Obesity, diabetes and their metabolic correlates in middle-aged adults with Down syndrome.

BACKGROUND: Obesity in adults without Down syndrome is associated with an adverse metabolic profile including high prevalence of pre-diabetes and diabetes, high levels of insulin, non-high-density lipoprotein (HDL) cholesterol, leptin and high-sensitivity C-reactive protein (hsCRP) and low levels of HDL and adiponectin. We examined whether obesity in middle-aged adults with Down syndrome is also related to an adverse metabolic profile. METHODS: This cross-sectional study included 143 adults with Down syndrome, with a mean age of 55.7 ± 5.7 years and 52.5% women. Body mass index (BMI) was classified as underweight (BMI < 18.5 kg/m2 ), normal (BMI 18.5-24.9 kg/m2 ), overweight (BMI 25-29.9 kg/m2 ) and obese (BMI ≥ 30 kg/m2 ). Diabetes was ascertained by history or by haemoglobin A1c (HbA1c) as normal glucose tolerance (HbA1c < 5.7%), pre-diabetes (HbA1c 5.7-6.4%) and diabetes (HbA1c ≥ 6.5%). We measured non-fasting lipids, hsCRP, insulin, adiponectin and leptin. RESULTS: The majority of the sample had an overweight (46.9%) or obesity (27.3%) status. However, there was a relatively low prevalence of pre-diabetes (9.8%) and diabetes (6.9%). Overweight and obesity status were not associated with lower HDL and adiponectin and higher insulin, non-HDL cholesterol and hsCRP as expected in adults without Down syndrome. However, overweight and obesity were strongly associated with higher leptin (P < 0.001). CONCLUSIONS: The only metabolic correlate of obesity in middle-aged adults with Down syndrome was high leptin levels. Our findings are limited by non-fasting laboratory tests but suggest that middle-aged adults with Down syndrome do not have the adverse metabolic profile related to obesity found in adults without Down syndrome.

An improved method for detecting telomere size differences in T-lymphocyte interphases from older people with Down syndrome with and without mild cognitive impairment.

Telomere size (quantified by fluorescence intensity and physical lengths) in short-term T-lymphocyte cultures from adults with Down syndrome (DS) with and without mild cognitive impairment (MCI-DS) or dementia was compared. For these studies, dementia status was determined based on longitudinal assessments employing a battery of cognitive and functional assessments developed to distinguish adult-onset impairment from preexisting developmental disability. In the course of our studies using a MetaSystems Image Analyzer in combination with ISIS software and a Zeiss Axioskop 2, we found that Fluorescein isothiocyanate (FITC) telomere fluorescence referenced to chromosome 2-identified FITC probe fluorescence as a nontelomere standard (telomere/cen2 ratio) showed great promise as a biomarker of early decline associated with Alzheimer's disease (AD) in this high-risk population. We have now obtained a cen (2) CY3 probe that can clearly be distinguished from the blue-green FITC interphase telomere probe, providing a clear distinction between telomere and centromere fluorescence in both interphase and metaphase. We used FITC/CY3 light intensity ratios to compare telomere length in interphases in adults with DS with and without MCI-DS or dementia. Five age-matched female and five age-matched male pairs (n = 10) all showed clear evidence of telomere shortening associated with clinical progression of AD (P < 0.002 - P < 0.000001), with distributions of mean values for cases and controls showing no overlap. We also examined the time needed for microscopy using interphase versus metaphase fluorescence preparations. With interphase preparations, examination time was reduced by an order of magnitude compared with metaphase preparations, indicating that the methods employed herein have considerable practical promise for translation into broad diagnostic practice.

Estrogen receptor α variants affect age at onset of Alzheimer's disease in a multiethnic female cohort.

