The Historical Progression From ADL Scrutiny to IADL to Advanced ADL: Assessing Functional Status in the Earliest Stages of Dementia.

Background: Decrements in instrumental activities (IADL) have been observed in the prodromal phase of dementia. Given the long predementia stage in neurodegenerative diseases, it has been proposed that subtle functional changes may precede clinical IADL impairment. Incorporating more challenging advanced ADLs (eg, volunteer work) into the assessment process may increase the sensitivity of functional measures, thus expanding the window for monitoring or interventions. Methods: Longitudinal cohort study was used (follow-ups, 18-24 month), with subjects aged 60 and older (n = 3,635). To elucidate the relationship between cognitive ability and functional status we employed an IADL scale with an extended range (ADL-extended; includes IADL but also more challenging advanced ADLs) that meets item response theory properties of dimensionality, monotonicity, and item hierarchy. Procedures involved (a) a dynamic change model employed to inspect the temporal relationship between ADL-extended and cognitive status and (b) Cox proportional hazards to assess the risk of incident dementia based on ADL-extended scores. Results: Growth curve modeling: baseline ADL-extended was significantly associated with all four cognitive domains investigated. Worse baseline ADL-extended was associated with more rapid declines in speed/executive function, and worse baseline memory was associated with more rapid declines in ADL-extended; a concurrent association was found for language and ADL-extended. Cox model: the risk of dementia was decreased for each additional ADL-extended item endorsed (hazard ratio [HR], 0.85; 95% confidence interval = 0.81-0.90). Conclusions: An increased risk of dementia could be observed in the ADL-extended items, which reflects an area of the functional continuum beyond IADL competencies.

Interest in genetic testing in Ashkenazi Jewish Parkinson's disease patients and their unaffected relatives.

Our objective was to explore interest in genetic testing among Ashkenazi Jewish (AJ) Parkinson's Disease (PD) cases and first-degree relatives, as genetic testing for LRRK2 G2019S is widely available. Approximately 18 % of AJ PD cases carry G2019S mutations; penetrance estimations vary between 24 and 100 % by age 80. A Genetic Attitude Questionnaire (GAQ) was administered at two New York sites to PD families unaware of LRRK2 G2019S mutation status. The association of G2019S, age, education, gender and family history of PD with desire for genetic testing (outcome) was modeled using logistic regression. One-hundred eleven PD cases and 77 relatives completed the GAQ. Both PD cases and relatives had excellent PD-specific genetic knowledge. Among PD, 32.6 % "definitely" and 41.1 % "probably" wanted testing, if offered "now." Among relatives, 23.6 % "definitely" and 36.1 % "probably" wanted testing "now." Desire for testing in relatives increased incrementally based on hypothetical risk of PD. The most important reasons for testing in probands and relatives were: if it influenced medication response, identifying no mutation, and early prevention and treatment. In logistic regression, older age was associated with less desire for testing in probands OR = 0.921 95%CI 0.868-0.977, p = 0.009. Both probands and relatives express interest in genetic testing, despite no link to current treatment or prevention.

The relationship between obsessive-compulsive symptoms and PARKIN genotype: The CORE-PD study.

BACKGROUND: Few studies have systematically investigated the association between PARKIN genotype and psychiatric co-morbidities of Parkison's disease (PD). PARKIN-associated PD is characterized by severe nigral dopaminergic neuronal loss, a finding that may have implications for behaviors rooted in dopaminergic circuits such as obsessive-compulsive symptoms (OCS). METHODS: The Schedule of Compulsions and Obsessions Patient Inventory (SCOPI) was administered to 104 patients with early-onset PD and 257 asymptomatic first-degree relatives. Carriers of one and two PARKIN mutations were compared with noncarriers. RESULTS: Among patients, carriers scored lower than noncarriers in adjusted models (one-mutation: 13.9 point difference, P = 0.03; two-mutation: 24.1, P = 0.001), where lower scores indicate less OCS. Among asymptomatic relatives, a trend toward the opposite was seen: mutation carriers scored higher than noncarriers (one mutation, P = 0.05; two mutations, P = 0.13). CONCLUSIONS: First, a significant association was found between PARKIN mutation status and obsessive-compulsive symptom level in both PD and asymptomatic patients, suggesting that OCS might represent an early non-motor dopamine-dependent feature. Second, irrespective of disease status, heterozygotes were significantly different from noncarriers, suggesting that PARKIN heterozygosity may contribute to phenotype. © 2014 International Parkinson and Movement Disorder Society.

