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A study was conducted to evaluate the benefits of physical activity along with diet on a lowered risk of Alzheimer Disease (AD). Results indicated that both a Mediterranean-type diet and increased physical activity were independently associated with a reduced risk of AD.

A mutation in the presenilin 1 gene was found in eight out of 19 Caribbean Hispanic families with a family history of Alzheimer's disease that occurred before the age of 55. The families were not related to each other, indicating that they all had a common ancestor. The rate of Alzheimer's disease is higher in Caribbean Hispanics than in non-Hispanic whites.

The apolipoprotein E (APOE) epsilon4 gene does not appear to be a risk factor for Alzheimer's disease in African Americans and Hispanic Americans. Researchers tested 1,079 elderly patients in a multi-ethnic neighborhood for the gene and followed them for over five years. While the presence of the gene increased the risk of Alzheimer's disease in the whites, this was not true in the blacks and Hispanics. However, blacks and Hispanics who did not have the gene had a higher risk of Alzheimer's disease than whites. Other genes may be responsible for the increased risk in these ethnic groups., Context.--Although the association between Alzheimer disease (AD) and the apolipoprotein E [Epsilon] 4 (APOE-[Epsilon] 4) allele has been confirmed worldwide, it appears to be inconsistent among African Americans, Hispanics, and Nigerians. Objective.--To investigate the association between the APOE-[Epsilon] 4 allele and AD in elderly African Americans, Hispanics, and whites. Design.--Prospective, population-based, longitudinal study over a 5-year period (1991-1996). Setting.--The Washington Heights--Inwood community of New York City. Participants.--A total of 1079 Medicare recipients without AD or a related disorder at baseline. Main Outcome Measures.--Risk of clinically diagnosed AD in the 3 ethnic groups and among individuals with and without an APOE-[Epsilon] 4 allele. Results. Compared with individuals with the APOE-[Epsilon] 3/[Epsilon] 3 genotype, the relative risk (RR) of AD associated with 1 or more copies of the APOE-[Epsilon] 4 allele was significantly increased among whites (RR, 2.5; 95% confidence interval [CI], 1.1-6.4), but not among African Americans (RR, 1.0; 95% CI, 0.6-1.6) or Hispanics (RR, 1.1; 95% CI, 0.7-1.6). In the absence of the APOE-[Epsilon] 4 allele, the cumulative risks of AD to age 90 years, adjusted for education and sex, were 4 times higher for African Americans (RR, 4.4; 95% CI, 2.3-8.6) and 2 times higher for Hispanics (RR, 2.3; 95% CI, 1.2-4.3) than for whites. In the presence of an APOE-[Epsilon] 4 allele, the cumulative risk of AD to age 90 years was similar for individuals in all 3 ethnic groups. Conclusion.--The presence of an APOE-[Epsilon] 4 allele is a determinant of AD risk in whites, but African Americans and Hispanics have an increased frequency of AD regardless of their APOE genotype. These results suggest that other genes or risk factors may contribute to the increased risk of AD in African Americans and Hispanics. JAMA. 1998;279:751-755

An algorithm has been developed to predict the time a patient with Alzheimer's disease will need to be admitted to a nursing home and the time to death. It consists of tables that allow scores for different predictors to be added up. The predictors include age at onset, length of illness and presence of symptoms such as tremor, rigidity, gait disorders, delusions and hallucinations. The algorithm will give the number of months until nursing home placement and death. The algorithm accurately predicted outcomes in a validation sample., Objective.--To develop and validate an approach that uses clinical features that can be determined in a standard patient visit to estimate the length of time before an individual patient with Alzheimer disease (AD) requires care equivalent to nursing home placement or dies. Design.--Prospective cohort study of 236 patients, followed up semiannually for up to 7 years. A second validation cohort of 105 patients was also followed. Setting.--Three AD research centers. Patients.--All patients met National Institute of Neurological and Communicative Disorders and Stroke-Alzheimer's Disease and Related Disorders Association (NINCDS-ADRDA) criteria for probable AD and had mild dementia at the initial visit. Intervention.--Predictive features, ascertained at the initial visit, were sex, duration of illness, age at onset, modified Mini-Mental State Examination (mMMS) score, and the presence or absence of extrapyramidal signs or psychotic features. Main Outcome Measures.--(1) Requiring the equivalent of nursing home placement and (2) death. Results.--Prediction algorithms were constructed for the 2 outcomes based on Cox proportional hazard models. For each algorithm, a predictor index is calculated based on the status of each predictive feature at the initial visit. A table that specifies the number of months in which 25%, 50%, and 75% of patients with any specific predictor index value are likely to reach the end point is then consulted. Survival curves for time to need for care equivalent to nursing home placement and for time to death derived from the algorithms for selected predictor indexes fell within the 95% confidence bands of actual survival curves for patients.When the predictor variables from the initial visit for the validation cohort patients were entered into the algorithm, the predicted survival curves for time to death fell within the 95% confidence bands of actual survival curves for the patients. Conclusions.--The prediction algorithms are a first but promising step toward providing specific prognoses to patients, families, and practitioners. This approach also has clear implications for the design and interpretation of clinical trials in patients with AD. JAMA. 1997;277:806-812