BACKGROUND/AIMS: Few studies of gene variants that affect estrogen activity investigate their association with age at onset of Alzheimer's disease (AD) in women of different ethnicities. We examined the influence of ESR1 polymorphisms on age at onset of AD in a multiethnic cohort of women. METHODS: Among 1,436 women participating in the Washington Heights Inwood Columbia Aging Project, association with age at AD onset was assessed for 41 single-nucleotide polymorphisms (SNPs) on the ESR1 gene using Cox proportional hazard models, adjusting for presence of an APOE ε4 allele, years of education, and body mass index. RESULTS: Six SNPs in self-identified White women were protectively associated with delayed age of AD onset in this self-identified group, including the two restriction fragment length polymorphisms PvuII (rs2234693) and XbaI (rs9340799) (HR range = 0.420-0.483). Two separate SNPs were found to affect age of AD onset in self-identified Black women. CONCLUSIONS: ESR1 polymorphisms affect age of onset of AD in women, and risk alleles vary by ethnicity. These effects are possibly due to different linkage disequilibrium patterns or differences in comorbid environmental or cultural risk factors mediating the SNP effect on risk for AD.

A genome-wide association meta-analysis of plasma Aß peptides concentrations in the elderly.

Amyloid beta (Aß) peptides are the major components of senile plaques, one of the main pathological hallmarks of Alzheimer disease (AD). However, Aß peptides' functions are not fully understood and seem to be highly pleiotropic. We hypothesized that plasma Aß peptides concentrations could be a suitable endophenotype for a genome-wide association study (GWAS) designed to (i) identify novel genetic factors involved in amyloid precursor protein metabolism and (ii) highlight relevant Aß-related physiological and pathophysiological processes. Hence, we performed a genome-wide association meta-analysis of four studies totaling 3 528 healthy individuals of European descent and for whom plasma Aß1-40 and Aß1-42 peptides levels had been quantified. Although we did not observe any genome-wide significant locus, we identified 18 suggestive loci (P<1 × 10(-)(5)). Enrichment-pathway analyses revealed canonical pathways mainly involved in neuronal functions, for example, axonal guidance signaling. We also assessed the biological impact of the gene most strongly associated with plasma Aß1-42 levels (cortexin 3, CTXN3) on APP metabolism in vitro and found that the gene protein was able to modulate Aß1-42 secretion. In conclusion, our study results suggest that plasma Aß peptides levels are valid endophenotypes in GWASs and can be used to characterize the metabolism and functions of APP and its metabolites.

Aromatase variants modify risk for Alzheimer's disease in a multiethnic female cohort.

BACKGROUND/AIMS: Few studies of gene variants that affect estrogen activity investigate their association with risk for Alzheimer's disease (AD) in women of different ethnicities. We investigated the influence of CYP19 polymorphisms on risk for AD in a multiethnic cohort of women, with individual ethnicity assessed by genetic population ancestry informative markers (AIMs) as well as by self-identified ethnicity. METHODS: Among 1,686 women participating in the Washington Heights Inwood Columbia Aging Project, association with risk for AD was assessed for 41 single nucleotide polymorphisms (SNPs) on the CYP19 gene using multivariable logistic regression, adjusting for age, presence of an APOE ε4 allele, years of education, and body mass index. RESULTS: Risk for AD was associated with 6 SNPs in women of predominantly Caucasian AIMs-defined ancestry. Of these, 2 were also associated with decreased risk of AD in women of admixed/Hispanic AIMs ancestry. Two separate SNPs were found to be protective in women of predominantly African AIMs-based ancestry. CONCLUSIONS: CYP19 polymorphisms affect risk for AD in women, and risk alleles vary by AIMs-defined ancestry. These effects are possibly due to linkage disequilibrium patterns or differences in the prevalence of comorbid risk factors mediating the SNP effect on risk for AD by group.

Nutrient intake and plasma ß-amyloid.

