. On the contrary, patients with elevated CA 19-9 have an increased probability of metastatic disease, and these patients may benefit from diagnostic laparoscopy.

OBJECTIVES: To examine the natural course of depressive symptoms in patients with probable Alzheimer's disease (AD), specifically, the temporal relationship between depressive symptoms, function, and cognitive status. DESIGN: Multicenter cohort study with follow-up of up to 14 years. SETTING: Patients from the two Multicenter Study of Predictors of Disease Course in Alzheimer's Disease (Predictors Study) cohorts were recruited at five sites in the United States and Europe. PARTICIPANTS: Patients diagnosed with probable AD (n=536) enrolled in a longitudinal study (Predictors Study). MEASUREMENTS: Depressive symptoms were evaluated at 6-month intervals using the Columbia Scale for Psychopathology in Alzheimer's Disease. The Modified Mini-Mental State (3MS) and Blessed Dementia Rating Scale (BDRS) were used to assess cognitive status and functional activity, respectively. RESULTS: The prevalence of depressive symptoms was stable over the first 3 years of follow-up, at approximately 40%. There was a significant drop to 28% and 24% in the fourth and fifth years of follow-up, respectively. Time-dependent Cox analysis revealed that functional activity (BDRS) but not cognitive status (3MS) was a significant predictor of the first episode of depressive symptoms during follow-up. Generalized estimating equation analyses showed that AD duration and functional activity but not cognitive status were significantly related to depressive symptoms over the entire follow-up period. CONCLUSION: Depressive symptoms are common in AD, but their prevalence decreases over time. Examination of the temporal relationship between depressive symptoms and risk factors suggests that decline in function but not in cognition precedes the first episode of depressive symptoms in patients with probable AD.

BACKGROUND: Cognitive reserve (CR) is the ability of an individual to cope with advancing brain pathological abnormalities so that he or she remains free of symptoms. Epidemiological data and evidence from positron emission tomography suggest that it may be mediated through education or IQ. OBJECTIVE: To investigate CR-mediated differential brain activation in Alzheimer disease (AD) subjects compared with healthy elderly persons. PARTICIPANTS: Using radioactive water positron emission tomography, we scanned 12 AD patients and 17 healthy elderly persons while performing a serial recognition memory task for nonverbalizable shapes under 2 conditions: low demand, in which one shape was presented in each study trial, and titrated demand, in which the study list length was adjusted so that each subject recognized shapes at approximately 75% accuracy. Positron emission tomographic scan acquisition included the encoding and recognition phases. A CR factor score that summarized years of education, National Adult Reading Test estimated IQ, and Wechsler Adult Intelligence Scale-Revised vocabulary subtest score (explaining 71% of the total variance) was used as an index of CR. Voxel-wise, multiple regression analyses were performed with the "activation" difference (titrated demand-low demand) as the dependent variables and the CR factor score as the independent one. Brain regions where regression slopes differed between the 2 groups were identified. RESULTS: The slopes were significantly more positive for the AD patients in the left precentral gyrus and in the left hippocampus and significantly more negative in the right fusiform, right middle occipital, left superior occipital, and left middle temporal gyri. CONCLUSION: Brain regions where systematic relationships (slopes) between subjects' education-IQ and brain activation differ as a function of disease status may mediate the differential ability to cope with (ie, delay or modify) clinical manifestations of AD.