The apolipoprotein E (APOE) epsilon4 gene appears to increase the risk of developing dementia associated with atherosclerosis and strokes. Researchers used genetic testing for the APOE epsilon4 gene in 187 people with dementia and stroke and 507 healthy volunteers (the control group). One copy of the APOE epsilon4 gene increased the risk of dementia with stroke 2-fold and two copies of the gene increased the risk by a factor of 7. The risks were especially great in African Americans and Hispanics. The APOE epsilon4 gene has also been implicated in Alzheimer's disease., Objective.--To investigate the association between the apolipoprotein E (APOE) genotypes and dementia in patients with stroke, defined as either vascular dementia (VaD) or Alzheimer disease with cerebrovascular disease (AD with CVD). Design and Setting.--Population-based, case-control study from Rotterdam, the Netherlands, and New York City. Participants.--A total of 187 patients with dementia and stroke were compared with 507 controls similar in age and ethnic group. Main Outcome Measures.--The APOE allele frequencies in patients and controls; the odds ratio of dementia with stroke, VaD, and AD with CVD, adjusted for age, sex, residency, and education; and the percent attributable risk related to the APOE [epsilon]4 allele. Results.--Overall, patients with dementia and stroke had a higher APOE [epsilon]4 allele frequency than controls. Compared with APOE [epsilon]3 homozygote individuals, APOE [epsilon]4 homozygotes had a 7-fold increased risk of dementia with stroke (OR=6.9; 95% CI, 1.6-29.4), while APOE [epsilon]4 heterozygotes had nearly a 2-fold increase in risk (OR=1.8; 95% CI, 1.2-2.7). Risks associated with APOE [epsilon]4 were elevated regardless of the subtype of dementia with stroke or age or sex. The percent attributable risk related to the APOE [epsilon]4 allele among demented patients with stroke was 41% overall, 33% among those with VaD, and 44% among those with AD with CVD. Conclusion.--The APOE [epsilon]4 allele is a genetic risk factor for dementia with stroke, including VaD and AD with CVD: This may imply shared genetic susceptibility to dementia associated with stroke and AD. Alternatively, the category of patients with dementia and stroke, including VaD as currently defined, may include patients with AD. JAMA. 1997;277:818-821

Higher educational and occupational levels appear to be associated with a decreased risk of developing Alzheimer's disease. A total of 593 participants 60 years old or older classified as nondemented at an initial exam were re-examined between one and four years later. A total of 106 were classified as demented at their follow-up exam. Statistical analysis indicated that those with a low education level were approximately twice as likely to develop Alzheimer's as those with more years of education. Those with a lower occupational level were approximately 2.25 times as likely to develop Alzheimer's disease as those in the higher occupational groups. Those with low educational and occupational levels were almost three times more likely to develop Alzheimer's disease. It is unclear how higher educational and occupational levels reduce the risk of Alzheimer's disease., Objective. - Several cross-sectional studies have found an association between Alzheimer's disease (AD) and limited educational experience. it has been difficult to establish whether educational experience is a risk factor for AD because educational attainment can influence performance on diagnostic tests. This study was designed to determine whether limited educational level and occupational attainment are risk factors for incident dementia. Design. - Cohort incidence study. Setting. - General community. Participants. - A total of 593 nondemented individuals aged 60 years or older who were listed in a registry of individuals at risk for dementia in North Manhattan, NY, were identified and followed up. Interventions. - We reexamined subjects 1 to 4 years later with the identical standardized neurological and neuropsychological measures. Main Outcome Measure. - Incident dementia. Results. - We used Cox proportional hazards models, adjusting for age and gender, to estimate the relative risk (RR) of incident dementia associated with low educational and occupational attainment. Of the 593 subjects, 106 became demented; all but five of these met research criteria for AD. The risk of dementia was increased in subjects with either low education (RR, 2.02; 95% confidence interval [CI], 1.33 to 3.06) or low lifetime occupational attainment (RR, 2.25; 95% CI, 1.32 to 3.84). Risk was greatest for subjects with both low education and low lifetime occupational attainment (RR, 2.67; 95% CI, 1.32 to 3.84). Conclusions. - The data suggest that increased educational and occupational attainment may reduce the risk of incident AD, either by decreasing ease of clinical detection of AD or by imparting a reserve that delays the onset of clinical manifestations.

While it is clear that a small fraction of cases of Alzheimer's disease (AD) may be familial, it remains uncertain to what degree genetic predisposition might contribute to the development of AD in the majority of cases. Studies have shown that first-degree relatives of Alzheimer's disease patients have a greater likelihood of developing AD than the general population, but further investigation has revealed that the increased risk of AD for these relatives is no greater than the increased risk of developing AD for the relatives of patients with other neurological diseases such as Parkinson's disease. It is unclear whether this represents a non-specific predisposition to neurological disease or whether relatives of patients with neurological diseases are subjected to more scrutiny and are thus merely more likely to be diagnosed with AD. To further elucidate the relationship of Alzheimer's disease risk to kinship, the families of 110 patients with Alzheimer's disease, 25 patients with other forms of dementia, and 55 patients with neurological disease without dementia were studied. Fifty-nine healthy elderly subjects were also included in the study. The results were consistent with those obtained by previous studies; about 50 percent of the first-degree relatives of patients with AD had themselves developed AD by the age of 91 (the cumulative percentage increased with age). This proportion was not reached by the healthy elderly controls; however, a similar proportion was reached by the relatives of patients with other neurological conditions. Among the relatives of both patient groups, the odds for dementia in a first-degree relative were six times greater than for the healthy elderly subjects. While the results neither confirm nor deny a contribution of genetics to the development of Alzheimer's disease among the elderly patients and their relatives, the similar risks for relatives of patients with other neurological diseases indicate that other risk factors must be considered in the search for the cause of Alzheimer's disease. (Consumer Summary produced by Reliance Medical Information, Inc.)