OBJECTIVE: The widely reported associations between various nutrients and cognition may occur through many biologic pathways including those of ß-amyloid (Aß). However, little is known about the possible associations of dietary factors with plasma Aß40 or Aß42. The aim of the current study was to evaluate the association between nutrient intake and plasma Aß levels. METHODS: In this cross-sectional study, plasma Aß40 and Aß42 and dietary data were obtained from 1,219 cognitively healthy elderly (age >65 years), who were participants in a community-based multiethnic cohort. Information on dietary intake was obtained 1.2 years, on average, before Aß assay. The associations of plasma Aß40 and Aß42 levels and dietary intake of 10 nutrients were examined using linear regression models, adjusted for age, gender, ethnicity, education, caloric intake, apolipoprotein E genotype, and recruitment wave. Nutrients examined included saturated fatty acid, monounsaturated fatty acid, ω-3 polyunsaturated fatty acid (PUFA), ω-6 PUFA, vitamin E, vitamin C, ß-carotene, vitamin B(12), folate, and vitamin D. RESULTS: In unadjusted models that simultaneously included all nutrients, higher intake of ω-3 PUFA was associated with lower levels of Aß40 (ß = -24.7, p < 0.001) and lower levels of Aß42 (ß = -12.3, p < 0.001). In adjusted models, ω-3 PUFA remained a strong predictor of Aß42 (ß = -7.31, p = 0.02), whereas its association with Aß40 was attenuated (ß = -11.96, p = 0.06). Other nutrients were not associated with plasma Aß levels. CONCLUSIONS: Our data suggest that higher dietary intake of ω-3 PUFA is associated with lower plasma levels of Aß42, a profile linked with reduced risk of incident AD and slower cognitive decline in our cohort.

Memory after silent stroke: hippocampus and infarcts both matter.

OBJECTIVE: Memory decline commonly occurs among elderly individuals. This observation is often attributed to early neurodegenerative changes in the hippocampus and related brain regions. However, the contribution of vascular lesions, such as brain infarcts, to hippocampal integrity and age-associated memory decline remains unclear. METHODS: We studied 658 elderly participants without dementia from a prospective, community-based study on aging and dementia who received high-resolution structural MRI. Cortical and subcortical infarcts were identified, and hippocampal and relative brain volumes were calculated following standard protocols. Summary scores reflecting performance on tasks of memory, language, processing speed, and visuospatial function were derived from a comprehensive neuropsychological battery. We used multiple regression analyses to relate cortical and subcortical infarcts, hippocampal and relative brain volume, to measures of cognitive performance in domains of memory, language, processing speed, and visuospatial ability. RESULTS: Presence of brain infarcts was associated with a smaller hippocampus. Smaller hippocampus volume was associated with poorer memory specifically. Brain infarcts were associated with poorer memory and cognitive performance in all other domains, which was independent of hippocampus volume. CONCLUSIONS: Both hippocampal volume and brain infarcts independently contribute to memory performance in elderly individuals without dementia. Given that age-associated neurodegenerative conditions, such as Alzheimer disease, are defined primarily by impairment in memory, these findings have clinical implications for prevention and for identification of pathogenic factors associated with disease symptomatology.

Plasma Aß and PET PiB binding are inversely related in mild cognitive impairment.

