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Background and Objectives: The cognitive reserve hypothesis posits that cognitively stimulating work delays the onset of mild cognitive impairment (MCI) and dementia. However, the effect of occupational cognitive demands across midlife on the risk of these conditions is unclear., Methods: Using a cohort study design, we evaluated the association between registry-based trajectories of occupational cognitive demands from ages 30-65 years and clinically diagnosed MCI and dementia in participants in the HUNT4 70+ Study (2017-19). Group-based trajectory modeling identified trajectories of occupational cognitive demands, measured by the routine task intensity (RTI) index (lower RTI indicates more cognitively demanding occupation) from the Occupational Information Network. Multinomial regression was implemented to estimate the relative risk ratios (RRRs) of MCI and dementia, after adjusting for age, sex, education, income, baseline hypertension, obesity, diabetes, psychiatric impairment, hearing impairment, loneliness, smoking status, and physical inactivity assessed at HUNT1-2 in 1984-1986 and 1995-1997. To handle missing data, we used inverse probability weighting to account for nonparticipation in cognitive testing and multiple imputation., Results: Based on longitudinal RTI scores for 305 unique occupations, 4 RTI trajectory groups were identified (n = 7,003, 49.8% women, age range 69-104 years): low RTI (n = 1,431, 20.4%), intermediate-low RTI (n = 1,578, 22.5%), intermediate-high RTI (n = 2,601, 37.1%), and high RTI (n = 1,393, 19.9%). Participants in the high RTI group had a higher risk of MCI (RRR 1.74, 95% CI 1.41-2.14) and dementia (RRR 1.37, 95% CI 1.01-1.86), after adjusting for age, sex, and education compared with participants in the low RTI group. In a sensitivity analysis, controlling for income and baseline health-related factors, the point estimates were not appreciably changed (RRR 1.66, 95% CI 1.35-2.06 for MCI, and RRR 1.31, 95% CI 0.96-1.78 for dementia)., Discussion: People with a history of cognitively stimulating occupations during their 30s, 40s, 50s, and 60s had a lower risk of MCI and dementia older than 70 years, highlighting the importance of occupational cognitive stimulation during midlife for maintaining cognitive function in old age. Further research is required to pinpoint the specific occupational cognitive demands that are most advantageous for maintaining later-life cognitive function.

Objectives: Earlier studies suggest that being married in later life protects against dementia, and that being single in old age increases the risk of dementia. In this study, we examine midlife marital status trajectories and their association with dementia and mild cognitive impairment (MCI) at ages 70 plus using a large population based sample from Norway. Methods: Based on a general population sample linked to population registries ( N = 8706), we used multinomial logistic regression to examine the associations between six types of marital trajectories (unmarried, continuously divorced, intermittently divorced, widowed, continuously married, intermittently married) between age 44 and 68 years from national registries and a clinical dementia or a MCI diagnosis after age 70. We estimated relative risk ratios (RRR) and used mediation analyses adjusting for education, number of children, smoking, hypertension, obesity, physical inactivity, diabetes, mental distress, and having no close friends in midlife. Inverse probability weighting and multiple imputations were applied. The population attributable fraction was estimated to assess the potential reduction in dementia cases due to marital histories. Results: Overall, 11.6% of the participants were diagnosed with dementia and 35.3% with MCI. Dementia prevalence was lowest among the continuously married (11.2%). Adjusting for confounders, the risk of dementia was higher for the unmarried (RRR = 1.73; 95% CI: 1.24, 2.40), continuously divorced (RRR = 1.66; 95% CI: 1.14, 2.43), and intermittently divorced (RRR = 1.50; 95% CI: 1.09, 2.06) compared to the continuously married. In general, marital trajectory was less associated with MCI than with dementia. In the counterfactual scenario, where all participants had the same risk of receiving a dementia diagnosis as the continuously married group, there would be 6.0% fewer dementia cases. Discussion: Our data confirm that staying married in midlife is associated with a lower risk of dementia and that divorced people account for a substantial share of dementia cases.

Background: Research shows that retirement age is associated with later-life cognition but has not sufficiently distinguished between retirement pathways. We examined how retirement age was associated with later-life dementia and mild cognitive impairment (MCI) for people who retired via the disability pathway (received a disability pension prior to old-age pension eligibility) and those who retired via the standard pathway., Methods: The study sample comprised 7210 participants from the Norwegian Trøndelag Health Study (HUNT4 70+, 2017-2019) who had worked for at least one year in 1967-2019, worked until age 55+, and retired before HUNT4. Dementia and MCI were clinically assessed in HUNT4 70+ when participants were aged 69-85 years. Historical data on participants' retirement age and pathway were retrieved from population registers. We used multinomial regression to assess the dementia/MCI risk for women and men retiring via the disability pathway, or early (<67 years), on-time (age 67, old-age pension eligibility) or late (age 68+) via the standard pathway., Results: In our study sample, 9.5% had dementia, 35.3% had MCI, and 28.1% retired via the disability pathway. The disability retirement group had an elevated risk of dementia compared to the on-time standard retirement group (relative risk ratio [RRR]: 1.64, 95% CI 1.14-2.37 for women, 1.70, 95% CI 1.17-2.48 for men). MCI risk was lower among men who retired late versus on-time (RRR, 0.76, 95% CI 0.61-0.95)., Conclusion: Disability retirees should be monitored more closely, and preventive policies should be considered to minimize the dementia risk observed among this group of retirees., (© 2023 The Authors. International Journal of Geriatric Psychiatry published by John Wiley & Sons Ltd.)

Background: Misidentification of dementia in Medicare claims is quite common., Objective: We examined potential race/ethnic disparities in misidentification of dementia in Medicare claims in a diverse cohort of older adults who underwent careful clinical assessment., Methods: Participants were enrolled in the Washington Heights-Inwood Columbia Aging Project (WHICAP), a multiethnic, population-based, prospective study of cognitive aging in which dementia status was assessed using a rigorous clinical protocol. ICD-9-CM and ICD-10-CM diagnosis codes in all available Medicare claims (1999-2019) were compared to clinical dementia diagnosis and categorized into three mutually exclusive groups: 1) congruent-, 2) over-, and 3) under- identification during the study period. Multinomial logistic regression model was used to examine the relationship between race (White, African American/Black, other) and ethnicity (Hispanic/Latinx, non-Hispanic/Latinx) and congruency of dementia identification after controlling for clinical (cognition, function, comorbidities) and demographic characteristics (age, sex, education), and inpatient and outpatient utilization., Results: Across all person-years, 88.4% had congruent identification of dementia compared to clinical diagnosis, in 4.1% of the times participants were over-identified with dementia, and 7.5% of the times the participants were under-identified. Rates of misidentification was higher in minority participants than in White, non-Hispanic participants. Multivariable estimation results showed that the probability of over-identification with dementia was 2.2% higher for African American/Black than White (p = 0.05) and 2.7% higher for Hispanic participants than non-Hispanics (p = 0.03) participants. Differences in under-identification by race/ethnicity were not statistically significant., Conclusions: African American/Black and Hispanic participants were more likely over-identified with dementia in Medicare claims.

Background: Variability in dementia rates across racial and ethnic groups has been estimated at 60%. Studies suggest disparities in Caribbean Hispanic and Black populations, but community-based data are limited., Objective: Estimate the prevalence of mild cognitive impairment (MCI) and dementia in the racially and ethnically diverse community-based Northern Manhattan Study cohort and examine sociodemographic, vascular risk factor, and brain imaging correlates., Methods: Cases of MCI and dementia were adjudicated by a team of neuropsychologists and neurologists and prevalence was estimated across race/ethnic groups. Ordinal proportional odds models were used to estimate race/ethnic differences in the prevalence of MCI or dementia adjusting for sociodemographic variables (model 1), model 1 plus potentially modifiable vascular risk factors (model 2), and model 1 plus structural imaging markers of brain integrity (model 3)., Results: There were 989 participants with cognitive outcome determinations (mean age 69±9 years; 68% Hispanic, 16% Black, 14% White; 62% women; mean (±SD) follow-up five (±0.6) years). Hispanic and Black participants had greater likelihood of MCI (20%) and dementia (5%) than White participants accounting for age and education differences. Hispanic participants had greater odds of MCI or dementia than both White and Black participants adjusting for sociodemographic variables, vascular risk factors, and brain imaging factors. White matter hyperintensity burden was significantly associated with greater odds of MCI or dementia (OR = 1.3, 1.1 to 1.6), but there was no significant interaction by race/ethnicity., Conclusion: In this diverse community-based cohort, cross-sectional data revealed significant race/ethnic disparities in the prevalence of MCI and dementia. Longer follow-up and incidence data are needed to further clarify these relationships.