Parkinson disease phenotype in Ashkenazi Jews with and without LRRK2 G2019S mutations.

The phenotype of Parkinson's disease (PD) in patients with and without leucine-rich repeat kinase 2 (LRRK2) G2019S mutations reportedly is similar; however, large, uniformly evaluated series are lacking. The objective of this study was to characterize the clinical phenotype of Ashkenazi Jewish (AJ) PD carriers of the LRRK2 G2019S mutation. We studied 553 AJ PD patients, including 65 patients who were previously reported, from three sites (two in New York and one in Tel-Aviv). Glucocerebrosidase (GBA) mutation carriers were excluded. Evaluations included the Montreal Cognitive Assessment (MoCA), the Unified Parkinson's Disease Rating Scale (UPDRS), the Geriatric Depression Scale (GDS) and the Non-Motor Symptoms (NMS) questionnaire. Regression models were constructed to test the association between clinical and demographic features and LRRK2 status (outcome) in 488 newly recruited participants. LRRK2 G2019S carriers (n = 97) and non-carriers (n = 391) were similar in age and age at onset of PD. Carriers had longer disease duration (8.6 years vs. 6.1 years; P < 0.001), were more likely to be women (51.5% vs. 37.9%; P = 0.015), and more often reported first symptoms in the lower extremities (40.0% vs. 19.2%; P < 0.001). In logistic models that were adjusted for age, disease duration, sex, education, and site, carriers were more likely to have lower extremity onset (P < 0.001), postural instability and gait difficulty (PIGD) (P = 0.043), and a persistent levodopa response for >5 years (P = 0.042). Performance on the UPDRS, MoCA, GDS, and NMS did not differ by mutation status. PD in AJ LRRK2 G2019S mutation carriers is similar to idiopathic PD but is characterized by more frequent lower extremity involvement at onset and PIGD without the associated cognitive impairment.

Late-life depression, mild cognitive impairment, and dementia.

OBJECTIVE: To evaluate the association of late-life depression with mild cognitive impairment (MCI) and dementia in a multiethnic community cohort. DESIGN AND SETTING: A cohort study was conducted in Northern Manhattan, New York, New York. PARTICIPANTS: A total of 2160 community-dwelling Medicare recipients aged 65 years or older were included in the study. METHODS: Depression was assessed using the 10-item version of the Center for Epidemiological Studies Depression scale (CES-D) and defined by a CES-D score of 4 or more. We used logistic regression for cross-sectional association analyses and proportional hazards regression for longitudinal analyses. MAIN OUTCOME MEASURES: Mild cognitive impairment dementia, and progression from MCI to dementia were the main outcome measures. We also used subcategories of MCI (amnestic and nonamnestic), and dementia (probable Alzheimer disease and vascular dementia, including possible Alzheimer disease with stroke). RESULTS: Baseline depression was associated with prevalent MCI (odds ratio, 1.4; 95% CI, 1.1-1.9) and dementia (2.2; 1.6-3.1). Baseline depression was associated with an increased risk of incident dementia (hazard ratio [HR], 1.7; 95% CI, 1.2-2.3) but not with incident MCI (0.9; 0.7-1.2). Persons with MCI and coexisting depression at baseline had a higher risk of progression to dementia (HR, 2.0; 95% CI, 1.2-3.4), especially vascular dementia (4.3; 1.1-17.0), but not Alzheimer disease (1.9; 1.0-3.6). CONCLUSION: The association of depression with prevalent MCI and with progression from MCI to dementia, but not with incident MCI, suggests that depression accompanies cognitive impairment but does not precede it.

Course and etiology of dysexecutive MCI in a community sample.

