Publications by authors named "Deborah Blacker"

148 Publications

Longitudinal Differences in Everyday Preferences: Comparisons Between People with Cognitive Impairment and their Care Partners.

Int J Geriatr Psychiatry 2021 Sep 8. Epub 2021 Sep 8.

Massachusetts Alzheimer's Disease Research Center, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, Boston, MA.

Objectives: Persons with progressive cognitive impairment (CI) increasingly rely on surrogate decision-makers for everyday activities. Yet, little is known about changes in everyday preferences over time or about concordance between persons with CI and their care partners regarding longitudinal changes.

Methods: The sample included 48 dyads of persons with CI (Clinical Dementia Rating Scale score ≥ 0.5) and their care partners. The Preferences for Everyday Living Inventory was used to assess importance of preferences among persons with CI at baseline and follow-up (mean 486 days). Care partners separately completed concurrent proxy assessments. Mixed random and fixed effects longitudinal models were used to evaluate changes in ratings and concordance levels between persons with CI and care partners.

Results: There were significant gender differences regarding importance ratings of "autonomous choice" and "social engagement" preferences over time: women with CI rated these preferences as more important across time as a whole. Higher levels of neuropsychiatric symptoms were associated with less importance of "social engagement" preferences across time as a whole for persons with CI and a more negative discrepancy between persons with CI and care partner proxy assessments as time went on.

Conclusion: This study yields new insights into predictors of longitudinal change in everyday preferences among persons with CI and their care partners. Although preferences were largely stable over time, there is increasing support for the relationship between differences in "social engagement" preferences and neuropsychiatric symptoms, which may have implications for monitoring and/or treatment in the context of cognitive impairment. This article is protected by copyright. All rights reserved.
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http://dx.doi.org/10.1002/gps.5620DOI Listing
September 2021

Long-term Dietary Flavonoid Intake and Subjective Cognitive Decline in US Men and Women.

Neurology 2021 09 28;97(10):e1041-e1056. Epub 2021 Jul 28.

From the Departments of Epidemiology (T.-S.Y., A.A., W.W., D.B.), Nutrition (T.-S.Y., A.A., W.W., C.Y.), and Biostatistics (B.R.), Harvard T.H. Chan School of Public Health, Harvard University; Channing Division of Network Medicine (T.-S.Y., A.A., W.W., C.Y., B.R.), Brigham and Women's Hospital and Harvard Medical School, Boston, MA; School of Public Health (C.Y.), Zhejiang University, Hangzhou, China; Department of Medicine (B.R.), Harvard Medical School; and Department of Psychiatry (D.B.), Massachusetts General Hospital, Harvard Medical School, Boston.

Objective: To prospectively examine the associations between long-term dietary flavonoids and subjective cognitive decline (SCD).

Methods: We followed 49,493 women from the Nurses' Health Study (NHS) (1984-2006) and 27,842 men from the Health Professionals Follow-Up Study (HPFS) (1986-2002). Poisson regression was used to evaluate the associations between dietary flavonoids (flavonols, flavones, flavanones, flavan-3-ols, anthocyanins, polymeric flavonoids, and proanthocyanidins) and subsequent SCD. For the NHS, long-term average dietary intake was calculated from 7 repeated semiquantitative food frequency questionnaires (SFFQs), and SCD was assessed in 2012 and 2014. For the HPFS, average dietary intake was calculated from 5 repeated SFFQs, and SCD was assessed in 2008 and 2012.

Results: Higher intake of total flavonoids was associated with lower odds of SCD after adjustment for age, total energy intake, major nondietary factors, and specific dietary factors. In a comparison of the highest vs the lowest quintiles of total flavonoid intake, the pooled multivariable-adjusted odds ratio (OR) of 3-unit increments in SCD was 0.81 (95% confidence interval [CI] 0.76, 0.89). In the pooled results, the strongest associations were observed for flavones (OR 0.62 [95% CI 0.57, 0.68]), flavanones (0.64 [0.58, 0.68)]), and anthocyanins (0.76 [0.72, 0.84]) ( trend <0.001 for all groups). The dose-response curve was steepest for flavones, followed by anthocyanins. Many flavonoid-rich foods such as strawberries, oranges, grapefruits, citrus juices, apples/pears, celery, peppers, and bananas, were significantly associated with lower odds of SCD.

Conclusion: Our findings support a benefit of higher flavonoid intakes for maintaining cognitive function in US men and women.
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http://dx.doi.org/10.1212/WNL.0000000000012454DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8448553PMC
September 2021

Seizure Prophylaxis After Spontaneous Intracerebral Hemorrhage.

JAMA Neurol 2021 Sep;78(9):1128-1136

Department of Neurology, Massachusetts General Hospital, Boston.

Importance: Limited evidence is available concerning optimal seizure prophylaxis after spontaneous intracerebral hemorrhage (sICH).

Objective: To evaluate which of 4 seizure prophylaxis strategies provides the greatest net benefit for patients with sICH.

Design, Setting, And Participants: This decision analysis used models to simulate the following 4 common scenarios: (1) a 60-year-old man with low risk of early (≤7 days after stroke) (10%) and late (3.6% or 9.8%) seizures and average risk of short- (9%) and long-term (30%) adverse drug reaction (ADR); (2) an 80-year-old woman with low risk of early (10%) and late (3.6% or 9.8%) seizures and high short- (24%) and long-term (80%) ADR risks; (3) a 55-year-old man with high risk of early (19%) and late (34.8% or 46.2%) seizures and low short- (9%) and long-term (30%) ADR risks; and (4) a 45-year-old woman with high risk of early (19%) and late (34.8% or 46.2%) seizures and high short- (18%) and long-term (60%) ADR risks.

Interventions: The following 4 antiseizure drug strategies were included: (1) conservative, consisting of short-term (7-day) secondary early-seizure prophylaxis with long-term therapy after late seizure; (2) moderate, consisting of long-term secondary early-seizure prophylaxis or late-seizure therapy; (3) aggressive, consisting of long-term primary prophylaxis; and (4) risk guided, consisting of short-term secondary early-seizure prophylaxis among low-risk patients (2HELPS2B score, 0), short-term primary prophylaxis among patients at higher risk (2HELPS2B score, ≥1), and long-term secondary therapy for late seizure.

