Effects of Vascular Risk Factors on the Association of Blood-Based Biomarkers with Alzheimer's Disease.

Background: Comorbidities may influence the levels of blood-based biomarkers for Alzheimer's disease (AD). We investigated whether differences in risk factors or comorbid conditions might explain the discordance between clinical diagnosis and biomarker classifications in a multi-ethnic cohort of elderly individuals. Aims: To evaluate the relationship of medical conditions and other characteristics, including body mass index (BMI), vascular risk factors, and head injury, with cognitive impairment and blood-based biomarkers of AD, phosphorylated tau (P-tau 181, P-tau 217), in a multi-ethnic cohort. Methods: Three-hundred individuals, aged 65 and older, were selected from a prospective community-based cohort for equal representation among three racial/ethnic groups: non-Hispanic White, Hispanic/Latino and African American/Black. Participants were classified into four groups based on absence (Asym) or presence (Sym) of cognitive impairment and low (NEG) or high (POS) P-tau 217 or P-tau 181 levels, determined previously in the same cohort: (Asym/NEG, Asym/POS, Sym/NEG, Sym/POS). We examined differences in individual characteristics across the four groups. We performed post-hoc analysis examining the differences across biomarker and cognitive status. Results: P-tau 217 or P-tau 181 positive individuals had lower BMI than P-tau negative participants, regardless of symptom status. Symptomatic and asymptomatic participants did not differ in terms of BMI. BMI was not a mediator of the effect of P-tau 217 or P-tau 181 on dementia. Frequencies of other risk factors did not differ between the four groups of individuals. Conclusions: Participants with higher levels of P-tau 217 or P-tau 181 consistent with AD had lower BMI regardless of whether the individual was symptomatic. These findings suggest that weight loss may change with AD biomarker levels before onset of cognitive decline. They do not support BMI as a confounding variable. Further longitudinal studies could explore the relationship of risk factors with clinical diagnoses and biomarkers.

Dietary fatty acids and risk of Alzheimer's disease and related dementias: Observations from the Washington Heights-Hamilton Heights-Inwood Columbia Aging Project (WHICAP).

INTRODUCTION: High dietary intake of long chain, polyunsaturated fatty acids is associated with lower Alzheimer's disease (AD) risk. METHODS: Washington Heights-Hamilton Heights-Inwood Columbia Aging Project is a multiethnic, prospective observational study of aging and dementia among elderly (≥ 65 years). Dietary intake was measured using a food frequency questionnaire. Dietary short-, medium-, and long-chain fatty acid intakes were categorized by number of carbons and double bonds. Consensus AD diagnoses were made. Associations between AD risk and dietary fatty acid and cholesterol intakes were estimated using multivariable Cox proportional hazards regression models. RESULTS: Of 2612 multiethnic women (67%) and men (baseline age 76.3 [6.4] years), 380 developed AD over an average 4.5 years follow-up. Lower risk of AD was associated with increasing intakes of docosahexaenoic acid (DHA; hazard ratio [HR] = 0.73, 95% confidence interval [CI]: 0.57 to 0.95, P = 0.018) and eicosapentaenoic acid (EPA; HR = 0.74, 95% CI: 0.57 to 0.95, P = 0.021), and longer AD-free survival (P < 0.05). DISCUSSION: Higher intake of DHA and EPA are protective for AD.

Anxiety symptoms bias memory assessment in older adults.

BACKGROUND: Older adults with anxiety and/or depression experience additional memory dysfunction beyond that of the normal aging process. However, few studies have examined test bias in memory assessments due to anxiety and/or depressive symptoms. The current study investigated the influence of self-reported symptoms of anxiety and depression on the measurement equivalence of memory tests in older adults. METHOD: This is a secondary analysis of the Advanced Cognitive Training for Independent and Vital Elderly dataset, a randomized controlled trial of community-dwelling older adults. Baseline data were included in this study (n = 2802). Multiple indicators multiple causes modeling was employed to assess for measurement equivalence, differential item functioning (DIF), in memory tests. RESULTS: The DIF was present for anxiety symptoms but not for depressive symptoms, such that higher anxiety placed older adults at a disadvantage on measures of memory performance. Analysis of DIF impact showed that compared with participants scoring in the bottom quartile of anxious symptoms, participants in the upper quartile exhibited memory performance scores that were 0.26 standard deviation lower. CONCLUSION: Anxious but not depressive symptoms introduce test bias into the measurement of memory in older adults. This indicates that memory models for research and clinical purposes should account for the direct relationship between anxiety symptoms and memory tests in addition to the true relationship between anxiety symptoms and memory construct. These findings support routine assessments of anxiety symptoms among older adults in settings in which cognitive testing is being conducted. Copyright © 2016 John Wiley & Sons, Ltd.

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.

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.

Education and rates of cognitive decline in incident Alzheimer's disease.

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

Neuropsychological test performance: a study of non-Hispanic White elderly.

This study examined within-group differences in neuropsychological test performance between US versus foreign-born English-speaking White elders. Participants included 193 randomly selected English-speaking elderly community residents who self-identified as non-Hispanic White. Participants were classified as US (n = 106) or foreign-born (n = 87). All participants were independently diagnosed by a physician as nondemented. After controlling for years of education, participants born in the United States obtained significantly higher scores on measures of verbal abstract reasoning, naming, and fluency than foreign-born elders. These results suggest that although non-Hispanics White are often treated as a homogeneous group, performance differences exist even within this group. Effects of acculturation level and language use on cognitive styles may help explain these findings.

Endogenous estrogen levels and Alzheimer's disease among postmenopausal women.