BACKGROUND: Motor signs (MOSIs) are common in Alzheimer disease (AD) and may be associated with rates of cognitive decline, mortality, and cost of care. OBJECTIVE: To describe the progression and identify predictors of individual MOSIs in AD. METHODS: A cohort of 474 patients with AD at early stages was followed semiannually for up to 13.1 years (mean 3.6 years) in five centers in Europe and the United States. MOSIs were rated using a standardized portion of the Unified Parkinson's Disease Rating Scale. Overall, 3,030 visits/assessments of MOSIs (average 6.4/patient) were performed. Prevalence and incidence rates were calculated, and cumulative risk graphs were plotted for individual non-drug-induced MOSI domains. Rates of change over time taking into account potential covariates were also estimated. With use of each MOSI domain as outcome in Cox models, predictors of MOSI incidence were identified. RESULTS: At least one MOSI was detected in 13% of patients at first examination and in 36% for the last evaluation. Total MOSI score increased at an annual rate of 3% of total possible score. Rates of annual change for speech/facial expression (4%), rigidity (2.45%), posture/gait (3.9%), and bradykinesia (3.75%) were of similar magnitude, and their occurrence increased from first (3 to 6%) to last (22 to 29%) evaluation. Tremor was less frequent throughout the course of the disease (4% at first and 7% at last evaluation) and worsened less (0.75% increase/year). CONCLUSIONS: Most motor signs occur frequently and progress rapidly in Alzheimer disease. Tremor is an exception in that it occurs less frequently and advances at slower rates.

Using H2(15)O PET, the authors imaged 13 patients with Alzheimer disease (AD) while performing a serial nonverbal recognition memory task. Patterns of brain activation differed as a function of APOE genotype: epsilon4 carriers exhibited lower activation in the left lingual gyrus and higher activation in left cuneus, precuneus, parahippocampal, and right precentral gyrus. The APOE genotype seems to play a role in cerebral physiologic activity even after onset of clinical manifestations of AD.

Epidemiologic evidence suggests that higher occupational attainment and education, as well as increased participation in intellectual, social, and physical aspects of daily life, are associated with slower cognitive decline in healthy elderly and may reduce the risk of incident Alzheimer's disease (AD). There is also evidence from structural and functional imaging studies that patients with such life experiences can tolerate more AD pathology before showing signs of clinical dementia. It has been hypothesized that such aspects of life experience may result in functionally more efficient cognitive networks and, therefore, provide a cognitive reserve that delays the onset of clinical manifestations of dementia. In this article, we review some of the relevant literature of the noted associations between markers of cognitive reserve and AD and discuss the possible mechanisms that may explain these associations.

Although multivariate analytic techniques might identify diagnostic patterns that are not captured by univariate methods, they have rarely been used to study the neural correlates of Alzheimer's disease (AD) or cognitive impairment. Nonquantitative H2(15)O PET scans were acquired during rest in 17 probable AD subjects selected for mild severity [mean-modified Mini Mental Status Examination (mMMS) 46/57; SD 5.1], 16 control subjects (mMMS 54; SD 2.5) and 23 subjects with minimal to mild cognitive impairment but no dementia (mMMS 53; SD 2.8). Expert clinical reading had low success in discriminating AD and controls. There were no significant mean flow differences among groups in traditional univariate SPM Noxel-wise analyses or region of interest (ROI) analyses. A covariance pattern was identified whose mean expression was significantly higher in the AD as compared to controls (P = 0.03; sensitivity 76-94%; specificity 63-81%). Sites of increased concomitant flow included insula, cuneus, pulvinar, lingual, fusiform, superior occipital and parahippocampal gyri, whereas decreased concomitant flow was found in cingulate, inferior parietal lobule, middle and inferior frontal, supramarginal and precentral gyri. The covariance analysis-derived pattern was then prospectively applied to the cognitively impaired subjects: as compared to subjects with Clinical Dementia Rating (CDR) = 0, subjects with CDR = 0.5 had significantly higher mean covariance pattern expression (P = 0.009). Expression of this pattern correlated inversely with Selective Reminding Test total recall (r = -0.401, P = 0.002), delayed recall (r = -0.351, P = 0.008) and mMMS scores (r = -0.401, P = 0.002) in all three groups combined. We conclude that patients with AD may differentially express resting cerebral blood flow covariance patterns even at very early disease stages. Significant alterations in expression of resting flow covariance patterns occur even for subjects with cognitive impairment. Expression of covariance patterns correlates with cognitive and functional performance measures, holding promise for meaningful associations with underlying biopathological processes.