Main Outcomes And Measures: Quality-adjusted life-years (QALYs).

Results: For scenario 1, the risk-guided strategy (8.13 QALYs) was preferred over the conservative (8.08 QALYs), moderate (8.07 QALYs), and aggressive (7.88 QALYs) strategies. For scenario 2, the conservative strategy (2.18 QALYs) was preferred over the risk-guided (2.17 QALYs), moderate (2.09 QALYs), and aggressive (1.15 QALYs) strategies. For scenario 3, the aggressive strategy (9.21 QALYs) was preferred over the risk-guided (8.98 QALYs), moderate (8.93 QALYs), and conservative (8.77 QALYs) strategies. For scenario 4, the risk-guided strategy (11.53 QALYs) was preferred over the conservative (11.23 QALYs), moderate (10.93 QALYs), and aggressive (8.08 QALYs) strategies. Sensitivity analyses suggested that short-term strategies (conservative and risk guided) are preferred under most scenarios, and the risk-guided strategy performs comparably to or better than alternative strategies in most settings.

Conclusions And Relevance: This decision analytical model suggests that short-term (7-day) prophylaxis dominates longer-term therapy after sICH. Use of the 2HELPS2B score to guide clinical decisions for initiation of short-term primary vs secondary early-seizure prophylaxis should be considered for all patients after sICH.
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http://dx.doi.org/10.1001/jamaneurol.2021.2249DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8314179PMC
September 2021

Long-term dietary protein intake and subjective cognitive decline in US men and women.

Am J Clin Nutr 2021 Jul 22. Epub 2021 Jul 22.

Department of Epidemiology, Harvard T. H. Chan School of Public Health, Harvard University, Boston, MA, USA.

Background: Diet is one of the modifiable risk factors for cognitive decline. However, studies on dietary protein intake and cognitive decline have remained limited and inconclusive.

Objectives: In this study, we aimed to investigate the associations between long-term dietary protein intake and subsequent subjective cognitive decline (SCD).

Methods: We included 49,493 women from the Nurses' Health Study (NHS) (1984-2006) and 27,842 men from the Health Professionals Follow-up Study (HPFS) (1986-2002). For the NHS, average dietary intake was calculated from 7 repeated semi-quantitative FFQs (SFFQs), and SCD was assessed in 2012 and 2014. For the HPFS, average dietary intake was calculated from 5 repeated SFFQs, and SCD was assessed in 2008 and 2012. Poisson regression was used to examine the associations between dietary protein, amino acids, and various protein food sources with subsequent SCD.

Results: Higher protein intake compared with total carbohydrates was associated with lower odds of SCD. When substituting 5% energy from protein for the equivalent percentage of energy from total carbohydrates, the pooled multivariable-adjusted ORs (95% CIs) were 0.89 (0.85, 0.94) for total protein, 0.89 (0.84, 0.94) for animal protein, and 0.74 (0.62, 0.88) for plant protein. When substituting 5% of energy from animal protein with plant protein, the OR was 0.84 (95% CI: 0.72, 0.97). For protein food sources, higher intakes of beans/legumes, fish, and lean poultry were significantly associated with lower odds of SCD, but higher intake of hotdogs was associated with higher odds of SCD.

Conclusions: Higher protein intake was associated with lower odds of SCD when compared isocalorically with carbohydrate. Plant protein sources were also associated with lower odds when compared with animal protein sources. Our findings suggest that adequate protein intake, and choices of protein sources could play a role in the maintenance of cognition and should be studied further.
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http://dx.doi.org/10.1093/ajcn/nqab236DOI Listing
July 2021

Anticonvulsant Primary and Secondary Prophylaxis for Acute Ischemic Stroke Patients: A Decision Analysis.

Stroke 2021 Aug 15;52(9):2782-2791. Epub 2021 Jun 15.

Department of Neurology (F.J.S.J., P.R.S., J.R.S., S.F.Z., L.H.S., M.B.W., L.M.V.R.M.), Massachusetts General Hospital, Boston.

[Figure: see text].
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http://dx.doi.org/10.1161/STROKEAHA.120.033299DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8384723PMC
August 2021

To meat or not to meat? Processed meat and risk of dementia.

Am J Clin Nutr 2021 07;114(1):7-8

Department of Nutrition, Harvard T. H. Chan School of Public Health, Harvard University, Boston, MA, USA.

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http://dx.doi.org/10.1093/ajcn/nqab139DOI Listing
July 2021

Modeling semi-competing risks data as a longitudinal bivariate process.

Biometrics 2021 Apr 28. Epub 2021 Apr 28.

Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA.

As individuals age, death is a competing risk for Alzheimer's disease (AD) but the reverse is not the case. As such, studies of AD can be placed within the semi-competing risks framework. Central to semi-competing risks, and in contrast to standard competing risks , is that one can learn about the dependence structure between the two events. To-date, however, most methods for semi-competing risks treat dependence as a nuisance and not a potential source of new clinical knowledge. We propose a novel regression-based framework that views the two time-to-event outcomes through the lens of a longitudinal bivariate process on a partition of the time scales of the two events. A key innovation of the framework is that dependence is represented in two distinct forms, local and global dependence, both of which have intuitive clinical interpretations. Estimation and inference are performed via penalized maximum likelihood, and can accommodate right censoring, left truncation, and time-varying covariates. An important consequence of the partitioning of the time scale is that an ambiguity regarding the specific form of the likelihood contribution may arise; a strategy for sensitivity analyses regarding this issue is described. The framework is then used to investigate the role of gender and having ≥1 apolipoprotein E (APOE) ε4 allele on the joint risk of AD and death using data from the Adult Changes in Thought study.
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http://dx.doi.org/10.1111/biom.13480DOI Listing
April 2021

Visit-to-Visit Blood Pressure Variability, Neuropathology, and Cognitive Decline.

Neurology 2021 06 26;96(23):e2812-e2823. Epub 2021 Apr 26.