The decline in cognitive function is the principal symptom of Alzheimer's disease (AD). However, other symptoms are related to the slowly progressive AD process as well. These include extrapyramidal signs, which represent a particular class of movement disorders; psychosis, which is hallucinatory or delusional mental illness; and myoclonus, the jerking seizure of muscles. The appearance of any of these symptoms is generally considered to be an indicator of poor prognosis and more advanced disease. A study was undertaken to tabulate the occurrence of these symptoms over time in the progression of disease among 72 patients with AD. It was found that the presence of all three symptoms increased with disease progression, but that extrapyramidal signs and psychosis were more likely to occur before myoclonus. At the first clinical evaluation of the patients, extrapyramidal signs were present in 28 percent, psychosis in 25 percent, and myoclonus in 7 percent. By the last clinical evaluation, about 5 years later, these prevalences had increased to 51, 47, and 39 percent, respectively. It seems likely that each of these symptoms results from the progressive destruction of brain cells which occurs during the downward course of Alzheimer's disease. The present study found no evidence to support the notion that these various symptoms reflect the existence of distinct subtypes of Alzheimer's disease. (Consumer Summary produced by Reliance Medical Information, Inc.)

Extrapyramidal signs are movement difficulties arising from abnormalities that lie outside the so-called pyramidal tract of nerve fibers in the brain. The movement disorders associated with Parkinson's disease, such as tremor and rigidity, are classic examples. Such extrapyramidal signs are hardly limited to Parkinson's disease, and may occur in a variety of disorders, including Alzheimer's disease (AD). In AD, these signs are significant for several reasons. They may provide insight into the pathological mechanisms of the disorder, and may indicate abnormal changes in certain parts of the brain, including the substantia nigra. Furthermore, some researchers suspect that the occurrence of extrapyramidal signs may be an indicator of particularly aggressive progression of Alzheimer's disease. If further research is to clarify these questions, it is important for the evaluation of extrapyramidal signs to be quantitative and reliable. Therefore, a study was conducted to evaluate how well three different clinical examiners agreed on the rating of extrapyramidal signs in 20 patients with cognitive disorders. Sixteen of the patients were believed to have Alzheimer's disease, one had dementia due to cerebrovascular disease, and three had mental changes of unknown cause. The three different examiners rated the patients according to a quantitative scale; zero was assigned for normal, and one through four were assigned for increasing degrees of severity for each of the most important extrapyramidal signs. It was found that there was good agreement on whether particular extrapyramidal signs were present or not. However, the raters agreed the least in evaluating the most mild symptoms. That is, when the extrapyramidal sign was very close to normal, the raters sometimes disagreed on whether the score should be zero for normal or one, indicating the mildest degree of abnormality. (Consumer Summary produced by Reliance Medical Information, Inc.)

High blood cholesterol levels may be associated with an increased risk of dementia and stroke in the elderly. Researchers evaluated 1,111 nondemented people aged 75 for about 2 years. Dementia developed in 26% of the research participants, likely caused by stroke in 21% and Alzheimer's disease in 79% of the patients with dementia. Research patients with the highest levels of low-density lipoprotein (LDL) cholesterol had three times the risk of dementia with stroke as those with the lowest blood levels of LDL cholesterol.

Dementia and depression are both common features of Parkinson's disease, but their precise prevalence among patients remains controversial. In a review of 339 consecutive cases of idiopathic Parkinson's disease, 10.9 percent of the patients had dementia without depression, 51 percent had depression without dementia, and the two co-existed in 5.4 percent of the patients. To determine whether the co-existence of depression and dementia is coincidental or possibly the reflection of some common underlying biochemical process, metabolites of biogenic amines, such as dopamine and serotonin, were measured in the cerebrospinal fluid (CSF) of 110 Parkinson patients. Homovanillic acid was reduced in the CSF of patients who were both depressed and demented, but the reduction was not statistically significant. No changes were seen among patients in the levels of 3-methoxy-4-hydroxy-phenylglycol. However, both demented patients and depressed patients had significant reductions of 5-hydroxyindoleacetic acid, or 5-HIAA. The patients who were both depressed and demented had the lowest levels of 5-HIAA, which is a metabolite of the neurotransmitter substance serotonin. The results suggest that the brain's serotonergic systems may play a role in the development of both depression and dementia in patients with Parkinson's disease. (Consumer Summary produced by Reliance Medical Information, Inc.)