BACKGROUND: Amnestic mild cognitive impairment (aMCI) is associated with an elevated risk of progressing to Alzheimer's disease. Much less is known about the course of dysexecutive mild cognitive impairment (dMCI). The goals of this study were to determine how the profile of cognitive deficits differs over time between patients with dMCI and aMCI, and control subjects; if the type of dementia differs between dMCI and aMCI in patients who progress to dementia; and if dMCI is more associated with stroke and white matter hyperintensity on magnetic resonance imaging (MRI) than aMCI. METHODS: The authors undertook a prospective evaluation of an inception cohort of 1167 ethnically diverse elders recruited from an urban community-based sample monitored with clinical and neuropsychological testing for an average of 4.5 years (standard deviation, 0.8 year). A subset of the subjects underwent MRI. We compared four groups of MCI patients: single-domain amnestic and dysexecutive MCI, and multiple-domain MCI with and without executive dysfunction. RESULTS: Compared with aMCI, dMCI was less likely to involve other areas of cognition over time and progress to dementia. None of the 33 single-domain dMCI patients progressed to dementia. The presence of executive dysfunction in multiple-domain MCI did not increase risk of progression to dementia. Patients with multiple-domain MCI with executive dysfunction who progressed to dementia were less likely to have an Alzheimer's-type dementia than MCI patients without executive dysfunction. Patients with dMCI were more likely to experience stroke, but not white matter hyperintensity, detected via MRI than patients with aMCI. CONCLUSIONS: dMCI appears to follow a different course, and is less associated with Alzheimer's disease and more associated with stroke than aMCI.

Telephone-based identification of mild cognitive impairment and dementia in a multicultural cohort.

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.

Neuropsychological Profile of Parkin Mutation Carriers with and without Parkinson Disease: The CORE-PD Study.

The cognitive profile of early onset Parkinson's disease (EOPD) has not been clearly defined. Mutations in the parkin gene are the most common genetic risk factor for EOPD and may offer information about the neuropsychological pattern of performance in both symptomatic and asymptomatic mutation carriers. EOPD probands and their first-degree relatives who did not have Parkinson's disease (PD) were genotyped for mutations in the parkin gene and administered a comprehensive neuropsychological battery. Performance was compared between EOPD probands with (N = 43) and without (N = 52) parkin mutations. The same neuropsychological battery was administered to 217 first-degree relatives to assess neuropsychological function in individuals who carry parkin mutations but do not have PD. No significant differences in neuropsychological test performance were found between parkin carrier and noncarrier probands. Performance also did not differ between EOPD noncarriers and carrier subgroups (i.e., heterozygotes, compound heterozygotes/homozygotes). Similarly, no differences were found among unaffected family members across genotypes. Mean neuropsychological test performance was within normal range in all probands and relatives. Carriers of parkin mutations, whether or not they have PD, do not perform differently on neuropsychological measures as compared to noncarriers. The cognitive functioning of parkin carriers over time warrants further study.

Predictors of parkin mutations in early-onset Parkinson disease: the consortium on risk for early-onset Parkinson disease study.