Objectives: The main objective of this study was to estimate effects of dementia on Medicaid expenditures in an ethnically diverse community., Methods: The sample included 1,211 Medicare beneficiaries who did not have any Medicaid coverage and 568 who additionally had full Medicaid coverage enrolled in the Washington Heights-Inwood Columbia Aging Project (WHICAP), a multiethnic, population-based, prospective study of cognitive aging in northern Manhattan (1999-2010). Individuals' dementia status was determined using a rigorous clinical protocol. Relationship between dementia and Medicaid coverage and expenditures were estimated using a two-part model., Results: In participants who had full Medicaid coverage, average annual Medicaid expenditures were substantially higher for those with dementia than those without dementia ($50,270 vs. $21,966, p < .001), but Medicare expenditures did not differ by dementia status ($8,458 vs. $9,324, p = .19). In participants who did not have any Medicaid coverage, average annual Medicare expenditures were substantially higher for those with dementia than those without dementia ($12,408 vs. $8,113, p = .02). In adjusted models, dementia was associated with a $6,278 increase in annual Medicaid spending per person after controlling for other characteristics., Discussion: Results highlight Medicaid's contribution to covering the cost of dementia care in addition to Medicare. Studies that do not include Medicaid are unlikely to accurately reflect the true cost of dementia., (Published by Oxford University Press on behalf of The Gerontological Society of America 2019.)

Importance: Early-life factors may be important for later dementia risk. The association between a more advantaged early-life environment, as reflected through an individual's height and socioeconomic status indicators, and decreases in dementia incidence by birth cohort is unknown., Objectives: To examine the association of birth cohort and early-life environment with dementia incidence among participants in the Adult Changes in Thought study from 1994 to 2015., Design, Setting, and Participants: This prospective cohort study included 4277 participants from the Adult Changes in Thought study, an ongoing longitudinal population-based study of incident dementia in a random sample of adults 65 years and older who were born between 1893 and 1949 and are members of Kaiser Permanente Washington in the Seattle region. Participants in the present analysis were followed up from 1994 to 2015. At enrollment, all participants were dementia-free and completed a baseline evaluation. Subsequent study visits were held every 2 years until a diagnosis of dementia, death, or withdrawal from the study. Participants were categorized by birth period (defined by historically meaningful events) into 5 cohorts: pre-World War I (1893-1913), World War I and Spanish influenza (1914-1920), pre-Great Depression (1921-1928), Great Depression (1929-1939), and World War II and postwar (1940-1949). Participants' height, educational level, childhood financial stability, and childhood household density were examined as indicators of early-life environment, and later-life vascular risk factors for dementia were assessed. Cox proportional hazards regression models, adjusted for competing survival risk, were used to analyze data. Data were analyzed from June 1, 2018, to April 29, 2020., Main Outcomes and Measures: Participants completed the Cognitive Abilities Screening Instrument every 2 years to assess global cognition. Those with scores indicative of cognitive impairment completed an evaluation for dementia, with dementia diagnoses determined during consensus conferences using criteria from the Diagnostic and Statistical Manual of Mental Disorders, 4th edition., Results: Among 4277 participants, the mean (SD) age was 74.5 (6.4) years, and 2519 participants (58.9%) were women. The median follow-up was 8 years (interquartile range, 4-12 years), with 730 participants developing dementia over 24 378 person-years. The age-specific dementia incidence was lower for those born in 1929 and later compared with those born earlier. Compared with participants born in the pre-Great Depression years (1921-1928), the age- and sex-adjusted hazard ratio was 0.67 (95% CI, 0.53-0.85) for those born in the Great Depression period (1929-1939) and 0.62 (95% CI, 0.29-1.31) for those born in the World War II and postwar period (1940-1949). Although indicators of a more advantaged early-life environment and higher educational level (college or higher) were associated with a lower incidence of dementia, these variables did not explain the association between birth cohort and dementia incidence, which remained when vascular risk factors were included and were similar by sex., Conclusions and Relevance: Age-specific dementia incidence was lower in participants born after the mid-1920s compared with those born earlier. In this population, the decrease in dementia incidence may reflect societal-level changes or individual differences over the life course rather than early-life environment, as reflected through recalled childhood socioeconomic status and measured height, educational level, and later-life vascular risk.

Introduction: Odor identification deficits characterize Alzheimer's disease and other dementias. We examined if intact performance on brief cognitive and odor identification tests predicts lack of transition to dementia., Methods: In an urban community, 1037 older adults without dementia completed the 40-item University of Pennsylvania Smell Identification Test, which includes the 12-item Brief Smell Identification Test (B-SIT). Data from 749 participants followed up for 4 years were analyzed., Results: In covariate-adjusted survival analyses, impairment on the Blessed Orientation Memory Concentration Test and B-SIT each predicted dementia (n = 109), primarily Alzheimer's disease (n = 101). Among participants with intact olfactory (B-SIT ≥ 11/12 correct) and cognitive (Blessed Orientation Memory Concentration Test ≤ 5/28 incorrect) ability, 3.4% (4/117) transitioned to dementia during follow-up with no transitions in the 70-75 and 81-83 years age group quartiles., Discussion: Odor identification testing adds value to global cognitive testing, and together can identify individuals who rarely transition to dementia, thereby avoiding unnecessary diagnostic investigation., (© 2019 the Alzheimer's Association.)

Background: The concept of reserve was established to account for the observation that a given degree of neurodegenerative pathology may result in varying degrees of symptoms in different individuals. There is a large amount of evidence on epidemiological risk and protective factors for neurodegenerative diseases and dementia, yet the biological mechanisms that underpin the protective effects of certain lifestyle and physiological variables remain poorly understood, limiting the development of more effective preventive and treatment strategies. Additionally, different definitions and concepts of reserve exist, which hampers the coordination of research and comparison of results across studies., Discussion: This paper represents the consensus of a multidisciplinary group of experts from different areas of research related to reserve, including clinical, epidemiological and basic sciences. The consensus was developed during meetings of the working groups of the first International Conference on Cognitive Reserve in the Dementias (24-25 November 2017, Munich, Germany) and the Alzheimer's Association Reserve and Resilience Professional Interest Area (25 July 2018, Chicago, USA). The main objective of the present paper is to develop a translational perspective on putative mechanisms underlying reserve against neurodegenerative disease, combining evidence from epidemiological and clinical studies with knowledge from animal and basic research. The potential brain functional and structural basis of reserve in Alzheimer's disease and other brain disorders are discussed, as well as relevant lifestyle and genetic factors assessed in both humans and animal models., Conclusion: There is an urgent need to advance our concept of reserve from a hypothetical model to a more concrete approach that can be used to improve the development of effective interventions aimed at preventing dementia. Our group recommends agreement on a common dictionary of terms referring to different aspects of reserve, the improvement of opportunities for data sharing across individual cohorts, harmonising research approaches across laboratories and groups to reduce heterogeneity associated with human data, global coordination of clinical trials to more effectively explore whether reducing epidemiological risk factors leads to a reduced burden of neurodegenerative diseases in the population, and an increase in our understanding of the appropriateness of animal models for reserve research.