Background: New-onset Alzheimer disease (AD) is often attributed to degenerative changes in the hippocampus. However, the contribution of regionally distributed small vessel cerebrovascular disease, visualized as white matter hyperintensities (WMHs) on magnetic resonance imaging, remains unclear. Objective: To determine whether regional WMHs and hippocampal volume predict incident AD in an epidemiological study. Design: A longitudinal community-based epidemiological study of older adults from northern Manhattan, New York. Setting: The Washington Heights/Inwood Columbia Aging Project. Participants: Between 2005 and 2007, 717 participants without dementia received magnetic resonance imaging scans. A mean (SD) of 40.28 (9.77) months later, 503 returned for follow-up clinical examination and 46 met criteria for incident dementia (45 with AD). Regional WMHs and relative hippocampal volumes were derived. Three Cox proportional hazards models were run to predict incident dementia, controlling for relevant variables. The first included all WMH measurements; the second included relative hippocampal volume; and the third combined the 2 measurements. Main Outcome Measure: Incident AD. Results: White matter hyperintensity volume in the parietal lobe predicted time to incident dementia (hazard ratio [HR]=1.194; P=.03). Relative hippocampal volume did not predict incident dementia when considered alone (HR=0.419; P=.77) or with the WMH measures included in the model (HR= 0.302; P = .70). Including hippocampal volume in the model did not notably alter the predictive utility of parietal lobe WMHs (HR=1.197; P=.049). Conclusions: The findings highlight the regional specificity of the association of WMHs with AD. It is not clear whether parietalWMHssolely represent a marker for cerebrovascular burden or point to distinct injury compared with other regions. Future work should elucidate pathogenic mechanisms linking WMHs and AD pathology. [ABSTRACT FROM AUTHOR]

Background: Telephone-based interviews can be used for screening and to obtain key study outcomes when participants in longitudinal studies die or cannot be seen in person, but must be validated among ethnically and educationally diverse people. Objective: To determine the accuracy of a telephone interview in classifying (1) demented from nondemented participants, (2) cognitively impaired participants from cognitively normal participants, and (3) participants with mild cognitive impairment (MCI) from those with normal cognition or (4) MCI from dementia among an ethnically and educationally diverse community-based sample. Method: The sample consisted of 377 (30.5% non-Hispanic white, 34.7% non-Hispanic black, and 33.7% Caribbean Hispanic) older adults. The validation standard was diagnosis of dementia and MCI based on in-person evaluation. The Telephone Interview for Cognitive Status (TICS) and the Dementia Questionnaire (DQ) were administered within the same assessment wave. Results: The sample included 256 people (67.9%) with normal cognition, 68 (18.0%) with MCI, and 53 (14.1%) with dementia. Validity of the TICS was comparable among non-Hispanic whites, non-Hispanic blacks, and Hispanics. Among non-Hispanic whites, the DQ had better discrimination of those with dementia from those without dementia and from those with MCI than among other racial/ethnic groups. Telephone measures discriminated best when used to differentiate demented from nondemented participants (88% sensitivity and 87% specificity for the TICS; 66% sensitivity and 89% specificity for DQ) and when used to differentiate cognitively normal participants from those with cognitive impairment (ie, MCI and dementia combined; 73% sensitivity and 77% specificity for the TICS; 49% sensitivity and 82% specificity for DQ). When demographics and prior memory test performance were used to calculate pretest probability, consideration of the telephone measures significantly improved diagnostic validity. Conclusions: The TICS has high diagnostic validity for identification of dementia among ethnically diverse older adults, especially when supported by the DQ and prior visit data. However, telephone interview data were unable to reliably distinguish MCI from normal cognition. [ABSTRACT FROM AUTHOR]

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 4½ 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. [ABSTRACT FROM AUTHOR]

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 ⩾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 ADrelated nutrients: saturated fatty acids, monounsaturated fatty acids,ω-3 polyunsaturated fatty acids,ω-6 polyunsaturated fatty acids, vitamin E, vitamin B12, 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. [ABSTRACT FROM AUTHOR]

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 modelof change, totalEPSscore 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. [ABSTRACT FROM AUTHOR]

The article discusses a study which investigated the combined association of diet and physical activity with Alzheimer's disease risk. The study involved 1,880 community-dwelling elders without dementia in New York City with both diet and physical activity information available. The participants undertook standardized neurological and neuropsychological measures from 1992 through 2006. An association between both higher Mediterranean-type diet and higher physical activity with reduced risk for Alzheimer's disease were found by the researchers.

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, κ=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 personyears 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. [ABSTRACT FROM AUTHOR]

Background: Vascular factors including medical history (heart disease, stroke, diabetes, and hypertension), smoking, and prediagnosis blood lipid measurements (cholesterol: total, high-density lipoprotein, lowdensity 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 ε4 (APOE-ε4) 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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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 (β=-0.316; P=.04), the severity of WMH ((β=-0.173; P=.03), and their interaction ((β=-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. [ABSTRACT FROM AUTHOR]