OBJECTIVE: Few previous studies have investigated the association between APOE genotype and brain activation during performance of cognitive tasks in healthy middle-aged and elderly subjects, and the results have been mixed. The authors investigated APOE-mediated differential brain activation in a group of healthy elderly subjects. METHODS: Using H215O positron emission tomography (PET), they imaged 32 healthy subjects (26 non-epsilon4 carriers and 6 epsilon4 carriers) performing a serial shape-recognition memory task under two conditions: Simple Demand (SD), in which one shape was presented in each study trial, and Titrated Demand (TD), in which study list length was adjusted so that each subject recognized words at approximately 75% accuracy. Multiple-regression analyses were performed, with the "activation" difference (TD-SD PET counts) as the dependent variable and the APOE genotype (presence versus absence of the epsilon4 allele) as the independent variable. RESULTS: Compared with non-carriers, epsilon4 carriers exhibited significantly decreased TD-SD activation differences in the left superior temporal, right superior frontal, left postcental, left precuneus, and posterior cingulate gyrus because epsilon4 carriers (versus non-carriers) showed increased activation during the SD and decreased activation during the TD condition. CONCLUSION: Patterns of brain activation during a nonverbal memory task differed as a function of APOE genotype and, therefore, of genetic risk for Alzheimer disease (AD). Differences in activation were not a reflection of task difficulty, but indicate memory-related altered cognitive processing. Brain regions with decreased activation in the epsilon4 subjects may result from subclinical incipient AD pathology and/or APOE-related neurophysiologic heterogeneity.

The study aimed to identify task-related brain activation networks whose change in expression exhibits subject differences as a function of differential susceptibility to sleep deprivation. Brain activity during a non-verbal recognition memory task was investigated in an event-related functional MRI paradigm both prior to and after 48 h of sleep deprivation. Nineteen healthy subjects participated. Regional covariance analysis was applied to data. An activation network pattern was identified whose expression decreased from pre- to post-sleep deprivation in 15 out 19 subjects (P < 0.05). Differential decrease in expression correlated with worsening performance in recognition accuracy (P < 0.05). Sites of de-activation were found in the posterior cerebellum, right fusiform gyrus and precuneus, and left lingual and inferior temporal gyri; increased activation was found in the bilateral insula, claustrum and right putamen. A network whose expression decreased after sleep deprivation and correlated with memory performance was identified. We conclude that this activation network plays a role in cognitive function during sleep deprivation.

OBJECTIVES: To evaluate the predictive value of serum beta2-microglobulin (beta2m) levels for virological breakthrough in hepatitis B e antigen-negative chronic hepatitis B patients under long term lamivudine monotherapy. METHODS: Serum beta2m levels were calculated at baseline and every three months during lamivudine monotherapy in 25 patients with chronic hepatitis B, using microparticle enzyme immunoassay technology to investigate their association with biochemical, virological and histological outcome data. Cox proportional hazard models were used to investigate the association between serum beta2m levels and virological breakthrough. RESULTS: Seven of 25 (28%), nine of 25 (36%) and 14 of 25 (56%) chronic hepatitis B patients exhibited virological breakthrough at months 12, 24 and 36 of treatment, respectively. All chronic hepatitis B patients who did not show virological breakthrough in the follow-up period exhibited beta2m elevation in month 3 of treatment. The duration (in months) of serum beta2m elevation was significantly higher in the responders group than the nonresponders group (7.3 +/- 2.6 versus 3.8 +/- 3.4, P=0.02). In contrast to patients whose serum beta2m levels were increased at three months, patients whose beta2m levels were decreased had a 4.6 times higher risk of experiencing virological breakthrough (hazards ratio 4.6, 95% CI 1.22 to 17.36). When age, pretreatment serum alanine aminotransferase and hepatitis B virus DNA levels, and grade of liver disease were simultaneously included in the same Cox model, decreased beta2m status was still associated with increased risk of virological breakthrough (hazards ratio 12.2, 95% CI 1.28 to 116.8). CONCLUSIONS: In hepatitis B e antigen-negative chronic hepatitis B patients under long term lamivudine monotherapy, serum b2m levels at three months of treatment, compared with baseline levels, are good predictors of risk for virological breakthrough.