From the Department of Epidemiology (Y.M., D. Blacker, A.H.), Harvard T.H. Chan School of Public Health; Departments of Neurology (Y.M., A.V., S.J.v.V., B.T.H., S.D.) and Psychiatry (D. Blacker), Massachusetts General Hospital, Harvard Medical School, Boston; Departments of Epidemiology (D. Bos, M.W.V., A.H.) and Radiology and Nuclear Medicine (D. Bos, M.W.V.), Erasmus MC University Medical Center, Rotterdam, the Netherlands; and University of Bordeaux (C.T.), Inserm, Bordeaux Population Health Research Center, UMR 1219, CHU Bordeaux, France.

Objective: Large systolic blood pressure (SBP) variability has been proposed as a novel risk factor for dementia above and beyond SBP levels, but the underlying neuropathology is largely unknown. We investigated the relationship among visit-to-visit SBP variability, cognitive deterioration, and underlying neuropathologic changes.

Methods: We used longitudinal data (between 2005 and 2019) from the National Alzheimer's Coordinating Center. A total of 13,284 dementia-free participants ≥50 years of age were followed up over a median of 5.0 (interquartile range 3.1-7.6) years. Neuropathology data were available in 1,400 autopsied participants. Visit-to-visit SBP variability was quantified from repeated annual SBP measurements. Cognitive deterioration was defined as conversion from normal cognition to mild cognitive impairment (MCI) or dementia or from MCI to dementia.

Results: Larger visit-to-visit SBP variability was associated with cognitive deterioration (adjusted odds ratio comparing extreme quintiles 2.64, 95% confidence interval 2.29-3.04, < 0.001). It was also associated with a higher burden of vascular pathology (including microinfarcts, white matter lesions, atherosclerosis of the circle of Willis, and arteriolosclerosis) and with neurofibrillary tangle pathology assessed by Braak staging (all < 0.05). The association with cognitive deterioration and vascular pathology appeared stronger among those with normal cognition vs those with MCI at baseline. These findings were observed after adjustment for age, sex, mean SBP, and other confounding variables. Similar results were observed for diastolic blood pressure variability.

Conclusion: Larger visit-to-visit SBP variability was associated with cognitive deterioration. It was also associated with cerebrovascular pathology and neurofibrillary tangles. These results suggest the intertwined role of vascular and Alzheimer disease pathology in the etiology of dementia.
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http://dx.doi.org/10.1212/WNL.0000000000012065DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8205457PMC
June 2021

Identifying Medicare beneficiaries with dementia.

J Am Geriatr Soc 2021 Aug 26;69(8):2240-2251. Epub 2021 Apr 26.

Mongan Institute, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.

Background/objectives: No data exist regarding the validity of International Classification of Disease (ICD)-10 dementia diagnoses against a clinician-adjudicated reference standard within Medicare claims data. We examined the accuracy of claims-based diagnoses with respect to expert clinician adjudication using a novel database with individual-level linkages between electronic health record (EHR) and claims.

Design: In this retrospective observational study, two neurologists and two psychiatrists performed a standardized review of patients' medical records from January 2016 to December 2018 and adjudicated dementia status. We measured the accuracy of three claims-based definitions of dementia against the reference standard.

Setting: Mass-General-Brigham Healthcare (MGB), Massachusetts, USA.

Participants: From an eligible population of 40,690 fee-for-service (FFS) Medicare beneficiaries, aged 65 years and older, within the MGB Accountable Care Organization (ACO), we generated a random sample of 1002 patients, stratified by the pretest likelihood of dementia using administrative surrogates.

Intervention: None.

Measurements: We evaluated the accuracy (area under receiver operating curve [AUROC]) and calibration (calibration-in-the-large [CITL] and calibration slope) of three ICD-10 claims-based definitions of dementia against clinician-adjudicated standards. We applied inverse probability weighting to reconstruct the eligible population and reported the mean and 95% confidence interval (95% CI) for all performance characteristics, using 10-fold cross-validation (CV).

Results: Beneficiaries had an average age of 75.3 years and were predominately female (59%) and non-Hispanic whites (93%). The adjudicated prevalence of dementia in the eligible population was 7%. The best-performing definition demonstrated excellent accuracy (CV-AUC 0.94; 95% CI 0.92-0.96) and was well-calibrated to the reference standard of clinician-adjudicated dementia (CV-CITL <0.001, CV-slope 0.97).

Conclusion: This study is the first to validate ICD-10 diagnostic codes against a robust and replicable approach to dementia ascertainment, using a real-world clinical reference standard. The best performing definition includes diagnostic codes with strong face validity and outperforms an updated version of a previously validated ICD-9 definition of dementia.
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http://dx.doi.org/10.1111/jgs.17183DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8373730PMC
August 2021

Cognitive and social activities and long-term dementia risk: the prospective UK Million Women Study.

Lancet Public Health 2021 02;6(2):e116-e123

Cancer Epidemiology Unit, University of Oxford, Oxford, UK.

Background: Although dementia is associated with non-participation in cognitive and social activities, this association might merely reflect the consequences of dementia, rather than any direct effect of non-participation on the subsequent incidence of dementia. Because of the slowness with which dementia can develop, unbiased assessment of any such direct effects must relate non-participation in such activities to dementia detection rates many years later. Prospective studies with long-term follow-up can help achieve this by analysing separately the first and second decade of follow-up. We report such analyses of a large, 20-year study.

Methods: The UK Million Women Study is a population-based prospective study of 1·3 million women invited for National Health Service (NHS) breast cancer screening in median year 1998 (IQR 1997-1999). In median year 2001 (IQR 2001-2003), women were asked about participation in adult education, groups for art, craft, or music, and voluntary work, and in median year 2006 (IQR 2006-2006), they were asked about reading. All participants were followed up through electronic linkage to NHS records of hospital admission with mention of dementia, the first mention of which was the main outcome. Comparing non-participation with participation in a particular activity, we used Cox regression to assess fully adjusted dementia risk ratios (RRs) during 0-4, 5-9, and 10 or more years, after information on that activity was obtained.