Objective: To determine whether β-amyloid (Aβ) 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 Aβ40 and Aβ42 were quantified in each biochemical compartment by enzyme-linked immunosorbent assay. Results: The Aβ42 level in all biochemical compartments was significantly elevated in patients with AD vs controls (P<.01). The Aβ40 levels in the TRIS and formic acid fractions were elevated in patients with AD(temporal, P<.01; cingulate, P=.03); however, Triton and SDS Aβ40 levels were similar in patients with AD and in controls. Functional impairment proximal to death correlated with Triton Aβ42 (r=0.48, P=.02) and SDS Aβ42 (r=0.41, P=.04) in the temporal cortex. Faster cognitive decline was associated with elevated temporal SDS Aβ42 levels (P.001), whereas slower decline was associated with elevated cingulate formic acid Aβ42 and SDS Aβ42 levels (P=.02 and P=.01, respectively). Conclusion: Intracellular and membrane-associated Aβ, especially Aβ42 in the temporal neocortex, may be more closely related to AD symptoms than other measured A species. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Objective: To investigate the association between Alzheimer disease (AD) and variant alleles in SORL1 using a series of single nucleotide polymorphisms (SNPs) in an urban, multiethnic, community-based population. Design: We used a nested case-control analysis in a population-based, prospective study of aging and dementia in Medicare recipients, 65 years and older. Setting: Northern Manhattan, NY. Participants: There were 296 patients with probable AD and 428 healthy, elderly controls. The participants were African American (34%), Caribbean Hispanic (51%), or non-Hispanic white (15%). Main Outcome Measures: We genotyped all 29 SNPs in SORL1 that were examined in the earlier report. We assessed allelic association with AD using standard casecontrol methods, which included apolipoprotein E genotype as a covariate. Results: Several individual SNPs and SNP haplotypes were significantly associated with AD in this prospectively collected community-based cohort, confirming the previously reported positive association of SORL1 with AD. Single nucleotide polymorphism 12, near the 5' region, was associated with AD in African American and Hispanic individuals. Two SNPs in the 3 ' region were also associated with AD in African American (SNP 26) and non-Hispanic white (SNP 20) individuals. A single haplotype in the 3' region was associated with AD in Hispanic individuals. However, several different haplotypes were associated with AD in African American and white individuals, including the TTC haplotypes at SNPs 23 through 25 (P=.035), which was significantly associated with AD in the North European white individuals in our previous report. Conclusions: This study confirms the association between genetic variants in SORL1 and AD. While the associations observed in these data sets overlap with those previously reported, the finding of novel SNP and haplotype associations suggests that there may be extensive allelic heterogeneity in SORL1. Broad regions of the SORL1 gene will therefore need to be scrutinized for functional pathogenic variants. [ABSTRACT FROM AUTHOR]

Background: Several markers of immune activation have been identified as potential prognostic markers for human immunodeficiency virus (HIV)-associated morbidity and mortality, but the results from studies are conflicting. Objective: To evaluate whether neurocognitive status and baseline levels of plasma and cerebrospinal fluid tumor necrosis factor a (TNF-a), macrophage chemoattractant protein 1 (MCP-1), matrix metalloproteinase 2 (MMP-2), or macrophage colony-stimulating factor (M-CSF) are associated with time to death in a cohort with advanced HIV infection. Design: Cohort study. Setting: Enrollees in the Northeast AIDS Dementia Study. Participants: Three hundred twenty-nine subjects who were positive for HIV-1 and had a CD4 cell count of less than 200/μL (or <300/μL but with cognitive impairment at baseline) were assessed for CD4 cell count, neurocognitive status, pertinent demographic and clinical variables, and plasma and cerebrospinal fluid HIV RNA, TNF-α, MCP-1, MMP-2, and M-CSF levels. Main Outcome Measures: Cox proportional hazards regression models were used to examine the associations between the variables of interest (using time dependent covariates, where applicable) and time to death, adjusting for possible confounders. Results: There were 50 deaths in the cohort after a median of 25.2 months of follow-up. The cumulative incidences of death were 7% at 1 year and 16% at 2 years. In Cox proportional hazards regression analyses adjusting for demographic, clinical, and immunological variables, HIV-associated dementia (hazard rate, 6.10; P=.001) was significantly associated with time to death; (log) plasma MCP-1 level (hazard rate, 3.38; P =.08) trended toward significance. Conclusion: In patients with advanced HIV infection, HIV-associated dementia is an independent predictor of time to death. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Objectives: To identify novel candidate regions for lateonset Alzheimer disease (LOAD) and to confirm linkage in previously identified chromosomal regions. Design: Family-based linkage analysis. Setting: Probands with familial LOAD identified in clinics in the Dominican Republic, Puerto Rico, and the United States. Patients: We conducted a genome scan in 1161 members primarily clinically diagnosed as having LOAD; these members were from 209 families of Caribbean Hispanic ancestry. Main Outcome Measures: We analyzed 376 microsatellite markers with an average intermarker distance of 9.3 centimorgan. We conducted linkage analysis using possible and probable LOAD, and we performed affecteds-only 2-point linkage analyses assuming either an autosomal dominant or a recessive model. Subsequently, we conducted a multipoint affected sibling pair linkage analysis. Results: Two-point parametric linkage analysis identified a locus at 3q28 with a genomewide empirical P value of .03 (logarithm of odds [LOD],3.09) in a dominant model for probable and possible LOAD. Other regions suggestive of linkage included 2p25.3 (LOD, 1.77), 7p21.1 (LOD, 1.82), and 9q32 (LOD, 1.94). Under a recessive model, we also identified loci at 5p15.33 (LOD, 1.86), 12q24.21 (LOD, 2.43), 14q22.3 (LOD, 2.53), and 14q23.1 (LOD, 2.16) as suggestive for linkage. Restricted to probable LOAD, many of these loci continued to meet criteria suggestive for linkage, as did loci at2p25.3 (LOD, 2.72), 3q28 (LOD, 2.28), 6p21.31 (LOD, 2.19), and 7p21.1 (LOD, 2.05). APOE conditional analysis indicated that the observed linkage at 3q28 was independent of the APOE £4 allele. Multipoint nonparametric affected sibling pair linkage analysis provided confirmation of suggestive linkage for most, but not all, loci. Conclusions: Seven loci with LOD scores greater than 2.0 were identified among multiple affected Caribbean Hispanic families with LOAD. The highest LOD score was found at chromosome 3q28. At least 2 other independent studies have observed support for significant linkage at chromosome 3q28, highlighting this region as a locus for further genetic exploration. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background: Lewy bodies (LBs) and Lewy neurites are frequent concomitant neuropathologic observations in clinical and neuropathologically defined Alzheimer disease (AD), but their relation to clinical features in AD is uncertain. Most studies used semiquantitative measures to determine the presence or absence of LB abnormalities. Objective: To determine the clinical consequences of LB abnormalities in the setting of AD. Design: Prospective study. Setting: Three outpatient research and treatment centers. Participants: Fourteen autopsy cases with a pathologic diagnosis of AD abnormalities and concomitant LBs followed semiannually for up to 8 years (mean age at intake, 72 years; mean age at death, 77 years; mean education, 15 years; 12 women). Main Outcome Measures: The modified Mini-Mental State Examination was used to assess cognitive function. The Unified Parkinson Disease Rating Scale was used to rate extrapyramidal motor signs. Hallucinations were evaluated using the Columbia University Scale for Psychopathology in Alzheimer's Disease. Time from the first evaluation in which diagnostic criteria for probable AD were met to death was used to determine illness duration. Quantitative measures of LB abnormalities were obtained for the frontal cortex, entorhinal cortex, substantia nigra, and hippocampus. Results: Independent-samples t tests were used to assess whether the degree of LB abnormality varied as a function of the presence or absence of hallucinations and extrapyramidal signs. Pearson r correlations were run to examine whether there was a relation among LB abnormalities, cognitive function, and illness duration. There was no relation between quantitative neuropathologic indexes of LB abnormalities and clinical outcome. Conclusion: The variability of clinical features in AD was not related to the presence or degree of LB abnormalities. [ABSTRACT FROM AUTHOR]