OBJECTIVE: To evaluate the relations between PET Pittsburgh compound B (PiB-PET) binding (amyloid imaging) and plasma Aß in patients with mild cognitive impairment (MCI) and similarly aged controls. METHODS: In 20 patients with MCI and 19 cognitively intact controls (case-control study), PiB binding potential (BP(nd)) was assessed in 4 regions, and total brain excluding cerebellum, referenced to cerebellar binding. The mean of plasma Aß levels measured in duplicate was analyzed. RESULTS: Plasma Aß42/Aß40 ratio was decreased in MCI compared to controls (mean 0.15 SD 0.04 vs mean 0.19 SD 0.07, p = 0.03) but Aß40 (p = 0.3) and Aß42 (p = 0.06) levels did not differ between the 2 groups. PiB BP(nd) was increased in MCI compared to controls in the cingulate (p = 0.02), parietal (p = 0.02), and total brain (p = 0.03), but not in prefrontal cortex (p = 0.08) or parahippocampal gyrus (p = 0.07). Linear regression analyses adjusting for age, sex, and cognitive test scores showed that low Aß42/Aß40 ratio was associated with high cingulate, parietal, and total brain PiB binding (0.01< p ≤ 0.05). These associations between PiB binding and the Aß42/Aß40 ratio were strongest in PiB-positive subjects and within the MCI group. CONCLUSIONS: Though cross-sectional, the findings support the "sink" hypothesis that increased brain Aß is accompanied by lower peripheral levels of Aß, particularly the Aß42/Aß40 ratio in patients with MCI. The association between PiB binding and the plasma Aß42/Aß40 ratio suggests possible use of plasma Aß combined with PiB binding as a risk biomarker with potential clinical application.

Type 2 diabetes and late-onset Alzheimer's disease.

BACKGROUND/AIMS: To confirm in a cohort recruited in 1999-2001 our finding in a cohort recruited in 1992-1994 relating type 2 diabetes (T2D) to late-onset Alzheimer's disease (LOAD). METHODS: Participants were 1,488 persons aged 65 years and older without dementia at baseline from New York City. T2D was ascertained by self-report. Dementia and LOAD were ascertained by standard research procedures. Proportional hazard regression was used for analyses relating T2D and LOAD. RESULTS: The prevalence of T2D was 17%. There were 161 cases of dementia and 149 cases of LOAD. T2D was related to dementia (hazard ratio = 1.7; 95% confidence interval = 1.4-2.9) and LOAD (1.6; 1.0-2.6) after adjustment for age, sex, education, ethnic group and apolipoprotein E ε4. This association was weaker when only AD - excluding cases of mixed dementia - was considered (hazard ratio = 1.3; 95% confidence interval = 0.8-2.2). CONCLUSION: T2D is associated with LOAD. Cerebrovascular disease may be an important mediator.

Change in plasma Aß peptides and onset of dementia in adults with Down syndrome.

OBJECTIVE: To examine changes in levels of plasma amyloid-ß (Aß) peptides, Aß42 and Aß40, in relation to onset of Alzheimer disease (AD) in adults with Down syndrome (DS). METHODS: Plasma Aß42 and Aß40 were measured at initial examination and at follow-up in a community-based cohort of 225 adults with DS who did not have dementia at baseline and were assessed for cognitive/functional abilities and health status and followed at 14- to 20-month intervals. We used Cox proportional hazards modeling to estimate the cumulative incidence of AD by Aß peptide change group (increasing, no change, or decreasing), adjusting for covariates. RESULTS: Sixty-one (27.1%) of the participants developed AD. At follow-up, a decrease in Aß42 levels, a decrease in the Aß42/Aß40 ratio, and an increase in Aß40 levels were related to conversion to AD. Compared with the group with increasing levels of Aß42, the likelihood of developing AD was 5 times higher for those whose plasma Aß42 levels decreased over follow-up (hazard ratio [HR] = 4.9, 95% confidence interval [CI] 2.1-11.4). Decreasing Aß42/Aß40 was also strongly related to AD risk (HR = 4.9, 95% CI 1.8-13.2), while decreasing Aß40 was associated with lower risk (HR = 0.4, 95% CI 0.2-0.9). CONCLUSIONS: Among adults with DS, decreasing levels of plasma Aß42, a decline in the Aß42/Aß40 ratio, or increasing levels of Aß40 may be sensitive indicators of conversion to AD, possibly reflecting compartmentalization of Aß peptides in the brain.

Plasma beta-amyloid and duration of Alzheimer's disease in adults with Down syndrome.