Findings: In 2001, 851 307 women with a mean age of 60 years (SD 5) provided information on participation in adult education, groups for art, craft, or music, and voluntary work. After 10 years, only 9591 (1%) had been lost to follow-up and 789 339 (93%) remained alive with no recorded dementia. Follow-up was for a mean of 16 years (SD 3), during which 31 187 (4%) had at least one hospital admission with mention of dementia, including 25 636 (3%) with a hospital admission with dementia mentioned for the first time 10 years or more after follow-up began. Non-participation in cognitive or social activities was associated with higher relative risks of dementia detection only during the first decade after participation was recorded. During the second decade, there was little association. This was true for non-participation in adult education (RR 1·04, 99% CI 0·98-1·09), in groups for art, craft, or music (RR 1·04, 0·99-1·09), in voluntary work (RR 0·96, 0·92-1·00), or in any of these three (RR 0·99, 0·95-1·03). In 2006, 655 118 women provided information on reading. For non-reading versus any reading, there were similar associations with dementia, again with strong attenuation over time since reading was recorded, but longer follow-up is needed to assess this reliably.

Interpretation: Life has to be lived forwards, but can be understood only backwards. Long before dementia is diagnosed, there is a progressive reduction in various mental and physical activities, but this is chiefly because its gradual onset causes inactivity and not because inactivity causes dementia.

Funding: UK Medical Research Council, Cancer Research UK.
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http://dx.doi.org/10.1016/S2468-2667(20)30284-XDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7848753PMC
February 2021

MarkVCID cerebral small vessel consortium: I. Enrollment, clinical, fluid protocols.

Alzheimers Dement 2021 04 21;17(4):704-715. Epub 2021 Jan 21.

Alzheimer's Clinical and Translational Research Unit, Massachusetts General Hospital, Boston, Massachusetts, USA.

The concept of vascular contributions to cognitive impairment and dementia (VCID) derives from more than two decades of research indicating that (1) most older individuals with cognitive impairment have post mortem evidence of multiple contributing pathologies and (2) along with the preeminent role of Alzheimer's disease (AD) pathology, cerebrovascular disease accounts for a substantial proportion of this contribution. Contributing cerebrovascular processes include both overt strokes caused by etiologies such as large vessel occlusion, cardioembolism, and embolic infarcts of unknown source, and frequently asymptomatic brain injuries caused by diseases of the small cerebral vessels. Cerebral small vessel diseases such as arteriolosclerosis and cerebral amyloid angiopathy, when present at moderate or greater pathologic severity, are independently associated with worse cognitive performance and greater likelihood of dementia, particularly in combination with AD and other neurodegenerative pathologies. Based on this evidence, the US National Alzheimer's Project Act explicitly authorized accelerated research in vascular and mixed dementia along with frontotemporal and Lewy body dementia and AD itself. Biomarker development has been consistently identified as a key step toward translating scientific advances in VCID into effective prevention and treatment strategies. Validated biomarkers can serve a range of purposes in trials of candidate interventions, including (1) identifying individuals at increased VCID risk, (2) diagnosing the presence of cerebral small vessel disease or specific small vessel pathologies, (3) stratifying study participants according to their prognosis for VCID progression or treatment response, (4) demonstrating an intervention's target engagement or pharmacodynamic mechanism of action, and (5) monitoring disease progression during treatment. Effective biomarkers allow academic and industry investigators to advance promising interventions at early stages of development and discard interventions with low success likelihood. The MarkVCID consortium was formed in 2016 with the goal of developing and validating fluid- and imaging-based biomarkers for the cerebral small vessel diseases associated with VCID. MarkVCID consists of seven project sites and a central coordinating center, working with the National Institute of Neurologic Diseases and Stroke and National Institute on Aging under cooperative agreements. Through an internal selection process, MarkVCID has identified a panel of 11 candidate biomarker "kits" (consisting of the biomarker measure and the clinical and cognitive data used to validate it) and established a range of harmonized procedures and protocols for participant enrollment, clinical and cognitive evaluation, collection and handling of fluid samples, acquisition of neuroimaging studies, and biomarker validation. The overarching goal of these protocols is to generate rigorous validating data that could be used by investigators throughout the research community in selecting and applying biomarkers to multi-site VCID trials. Key features of MarkVCID participant enrollment, clinical/cognitive testing, and fluid biomarker procedures are summarized here, with full details in the following text, tables, and supplemental material, and a description of the MarkVCID imaging biomarker procedures in a companion paper, "MarkVCID Cerebral small vessel consortium: II. Neuroimaging protocols." The procedures described here address a range of challenges in MarkVCID's design, notably: (1) acquiring all data under informed consent and enrollment procedures that allow unlimited sharing and open-ended analyses without compromising participant privacy rights; (2) acquiring the data in a sufficiently wide range of study participants to allow assessment of candidate biomarkers across the various patient groups who might ultimately be targeted in VCID clinical trials; (3) defining a common dataset of clinical and cognitive elements that contains all the key outcome markers and covariates for VCID studies and is realistically obtainable during a practical study visit; (4) instituting best fluid-handling practices for minimizing avoidable sources of variability; and (5) establishing rigorous procedures for testing the reliability of candidate fluid-based biomarkers across replicates, assay runs, sites, and time intervals (collectively defined as the biomarker's instrumental validity). Participant Enrollment Project sites enroll diverse study cohorts using site-specific inclusion and exclusion criteria so as to provide generalizable validation data across a range of cognitive statuses, risk factor profiles, small vessel disease severities, and racial/ethnic characteristics representative of the diverse patient groups that might be enrolled in a future VCID trial. MarkVCID project sites include both prospectively enrolling centers and centers providing extant data and samples from preexisting community- and population-based studies. With approval of local institutional review boards, all sites incorporate MarkVCID consensus language into their study documents and informed consent agreements. The consensus language asks prospectively enrolled participants to consent to unrestricted access to their data and samples for research analysis within and outside MarkVCID. The data are transferred and stored as a de-identified dataset as defined by the Health Insurance Portability and Accountability Act Privacy Rule. Similar human subject protection and informed consent language serve as the basis for MarkVCID Research Agreements that act as contracts and data/biospecimen sharing agreements across the consortium. Clinical and Cognitive Data Clinical and cognitive data are collected across prospectively enrolling project sites using common MarkVCID instruments. The clinical data elements are modified from study protocols already in use such as the Alzheimer's Disease Center program Uniform Data Set Version 3 (UDS3), with additional focus on VCID-related items such as prior stroke and cardiovascular disease, vascular risk factors, focal neurologic findings, and blood testing for vascular risk markers and kidney function including hemoglobin A1c, cholesterol subtypes, triglycerides, and creatinine. Cognitive assessments and rating instruments include the Clinical Dementia Rating Scale, Geriatric Depression Scale, and most of the UDS3 neuropsychological battery. The cognitive testing requires ≈60 to 90 minutes. Study staff at the prospectively recruiting sites undergo formalized training in all measures and review of their first three UDS3 administrations by the coordinating center. Collection and Handling of Fluid Samples Fluid sample types collected for MarkVCID biomarker kits are serum, ethylenediaminetetraacetic acid-plasma, platelet-poor plasma, and cerebrospinal fluid (CSF) with additional collection of packed cells to allow future DNA extraction and analyses. MarkVCID fluid guidelines to minimize variability include fasting morning fluid collections, rapid processing, standardized handling and storage, and avoidance of CSF contact with polystyrene. Instrumental Validation for Fluid-Based Biomarkers Instrumental validation of MarkVCID fluid-based biomarkers is operationally defined as determination of intra-plate and inter-plate repeatability, inter-site reproducibility, and test-retest repeatability. MarkVCID study participants both with and without advanced small vessel disease are selected for these determinations to assess instrumental validity across the full biomarker assay range. Intra- and inter-plate repeatability is determined by repeat assays of single split fluid samples performed at individual sites. Inter-site reproducibility is determined by assays of split samples distributed to multiple sites. Test-retest repeatability is determined by assay of three samples acquired from the same individual, collected at least 5 days apart over a 30-day period and assayed on a single plate. The MarkVCID protocols are designed to allow direct translation of the biomarker validation results to multicenter trials. They also provide a template for outside groups to perform analyses using identical methods and therefore allow direct comparison of results across studies and centers. All MarkVCID protocols are available to the biomedical community and intended to be shared. In addition to the instrumental validation procedures described here, each of the MarkVCID kits will undergo biological validation to determine whether the candidate biomarker measures important aspects of VCID such as cognitive function. Analytic methods and results of these validation studies for the 11 MarkVCID biomarker kits will be published separately. The results of this rigorous validation process will ultimately determine each kit's potential usefulness for multicenter interventional trials aimed at preventing or treating small vessel disease related VCID.
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http://dx.doi.org/10.1002/alz.12215DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8122220PMC
April 2021