Objectives: To examine how misidentification of dementia affects estimation of Medicare costs in a largely minority cohort of participants for whom accurate in-person diagnoses are available., Design: Prospective cohort study., Setting: Washington Heights-Inwood Columbia Aging Project, a multiethnic, population-based, prospective study of cognitive aging of Medicare beneficiaries aged 65 and older., Participants: Individuals clinically diagnosed with dementia (n=495) and individuals clinically diagnosed without dementia (n=1,701)., Measurements: Medicare claims-identified dementia was defined according to the presence of any International Classification of Diseases, Ninth Revision, Clinical Modification diagnosis codes for Alzheimer's disease and related dementias in all available claims during the study period. Participant characteristics associated with claims misidentification of dementia were estimated using logistic regression. Effects of dementia misidentification on Medicare expenditures were estimated using generalized linear models., Results: Medicare claims correctly identified 250 of the 495 (51%) dementia cases and 1,565 of the 1,701 (92%) nondementia cases. Sensitivity of claims-identified dementia was 0.51, and specificity was 0.92. Average annual Medicare expenditures were $14,721 for a beneficiary with a clinical diagnosis of dementia, and $18,208 for a beneficiary with claim-identified dementia, suggesting an overestimation of $3,487 per person per year when Medicare claims were used to identify dementia. Total annual expenditures for all beneficiaries with claims-identified dementia were $258,707 lower than that for all those who were clinically diagnosed, suggesting an overall underestimation of total Medicare expenditures if Medicare claims were used to identify dementia. Different types of misidentification have different effects on dementia-related cost estimates. Average annual expenditures per person were highest for false positives., Conclusion: Misidentification of dementia in Medicare claims is common. Using claims to identify dementia may result in significantly biased estimates of the cost of dementia. J Am Geriatr Soc 67:269-276, 2019., (© 2018, Copyright the Author Journal compilation © 2018, The American Geriatrics Society.)

Cognitive reserve is a latent construct theorized to account for the discrepancy between observed brain deterioration and ultimate clinical outcomes. This review outlines the theoretical development of the reserve concept and presents major trends within epidemiological and neuroimaging research literatures in support of such a construct. Particular focus is placed on the implications for cognitive aging and dementia., (Copyright © 2019 Elsevier B.V. All rights reserved.)

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.

Introduction: While individuals live with dementia for many years, utilization and expenditures from disease onset through the end-of-life period have not been examined in ethnically diverse samples., Methods: We used a multiethnic, population-based, prospective study of cognitive aging (Washington Heights-Inwood Columbia Aging Project) linked to Medicare claims to examine total Medicare expenditures and health care utilization among individuals with clinically diagnosed incident dementia from disease onset to death., Results: High-intensity treatment (hospitalizations, life-sustaining procedures) was common and mean Medicare expenditures per year after diagnosis was $69,000. Non-Hispanic blacks exhibited higher spending relative to Hispanics and non-Hispanic whites 1 year after diagnosis. Non-Hispanic blacks had higher total (mean=$205,000) Medicare expenditures from diagnosis to death compared with non-Hispanic whites (mean=$118,000). Hispanics' total expenditures and utilization after diagnosis was similar to non-Hispanic whites despite living longer with dementia., Discussion: Health care spending for patients with dementia after diagnosis through the end-of-life is high and varies by ethnicity.

Background: The concept of dependence has been proposed as a unified representation of disease severity to quantify and stage disease progression in a manner more informative to patients, caregivers, and healthcare providers., Methods: This paper provides a review of the Dependence Scale (DS) as a quantitative measure of Alzheimer's disease severity, its properties as an outcome measure, a metric of disease progression, and a correlate of medical costs., Results: The literature supports the notion that the DS is related to, but distinct from, key severity measures, including cognition, function, and behavior, and captures the full spectrum of patient needs. It also presents as a useful measure for assessing disease progression., Conclusions: Results underscore the importance of the DS as a unique endpoint in Alzheimer's disease clinical trials, providing important information about the impact of therapeutic interventions. The DS also is a useful measure for economic evaluation of novel interventions aimed at delaying progression.

Objectives: To determine whether observed hearing loss (OHL) is associated with incident dementia in a multiethnic population., Design: Prospective epidemiological cohort study., Setting: Community in northern Manhattan., Participants: Participants in the Washington Heights-Inwood Columbia Aging Project, a longitudinal study on aging and dementia in an ethnically diverse community (n = 1,881)., Measurements: OHL was defined when the examiner observed it or according to self-reported hearing aid use. A consensus panel diagnosed dementia using standard research criteria. A Cox proportional hazards model was used to examine the relationship between OHL at baseline and risk of incident dementia (mean 7.3 ± 4.4 years of longitudinal followup, range 0.9-20 years)., Results: OHL was associated with 1.69 (95% confidence interval (CI) = 1.3-2.3, P < .010) times the risk of incident dementia, adjusting for demographic characteristics, cardiovascular risk factors, apolipoprotein E4 genotype, and stroke. When stratified according to race, the association between OHL and incident dementia was high in all groups but was statistically significant only in blacks (hazard ratio = 2.62, 95% CI = 1.5-4.5, P < .010)., Conclusion: OHL was associated with greater risk of incident dementia in a multiethnic cohort. More study is needed to determine whether HL contributes to dementia and whether treating HL can reduce the risk of dementia., (© 2017, Copyright the Authors Journal compilation © 2017, The American Geriatrics Society.)

Background: Few studies have examined how dementia and comorbidities may interact to affect healthcare expenditures., Objective: To examine whether effects of dementia severity on Medicare expenditures differed for individuals with different levels of comorbidities., Methods: Data are drawn from the Washington Heights-Inwood Columbia Aging Project (WHICAP). Comprehensive clinical assessments of dementia severity were systematically carried out at ∼18 month intervals. Dementia severity was measured by Clinical Dementia Rating (CDR). Comorbidities were measured by a modified Elixhauser comorbidities index. Generalized linear models examined effects of dementia severity, comorbidities, and their interactions on Medicare expenditures (1999-2010)., Results: At baseline, 1,280 subjects were dementia free (CDR = 0, 66.4%), 490 had very mild dementia (CDR = 0.5, 25.4%), 108 had mild dementia (CDR = 1, 5.6%), and 49 had moderate/severe dementia (CDR = 2/3, 2.5%). Average annual Medicare expenditures for individuals with moderate/severe dementia were more than twice as high as those who were dementia free (CDR = 0: $9,108, CDR = 0.5/1: $11,664, CDR≥2: $19,604, p < 0.01). Expenditures were approximately 10 times higher among those with≥3 comorbidities than among those with no comorbidities ($2,612 for those with no comorbidities, to $6,109 for those with 1, $10,656 for those with 2, and $30,244 for those with≥3 comorbidities, p < 0.001). Dementia severity was associated with higher expenditures, but comorbidities were the most important predictor of expenditures. We did not find strong interaction effects between number of comorbidities and dementia severity., Conclusions: Increasing dementia severity and higher comorbidities are associated with higher Medicare expenditures. Care of individuals with dementia should focus on management of comorbidities.

Objective: The association between higher education and increased mortality in Alzheimer's disease (AD) is controversial. Further it is unknown whether education predicts survival in all dementia subtypes. We assessed mortality rates and death causes of persons with dementia compared to participants without dementia., Methods: Participants derive from the Neurological Disorders in Central Spain, a prospective population- based cohort study of older adults. We compared 269 persons with dementia to 2944 participants without dementia. We carried out Cox regression models to predict the risk of mortality dependent on the educational attainment adjusting for covariates. Reasons of death were obtained from the National Population Register., Results: During a median follow-up of 5.4 years, 400 individuals died (171 with dementia, 229 without dementia). Among the participants with dementia, those with higher educational attainment had an increased risk of death than those with lower education; the adjusted hazard ratio (HRa) was 1.40 (95% confidence interval [CI], 1.01 to 1.94). When the analysis was restricted to patients with AD the HRa increased to 1.51 (95% CI = 1.01-2.24). By contrast, educational attainment was not associated with increased mortality among participants without dementia (HRa = 0.92, 95% CI = 0.71-1.20, p = 0.55), whereas education did not influence mortality in QD., Conclusion: Our findings suggest that high educational attainment is associated with increased mortality risk in people with dementia. This observation implies that neuropathology is more advanced in patients with higher education at any level of clinical severity, leading these individuals to an earlier death after diagnosis., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

This project compares three neuroimaging biomarkers to predict progression to dementia in subjects with mild cognitive impairment (MCI). Eighty-eight subjects with MCI and 40 healthy controls (HCs) were recruited. Subjects had a 3T magnetic resonance imaging (MRI) scan, and two positron emission tomography (PET) scans, one with Pittsburgh compound B ([11C]PIB) and one with fluorodeoxyglucose ([18F]FDG). MCI subjects were followed for up to 4 y and progression to dementia was assessed on an annual basis. MCI subjects had higher [11C]PIB binding potential (BPND) than HCs in multiple brain regions, and lower hippocampus volumes. [11C]PIB BPND, [18F]FDG standard uptake value ratio (SUVR), and hippocampus volume were associated with time to progression to dementia using a Cox proportional hazards model. [18F]FDG SUVR demonstrated the most statistically significant association with progression, followed by [11C]PIB BPND and then hippocampus volume. [11C]PIB BPND and [18F]FDG SUVR were independently predictive, suggesting that combining these measures is useful to increase accuracy in the prediction of progression to dementia. Hippocampus volume also had independent predictive properties to [11C]PIB BPND, but did not add predictive power when combined with the [18F]FDG SUVR data. This work suggests that PET imaging with both [11C]PIB and [18F]FDG may help to determine which MCI subjects are likely to progress to AD, possibly directing future treatment options.