OBJECTIVES: To investigate the relation of plasma levels of Abeta peptides (Abeta1-40 and Abeta1-42) and apolipoprotein E (APOE) genotype to dementia status, and the duration of Alzheimer's disease (AD) in adults with Down syndrome (DS). METHODS: Adults with DS were recruited from community settings and followed up for a mean period of 6.7 years. Plasma levels Abeta1-40 and Abeta1-42 and APOE genotype were determined at the last visit. RESULTS: There were 83 nondemented participants and 44 participants with prevalent AD. Overall, plasma levels of Abeta1-42, Abeta1-40 and the ratio Abeta1-42/Abeta1-40 did not differ significantly between the adults with DS. Among demented participants, the mean level of Abeta1-40 was significantly lower (157.0 vs. 195.3) and the ratio of Abeta1-42/Abeta1-40 was significantly higher (0.28 vs. 0.16) in those with more than 4 years duration of dementia than in those with 4 or fewer years' duration of dementia. This pattern was generally similar in those with and without an APOE epsilon4 allele. CONCLUSIONS: There is an association between plasma Abeta peptide levels and the duration of AD in older persons with DS. The predictive and diagnostic roles of Abeta1-42 and Abeta1-40 measurements for AD, however, remain controversial. Change in Abeta peptide levels with onset of AD and with the duration of dementia may account for a lack of difference between prevalent cases and nondemented individuals and for variation in the predictive power of Abeta peptide levels.

Subclinical cerebrovascular disease in mild cognitive impairment.

BACKGROUND: Cerebrovascular disease (CVD) may contribute to mild cognitive impairment (MCI). We sought to determine the relation of white matter hyperintensity (WMH) volume and infarcts in brain MRI to MCI in a community-based sample. METHODS: A total of 679 elderly persons without dementia underwent brain MRI. WMH and infarcts were quantified using research methods. WMH was adjusted for total cranial volume. The Petersen criteria were used to define MCI. MCI was further subclassified into amnestic and non-amnestic. We used logistic regression to relate WMH and infarcts to prevalent MCI. RESULTS: WMH were associated with amnestic MCI (odds ratio [OR] = 1.9; 95% confidence interval [CI] 1.1, 3.4) but not non-amnestic MCI (OR = 1.2; 95% CI 0.4, 1.6) after adjusting for age, gender, ethnic group, education, and APOE-epsilon4. Infarcts were more strongly associated with non-amnestic MCI (OR = 2.7; 95% CI 1.5, 4.8) than amnestic MCI (OR = 1.4; 95% CI 0.9, 2.3). In secondary analyses using continuous cognitive scores as outcomes, WMH, but not infarcts, were related to memory, while infarcts were more strongly related with non-amnestic domains. CONCLUSION: White matter hyperintensity (WMH) is more strongly related to amnestic mild cognitive impairment (MCI). Infarcts are more strongly related to non-amnestic MCI. The nature of WMH in amnestic MCI requires further study.

Survival in Alzheimer disease: a multiethnic, population-based study of incident cases.

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

Significant effect of APOE epsilon 4 genotype on the risk of dementia in Alzheimer's disease and mortality in persons with Down syndrome.

OBJECTIVE: Virtually all adults with Down syndrome (DS) have neuropathological manifestations of Dementia in Alzheimer's disease (DAD) but not all develop clinical psychopathology. The effect of allelic variants of Apolipoprotein (APOE) gene in development and progression of DAD and mortality in persons with DS is examined. METHODS: Recruited participants with DS underwent two to 14 sequential assessments over a follow up period of 6 years on average and their APOE genotype determined. Dementia status was confirmed as recommended by the Working Group for the Establishment of Criteria for the Diagnosis of Dementia in Individuals with Intellectual Disability. RESULTS: APOE genotype results were available for 252 individuals. Participants with APOE epsilon 4 allele had significantly higher risk of developing DAD (HR = 1.8, 95% CI: 1.12-2.79), had an earlier onset of DAD (55.0 vs 57.0 years; p = 0.0027) and a more rapid progression to death compared with participants with epsilon 3 allele (4.2 years vs. 5.4 years, respectively, p = 0.048). In non-demented persons with DS, epsilon 4 allele was associated with earlier death by 17 years (mean survival age, 55.7 vs. 72.7 years; HR = 5.9, 95% CI: 1.7-21.3). CONCLUSIONS: This study highlights the relationship of APOE genotype to morbidity and mortality in persons with DS which has important clinical implications. We recommend screening for APOE genotype in persons with DS to identify those at risk of DAD and premature death. Further research is required to investigate the underlying reasons for the early mortality in non-demented DS persons with an epsilon 4 allele.