Predictors of the importance of everyday preferences for older adults with cognitive impairment.

Int Psychogeriatr 2021 Jan 18:1-8. Epub 2021 Jan 18.

Harvard Medical School, Boston, MA, USA.

Objectives: Among older people with cognitive impairment and mild dementia, relatively little is known about the factors that predict preferences for everyday living activities and experiences and that influence the relative importance of those activities and experiences.

Design: Cross-sectional study.

Setting: Participants were recruited from the Massachusetts Alzheimer's Disease Research Center (MADRC) Clinical Core longitudinal cohort.

Participants: The sample included 62 community-dwelling older adults with cognitive impairment (Clinical Dementia Rating global score ≥ 0.5).

Measurements: We used the Preferences for Everyday Living Inventory (PELI) to assess preferences for activities and lifestyle experiences among persons with cognitive impairment. Within-subjects analysis of variance was used to test for significant differences in the mean ratings of importance for four domains of the PELI ("autonomous choice," "social engagement," "personal growth," and "keeping a routine"). Multiple regression models were used to relate predictors, including neuropsychiatric symptoms, to importance ratings for each domain.

Results: Significant differences were noted in the mean importance ratings of the preferences domains: "social engagement" preferences were rated as most important, followed by "autonomous choice," "personal growth," and "keeping a routine." For the "social engagement" preferences domain, female sex was significantly associated with higher importance of "social engagement," while depressive symptoms (Geriatric Depression Scale-15 scores) were significantly associated with lower importance.

Conclusions: This study adds novel insight into the everyday preferences of community-dwelling older adults with cognitive impairment and highlights the impact of a number of factors, particularly level of depression, on how important various everyday experiences are perceived.
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http://dx.doi.org/10.1017/S1041610220003956DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8286271PMC
January 2021

Characterizing Clinical and Neuropathological Traits of APOE Haplotypes in African Americans and Europeans.

J Alzheimers Dis 2020 ;78(1):467-477

MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Charlestown, MA, USA.

Background: The APOEɛ4 allele is the largest genetic risk factor for late-onset Alzheimer's disease (AD). Recent literature suggested that the contribution of APOEɛ4 to AD risk could be population-specific, with ɛ4 conferring a lower risk to Blacks or African Americans.

Objective: To investigate the effect of APOE haplotypes on AD risk in individuals with European ancestry (EU) and Blacks or African Americans (AA).

Methods: We selected data from 1) the National Alzheimer's Coordinating Center: a total of 3,486 AD cases and 4,511 controls (N = 7,997, 60% female) with genotypes from the Alzheimer's Disease Genetics Consortium (ADGC), and 2) the Rush University Religious Orders Study and Memory and Aging Project (ROSMAP) cohort with 578 AD and 670 controls (N = 1,248, 60% female). Using ɛ3 homozygotes as the reference, we compared the association of various APOE haplotypes with the clinical and neuropathological correlates of dementia in AA and EU.

Results: In both cohorts, we find no difference in the odds or age of onset of AD among the ɛ4-linked haplotypes defined by rs769449 within either AA or EU. Additionally, while APOEɛ4 was associated with a faster rate of decline, no differences were found in rate of decline, clinical or neuropathological features among the ɛ4-linked haplotypes. Further analysis with other variants near the APOE locus failed to identify any effect modification.