Background Reported rates of mild cognitive impairment (MCI) range widely depending on methodologic differences, including specific sample characteristics, cognitive measures used, normative samples used for neuropsychological tests, and diagnostic criteria. Objectives To operationalize diagnostic criteria for MCI and examine the frequency of MCI in ethnically and linguistically diverse elders (individuals older than 65 years). Design Prospective, community-based longitudinal cohort study. Setting Northern Manhattan, New York, NY. Participants A cohort of 1315 nondemented elderly participants. Main Outcome Measure A diagnosis of MCI was assigned retrospectively on the basis of comprehensive neuropsychological, functional, and neurologic assessments. Amnestic MCI, as well as forms of mild impairment with other cognitive characteristics, were classified. Results The frequency of amnestic MCI was 5.0% (95% confidence interval, 3.8-6.2). Other subtypes of MCI ranged in frequency from 2.1% to 6.2%. Mild cognitive impairment was more common among those older than 75 years compared with those aged 65 to 75 years. Individuals with fewer than 9 years of schooling were more likely to meet MCI criteria. Apolipoprotein (APOE) E4 allele was more frequent among those with amnestic MCI. Conclusions When proper normative values are used, only age and education, and not race or ethnicity, are associated with higher frequency of MCI. The proportion of nondemented elders with isolated memory deficits is smaller than the proportion with deficits in multiple cognitive domains. The strong association of the APOE E4 allele with only amnestic MCI suggests that there are likely to be multiple causes of cognitive impairment and differential rates of conversion to Alzheimer disease within the cognitive subtypes of MCI. [ABSTRACT FROM AUTHOR]

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 ≤20/57 [approximate Folstein MMSE score of ≤10/30]), functional (Blessed Dementia Rating Scale [parts I and II] score of ≥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. [ABSTRACT FROM AUTHOR]

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 ℇ4 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 ℇ4 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 ℇ4 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 ℇ4 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 ℇ4 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 ℇ4 carrier status was associated with conversion to AD in older outpatients after controlling for known demographic and clinical risk factors, and APOE ℇ4 homozygosity was associated with increased risk of conversion to AD. However, APOE ℇ4 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. [ABSTRACT FROM AUTHOR]