Body mass index, dementia, and mortality in the elderly.

OBJECTIVES: To explore the association between body mass index and mortality in the elderly taking the diagnosis of dementia into account. DESIGN: Cohort study. SETTING: cohort study of aging in Medicare recipients in New York City. PARTICIPANTS: 1,452 elderly individuals 65 years and older of both genders. MEASUREMENTS: We used proportional hazards regression for longitudinal multivariate analyses relating body mass index (BMI) and weight change to all-cause mortality. RESULTS: There were 479 deaths during 9,974 person-years of follow-up. There were 210 cases of prevalent dementia at baseline, and 209 cases of incident dementia during follow-up. Among 1,372 persons with BMI information, the lowest quartile of BMI was associated with a higher mortality risk compared to the second quartile (HR=1.5; 95% CI: 1.1,2.0) after adjustment for age, gender, education, ethnic group, smoking, cancer, and dementia. When persons with dementia were excluded, both the lowest (HR=1.9; 95% CI=.3,2.6) and highest (HR=1.6; 95% CI: 1.1,2.3) quartiles of BMI were related to higher mortality. Weight loss was related to a higher mortality risk (HR=1.5; 95% CI: 1.2,1.9) but this association was attenuated when persons with short follow-up or persons with dementia were excluded. CONCLUSION: The presence of dementia does not explain the association between low BMI and higher mortality in the elderly. However, dementia may explain the association between weight loss and higher mortality.

Unbalanced placental expression of imprinted genes in human intrauterine growth restriction.

Imprinted genes control fetal and placental growth in mice and in rare human syndromes, but the role of these genes in sporadic intrauterine growth restriction (IUGR) is less well-studied. We measured the ratio of mRNA from a maternally expressed imprinted gene, PHLDA2, to that from a paternally expressed imprinted gene, MEST, by Northern blotting in 38 IUGR-associated placentae and 75 non-IUGR placentae and found an increase in the PHLDA2/MEST mRNA ratio in IUGR (p=0.0001). Altered expression of PHLDA2 and MEST was not accompanied by changes in DNA methylation within their imprinting centers, and immunohistochemistry showed PHLDA2 protein appropriately restricted to villous and intermediate cytotrophoblast in the IUGR placentae. We next did a genome-wide survey of mRNA expression in 14 IUGR placentae with maternal vascular under-perfusion compared to 15 non-IUGR placentae using Affymetrix U133A microarrays. In this series six imprinted genes were differentially expressed by ANOVA with a Benjamini-Hochberg false discovery rate of 0.05, with increased expression of PHLDA2 and decreased expression of MEST, MEG3, GATM, GNAS and PLAGL1 in IUGR placentae. At lower significance, we found IGF2 mRNA decreased and CDKN1C mRNA increased in the IUGR cases. We confirmed the significant reduction in MEG3 non-translated RNA in IUGR placentae by Northern blotting. In addition to imprinted genes, the microarray data highlighted non-imprinted genes acting in endocrine signaling (LEP, CRH, HPGD, INHBA), tissue growth (IGF1), immune modulation (INDO, PSG-family genes), oxidative metabolism (GLRX), vascular function (AGTR1, DSCR1) and metabolite transport (SLC-family solute carriers) as differentially expressed in IUGR vs. non-IUGR placentae.