Background: Few studies have examined patterns of health care utilization and costs during the period around incident dementia., Methods: Participants were drawn from the Washington Heights-Inwood Columbia Aging Project, a multiethnic, population-based, prospective study of cognitive aging of Medicare beneficiaries in a geographically defined area of northern Manhattan. Medicare utilization and expenditure were examined in individuals with clinically diagnosed dementia from 2 years before until 2 years after the initial diagnosis. A sample of non-demented individuals who were matched on socio-demographic and clinical characteristics at study enrollment was used as controls. Multivariable regression analysis estimated effects on Medicare utilization and expenditures associated with incident dementia., Results: During the 2 years before incident dementia, rates of inpatient admissions and outpatient visits were similar between dementia patients and non-demented controls, but use of home health and skilled nursing care and durable medical equipment were already higher in dementia patients. Results showed a small but significant excess increase associated with incident dementia in inpatient admissions but not in other areas of care. In the 2 years before incident dementia, total Medicare expenditures were already higher in dementia patients than in non-demented controls. But we found no excess increases in Medicare expenditures associated with incident dementia., Conclusions: Demand for medical care already is increasing and costs are higher at the time of incident dementia. There was a small but significant excess risk of inpatient admission associated with incident dementia., (Published by Oxford University Press on behalf of the Gerontological Society of America 2015.)

The trajectory, or slope, of cognitive decline may provide differentiation of older adults with and without incipient neurodegenerative disease. Cognitive aging phenotypes based on memory trajectories could be used as outcome measures for clinical trials or observational studies of risk and protective factors for dementia. This study used growth mixture modeling (GMM) to identify trajectory groups based on age- and education-corrected composite memory scores derived from immediate, delayed and recognition trials of the Selective Reminding Test. Participants included 2593 participants initially without dementia (mean age at entry = 76) in a community-based study of aging and dementia in northern Manhattan. Trajectory groups were compared on consensus diagnoses of dementia and structural MRI measures of hippocampal volume and entorhinal cortical thickness. Heterogeneity in memory trajectories allowed us to identify four groups: Stable-High (43.5 %), Stable-Low (17.1 %), Decliner (26.8 %), and Rapid Decliner (12.5 %). Decliners had more brain atrophy and higher rates of conversion to dementia. This study highlights the heterogeneity in cognitive aging and provides evidence that most elderly maintain memory function as they age. Associations with dementia and imaging measures validate subgroups of older adults identified with GMM based on their memory trajectories. Future research should use these memory trajectory phenotypes to determine whether dementia risk and protective factors differ for individuals following different memory trajectories.

Objectives: The aim of this study is to examine the relative contribution of functional impairment and cognitive deficits on risk of hospitalization and costs., Methods: A prospective cohort of Medicare beneficiaries aged 65 and older who participated in the Washington Heights-Inwood Columbia Aging Project (WHICAP) were followed approximately every 18 months for over 10 years (1805 never diagnosed with dementia during study period, 221 diagnosed with dementia at enrollment). Hospitalization and Medicare expenditures data (1999-2010) were obtained from Medicare claims. Multivariate analyses were conducted to examine (1) risk of all-cause hospitalizations, (2) hospitalizations from ambulatory care sensitive (ACSs) conditions, (3) hospital length of stay (LOS), and (4) Medicare expenditures. Propensity score matching methods were used to reduce observed differences between demented and non-demented groups at study enrollment. Analyses took into account repeated observations within each individual., Results: Compared to propensity-matched individuals without dementia, individuals with dementia had significantly higher risk for all-cause hospitalization, longer LOS, and higher Medicare expenditures. Functional and cognitive deficits were significantly associated with higher risks for hospitalizations, hospital LOS, and Medicare expenditures. Functional and cognitive deficits were associated with higher risks of for some ACS but not all admissions., Conclusions: These results allow us to differentiate the impact of functional and cognitive deficits on hospitalizations. To develop strategies to reduce hospitalizations and expenditures, better understanding of which types of hospitalizations and which disease characteristics impact these outcomes will be critical., (Copyright © 2014 John Wiley & Sons, Ltd.)

Objective: To examine the effects of caregiver and patient characteristics on caregivers' medical care use and cost., Methods: One hundred forty-seven caregiver/patient dyads were followed annually for 6 years in three academic Alzheimer's disease centers in the United States. Logistic, negative binomial, and generalized linear mixed models were used to examine overall effects of caregiver/patient characteristics on caregivers' hospitalizations, doctor visits, outpatient tests and procedures, and prescription and over-the-counter medications., Results: Patients' comorbid conditions and dependence were associated with increased health-care use and costs of caregivers. Increases in caregiver depressive symptoms are associated with increases in multiple domains of caregivers' health-care use and costs., Discussion: Findings suggest expanding our focus on dementia patients to include family caregivers to obtain a fuller picture of effects of caregiving. Primary care providers should integrate caregivers' needs in health-care planning and delivery. Clinical interventions that treat patients and caregivers as a whole will likely achieve the greatest beneficial effects., (Copyright © 2015 The Alzheimer's Association. All rights reserved.)

Background: A large proportion of dementia cases are still undiagnosed. Although early dementia care has been hypothesized to benefit both patients and families, evidence-based benefits are lacking. Thus, investigating the benefits for newly demented persons according to their recourse to care in the "real life" appears critical., Methods: We examined the relation between initial care recourse care and demented individuals' survival in a large cohort of incident dementia cases screened in a prospective population-based cohort, the Three-City Study. We assessed recourse to care for cognitive complaint at the early beginning of dementia when incident cases were screened. We classified patients in three categories: no care recourse, general practitioner consultation or specialist consultation. We used proportional hazard regression models to test the association between recourse to care and mortality, adjusting on socio-demographical and clinical characteristics., Results: Two hundred and fifty-three incident dementia participants were screened at the 2 year or 4 year follow-up. One third of the incident demented individuals had not consulted a physician for cognitive problems. Eighty-six (34.0%) individuals had reported a cognitive problem only to their general practitioner (GP) and 80 (31.6%) had consulted a specialist. Mean duration of follow-up after incident dementia was 5.1 years, during which 146 participants died. After adjustment on potential confounders, participants who had consulted a specialist early in the disease course presented a poorer survival than those who did not consult any physician (hazard ratio = 1.64, 95% confidence interval 1.03-2.62). There was a trend but no significant differential survival profile between participants who complained to their GP and those without any care recourse., Conclusion: Neither recourse to a specialist nor recourse to GP improve survival of new dementia cases. Those who had consulted a specialist early in the disease course even reported a worse life expectancy than those who did not., (Copyright © 2015 The Alzheimer's Association. Published by Elsevier Inc. All rights reserved.)

Objective: Clinic-based studies suggest that dementia is diagnosed at older ages in bilinguals compared with monolinguals. The current study sought to test this hypothesis in a large, prospective, community-based study of initially nondemented Hispanic immigrants living in a Spanish-speaking enclave of northern Manhattan., Method: Participants included 1,067 participants in the Washington/Hamilton Heights Inwood Columbia Aging Project (WHICAP) who were tested in Spanish and followed at 18-24 month intervals for up to 23 years. Spanish-English bilingualism was estimated via both self-report and an objective measure of English reading level. Multilevel models for change estimated the independent effects of bilingualism on cognitive decline in 4 domains: episodic memory, language, executive function, and speed. Over the course of the study, 282 participants developed dementia. Cox regression was used to estimate the independent effect of bilingualism on dementia conversion. Covariates included country of origin, gender, education, time spent in the United States, recruitment cohort, and age at enrollment., Results: Independent of the covariates, bilingualism was associated with better memory and executive function at baseline. However, bilingualism was not independently associated with rates of cognitive decline or dementia conversion. Results were similar whether bilingualism was measured via self-report or an objective test of reading level., Conclusions: This study does not support a protective effect of bilingualism on age-related cognitive decline or the development of dementia. In this sample of Hispanic immigrants, bilingualism is related to higher initial scores on cognitive tests and higher educational attainment and may not represent a unique source of cognitive reserve., (PsycINFO Database Record (c) 2014 APA, all rights reserved.)