BACKGROUND: Mutations in the parkin gene are the most common genetic cause of early-onset Parkinson disease (PD). Results from a multicenter study of patients with PD systematically sampled by age at onset have not been reported to date. OBJECTIVE: To determine risk factors associated with carrying parkin mutations. DESIGN: Cross-sectional observational study. SETTING: Thirteen movement disorders centers. PARTICIPANTS: A total of 956 patients with early-onset PD, defined as age at onset younger than 51 years. MAIN OUTCOME MEASURES: Presence of heterozygous, homozygous, or compound heterozygous parkin mutations. RESULTS: Using a previously validated interview, 14.7% of patients reported a family history of PD in a first-degree relative. Sixty-four patients (6.7%) had parkin mutations (3.9% heterozygous, 0.6% homozygous, and 2.2% compound heterozygous). Copy number variation was present in 52.3% of mutation carriers (31.6% of heterozygous, 83.3% of homozygous, and 81.0% of compound heterozygous). Deletions in exons 3 and 4 and 255delA were common among Hispanics (specifically Puerto Ricans). Younger age at onset (<40 years) (odds ratio [OR], 5.0; 95% confidence interval [CI], 2.8-8.8; P = .001), Hispanic race/ethnicity (OR compared with white non-Hispanic race/ethnicity, 2.7; 95% CI, 1.3-5.7; P = .009), and family history of PD in a first-degree relative (OR compared with noncarriers, 2.8; 95% CI, 1.5-5.3; P = .002) were associated with carrying any parkin mutation (heterozygous, homozygous, or compound heterozygous). Hispanic race/ethnicity was associated with carrying a heterozygous mutation (OR compared with white non-Hispanic race/ethnicity, 2.8; 95% CI, 1.1-7.2; P = .03) after adjustment for covariates. CONCLUSIONS: Age at onset, Hispanic race/ethnicity, and family history of PD are associated with carrying any parkin mutation (heterozygous, homozygous, or compound heterozygous) and heterozygous mutations alone. The increased odds of carrying a parkin mutation among Hispanics warrants further study.

Self-report of cognitive impairment and mini-mental state examination performance in PRKN, LRRK2, and GBA carriers with early onset Parkinson's disease.

While little is known about risk factors for cognitive impairment in early onset Parkinson disease (EOPD), postmortem studies have shown an association between dementia with Lewy bodies (DLB) and glucocerebrosidase (GBA) mutation. We compared Mini-Mental State Examination (MMSE) performance and self-reported cognitive impairment in 699 EOPD participants genotyped for mutations in parkin (PRKN), leucine-rich repeat kinase-2 (LRRK2), and GBA. Logistic regression was used to assess the association between reported cognitive impairment and MMSE score, as well as between GBA group membership and self-reported impairment and MMSE. GBA carriers reported more impairment, but MMSE performance did not differ among genetic groups. Detailed neuropsychological testing is required to explore the association between cognitive impairment and GBA mutations.

Mild parkinsonian signs are associated with increased risk of dementia in a prospective, population-based study of elders.

There is some evidence that mild parkinsonian signs (MPSs) are associated with increased risk of dementia, suggesting that MPS could be an early biomarker for dementia. Our aims, in a new cohort, were to determine whether (1) baseline MPS are a predictor of incident dementia and (2) there is an interaction between MPS and other baseline risk factors for dementia (i.e., the presence of both together greatly elevates the risk of dementia) was the objective. In a prospective, longitudinal study of community-dwelling elders in northern Manhattan, NY, Parkinsonian signs were rated with an abbreviated Unified Parkinson's Disease Rating Scale. Risk of incident dementia was assessed using Cox proportional hazards models. There were 1,851 participants (mean follow-up = 3.7 years). Participants with baseline MPS were twice as likely to develop dementia as participants without MPS: 16.3% versus 7.7%, unadjusted hazards ratio (HR) = 2.24 (P< 0.001), adjusted HR = 1.98 (P < 0.001). MPS were divided into three subtypes: adjusted HR(axial dysfunction) = 2.45 (P < 0.001), adjusted HR(tremor) = 2.38 (P = 0.006), and adjusted HR(rigidity) = 1.16 (P = 0.58). When MPS were treated as a continuous variable, the adjusted HR = 1.15 (P = 0.001). There were no interactions between MPS and other baseline risk factors for dementia, including gender, education, race, family history of dementia, stroke, and apolipoprotein E-e4. Baseline MPS seems to be a predictor of incident dementia. These motor signs might, therefore, serve as a useful biomarker for emerging dementia.

Physical activity, diet, and risk of Alzheimer disease.

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.

Validity of self-reported stroke in elderly African Americans, Caribbean Hispanics, and Whites.