Decline in cognitive and functional skills increases mortality risk in nondemented elderly.

OBJECTIVE: To investigate the relation between rate of decline in cognitive and functional/physical abilities and risk of death in nondemented elderly. METHODS: Data were included from individuals participating in a prospective study of aging and dementia in Medicare recipients, 65 years and older, residing in northern Manhattan. The authors included 878 members of the cohort who had measures of memory, cognitive, language, or functional scores over three study intervals, excluding all participants who were demented or had more than one problem in activity of daily living (ADL) skills at baseline. Participants were classified as showing no decline, slow, medium, or rapid rate of decline, based on the slope of change in cognitive and functional/physical factors. The authors used survival methods to examine the relation of rate of decline in cognitive and functional performance to subsequent mortality in younger and older nondemented elderly and across three ethnic groups, adjusting for potential confounders. RESULTS: Nondemented elderly with preserved ADL skills who showed rapid rates of decline on measures of visuospatial reasoning/cognitive, language, ADL, and instrumental ADL functions were approximately twice as likely to die as nondemented elderly who showed no decline or slower rates of decline, while rate of decline in memory or in measures of extremity mobility was not related to risk of death. The association of the rate of decline to risk of death was stronger in relatively young (< or =75 years) than in older participants. CONCLUSIONS: Rate of decline in cognitive and functional skills predicts mortality in nondemented elderly.

Dementia of the Alzheimer's type and accelerated aging in Down syndrome.

This case study, of a woman with Down syndrome and dementia of the Alzheimer's type (DAT), follows the course of her decline over an 11-year period until death at age 57. Detailed neuropathological findings are also presented. This case illustrates features of premature aging that are typically associated with Down syndrome, and the progressive changes in memory and cognition that are usually associated with DAT. Although the subject's cardiovascular condition and thyroid disorder were treated, they may have contributed to the decline of her memory. This case shows the difficulty in diagnosing dementia in an individual with mental retardation who suffered comorbid episodes of depression and psychosis.

Association between mild parkinsonian signs and mild cognitive impairment in a community.

BACKGROUND: Mild parkinsonian signs (MPS) are associated with prevalent and incident dementia but it is not known whether they are associated with mild cognitive impairment (MCI). OBJECTIVE: To determine whether MPS and specific MPS (changes in axial function, rigidity, tremor) are associated with MCI in nondemented community-dwelling older people in northern Manhattan, NY. METHODS: Participants underwent neurologic assessment, including a modified motor portion of the Unified Parkinson Disease Rating Scale. MCI was diagnosed in nondemented participants who had cognitive impairment based on neuropsychological testing and no functional impairment. Participants with MCI were classified as having MCI with memory impairment (MCI+M) vs MCI without memory impairment (MCI-M). RESULTS: MCI was present in 608 (27.3%) of 2,230 participants, including 255 participants with MCI+M and 353 with MCI-M; 1,622 participants did not have MCI. MPS were present in 369 (16.5%) of 2,230 participants. In a univariate logistic regression model, odds of MCI+M (vs no MCI) were 51% higher in participants with MPS compared to those with no MPS (OR = 1.51, 95% CI = 1.09 to 2.09, p = 0.01). Multivariate models yielded similar results (OR = 1.45, 95% CI = 1.03 to 2.05, p = 0.03). Rigidity was present in a higher proportion of participants with MCI+M compared to participants without MCI. CONCLUSIONS: Mild parkinsonian signs, especially rigidity, are associated with amnestic mild cognitive impairment. Mild parkinsonian signs and mild cognitive impairment may share similar pathogeneses. Whether this involves Alzheimer-type pathology, Lewy bodies, or vascular changes in the basal ganglia or basal ganglia circuitry deserves further investigation in postmortem studies.