Caregiving may be burdensome to caregivers, negatively affecting health and impacting decisions to institutionalize patients. It is unclear how caregiver depression changes over longer periods or whether heterogeneous trajectories for caregivers are apparent. The goals of this article are to characterize the course of depressive symptoms among caregivers over time and to examine the impact of baseline patient and caregiver characteristics on these trajectories. Patients with dementia and their caregivers were followed every 6 months for up to 6 years or until death (n = 133). Growth mixture modeling identified trajectories of caregiver depression over time. Most caregivers had stable trajectories of symptoms, with a smaller subset showing evidence of wear-and-tear. Patient clinical characteristics had no impact on symptom course for caregivers. Future work should utilize a longitudinal perspective and consider that there may be heterogeneous trajectories for caregivers. Those caregivers who follow a wear-and-tear trajectory may require targeted interventions to improve outcomes.

Background: A large number of longitudinal studies of population-based ageing cohorts are in progress internationally, but the insights from these studies into the risk and protective factors for cognitive ageing and conditions like mild cognitive impairment and dementia have been inconsistent. Some of the problems confounding this research can be reduced by harmonising and pooling data across studies. COSMIC (Cohort Studies of Memory in an International Consortium) aims to harmonise data from international cohort studies of cognitive ageing, in order to better understand the determinants of cognitive ageing and neurocognitive disorders., Methods/design: Longitudinal studies of cognitive ageing and dementia with at least 500 individuals aged 60 years or over are eligible and invited to be members of COSMIC. There are currently 17 member studies, from regions that include Asia, Australia, Europe, and North America. A Research Steering Committee has been established, two meetings of study leaders held, and a website developed. The initial attempts at harmonising key variables like neuropsychological test scores are in progress., Discussion: The challenges of international consortia like COSMIC include efficient communication among members, extended use of resources, and data harmonisation. Successful harmonisation will facilitate projects investigating rates of cognitive decline, risk and protective factors for mild cognitive impairment, and biomarkers of mild cognitive impairment and dementia. Extended implications of COSMIC could include standardised ways of collecting and reporting data, and a rich cognitive ageing database being made available to other researchers. COSMIC could potentially transform our understanding of the epidemiology of cognitive ageing, and have a world-wide impact on promoting successful ageing.

The theory of cognitive reserve attempts to explain why some individuals are more resilient to age-related brain pathology. Efforts to explore reserve have been hindered by measurement difficulties. Reed et al. (2010) proposed quantifying reserve as residual variance in episodic memory performance that remains after accounting for demographic factors and brain pathology (whole brain, hippocampal, and white matter hyperintensity volumes). This residual variance represents the discrepancy between an individual’s predicted and actual memory performance. The goals of the present study were to extend these methods to a larger, community-based sample and to investigate whether the residual reserve variable is explained by age, predicts longitudinal changes in language, and predicts dementia conversion independent of age. Results support this operational measure of reserve. The residual reserve variable was associated with higher reading ability, lower likelihood of meeting criteria for mild cognitive impairment, lower odds of dementia conversion in dependent of age, and less decline in language abilities over 3 years. Finally, the residual reserve variable moderated the negative impact of memory variance explained by brain pathology on language decline. This method has the potential to facilitate research on the mechanisms of cognitive reserve and the efficacy of interventions designed to impart reserve.

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.

We compared the clinical and neuropsychological pattern of dementia with Lewy bodies (DLB) to Alzheimer's disease (AD) and Parkinson's disease with dementia (PD-d). Sixteen patients clinically diagnosed with DLB were compared with two groups of patients with PD-d (n = 15) and AD (n = 16) matched for level of dementia. Isolated cognitive impairment was the most common form of presentation in AD (93.8%) and DLB (31.3%) groups, while parkinsonism was in 100% of PD-d subjects. Psychoses associated with cognitive impairment at the beginning of the disease were more frequent in DLB patients (31.3%) than in AD (6.3%) and PD-d (0%) groups. There were no significant differences in Unified Parkinson Disease Rating Scale motor-subscale scores between DLB and PD-d patients. DLB and PD-d patients performed significantly worse on attentional functions and better on memory tests than AD. DLB patients also showed lower scores than AD subjects on visual memory, visuoperceptive, and visuoconstructive tests. No significant differences were found between PD-d group and DLB subjects on any neuropsychological test. We were unable to find any differences in cognitive tasks between PD-d and DLB subjects. Clinical features and neuropsychological deficiencies of DLB (attentional, visuoperceptive, and visuoconstructive deficits) and PD (attentional deficits) compared to AD (amnesic syndrome) can contribute to accurate identification of these entities and to the understanding of the neuropathological and neurochemical substrate underlying these diseases., (Copyright 2003 Movement Disorder Society)

Women with Down's syndrome experience early onset of both menopause and Alzheimer's disease. This timing provides an opportunity to examine the influence of endogenous estrogen deficiency, indicated by age at menopause, on risk of Alzheimer's disease. A community-based sample of 163 postmenopausal women with Down's syndrome, 40 to 60 years of age, was ascertained through the New York State Developmental Disability service system. Information from cognitive assessments, medical record review, neurological evaluation, and caregiver interviews was used to establish ages for onset of menopause and dementia. We used survival and multivariate regression analyses to determine the relation of age at menopause to age at onset of Alzheimer's disease, adjusting for age, level of mental retardation, body mass index, and history of hypothyroidism or depression. Women with early onset of menopause (46 years or younger) had earlier onset and increased risk of Alzheimer's disease (AD) compared with women with onset of menopause after 46 years (rate ratio, 2.7; 95% confidence interval [CI], 1.2-5.9). Demented women had higher mean serum sex hormone binding globulin levels than nondemented women (86.4 vs 56.6 nmol/L, p = 0.02), but similar levels of total estradiol, suggesting that bioavailable estradiol, rather than total estradiol, is associated with dementia. Our findings support the hypothesis that reductions in estrogens after menopause contribute to the cascade of pathological processes leading to AD.

Background and Objective: Population-based estimates of dementia can vary widely depending on the data source and methodology used to assess cognitive impairment. The aim of this study was to assess individual and composite measures of dementia constructed using survey and administratively collected medical data for the purpose of improving insight into inherent and avoidable biases and the interpretation of these measures., Methods: A national survey of 5089 community-dwelling elderly persons was linked to 5 years of Medicare claims. Kappa coefficients were used to assess dementia agreement between survey, cognitive screen, and claims. Odds ratios (ORs), adjusted for age, gender, and education, were computed to assess the relation of single- and multi-source dementia variables to cognitive symptoms and activity limitations., Results: Dementia prevalence among persons aged 65 and over ranged from 4.5% to 16.8% across sources. Agreement in case identification between data sources was low, ranging from 0.15 to 0.41. Despite low agreement, ORs were consistently increased for limitations in cognitively related activities/symptoms and non-overlapping dementia sources., Conclusion: The finding that non-overlapping dementia data sources are associated with significantly increased limitations in cognitive activities suggests that forecasts of national dementia-related resource use based on single-source data could produce serious underestimates of future need.

Test scores from a comprehensive neuropsychological battery administered to 1602 subjects consisting of 1347 subjects with probable Alzheimer's disease (AD), 100 subjects with questionable dementia (QD) and 155 non-demented elderly control subjects were cross-sectionally analyzed. Subjects with probable AD were categorized as mild (n = 244), moderate (n = 480), severe (n = 376), and very severe (n = 247) according to modified mini mental status exam (mMMSE) scores. Mean scores on individual neuropsychological tests are provided for each group of subjects. Stratified random sampling was performed to select a sample of mild AD subjects who were matched in age and education to non-demented elderly controls, and analyses focused on the performance of QD subjects and mild AD subjects, whose scores were compared to those of the elderly control subjects. Selected scores were organized by cognitive domain and logistic regressions were used to determine the domains and individual tests within each that were most predictive of group status. Results suggested a profile of scores associated with QD and mild AD including impaired recall of verbal information for both groups. Areas of lower functioning in QD subjects as compared to elderly controls included category fluency and visuospatial ability.