BACKGROUND: The validity of a self-reported stroke remains inconclusive. OBJECTIVE: To validate the diagnosis of self-reported stroke using stroke identified by magnetic resonance imaging (MRI) as the standard. DESIGN, SETTING, AND PARTICIPANTS: Community-based cohort study of nondemented, ethnically diverse elderly persons in northern Manhattan. METHODS: High-resolution quantitative MRIs were acquired for 717 participants without dementia. Sensitivity and specificity of stroke by self-report were examined using cross-sectional analyses and the chi(2) test. Putative relationships between factors potentially influencing the reporting of stroke, including memory performance, cognitive function, and vascular risk factors, were assessed using logistic regression models. Subsequently, all analyses were repeated, stratified by age, sex, ethnic group, and level of education. RESULTS: In analyses of the whole sample, sensitivity of stroke self-report for a diagnosis of stroke on MRI was 32.4%, and specificity was 78.9%. In analyses stratified by median age (80.1 years), the validity between reported stroke and detection of stroke on MRI was significantly better in the younger than the older age group (for all vascular territories: sensitivity and specificity, 36.7% and 81.3% vs 27.6% and 26.2%; P = .02). Impaired memory, cognitive skills, or language ability and the presence of hypertension or myocardial infarction were associated with higher rates of false-negative results. CONCLUSIONS: Using brain MRI as the standard, specificity and sensitivity of stroke self-report are low. Accuracy of self-report is influenced by age, presence of vascular disease, and cognitive function. In stroke research, sensitive neuroimaging techniques rather than stroke self-report should be used to determine stroke history.

Motor unit number estimation (MUNE) in diseases of the motor neuron: utility and comparative analysis in a multimodal biomarker study.

We prospectively studied 64 patients with motor neuron disease (amyotrophic lateral sclerosis (ALS), familial ALS (fALS), progressive muscular atrophy (PMA) and primary lateral sclerosis (PLS)) using multiple point stimulation motor unit number estimation (MUNE), transcranial magnetic stimulation (TMS), proton magnetic resonance spectroscopic imaging (1H MRSI), diffusion tensor imaging (MRDTI), and clinical measures at baseline and every 3 months thereafter for 15 months. Substantial differences in MUNE were noted among the motor neuron disease subgroups (P = 0.0005) and mean values for each motor neuron disease subgroup were significantly lower vs. controls (ALS = 76, fALS = 80, PMA = 29, and PLS = 174) vs. the normal control average (267). MUNE correlated well with % FVC (r = 0.32; P = 0.01), manual muscle testing (r = 0.52; P < 0.0005), grip strength (r = 0.34; P = 0.007), and pinch strength (r = 0.49; P < 0.0005). Overall, MUNE showed the greatest significant change over time of any measure, clinical or otherwise, tested in this study (-2.35 linear trend % change per month, mean). MUNE clearly delineates lower motor neuron dysfunction, strongly correlates with important clinical functions (such as strength and respiration) and is a highly sensitive marker of disease progression over time. These features make MUNE an important tool for both the study of the pathophysiology of the motor neuron diseases, as well as an important measure for incorporation into future clinical trials.

Peripheral Abeta subspecies as risk biomarkers of Alzheimer's disease.

Plasma Abeta42 and Abeta40 levels are putative biomarkers for Alzheimer's disease (AD), but their significance and predictive value have been inconclusive. In AD transgenic models, plasma and cerebrospinal fluid levels of Abeta42 and Abeta40 increase with age but subsequently decrease when Abeta begins to accumulate in brain and with the onset of cognitive impairment. To determine the predictive value of Abeta levels in elderly populations, we investigated how plasma Abeta42, Abeta40, and a protofibrillar subspecies of Abeta42 changed over time and with the onset of cognitive impairment or AD. In a cohort of 1,125 elderly persons without dementia, 104 (9.2%) of the participants developed AD over 4.6 years of follow-up. Higher plasma Abeta42 levels at the onset of the study were associated with a threefold increased risk of AD. However, conversion to AD was accompanied by a significant decline in plasma Abeta42, a decreased Abeta42/Abeta40 ratio and, with the onset of cognitive impairment, decreased protofibrillar Abeta42 levels. Our results suggest individuals with elevated plasma Abeta42 are at increased risk of AD and that with the onset of disease, the decline in some forms of Abeta may reflect compartmentalization of Abeta peptides in the brain.