Eighteen subjects (ages 18-35) underwent event-related functional magnetic resonance imaging (efMRI) while performing a delayed-match-to-sample (DMS) task before and immediately after 48 h of sustained wakefulness. The DMS trial events were: a 3-s study period of either a one-, three-, or six-letter visual array; a 7-s retention interval; and a 3-s probe period, where a button press indicated whether the probe letter was in the study array. Ordinal Trend Canonical Variates Analysis (OrT CVA) was applied to the data from the probe period for trials with six-letter study lists prior to and immediately following sleep deprivation to find an activation pattern whose expression decreased with sleep deprivation in as many subjects as possible, while being present in both conditions. The first principal component of the OrT analysis identified a covariance pattern whose expression decreased as a function of sleep deprivation in 17 of 18 subjects (p<0.001). While overall expression of the pattern showed a systematic decrease with sleep deprivation, the brain regions that make up the pattern show covarying increases and decreases in activation. Regions that decreased their activation were noted in the parietal (BA 7 and 40), temporal (BA 37, 38 and 39) and occipital (BA 18 and 19) lobes; regions that increased their activation were noted in the cerebellum, basal ganglia, thalamus and the anterior cingulate gyrus (BA 32). The reduction in pattern expression with sleep deprivation for each subject was related to the change in performance on the DMS task. Subject decreases in pattern expression were correlated with reductions in recognition accuracy (p<0.05), increased intra-individual variability in reaction time (p<0.005) and increased lapsing (p<0.005).

OBJECTIVE: To identify risk factors for fever among patients treated in a neurologic intensive care unit (NICU). METHODS: The authors prospectively studied the frequency and causes of fever, defined as a patient's first temperature > or =101 degrees F (38.3 degrees C), among 387 patients consecutively admitted to their NICU. After identifying risk factors for 1) any fever, 2) infectious fever, and 3) unexplained fever using logistic regression, they calculated disease-specific adjusted odds ratios for developing these types of fever among 12 diagnostic groups. RESULTS: Fever occurred in 23% (87/387) of patients. Fifty-two percent of fevers were explained by infection (predominantly pneumonia or bronchitis), and 28% were unexplained despite a complete diagnostic evaluation. NICU length of stay was a risk factor for all three types of fever (all p < 0.004); other risk factors included depressed level of consciousness for any fever (p = 0.005) and infectious fever (p = 0.048), endotracheal intubation for infectious fever (p = 0.01), and intraventricular catheterization for unexplained fever (p = 0.004). Subarachnoid hemorrhage increased the risk of both infectious and unexplained fever, even after adjusting for these risk factors (p = 0.006). CONCLUSION: Fever occurs in nearly 25% of NICU patients, and is associated with increased length of stay and depressed level of consciousness. Endotracheal intubation is a risk factor for infectious fever, whereas intraventricular catheterization is a risk factor for unexplained fever, which suggests a role for ventricular hemorrhage in the pathogenesis of "central" fever. Subarachnoid hemorrhage increases the risk of developing fever of all types.

BACKGROUND: Regional cerebral blood flow (CBF), a good indirect index of cerebral pathologic changes in Alzheimer disease (AD), is more severely reduced in patients with higher educational attainment and IQ when controlling for clinical severity. This has been interpreted as suggesting that cognitive reserve allows these patients to cope better with the pathologic changes in AD. OBJECTIVE: To evaluate whether premorbid engagement in various activities may also provide cognitive reserve. DESIGN: We evaluated intellectual, social, and physical activities in 9 patients with early AD and 16 healthy elderly controls who underwent brain H(2)(15)O positron emission tomography. In voxelwise multiple regression analyses that controlled for age and clinical severity, we investigated the association between education, estimated premorbid IQ, and activities, and CBF. RESULTS: In accordance with previous findings, we replicated an inverse association between education and CBF and IQ and CBF in patients with AD. In addition, there was a negative correlation between previous reported activity score and CBF in patients with AD. When both education and IQ were added as covariates in the same model, a higher activity score was still associated with more prominent CBF deficits. No significant associations were detected in the controls. CONCLUSIONS: At any given level of clinical disease severity, there is a greater degree of brain pathologic involvement in patients with AD who have more engagement in activities, even when education and IQ are taken into account. This may suggest that interindividual differences in lifestyle may affect cognitive reserve by partially mediating the relationship between brain damage and the clinical manifestation of AD.