Previous studies of depression after stroke have reported widely variable findings, possibly due to differences between studies in patient characteristics and methods for the assessment of depression, small sample sizes, and the failure to examine stroke-free reference groups to determine the base rate of depression in the general population. In an effort to address certain of those methodologic issues and further investigate the frequency and clinical determinants of depression after stroke, we administered the Structured Interview Guide for the Hamilton Depression Rating Scale (SIGH-D) and neurological, neuropsychological, and functional assessments to 421 patients (age = 71.5 +/- 8.0 years) 3 months after ischemic stroke and 249 stroke-free control subjects (age = 70.8 +/- 6.7 years). We required a SIGH-D total score > 11 for the identification of depression. We found that depression was less frequent (47/421 patients, or 11.2%, and 13/249 control subjects, or 5.2%), less severe, and less persistent in our stroke cohort than previously reported, possibly due to the underrepresentation of patients with a premorbid history of affective illness. Depression was associated with more severe stroke, particularly in vascular territories that supply limbic structures; dementia; and female sex. SIGH-D item analyses suggested that a reliance on nonsomatic rather than somatic symptoms would result in the most accurate diagnoses of depression after ischemic stroke.

We analyzed the association of neuropsychological test impairment at baseline with the development of dementia in idiopathic Parkinson's disease (PD) patients. A cohort of nondemented PD patients from northern Manhattan, NY was followed annually with neurological and neuropsychological evaluations. The neuropsychological battery included tests of verbal and nonverbal memory, orientation, visuospatial ability, language, and abstract reasoning. The association of baseline neuropsychological tests scores with incident dementia was analyzed using Cox proportional hazards models. The analysis controlled for age, gender, education, duration of PD, and the total Unified Parkinson's Disease Rating Scale motor score at baseline. Forty-five out of 164 patients (27%) became demented during a mean follow-up of 3.7 +/- 2.3 years. Four neuropsychological test scores were significantly associated with incident dementia in the Cox model: total immediate recall (RR: 0.92, 95% CI: 0.87-0.97, P = 0.001) and delayed recall (RR: 0.73, 95% CI: 0.59-0.91, P = 0.005) of the Selective Reminding Test (SRT), letter fluency (RR: 0.87, 95% CI: 0.77-0.99, P = 0.03), and Identities and Oddities of the Mattis Dementia Rating Scale (RR: 0.85, 95% CI: 0.73-0.98, P = 0.03). When the analysis was performed excluding patients with a clinical dementia rating of 0.5 (questionable dementia) at baseline evaluation, total immediate recall and delayed recall were still predictive of dementia in PD. Our results indicate that impairment in verbal memory and executive function are associated with the development of dementia in patients with PD., (Copyright 2002 Movement Disorder Society)

Background and Purpose: A number of cross-sectional epidemiological studies have reported that one fourth of elderly patients meet criteria for dementia 3 months after ischemic stroke, but few longitudinal studies of the incidence of dementia after stroke have been performed. We conducted the present study to investigate the incidence and clinical predictors of dementia after ischemic stroke., Methods: We administered neurological, neuropsychological, and functional assessments annually to 334 ischemic stroke patients (age, 70.4+/-7.5 years) and 241 stroke-free control subjects (age, 70.6+/-6.5 years), all of whom were nondemented in baseline examinations. We diagnosed incident dementia using modified Diagnostic and Statistical Manual of Mental Disorders, Revised Third Edition criteria requiring deficits in memory and > or =2 additional cognitive domains, as well as functional impairment., Results: The crude incidence rate of dementia was 8.49 cases per 100 person-years in the stroke cohort and 1.37 cases per 100 person-years in the control cohort. A Cox proportional-hazards analysis found that the relative risk (RR) of incident dementia associated with stroke was 3.83 (95% CI, 2.14 to 6.84), adjusting for demographic variables and baseline Mini-Mental State Examination score. Within the stroke cohort, intercurrent medical illnesses associated with cerebral hypoxia or ischemia were independently related to incident dementia (RR, 4.40; 95% CI, 2.20 to 8.85), adjusting for recurrent stroke, demographic variables, and baseline Mini-Mental State Examination score., Conclusions: The risk of incident dementia is high among patients with ischemic stroke, particularly in association with intercurrent medical illnesses that might cause cerebral hypoxia or ischemia, suggesting that cerebral hypoperfusion may serve as a basis for some cases of dementia after stroke.

Objective: Although dementia is typically considered to be a consequence of a variety of neurologic diseases, it can also serve as a risk factor for other adverse outcomes. The authors investigated dementia as a predictor of long-term survival among patients with ischemic stroke., Methods: Neurologic, neuropsychological, and functional assessments were administered to 453 patients (mean age +/- SD, 72.0 +/- 8.3 years) 3 months after ischemic stroke. The authors diagnosed dementia in 119 (26.3%) of the patients using modified Diagnostic and Statistical Manual of Mental Disorders, Revised 3rd Edition, criteria requiring deficits in memory and two or more additional cognitive domains as well as functional impairment. Dementia as a predictor of long-term survival during up to 10 years of follow-up was then investigated., Results: The mortality rate was 15.90 deaths per 100 person-years among patients with dementia and 5.37 deaths per 100 person-years among nondemented patients. A Cox proportional hazards analysis found that the relative risk (RR) of death was increased in association with dementia (RR = 2.4; 95% CI = 1.6 to 3.4), adjusting for the following: a major hemispheral stroke syndrome (RR = 1.4); a middle cerebral artery territory index stroke (RR = 1.7); a Stroke Severity Scale score of > or = 4, representing more severe stroke (RR = 1.8); atrial fibrillation (RR = 1.8); congestive heart failure (RR = 2.2); recurrent stroke occurring during follow-up (RR = 3.9); and demographic variables. The risk of death increased in association with the severity of dementia, but it did not differ by dementia subtype., Conclusions: Dementia is a significant independent risk factor for reduced survival after ischemic stroke, adjusting for other recognized predictors of mortality. The authors hypothesize that patients with dementia are at an elevated risk of mortality because of their increased burden of cerebrovascular disease, a tendency toward undertreatment for stroke prophylaxis among clinicians, or patient noncompliance with treatment regimens.

Age and severity of extrapyramidal signs have been consistently associated with incident dementia in Parkinson's disease. We evaluated the separate and combined effects of age and severity of extrapyramidal signs on the risk of incident dementia in Parkinson's disease in the setting of a population-based prospective cohort study. Age and the total Unified Parkinson's Disease Rating Scale motor score at baseline evaluation were dichotomized at the median. Four groups of Parkinson's disease patients were defined: younger age/low severity (reference), younger age/high severity, older age/low severity, and older age/high severity. Risk ratios for incident dementia were calculated with Cox proportional hazards models controlling for gender, education, ethnicity, and duration of Parkinson's disease. Of 180 patients, 52 (28.9%) became demented during a mean follow-up period of 3.6 +/- 2.2 years. The median age at baseline of the Parkinson's disease patients was 71.8 years (range, 38.5-95.9 years), and the median total Unified Parkinson's Disease Rating Scale motor score was 24 (range, 2-65). The group with older age/high severity had a significantly increased risk of incident dementia (relative risk, 9.7; 95% confidence interval, 3.9-24.4) compared with the group with younger age/low severity (reference), whereas the groups with older age/low severity (relative risk, 1.6; 95% confidence interval, 0.5-4.8) and younger age/high severity (relative risk, 1.2; 95% confidence interval, 0.5-3.2) did not. These findings suggest that the increased risk of incident dementia in Parkinson's disease associated with age and severity of extrapyramidal signs is related primarily to their combined effect rather than separate effects.