Brain morphology in older African Americans, Caribbean Hispanics, and whites from northern Manhattan.

BACKGROUND: Aging is accompanied by a decrease in brain volume and by an increase in cerebrovascular disease. OBJECTIVE: To examine the effects of age, sex, race/ethnicity, and vascular disease history on measures of brain morphology, including relative brain volume, ventricular volume, hippocampus and entorhinal cortex volumes, and white matter hyperintensity (WMH) burden, in a large community-based cohort of racially/ethnically diverse older adults without dementia. DESIGN: The associations of age, sex, race/ethnicity, and self-reported vascular disease history with brain morphology were examined in a cross-sectional study using multiple linear regression analyses. Sex x race/ethnicity interactions were also considered. SETTING: The Washington Heights-Inwood Columbia Aging Project, a community-based epidemiological study of older adults from 3 racial/ethnic groups (white, Hispanic, and African American) from northern Manhattan. PARTICIPANTS: Beginning in 2003, high-resolution quantitative magnetic resonance (MR) images were acquired in 769 participants without dementia. MAIN OUTCOME MEASURES: Relative brain volume (total brain volume/intracranial volume), ventricular volume, and hippocampus and entorhinal cortex volumes were derived manually on high-resolution MR images. White matter hyperintensities were quantified semiautomatically on fluid-attenuated inversion recovery-T2-weighted MR images. RESULTS: Older age was associated with decreased relative brain volume and with increased ventricular and WMH volumes. Hispanic and African American participants had larger relative brain volumes and more severe WMH burden than white participants, but the associations of these variables with age were similar across racial/ethnic groups. Compared with men, women had larger relative brain volumes. Vascular disease was associated with smaller relative brain volume and with higher WMH burden, particularly among African Americans. CONCLUSIONS: Older age and vascular disease, particularly among African Americans, are associated with increased brain atrophy and WMH burden. African American and Hispanic subjects have larger relative brain volumes and more WMH than white subjects. Racial/ethnic group differences in WMH severity seem to be partially attributable to differences in vascular disease. Future work will focus on the determinants and cognitive correlates of these differences.

Frequency and course of mild cognitive impairment in a multiethnic community.

OBJECTIVE: To examine incidence rates and antecedents of mild cognitive impairment (MCI) and Alzheimer's disease (AD) among diverse elders without dementia at the initial visit, and to examine the characteristics of elders with MCI who reverted to normal on follow-up examination. METHODS: A total of 2,364 Caribbean Hispanic, black, or non-Hispanic white subjects, aged 65 or older, who were free of dementia at initial evaluation were followed up every 18 to 24 months. Incidence rate of MCI and AD was determined by examination of neurological, medical, psychiatric, and neuropsychological function. RESULTS: Over 10,517 person-years, 21% of normal elderly subjects progressed to MCI (annual incidence rate, 5.1%; 95% confidence interval, 4.6-5.6%). Of those with MCI initially, 21.8% were subsequently diagnosed with AD (annual incidence rate, 5.4%; 95% confidence interval, 4.7-6.3%), 47% remained unchanged, and 31% reverted to normal. Those with MCI were 2.8 times more likely to experience development of AD than normal elderly subjects. MCI with impairment in memory and at least one other cognitive domain was associated with greatest risk for progression to AD and was also least likely to revert to normal at follow-up. Consistent diagnosis of MCI or incident probable or possible AD was 60% sensitive and 94% specific for the pathological diagnosis of AD. INTERPRETATION: Impaired memory and language were useful predictors of transition to AD. Reversion to normal from MCI was frequent, but those with impairment in more than one cognitive domain were more likely to progress or remain impaired than those with single-domain impairment. Clinical diagnosis of MCI does not always predict AD neuropathology.

Mild parkinsonian signs and plasma homocysteine concentration in community-dwelling elderly individuals.