Conclusion: Our study finds similar effects of the ɛ4-linked haplotypes defined by rs769449 on AD as compared to ɛ3 in both AA and EU. Future studies are required to understand the heterogeneity of APOE conferred risk of AD among various genotypes and populations.
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http://dx.doi.org/10.3233/JAD-200228DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7774865PMC
September 2021

Patterns of anticonvulsant use and adverse drug events in older adults.

Pharmacoepidemiol Drug Saf 2021 01 2;30(1):28-36. Epub 2020 Oct 2.

Department of Health Care Policy, Harvard Medical School, Boston, Massachusetts.

Purpose: To examine indications for, duration of use, and rate of adverse drug events (ADE) attributable to anticonvulsant initiation, as adjudicated by expert review of electronic health records (EHR) of older adults.

Methods: We identified a cohort of community dwelling Medicare beneficiaries with linked EHR (aged 65+, continuously enrolled with a large health system/until death between 2012 and 2014, n = 20 945) and drew a stratified EHR review sample (n = 1534). An expert reviewed all records to adjudicate anticonvulsant use, years of use, indication for use, and evidence of ADEs attributable to anticonvulsant initiation. After excluding patients with insufficient EHR data (n = 37; 2%), we reconstructed the cohort using inverse probability weights to resemble the original cohort of eligible beneficiaries (n = 20 380). Among incident users of a single anticonvulsant, we estimated the rate of ADEs and described the type and severity of ADEs.

Results: Overall, 12% (n = 2469) of eligible beneficiaries used at least one anticonvulsant in the 2012 to 2014 period (4% [n = 757] incident users, 8% [n = 1712] prevalent users). Incident users were most frequently prescribed gabapentin (n = 461/757, 61%), benzodiazepines (n = 122/757, 16%), and levetiracetam (n = 74/757, 10%); the most common indication was pain relief (n = 214; 28%) followed by epilepsy (n = 53; 7%). Among incident users, the overall ADE rate was 10/100 person-years (95% CI 4-20/100 person-years), of which 29% (n = 28/97) were life threatening (eg, somnolence). Most ADEs among incident monotherapy users were nervous system related (68%, n = 66/97).

Conclusion: Many older adult community dwelling traditional Medicare beneficiaries had clinically significant ADEs likely attributable to the initiation of anticonvulsant therapy, which was begun for a range of indications.
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http://dx.doi.org/10.1002/pds.5139DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7849867PMC
January 2021

Twenty-seven-year time trends in dementia incidence in Europe and the United States: The Alzheimer Cohorts Consortium.

Neurology 2020 08 1;95(5):e519-e531. Epub 2020 Jul 1.

From the Department of Epidemiology (F.J.W., L.B.C., R.W., D. Blacker, D. Bos, J.G., A.H.), Harvard T.H. Chan School of Public Health, Boston, MA; Departments of Epidemiology (F.J.W., D. Bos, S.K.L.D., M.A.I., M.K.I., A.H.), Radiology and Nuclear Medicine (D. Bos), and Neurology (M.K.I.), Erasmus MC, Rotterdam, the Netherlands; Department of Neurology (L.B.C.), Massachusetts General Hospital, Boston; Department of Infectious Disease Epidemiology (R.A., F.d.W., C. Hadjichrysanthou, K.M.-M., M.M.W.), School of Public Health, Imperial College London, UK; Neuropsychiatry and Epidemiology and Clinical Research (C. Berr), INSERM, UMR 1061 Montpellier, Universite de Montpellier, France; Boston University School of Medicine (A.B., M.P.P., C.L.S., S.S.); Framingham Heart Study (A.B., M.P.P., C.L.S., S.S.), MA; Department of Biostatistics (A.B., K.L.D.-P.), Boston University School of Public Health, MA; Cardiovascular Health Research Unit, Departments of Medicine (J.C.B., B.M.P.) and Epidemiology and Health Services (B.M.P.), University of Washington, Seattle; Department of Psychiatry (D. Blacker), Massachusetts General Hospital, Charlestown; University of Cambridge (C. Brayne), UK; Bordeaux Population Health Research Center (J.-F.D., S.D., C.D., L.G., C. Helmer), INSERM, UMR 1219, University of Bordeaux; Department of Neurology (S.D.), Memory Clinic, Bordeaux University Hospital, France; McGovern Medical School (M.F.), University of Texas Health Science Center at Houston; Icelandic Heart Association (V.G.), Kopavogur; Faculty of Medicine (V.G.), University of Iceland, Reykjavik; Institute of Neuroscience and Physiology (E.J., S.K., I.S., H.W., A.Z.), Sahlgrenska Academy, University of Gothenburg, Sweden; Department of Epidemiology, Graduate School of Public Health (L.H.K.), and Departments of Neurology and Psychiatry (O.L.L.), University of Pittsburgh, PA; Laboratory of Epidemiology and Population Sciences (L.L., O.M.), National Institute on Aging, Bethesda, MD; Institute of Health and Society (F.E.M., B.C.M.S.), Newcastle University, Newcastle upon Tyne, UK; MIND Center (T.H.M.), University of Mississippi Medical Center, Jackson; Melbourne Dementia Research Centre (M.P.P.), The Florey Institute for Neuroscience and Mental Health, Melbourne, Australia; Kaiser Permanente Washington Health Research Institute (B.M.P.), Seattle; and The Glenn Biggs Institute for Alzheimer's & Neurodegenerative Diseases (C.L.S., S.S.), UT Health San Antonio, TX.

Objective: To determine changes in the incidence of dementia between 1988 and 2015.

Methods: This analysis was performed in aggregated data from individuals >65 years of age in 7 population-based cohort studies in the United States and Europe from the Alzheimer Cohort Consortium. First, we calculated age- and sex-specific incidence rates for all-cause dementia, and then defined nonoverlapping 5-year epochs within each study to determine trends in incidence. Estimates of change per 10-year interval were pooled and results are presented combined and stratified by sex.

Results: Of 49,202 individuals, 4,253 (8.6%) developed dementia. The incidence rate of dementia increased with age, similarly for women and men, ranging from about 4 per 1,000 person-years in individuals aged 65-69 years to 65 per 1,000 person-years for those aged 85-89 years. The incidence rate of dementia declined by 13% per calendar decade (95% confidence interval [CI], 7%-19%), consistently across studies, and somewhat more pronouncedly in men than in women (24% [95% CI 14%-32%] vs 8% [0%-15%]).