The extent to which concomitant Alzheimer's disease (AD) is etiologically related to the development of dementia in Parkinson's disease (PD) remains controversial. We explored the association of four risk factors associated with AD, including head injury, smoking, hypertension, and diabetes mellitus, with incident dementia in PD. A cohort of 180 nondemented PD patients from the Washington Heights community in northern Manhattan, New York, completed a risk factor questionnaire at baseline and was followed annually with neurological and neuropsychological evaluations. The association of baseline variables with incident dementia was analyzed by using Cox proportional hazards models. All analyses controlled for age at baseline, gender, years of education, duration of PD, and total Unified Parkinson's Disease Rating Scale (UPDRS) motor score at baseline. Of 180 patients (mean age, 71.0 +/- 10.3 years), 52 (29%) became demented during a mean follow-up period of 3.6 +/- 2.2 years. Head injury risk ratio ([RR] 0.9; 95% confidence interval [CI], 0.4-2.2; P = 0.9), hypertension (RR, 0.7; 95% CI, 0.4-1.4, P = 0.3), and diabetes mellitus (RR, 0.8; 95% CI, 0.3-2.3; P = 0.7) were not significantly associated with incident dementia in the Cox models. Patients who reported having ever smoked were at increased risk for the development of dementia compared with nonsmokers (RR, 2.0; 95% CI, 1.0-3.9; P = 0.05). Current smoking was significantly associated with incident dementia (RR, 4.5; 95% CI, 1.2-16.4; P = 0.02), whereas past smoking approached significance (RR, 1.9; 95% CI, 0.9-3.7; P = 0.07). Although an inverse association between smoking and PD has been reported in several studies, our study showed a positive association between smoking and dementia in the setting of PD. The association of smoking with incident dementia in PD deserves further study., (Copyright 2002 Movement Disorder Society.)

INTRODUCTION: The Brazilian population in the United States (U.S.), a Latinx subgroup, is rapidly growing and aging but remains underrepresented in U.S. health research. In addition to group-specific genetic and environmental risks, Brazilian immigrants and their offspring in the U.S. likely have cumulative risks for health inequities.It is estimated that 71% of Brazilian immigrants in the U.S. are undocumented, which may limit healthcare access/utilization. Furthermore, mental health is reported as a health priority by Brazilian immigrants in the U.S., and there is a lack of research on Alzheimers disease and related dementia (AD/ADRD) in this population. METHODS: We reviewed the scientific literature using traditional (e.g., PubMed) sources and databases generated by U.S. and Brazilian governments, as well as international organizations, and press articles. RESULTS: This perspective review lists recommendations for researchers, health providers, and policymakers to promote greater inclusion of U.S. Brazilian populations in health research and care. The review identifies research areas in need of attention to address health inequities and promote mental/brain health in Brazilian immigrants and their offspring living in the U.S. These research areas are: 1) epidemiological studies to map the prevalence and incidence of mental/brain health conditions; 2) research on aging and AD/ADRD risk factors among Brazilian populations in the U.S.; and 3) the need for greater representation of U.S-residing Brazilian population in other relevant research areas involving genetics, neuropathology, and clinical trials. CONCLUSIONS: The recommendation and research efforts proposed should help to pave the way for the development of community-engagement research and to promote mental/brain health education, improvement of mental/brain health and AD/ADRD services, and the development of culturally-informed intervention to the U.S.-residing Brazilian communities. HIGHLIGHTS: The Brazilian population in the United States is growing but is underrepresented in U.S. health research.Approximately 71% of Brazilian immigrants in the United States are undocumented, with an increased risk for health inequities.Mental health is reported as a central health priority by Brazilian immigrants in the United States.There is a lack of research on Alzheimers disease and other dementias (ADRD) in Brazilian immigrants in the United States.Epidemiological research is needed to map the prevalence/incidence of mental health conditions and ADRD risk factors among Brazilian immigrants in the United States.

Apathy is one of the most common neuropsychiatric symptoms (NPS) and is associated with poor clinical outcomes. Research that helps define the apathy phenotype is urgently needed, particularly for clinical and biomarker studies. We used latent class analysis (LCA) with two independent cohorts to understand how apathy and depression symptoms co-occur statistically. We further explored the relationship between latent class membership, demographics, and the presence of other NPS. The LCA identified a four-class solution (no symptoms, apathy, depression, and combined apathy/depression), reproducible over both cohorts, providing robust support for an apathy syndrome distinct from depression and confirming that an apathy/depression syndrome exists, supported by the model fit test with the four-class solution scores evidencing better fitting (Bayesian information criterion adjusted and entropy R 2). Using a data-driven method, we show distinct and statistically meaningful co-occurrence of apathy and depressive symptoms. There was evidence that these classes have different clinical associations, which may help inform diagnostic categories for research studies and clinical practice.HighlightsWe found four classes: no symptoms, apathy, depression and apathy/depression.Apathy conferred a higher probability for agitation.Apathy diagnostic criteria should include accompanying neuropsychiatric symptoms.

In 2018, the US National Institute on Aging and the Alzheimer's Association proposed a purely biological definition of Alzheimer's disease that relies on biomarkers. Although the intended use of this framework was for research purposes, it has engendered debate and challenges regarding its use in everyday clinical practice. For instance, cognitively unimpaired individuals can have biomarker evidence of both amyloid β and tau pathology but will often not develop clinical manifestations in their lifetime. Furthermore, a positive Alzheimer's disease pattern of biomarkers can be observed in other brain diseases in which Alzheimer's disease pathology is present as a comorbidity. In this Personal View, the International Working Group presents what we consider to be the current limitations of biomarkers in the diagnosis of Alzheimer's disease and, on the basis of this evidence, we propose recommendations for how biomarkers should and should not be used for diagnosing Alzheimer's disease in a clinical setting. We recommend that Alzheimer's disease diagnosis be restricted to people who have positive biomarkers together with specific Alzheimer's disease phenotypes, whereas biomarker-positive cognitively unimpaired individuals should be considered only at-risk for progression to Alzheimer's disease.

In this study, we aimed to assess whether women are able to withstand more tau before exhibiting verbal memory impairment. Using data from 121 amyloid-β-positive Alzheimer's Disease Neuroimaging Initiative participants, we fit a linear model with Rey Auditory Verbal Learning Test score as the response variable and tau-PET standard uptake value ratio as the predictor and took the residuals as an estimate of verbal memory reserve for each subject. Women demonstrated higher reserve (i.e. residuals), whether the Learning (t = 2.78, P = 0.006) or Delay (t = 2.14, P = 0.03) score from the Rey Auditory Verbal Learning Test was used as a measure of verbal memory ability. To validate these findings, we examined 662 National Alzheimer's Coordinating Center participants with a C2/C3 score (Consortium to Establish a Registry for Alzheimer's Disease) at autopsy. We stratified our National Alzheimer's Coordinating Center sample into Braak 1/2, Braak 3/4 and Braak 5/6 subgroups. Within each subgroup, we compared Logical Memory scores between men and women. Men had worse verbal memory scores within the Braak 1/2 (Logical Memory Immediate: β = -5.960 ± 1.517, P

Alzheimer's disease and related dementias (ADRDs) are a global crisis facing the aging population and society as a whole. With the numbers of people with ADRDs predicted to rise dramatically across the world, the scientific community can no longer neglect the need for research focusing on ADRDs among underrepresented ethnoracial diverse groups. The Alzheimer's Association International Society to Advance Alzheimer's Research and Treatment (ISTAART; alz.org/ISTAART) comprises a number of professional interest areas (PIAs), each focusing on a major scientific area associated with ADRDs. We leverage the expertise of the existing international cadre of ISTAART scientists and experts to synthesize a cross-PIA white paper that provides both a concise "state-of-the-science" report of ethnoracial factors across PIA foci and updated recommendations to address immediate needs to advance ADRD science across ethnoracial populations.