OBJECTIVE: To determine whether plasma homocysteine (Hcy) concentration is associated with mild parkinsonian signs (MPS) in community-dwelling elderly individuals. DESIGN: Cross-sectional analyses of a population-based cohort study. SETTING: Washington Heights-Inwood, New York. Patients Persons without dementia 65 years and older. Main Outcome Measure Participants underwent an abbreviated motor portion of the Unified Parkinson's Disease Rating Scale. Each participant was assigned an MPS score (range, 0-40). The Hcy concentration was measured from plasma. All analyses were cross-sectional. RESULTS: There were 369 participants (mean +/- SD age, 77.8 +/- 6.0 years; mean +/- SD MPS score, 1.51 +/- 2.55; mean +/- SD plasma Hcy concentration, 17.3 +/- 6.5 mumol/L). Mean +/- SD MPS scores in plasma Hcy concentration quintiles were as follows: lowest quintile, 1.15 +/- 1.77; second quintile, 1.18 +/- 1.88; third quintile, 1.64 +/- 2.93; fourth quintile, 1.45 +/- 2.17; and highest quintile, 2.12 +/- 3.49 (84.3% higher than 1.15) (P = .02). In an unadjusted linear regression model, plasma Hcy concentration was associated with log MPS score (dependent variable) (P = .008). In a linear regression model that adjusted for confounding variables, plasma Hcy concentration was associated with log MPS score (P = .04). CONCLUSIONS: These data indicate that MPS are associated with higher plasma Hcy concentrations. Prospective neuroimaging as well as clinical-pathological studies would further our understanding of several mechanisms that could underlie the observed association.

The heritability of abstract reasoning in Caribbean Latinos with familial Alzheimer disease.

BACKGROUND: Alzheimer disease (AD) is under substantial genetic influence. To better understand the genetic influence on component phenotypes of AD, we estimated the heritability (h(2)) of abstract reasoning and examined its relation with apolipoprotein epsilon 4 (APOE-epsilon 4). METHODS: We studied abstract reasoning in 1,116 individuals from 210 Caribbean Hispanic families with late onset AD, using the similarities subtest scores from the Wechsler Adult Intelligence Scale. We computed h(2), then performed analysis of variance to examine the effect of APOE-epsilon 4. RESULTS: Abstract reasoning was highly heritable (h(2)(unadjusted) = 79.9%). After adjusting for covariates, the h(2) was reduced to 32.6%, with education accounting for 40.8% of the variance. The APOE-epsilon 4 allele had no effect. CONCLUSION: Abstract reasoning was strongly influenced by genetic factors and education. Genes other than APOE contribute to the inheritance of abstract reasoning ability.

Shorter telomeres are associated with mortality in those with APOE epsilon4 and dementia.

OBJECTIVE: Reduced telomere length may be a marker of biological aging. We hypothesized that telomere length might thus relate to increased risk for dementia and mortality. METHODS: This nested case-control study used stored leukocyte DNA from 257 individuals (mean age, 81.4 +/- 7.9 years; 64.6% female; 44.7% Hispanic, 33.5% non-Hispanic black, and 21.8% non-Hispanic white). Our assay used real-time polymerase chain reaction, with two separate reactions amplifying telomere sequence and reference single copy gene (ribosomal-protein-P0), providing a calculated telomere-to-single copy gene (T/S) ratio. RESULTS: Mean telomere length was shorter among subjects dying during follow-up than in those surviving (0.453 +/- 0.211 vs 0.525 +/- 0.226 [+/- standard deviation]; p < 0.009). It was also shorter in those with Alzheimer's disease compared with control subjects (0.458 +/- 0.207 vs 0.516 +/- 0.229; p < 0.03). For participants with Alzheimer's disease, compared with those with the longest telomeres, the mortality odds ratio (OR) was 4.8 (95% confidence interval [CI], 1.7-13.8) in those with intermediate-length telomeres and 7.3 (95% CI, 2.4-22.0) in those with the shortest telomeres. The presence of an epsilon4 allele also increased the mortality OR, with an OR of 5.8 (95% CI, 1.3-26.4) for intermediate-length telomeres and an OR of 9.0 (95% CI, 1.9-41) for the shortest telomeres. INTERPRETATION: Our findings suggest that leukocyte telomere length is related to both dementia and mortality and may be a marker of biological aging.