Conclusion: The incidence rate of dementia in Europe and North America has declined by 13% per decade over the past 25 years, consistently across studies. Incidence is similar for men and women, although declines were somewhat more profound in men. These observations call for sustained efforts to finding the causes for this decline, as well as determining their validity in geographically and ethnically diverse populations.
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http://dx.doi.org/10.1212/WNL.0000000000010022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7455342PMC
August 2020

Blood Pressure Variation and Subclinical Brain Disease.

J Am Coll Cardiol 2020 05;75(19):2387-2399

Department of Epidemiology, Erasmus MC University Medical Center, Rotterdam, the Netherlands; Department of Neurology, Erasmus MC University Medical Center, Rotterdam, the Netherlands.

Background: Large blood pressure (BP) variability may contribute to stroke and dementia, but the mechanisms are largely unknown.

Objectives: This study investigated the association of BP variation, considering its magnitude and direction, with the presence and progression of subclinical brain disease in the general population.

Methods: This study included 2,348 participants age ≥55 years from a prospective cohort study. BP was measured at each visit every 3 to 4 years from 1990 onward. Brain magnetic resonance imaging (MRI) was performed at all visits from 2005 onward. The authors primarily assessed variation as the absolute difference in BP divided by the mean over 2 sequential visits for both systolic BP (SBP) and diastolic BP (DBP), and further assessed the direction of the variation. The authors investigated the multivariate-adjusted associations of BP variation with subsequent measurements of MRI markers of cerebral small vessel disease, brain tissue volumes, and white matter microstructural integrity. Longitudinal changes in these markers also were assessed.

Results: A large SBP variation (top vs. bottom tertiles), measured on average 7 years preceding brain MRI, was associated with higher odds of having severe white matter hyperintensities (WMH) (odds ratio [OR]: 1.32; 95% confidence interval [CI]: 1.21 to 1.43), lacunes (OR: 1.25; 95% CI: 1.04 to 1.48), and microbleeds (OR: 1.16; 95% CI: 1.03 to 1.31). Similarly, this variation was associated with smaller total brain volume and worse white matter microstructural integrity (all p < 0.001). A large SBP variation was also associated with the progression of WMH (rate ratio [RR]: 1.14; 95% CI: 1.02 to 1.27). Higher burdens of these brain imaging markers were observed with both large rises and falls in SBP. Similar findings were observed for DBP variation.

Conclusions: Elevated BP variation was associated with a wide range of subclinical brain structural changes, including MRI markers of cerebral small vessel disease, smaller brain tissue volumes, and worse white matter microstructural integrity. These subclinical brain changes could be the underlying mechanisms linking BP variation to dementia and stroke.
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http://dx.doi.org/10.1016/j.jacc.2020.03.043DOI Listing
May 2020

Differences in Assessment of Everyday Preferences Between People With Cognitive Impairment and Their Care Partners: The Role of Neuropsychiatric Symptoms.

Am J Geriatr Psychiatry 2020 10 6;28(10):1070-1078. Epub 2020 Feb 6.

Harvard Medical School (JMW, JJL, JMG, LY, BTH, DB, BPF, OIO), Boston, MA; Massachusetts Alzheimer's Disease Research Center (JJL, JMG, LY, BTH, DB, OIO), Department of Neurology, Massachusetts General Hospital, Boston, MA; Department of Psychiatry (DB, OIO), Massachusetts General Hospital, Boston, MA.

Objective: As cognitive impairment progresses, people with dementia increasingly rely on surrogate decision-makers for everyday activities. Yet, little is known about concordance on everyday preferences between persons with cognitive impairment and their care partners.

Methods: The sample included 69 dyads of persons with cognitive impairment (Clinical Dementia Rating Scale ≥0.5) and their care partners. We used the Preferences for Everyday Living Inventory (PELI) to assess preferences for activities and lifestyle choices among persons with cognitive impairment. The PELI was concurrently but separately administered to care partners, who answered as surrogate decision-makers. Factor analysis was used to ascertain factor structure of the PELI; reliability measures were computed within the sample. Paired sample t-tests were used to estimate differences in scores of corresponding PELI items for each factor. Multiple regression models were used to relate predictors, including neuropsychiatric symptoms, to agreement levels.

Results: Four factors were identified from the PELI: autonomous choice, social engagement, personal growth, and keeping a routine. Significant participant-care partner discrepancy was found in "social engagement" preferences (e.g., regular contact with family, meeting new people, volunteering). Geriatric Depression Scale-15 score and care partner sex were significantly associated with participant-care partner discrepancies in "social engagement" preferences.

Conclusion: This study yields new insights regarding the most important preferences for persons with cognitive impairment and clarifies a path to optimizing surrogate decision-making around everyday preferences by highlighting areas of apparent disagreement and identifying potential predictors of discrepancy.
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http://dx.doi.org/10.1016/j.jagp.2020.01.189DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7415491PMC
October 2020

Narrative video scene description task discriminates between levels of cognitive impairment in Alzheimer's disease.

Neuropsychology 2020 May 30;34(4):437-446. Epub 2020 Jan 30.

Schepens Eye Research Institute.

The process of interpreting and acting upon the visual environment requires both intact cognitive and visual systems. The narrative description (ND) task, initially developed to detect changes in ecologically relevant visual function in people with impaired vision, is an objective measure of the ability to perceive, understand, and describe a visual scene in a movie clip.

Objective: Because the ND task draws heavily on semantic and working memory ability in addition to basic visual perception, we aimed to assess the discriminative performance of this task across levels of cognitive impairment.

Method: We recruited 56 participants with cognitive status ranging from normal cognition to mild dementia (median age 82, range 66 to 99 years) to watch 20 30-s video clips and describe the visual content without time constraints. These verbal responses were transcribed and processed to generate ND shared word scores using a "wisdom of the crowd," natural-language processing approach. We compared ND scores across diagnostic groups, and used linear mixed models to examine decrements in task performance.