BACKGROUND: Although several studies have suggested that hormone replacement therapy lowers the risk of AD among postmenopausal women, few studies have evaluated the relationship of endogenous estrogen levels and AD. The current study investigated whether serum estrone and estradiol levels were related to the presence of AD among postmenopausal women not currently taking hormone replacement therapy. METHODS: Using a case-control design, we examined an ethnically diverse sample of postmenopausal women who met National Institute of Neurological and Communicative Disorders and Stroke-Alzheimer's Disease and Related Disorders Association criteria for AD (n = 50) and nondemented controls (n = 93). All women were participants in a study of aging and dementia and were seen consecutively between August 1997 and October 1998. RESULTS: Patients with AD had lower estradiol (F[1,141] = 8.3, p = 0.005) levels than did normal controls. Patients also had lower estrone levels; however, this comparison did not quite meet significance criteria (F[1,141] = 3.6, p = 0.06). Compared to estradiol levels >20 pg/mL, women with AD were four to six times more likely to have levels <20 pg/mL after adjusting for age, years of education, presence of an APOE-epsilon4 allele, ethnicity, and body mass index. There were no significant differences in frequency of AD among women within different quartiles of estrone after adjusting for potential confounds. CONCLUSIONS: The results of this preliminary case-control study suggest that estradiol levels may decline significantly in women in whom AD develops.

Effect of literacy on neuropsychological test performance in nondemented, education-matched elders.

The current investigation compared neuropsychological test performance among nondemented literate and illiterate elders. The sample included participants in an epidemiological study of normal aging and dementia in the Northern Manhattan community. All participants were diagnosed as nondemented by a neurologist, and did not have history of Parkinson's disease, stroke, or head injury. Literacy level was determined by self-report. MANOVAs revealed a significant overall effect for literacy status (literate vs. illiterate) on neuropsychological test performance when groups were matched on years of education. The overall effect of literacy status remained significant after restricting the analyses to elders with no formal education, and after controlling for the effects of language of test administration. Specifically, illiterates obtained lower scores on measures of naming, comprehension, verbal abstraction, orientation, and figure matching and recognition. However tests of verbal list delayed recall, nonverbal abstraction, and category fluency were unaffected by literacy status, suggesting that these measures can be used to accurately detect cognitive decline among illiterate elders in this sample. Differences in organization of visuospatial information, lack of previous exposure to stimuli, and difficulties with interpretation of the logical functions of language are possible factors that contribute to our findings.

The effect of African-American acculturation on neuropsychological test performance in normal and HIV-positive individuals. The HIV Neurobehavioral Research Center (HNRC) Group.

Two studies were conducted to examine the relationship of acculturation to neuropsychological test performance among (1) medically healthy, neurologically normal African Americans (N = 170); and (2) HIV positive (HIV+) subgroups of African Americans and Whites (Ns = 20) matched on age, education, sex, and HIV disease stage. Acculturation was measured through self report for all participants, and linguistic behavior (Black English use) was assessed in a subset of medically healthy individuals (N = 25). After controlling for the effects of age, education, and sex, medically healthy African Americans who reported less acculturation obtained lower scores on the WAIS-R Information subtest and the Boston Naming Test than did more acculturated individuals. Black English use was associated with poor performance on Trails B and the WAIS-R Information subtest. HIV+ African Americans scored significantly lower than their HIV+ White counterparts on the Category Test, Trails B, WAIS-R Block Design and Vocabulary subtests, and the learning components of the Story and Figure Memory Tests. However, after accounting for acculturation, ethnic group differences on all measures but Story Learning became nonsignificant. These results suggest that there are cultural differences within ethnic groups that relate to neuropsychological test performance, and that accounting for acculturation may improve the diagnostic accuracy of certain neuropsychological tests.

Cognitive test performance among nondemented elderly African Americans and whites.

We examined the neuropsychological test performance of a randomly selected community sample of English-speaking non-Hispanic African American and white elders in northern Manhattan. All participants were diagnosed as nondemented by a neurologist, whose assessment was made independent of neuropsychological test scores. African American elders obtained significantly lower scores on measures of verbal and nonverbal learning and memory, abstract reasoning, language, and visuospatial skill than whites. After using a stratified random sampling technique to match groups on years of education, many of the discrepancies became nonsignificant; however, significant ethnic group differences on measures of figure memory, verbal abstraction, category fluency, and visuospatial skill remained. Discrepancies in test performance of education-matched African Americans and whites could not be accounted for by occupational attainment or history of medical conditions such as hypertension and diabetes. These findings emphasize the importance of using culturally appropriate norms when evaluating ethnically diverse elderly for dementia.

[Leu]enkephalin enhances active avoidance conditioning in rats and mice.

The effects of intraperitoneal (IP) administration of the endogenous opioid peptide, [Leu]enkephalin (LE), on avoidance conditioning in rodents were investigated. At a dose of 30 micrograms/kg (IP), LE enhanced acquisition of a one-way step-through active avoidance response when administered 2 minutes before training to Swiss Webster mice. [Leu]enkephalin produced a U-shaped dose-response function because both lower and higher doses of LE did not affect avoidance responding. [Leu]enkephalin-induced enhancement of avoidance acquisition was also observed in Sprague-Dawley rats; the intraperitoneal injection of 10 micrograms/kg LE, administered 5 minutes before training, enhanced acquisition of a jump-up one-way active avoidance response. When administered to Sprague-Dawley rats immediately after training, LE (30 micrograms/kg IP) enhanced jump-up avoidance responding at test 24 hours after peptide injection. Previously, we found LE to impair acquisition in the same tasks in both rats and mice, also at microgram doses, and also in a U-shaped manner. Thus, LE can either enhance or impair learning within the same species and the same task; these findings are in agreement with recent theoretical proposals regarding the nature of compounds, such as LE, that modulate learning and memory.