Cerebral small-vessel damage manifests as white matter hyperintensities and cerebral atrophy on brain MRI and is associated with aging, cognitive decline and dementia. We sought to examine the interrelationship of these imaging biomarkers and the influence of hypertension in older individuals. We used a multivariate spatial covariance neuroimaging technique to localize the effects of white matter lesion load on regional gray matter volume and assessed the role of blood pressure control, age and education on this relationship. Using a case-control design matching for age, gender, and educational attainment we selected 64 participants with normal blood pressure, controlled hypertension or uncontrolled hypertension from the Northern Manhattan Study cohort. We applied gray matter voxel-based morphometry with the scaled subprofile model to (1) identify regional covariance patterns of gray matter volume differences associated with white matter lesion load, (2) compare this relationship across blood pressure groups, and (3) relate it to cognitive performance. In this group of participants aged 60-86 years, we identified a pattern of reduced gray matter volume associated with white matter lesion load in bilateral temporal-parietal regions with relative preservation of volume in the basal forebrain, thalami and cingulate cortex. This pattern was expressed most in the uncontrolled hypertension group and least in the normotensives, but was also more evident in older and more educated individuals. Expression of this pattern was associated with worse performance in executive function and memory. In summary, white matter lesions from small-vessel disease are associated with a regional pattern of gray matter atrophy that is mitigated by blood pressure control, exacerbated by aging, and associated with cognitive performance.

ObjectiveTo estimate points along the spectrum of β-amyloid pathology at which rates of change of several measures of neuronal injury and cognitive decline begin to accelerate.MethodsIn 460 patients with mild cognitive impairment (MCI), we estimated the points at which rates of florbetapir PET, fluorodeoxyglucose (FDG) PET, MRI, and cognitive and functional decline begin to accelerate with respect to baseline CSF Aβ42. Points of initial acceleration in rates of decline were estimated using mixed-effects regression.ResultsRates of neuronal injury and cognitive and even functional decline accelerate substantially before the conventional threshold for amyloid positivity, with rates of florbetapir PET and FDG PET accelerating early. Temporal lobe atrophy rates also accelerate prior to the threshold, but not before the acceleration of cognitive and functional decline.ConclusionsA considerable proportion of patients with MCI would not meet inclusion criteria for a trial using the current threshold for amyloid positivity, even though on average, they are experiencing cognitive/functional decline associated with prethreshold levels of CSF Aβ42. Future trials in early Alzheimer disease might consider revising the criteria regarding β-amyloid thresholds to include the range of amyloid associated with the first signs of accelerating rates of decline.

ObjectiveTo examine sex differences in the relationship between clinical symptoms related to Alzheimer disease (AD) (verbal memory deficits) and neurodegeneration (hippocampal volume/intracranial volume ratio [HpVR]) across AD stages.MethodsThe sample included 379 healthy participants, 694 participants with amnestic mild cognitive impairment (aMCI), and 235 participants with AD and dementia from the Alzheimer's Disease Neuroimaging Initiative who completed the Rey Auditory Verbal Learning Test (RAVLT). Cross-sectional analyses were conducted using linear regression to examine the interaction between sex and HpVR on RAVLT across and within diagnostic groups adjusting for age, education, and APOE ε4 status.ResultsAcross groups, there were significant sex × HpVR interactions for immediate and delayed recall (p < 0.01). Women outperformed men among individuals with moderate to larger HpVR, but not among individuals with smaller HpVR. In diagnosis-stratified analyses, the HpVR × sex interaction was significant in the aMCI group, but not in the control or AD dementia groups, for immediate and delayed recall (p < 0.01). Among controls, women outperformed men on both outcomes irrespective of HpVR (p < 0.001). In AD dementia, better RAVLT performance was independently associated with female sex (immediate, p = 0.04) and larger HpVR (delayed, p = 0.001).ConclusionWomen showed an advantage in verbal memory despite evidence of moderate hippocampal atrophy. This advantage may represent a sex-specific form of cognitive reserve delaying verbal memory decline until more advanced disease stages.

ObjectiveTo investigate the association between periventricular white mater hyperintensities (PVWMH) and biomarkers of elevated cerebral β-amyloid (Aβ) in the Alzheimer's Disease Neuroimaging Initiative, a large prospective multicenter observational study.MethodsThe burden of frontal, parietal, and occipital PVWMH on 3T fluid-attenuated inversion recovery MRI was evaluated in 698 cognitively normal participants and participants with mild cognitive impairment (MCI) using a novel semiquantitative visual rating scale. Results were correlated with CSF-Aβ, florbetapir-PET, and fluorodeoxyglucose (FDG)-PET.ResultsIncreased burden of parietal, occipital, and frontal PVWMH was associated with elevated cerebral amyloid evidenced by high florbetapir-PET signal (p < 0.01) and low CSF-Aβ (p < 0.01). In logistic regression models, including PVWMH, age, sex, APOE status, vascular risk factors, pulse pressure, vascular secondary prevention medications, education, ethnicity, and race, parietal, occipital, and frontal PVWMH burden was independently associated with high florbetapir-PET uptake (p < 0.05). In a similar logistic regression model, parietal and occipital (p < 0.05) but not frontal (p = 0.05) PVWMH were independently associated with CSF-Aβ. Weaker associations were found between parieto-occipital PVWMH and elevated CSF-tau (p < 0.05) and occipital PVWMH and elevated CSF-phospho-tau (p < 0.05). PVWMH were associated with cerebral hypometabolism on FDG-PET independent of CSF-Aβ levels (p < 0.05). Absolute and consistency of agreement intraclass correlation coefficients were, respectively, 0.83 and 0.83 for frontal, 0.78 and 0.8 for parietal, and 0.45 and 0.75 for occipital PVWMH measurements.ConclusionsIncreased PVWMH were associated with elevated cerebral amyloid independent of potential confounders such as age, APOE genotype, and vascular risk factors. The mechanisms underlying the association between PVWMH and cerebral amyloid remain to be clarified.

ObjectiveWe investigated white matter lesion load and global and regional brain volumes in relation to domain-specific cognitive performance in the stroke-free Northern Manhattan Study (NOMAS) population.MethodsWe quantified white matter hyperintensity volume (WMHV), total cerebral volume (TCV), and total lateral ventricular (TLV) volume, as well as hippocampal and cortical gray matter (GM) lobar volumes in a subgroup. We used general linear models to examine MRI markers in relation to domain-specific cognitive performance, adjusting for key covariates.ResultsMRI and cognitive data were available for 1,163 participants (mean age 70 ± 9 years; 60% women; 66% Hispanic, 17% black, 15% white). Across the entire sample, those with greater WMHV had worse processing speed. Those with larger TLV volume did worse on episodic memory, processing speed, and semantic memory tasks, and TCV did not explain domain-specific variability in cognitive performance independent of other measures. Age was an effect modifier, and stratified analysis showed that TCV and WMHV explained variability in some domains above age 70. Smaller hippocampal volume was associated with worse performance across domains, even after adjusting for APOE ε4 and vascular risk factors, whereas smaller frontal lobe volumes were only associated with worse executive function.ConclusionsIn this racially/ethnically diverse, community-based sample, white matter lesion load was inversely associated with cognitive performance, independent of brain atrophy. Lateral ventricular, hippocampal, and lobar GM volumes explained domain-specific variability in cognitive performance.

ObjectiveWe studied the biomarker signatures and prognoses of 3 different subtle cognitive impairment (SCI) groups (executive, memory, and multidomain) as well as the subjective memory complaints (SMC) group.MethodsWe studied 522 healthy controls in the Alzheimer's Disease Neuroimaging Initiative (ADNI). Cutoffs for executive, memory, and multidomain SCI were defined using participants who remained cognitively normal (CN) for 7 years. CSF Alzheimer disease (AD) biomarkers, composite and region-of-interest (ROI) MRI, and fluorodeoxyglucose-PET measures were compared in these participants.ResultsUsing a stringent cutoff (fifth percentile), 27.6% of the ADNI participants were classified as SCI. Most single ROI or global-based measures were not sensitive to detect differences between groups. Only MRI-SPARE-AD (Spatial Pattern of Abnormalities for Recognition of Early AD), a quantitative MRI pattern-based global index, showed differences between all groups, excluding the executive SCI group. Atrophy patterns differed in memory SCI and SMC. The CN and the SMC groups presented a similar distribution of preclinical dementia stages. Fifty percent of the participants with executive, memory, and multidomain SCI progressed to mild cognitive impairment or dementia at 7, 5, and 2 years, respectively.ConclusionsOur results indicate that (1) the different SCI categories have different clinical prognoses and biomarker signatures, (2) longitudinally followed CN subjects are needed to establish clinical cutoffs, (3) subjects with SMC show a frontal pattern of brain atrophy, and (4) pattern-based analyses outperform commonly used single ROI-based neuroimaging biomarkers and are needed to detect initial stages of cognitive impairment.