Background Before the introduction of combination antiretroviral therapy (CART), neurological disease correlated with cerebrospinal fluid (CSF) levels of human immunodeficiency virus (HIV) RNA. Objective To investigate the relationships among HIV RNA levels, immune activation markers, and neurological status in patients receiving CART. Design Multicenter cohort study. Setting Academic neurology departments. Patients A total of 371 patients unselected for neurological complaints and with CD4 cell counts less than 200/μL or with cognitive symptoms and CD4 cell counts less than 300/μL were enrolled into the Northeastern AIDS Dementia cohort in 1998-2002. Diagnoses of HIV-associated dementia (HIV-D) and minor cognitive-motor disorder (MCMD) were obtained with a computerized algorithm. Plasma and CSF levels of HIV RNA, monocyte chemotactic protein 1, macrophage colony-stimulating factor, and tumor necrosis factor α were quantified. Results The mean ± SD age was 41.5 ± 7.2 years, and the mean ± SD educational level was 12.3 ± 2.2 years. Seventy percent of the cohort was black, and 30% were women. The mean ± SD CD4 cell count was 136.8 ± 87.9/μL, and CART was used in 71%. Twenty-nine percent of the patients were unimpaired (n = 106), 36% had MCMD (n = 133), and 35% had HIV-D (n = 128). Mean log10 CSF HIV RNA copies per milliliter was 2.6 ± 0.8, with no differences among the neurological groups, even after adjustments for baseline CD4 cell counts and antiretroviral therapy. Cerebrospinal fluid HIV RNA was undetectable in 47% of unimpaired, 46% of MCMD, and 43% of HIV-D patients (P = .91). Plasma levels of monocyte chemotactic protein type 1 and tumor necrosis factor α correlated weakly with HIV RNA levels but did not distinguish those with neurological deficits. Conclusions In contrast to observations in individuals not treated with CART, we found no relationshipbetween CSF markers and neurological status in this CART-using cohort with advanced HIV/AIDS. This was not explicable by demographic differences or plasma virological control. CART may substantially attenuate the degree of central nervous system HIV infection and immune activation, and in CART users, CSF HIV RNA and immune activation markers may fail to discriminate milder degrees of HIV-D and MCMD. [ABSTRACT FROM AUTHOR]

Background: The APOE ε4 allele is a genetic risk factor for Alzheimer disease (AD), though the strength of the association varies by ethnic group. Polymorphisms in regulatory sequences of APOE have also been related to AD, but the effects are inconsistent across studies. Methods: We examined the association between AD and variants in 3 APOE promoters and in the promoter of the adjacent APOC1 gene in African American and Caribbean Hispanic individuals. Polymorphisms tested were the -491A/T, -427T/C, and -219G/T (Th1/E47cs) in the APOE promoter and the HpaI variant in the APOC1 promoter. Using standard research criteria for AD, overall odds ratios were computed and repeated stratified by presence or absence of APOE ε4. Results: The APOC1 HpaI+ variant was associated with AD in Caribbean Hispanic individuals, but strong linkage disequilibrium with the APOE ε4 allele indicated that this was not an independent effect. No promoter variant in APOE or APOC1 was associated with AD before or after adjusting for age, education, sex, and multiple comparisons. Estimated haplotypes including -219G/T, APOE, and APOC1 differed significantly in Caribbean Hispanic patients and controls but not in African American participants. This effect was primarily owing to the -219G/ T-APOE haplotype, but we did not detect significant allele-specific differences in promoter activity comparing reporter constructs containing the APOE -219G and -219 T alleles. Conclusion: These findings exclude a strong or independent influence of APOE or APOC1 promoter polymorphisms on the variation in APOE-related risk of AD in African American and Caribbean Hispanic individuals. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background: Alzheimer disease (AD) and stroke are common in elderly individuals, but the relation between these 2 disorders remains uncertain. Objective: To investigate the association between a clinical history of stroke and subsequent risk of AD. Design: A cohort of 1766 Medicare recipients without dementia participated in a longitudinal follow-up study from 1992 through 1999 in upper Manhattan, New York, NY. History of stroke and presence of cardiovascular risk factors were ascertained at the onset of the study. Incidence rates for AD among those with and without stroke were calculated; proportional hazards ratios were computed using age at onset of the disease as the time-to-event variable. Results: The annual incidence for AD was 5.2% among individuals with stroke vs 4% for those without stroke. The hazards ratio for AD among those with a history of stroke was 1.6 (95% confidence interval, 1.0-2.4) compared with those without stroke. Of the vascular risk factors, hypertension, diabetes, and heart disease, only diabetes related to risk of AD in the absence of stroke. Stroke remained weakly associated with AD in the absence of these factors, but risk significantly increased with the additional factors of hypertension (relative risk, 2.3; 95% confidence interval, 1.4-3.6), diabetes (relative risk, 4.6; 95% confidence interval, 2.2-9.5), or heart disease (relative risk, 2.0; 95% confidence interval, 1.2-3.2). Conclusions: Stroke is associated with AD among elderly individuals. The relation is strongest in the presence of known vascular risk factors. The observed association between stroke and AD might relate to an underlying systemic vascular disease process, or alternatively, to the additive effects of stroke and AD pathologic features, leading to an earlier age at onset of disease. [ABSTRACT FROM AUTHOR]