Cognitive reserve (CR) is the ability of an individual to cope with advancing brain pathology so that he remains free of symptomatology. Epidemiological evidence and in vivo neurometabolic data suggest that CR may be mediated through education or IQ. The goal of this study was to investigate CR-mediated differential brain activation in 17 healthy young adults and 19 healthy elders. Using nonquantitative H(2)(15)O PET scanning, we assessed relative regional cerebral blood flow while subjects performed a serial recognition memory task under two conditions: nonmemory control (NMC), in which one shape was presented in each study trial; and titrated demand (TD), in which study list length was adjusted so that each subject recognized shapes at approximately 75% accuracy. A factor score that summarized years of education and scores on two IQ indices was used as an index of CR. Voxel-wise, multiple regression analyses were performed with TD minus NMC difference PET counts as the dependent variable and the CR variable as the independent variable of interest. We identified brain regions where regression slopes were different from zero in each separate group, and also those where regression slopes differed between the two age groups. The slopes were significantly more positive in the young in the right inferior temporal gyrus, right postcentral gyrus, and cingulate, while the elderly had a significantly more positive slope in left cuneus. Brain regions where systematic relationships between CR and brain activation differ as a function of aging are loci where compensation for aging has occurred. They may mediate differential ability to cope with brain changes in aging.

The concept of cognitive reserve (CR) suggests that innate intelligence or aspects of life experience like educational or occupational attainments may supply reserve, in the form of a set of skills or repertoires that allows some people to cope with progressing Alzheimer's disease (AD) pathology better than others. There is epidemiological evidence that lifestyle characterized by engagement in leisure activities of intellectual and social nature is associated with slower cognitive decline in healthy elderly and may reduce the risk of incident dementia. There is also evidence from functional imaging studies that subjects engaging in such leisure activities can clinically tolerate more AD pathology. It is possible that aspects of life experience like engagement in leisure activities may result in functionally more efficient cognitive networks and therefore provide a CR that delays the onset of clinical manifestations of dementia.

Several famous athletes have been affected by ALS, and some epidemiologic studies have indicated that vigorous physical activity (heavy labor or athletics) is a risk factor for the disease. In a case-control study of 279 patients with motor neuron diseases and 152 with other neurologic diseases, the authors found that subjects with motor neuron diseases were more likely than controls to report they had always been slim or they had been varsity athletes. For slimness, the odds ratio (OR) was 2.21; 95% CI, 1.40 to 3.47. For varsity athletics, the OR was 1.70; CI, 1.04 to 2.76.

BACKGROUND: Psychiatric symptoms occur frequently in the course of AD, are a frequent contributor to institutionalization, predict cognitive decline and death, and often require treatment with psychotropic medications. Previous studies investigating the association between APOE genotype and psychiatric symptomatology in AD have reported contradictory results. OBJECTIVE: To determine whether APOE genotype predicts incident psychiatric symptomatology in patients with AD. METHODS: Eighty-seven patients with AD at early stages and no psychiatric history were followed semiannually for up to 9.3 years (mean 5.5 years) for development of delusions, illusions, hallucinations, behavioral symptoms, and depression. Cox proportional hazards models were used to examine the relative risk for incident psychiatric symptomatology (outcome) in relation to APOE genotype (predictor). RESULTS: The presence of one epsilon4 allele carried a 2.5-fold risk, whereas the presence of two epsilon4 alleles carried a 5.6-fold risk for development of delusions. The associations remained significant even when age, ethnicity, sex, education, duration of disease, and cognitive and functional performance were controlled for. The presence of two epsilon4 alleles was associated with reduced risk for developing hallucinations in the adjusted analysis only. No significant associations were detected between APOE genotype and the incidence of illusions, behavioral symptoms, or depression. CONCLUSION: The presence of one or more epsilon4 alleles is a significant predictor for the incidence of delusions in the course of AD.