Background: Previous studies revealed that cognitive test scores were related to functional outcome in Alzheimer disease (AD). However, the relationship between the rate of cognitive decline at the initial disease phase and the risk of reaching clinical milestones in subsequent years has not yet been examined. Objective: To examine whether the rate of cognitive decline predicts the risk of reaching functional milestones in patients with probable AD. Design: A 5-year prospective study was conducted at 3 sites. Setting: Outpatient research and treatment centers. Participants: Patients diagnosed with probable AD (N = 236; mean age, 73 years; 59% women; mean years of education, 13). Main Outcome Measures: Modified Mini-Mental State Examination (mMMSE) scores were used to assess the rate of cognitive decline over time. Total dependence score and 2 clinical milestones: (1) the need to be dressed, groomed, and washed and (2) receiving a level of care equivalent to a placement in a health-related facility, were derived from the Dependence Scale. Results: General estimating equation analyses revealed that the rate of cognitive decline during the entire follow-up period was positively related to an increase in total dependence scores. Cox analyses showed that a fast rate of decline during the first year was related to an increase in the risk of reaching clinical milestones in subsequent years. Analyses controlled for age, sex, education, and baseline mMMSE scores. Conclusion: A fast rate of cognitive decline was associated with increasing risk of reaching clinical milestones in AD. [ABSTRACT FROM AUTHOR]

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[sub 2][sup 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. [ABSTRACT FROM AUTHOR]

Background: The Dependence Scale measures the amount of assistance patients with dementia require in performing daily activities. Validity and reliability of this scale have been demonstrated, but the progression throughout long periods in patients with Alzheimer disease (AD) has not previously been examined. Objective: To determine the longitudinal course of patient dependence in a cohort of prospectively followed AD patients. Methods: Two hundred thirty AD patients enrolled in the Predictors Study were followed up prospectively at 6-month intervals for an average of 6.5 visits. The Dependence Scale was administered to a caregiver, and patients were assessed with the modified Mini-Mental State Examination (mMMSE) and the Blessed Dementia Rating Scale. Dependence level and the additive sum of the Dependence Scale items were considered for analysis. Results: Generalized estimating equations to regression analyses were used to determine that both Dependence Scale scores and dependence level significantly decline with time. By covarying mMMSE scores and self-care deficits factor scores of the Blessed Dementia Rating Scale, generalized estimating equations analysis also demonstrated that change in patient dependence was independent of global cognitive decline and other measures of activities of daily living, respectively. Conclusions: This study shows the validity of the Dependence Scale and demonstrated that dependency in AD significantly declines with time independent of global cognition and other self-care deficits. The scale is a valuable instrument for outcomes research, efficacy trials, and behavioral research in AD. [ABSTRACT FROM AUTHOR]

Background: Although subtle cognitive injury as revealed by neuropsychological testing occurs in a substantial number of patients following carotid endarterectomy (CEA), there is controversy about whether this finding is a result of the surgery or the anesthesia. Objectives: To examine the changes in neuropsychological test performance in patients following CEA vs a control group of patients older than 60 years following spine surgery, so as to determine whether neuropsychological dysfunction after CEA is a result of surgery or anesthesia. Methods: Patients undergoing CEA (n = 80) and lumbar spine surgery (n = 25) were assessed with a battery of neuropsychological tests preoperatively and on postoperative days 1 and 30. The neuropsychological performance of patients in the control group was used to normalize performance for patients in the CEA group, by calculating z scores using the mean and SD of the change scores in the control group. Significant cognitive dysfunction was defined as performance that exceeded 2 SDs above the mean performance of patients in the control group. Results: Postoperative days 1 and 30 total deficit scores were significantly worse in the CEA group compared with the controls. When individual test results were examined, the CEA group performed significantly worse than the controls on the Rey Complex Figure test and Halstead-Reitan Trails B on day 1, and on the Rey Complex Figure on day 30. Overall, cognitive dysfunction was seen in 22 patients (28%) in the CEA group on day 1 and in 11 (23%) of 48 patients on day 30. Conclusions: Subtle cognitive decline following CEA occurs and persists for at least several weeks after surgery. This decline was absent in a control group. [ABSTRACT FROM AUTHOR]

Objectives: To reexamine the association between the apolipoprotein E ε4 allele (APOE ε4) and familial Alzheimer disease (AD), and to search for novel genes that may be associated with susceptibility in Caribbean Hispanic families with a history of AD. Methods: Families were identified in Caribbean Hispanic communities in the greater New York City area, the Dominican Republic, and Puerto Rico. Each family in the study cohort included at least 2 living relatives with a history of dementia. All family members underwent neuropsychological testing and medical and neurological examinations to establish the presence or absence of dementia and to specify the type of dementia. Results: Over a 2½-year period, 203 families were identified. Of these, 19 families had at least 1 family member with onset of dementia before age 55 years, with 8 of the 19 families showing an association with a previously unreported presenilin mutation. Multiple cases of AD were identified in 29 families. Overall, there were 236 affected sibling pairs with AD available for analysis. The average age at onset was 74 years. The presence of APOE ε4 was strongly associated with AD. Conclusions: Both early-onset and late-onset familial AD occur in Caribbean Hispanics. In contrast to sporadic AD, late-onset familial AD among Caribbean Hispanics is strongly associated with APOE ε4. Future attempts to identify additional susceptibility genes should consider the effects of APOE ε4. [ABSTRACT FROM AUTHOR]