OBJECTIVE: To evaluate the efficacy of an air-circulating cooling blanket for reducing body temperature in febrile neuro-ICU patients treated with acetaminophen. METHODS: Two-hundred twenty consecutively admitted neuro-ICU patients whose tympanic membrane temperature reached or exceeded 101 degrees F (38.3 degrees C) were randomly assigned to receive acetaminophen (650 mg every 4 hours) alone (n = 107) or acetaminophen plus air blanket therapy (n = 113). After 24 hours of treatment, the authors compared the proportion of subjects who attained treatment success (T < or = 99 degrees F) or treatment failure (T > or = 101 degrees F for 2 consecutive hours) using the chi(2) test and the time to reach these endpoints using Kaplan-Meier survival analysis. MAIN RESULTS: Air blanket therapy resulted in a small increase in the proportion of subjects with treatment success (44% versus 36%, chi(2) p = 0.19, log rank p = 0.10) and a similar small reduction in the proportion of patients with treatment failure (42% versus 53%, chi(2) p = 0.11, log-rank p = 0.21), compared with treatment with acetaminophen alone. Approximately one third of patients in both groups remained febrile after randomization and "failed" after the first 2 hours of treatment. Twelve percent of patients assigned to air blanket therapy refused or were unable to tolerate treatment, compared with 2% of patients treated with acetaminophen alone (p = 0.005). CONCLUSIONS: Treatment with an air-circulating cooling blanket did not effectively reduce body temperature in febrile neuro-ICU patients treated with acetaminophen. More effective interventions are needed to maintain normothermia in patients at risk for fever-related brain damage.

In this case study, we describe the symptoms, neuropsychological testing, and brain pathology of a retired mason's assistant with cortical basal ganglionic degeneration (CBGD). CBGD is an extremely rare neurodegenerative disease that is categorized under both Parkinsonian syndromes and frontal lobe dementias. It affects men and women nearly equally, and the age of onset is usually in the sixth decade of life. CBGD is characterized by Parkinson's-like motor symptoms and by deficits of movement and cognition, indicating focal brain pathology. Neuronal cell loss is ultimately responsible for the neurological symptoms.

OBJECTIVE: To determine whether leisure activities modify the risk for incident dementia. BACKGROUND: Although high educational and occupational attainments have been associated with reduced risk of incident dementia, the relation between leisure activities and dementia risk has not been adequately investigated. METHODS: A total of 1,772 nondemented individuals aged 65 years or older, living in northern Manhattan, New York, were identified and followed longitudinally in a community-based cohort incidence study. Subjects' leisure activities at baseline were assessed, annual examinations with the same standardized neurologic and neuropsychological measures were performed for up to 7 years (mean 2.9 years), and incident dementia was assessed as the main outcome measure. Cox proportional hazards models, adjusting for age, ethnic group, education, and occupation, were used to estimate the relative risk (RR) of incident dementia associated with high leisure activities. RESULTS: Of the 1,772 subjects, 207 became demented. The risk of dementia was decreased in subjects with high leisure activities (RR, 0.62; 95% CI 0.46 to 0.83). The association of high leisure with decreased RR of incident dementia was present even when baseline cognitive performance, health limitations interfering with desired leisure activities, cerebrovascular disease, and depression were considered. CONCLUSIONS: The data suggest that engagement in leisure activities may reduce the risk of incident dementia, possibly by providing a reserve that delays the onset of clinical manifestations of the disease.