Results: There was a stepwise decline of ND scores with increasing levels of cognitive impairment. Additional analyses showed that ND performance was highly related to performance on the Montreal Cognitive Assessment (MoCA) and domain-specific neuropsychological tests for semantic fluency and set shifting. Other models demonstrated differences in ND performance related video content between cognitively normal and impaired participants.

Conclusion: The ND test was able to detect decrements in task performance between levels of cognitive impairment and was related to other global neuropsychological measures. (PsycInfo Database Record (c) 2020 APA, all rights reserved).
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http://dx.doi.org/10.1037/neu0000621DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7182468PMC
May 2020

Blood Pressure Variability and Cerebral Small Vessel Disease: A Systematic Review and Meta-Analysis of Population-Based Cohorts.

Stroke 2020 01 27;51(1):82-89. Epub 2019 Nov 27.

From the Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA (Y.M., D.B., A.H., S.P.).

Background and Purpose- Blood pressure (BP) variability may increase the risk of stroke and dementia. It remains inconclusive whether BP variability is associated with cerebral small vessel disease, a common and potentially devastating subclinical disease that contributes significantly to both stroke and dementia. Methods- A systematic review and meta-analysis of prospective cohort studies that examined the association between BP variability and the presence or progression of established markers of cerebral small vessel disease, including white matter hyperintensities, lacunes, and microbleeds on magnetic resonance imaging. We searched MEDLINE, EMBASE, and Web of Science. Ten studies met the criteria for qualitative synthesis and 7 could be included in the meta-analysis. Data were synthetized using random-effect models. Results- These studies included a total of 2796 individuals aged 74 (mean) ±4 (SD) years, with a median follow-up of 4.0 years. A one SD increase in systolic BP variability was associated with increased odds of the presence or progression of white matter hyperintensities (odds ratio, 1.26 [95% CI, 1.06-1.50]). The association of systolic BP variability with the presence of lacunes (odds ratio, 0.93 [95% CI, 0.74-1.16]) and the presence of microbleeds (odds ratio, 1.13 [95% CI, 0.89-1.44]) were not statistically significant. Conclusions- A larger BP variability may be associated with a higher risk of having a higher burden of white matter hyperintensities. Targeting large BP variability has the potential to prevent cerebral small vessel disease and thereby reducing the risk of stroke and dementia. The potential issue of reverse causation and the heterogeneity in the assessment of cerebral small vessel disease markers should be better addressed in future studies.
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http://dx.doi.org/10.1161/STROKEAHA.119.026739DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7050788PMC
January 2020

Longitudinal Association of Depression Symptoms With Cognition and Cortical Amyloid Among Community-Dwelling Older Adults.

JAMA Netw Open 2019 08 2;2(8):e198964. Epub 2019 Aug 2.

Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston.

Importance: Depressive symptoms are prevalent among older adults and may be early manifestations of Alzheimer disease (AD) before onset of mild cognitive impairment. However, it remains unclear whether worsening depressive symptoms in the presence of AD pathology are associated with cognitive decline in older adults.

Objective: To determine the longitudinal association between depressive symptoms, cognition, and cortical amyloid in community-dwelling older adults.

Design, Setting, And Participants: Participants from the Harvard Aging Brain Study, a cohort study, underwent annual assessments of depression and cognition and baseline cortical amyloid measurement (mean, 4.42 years; range, 2-7 years). Data collection was from September 2010 to August 2017 in a convenience sample of community-dwelling adults (276 participants, all cognitively unimpaired) with at most mild depression at entry.

Main Outcomes And Measures: Depression (Geriatric Depression Scale [GDS]), cognition (Preclinical Alzheimer Cognitive Composite [PACC]), and a continuous measure of cortical amyloid (Pittsburgh Compound-B positron emission tomography imaging). Change in GDS and baseline amyloid were examined as interactive predictors of PACC decline in a linear mixed model with backward elimination, adjusting for age, sex, and education.

Results: Participants were 164 women and 112 men (mean [SD] age, 73.5 [6.0] years). At baseline, the mean (SD) GDS score was 3.0 (2.8) (range, 0-12), the mean (SD) PACC score was -0.004 (0.67) (range, -2.32 to 1.88), and the mean (SD) amyloid positron emission tomography distribution volume ratio was 1.16 (0.20) (range, 0.92-1.94). At last follow-up, the mean (SD) GDS score was 3.9 (2.9) (range, 0-12), and the mean (SD) PACC score was -0.09 (1.27) (range, -5.66 to 1.67). The interaction between cortical amyloid and increasing GDS was associated with declining cognition (β = -0.19; 95% CI, -0.27 to -0.12; P < .001).

Conclusions And Relevance: In this study, cortical amyloid moderated the association between worsening depressive symptoms and declining cognition in older adults. While future work is needed to better understand causal associations, these findings may enhance early detection and prevention of AD clinical symptoms.
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http://dx.doi.org/10.1001/jamanetworkopen.2019.8964DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6692684PMC
August 2019

Asymptomatic Cerebral Small Vessel Disease: Insights from Population-Based Studies.

J Stroke 2019 May 17;21(2):121-138. Epub 2019 Apr 17.

Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.

Cerebral small vessel disease (CSVD) is a common group of neurological conditions that confer a significant burden of morbidity and mortality worldwide. In most cases, CSVD is only recognized in its advanced stages once its symptomatic sequelae develop. However, its significance in asymptomatic healthy populations remains poorly defined. In population-based studies of presumed healthy elderly individuals, CSVD neuroimaging markers including white matter hyperintensities, lacunes, cerebral microbleeds, enlarged perivascular spaces, cortical superficial siderosis, and cerebral microinfarcts are frequently detected. While the presence of these imaging markers may reflect unique mechanisms at play, there are likely shared pathways underlying CSVD. Herein, we aim to assess the etiology and significance of these individual biomarkers by focusing in asymptomatic populations at an epidemiological level. By primarily examining population-based studies, we explore the risk factors that are involved in the formation and progression of these biomarkers. Through a critical semi-systematic review, we aim to characterize "asymptomatic" CSVD, review screening modalities, and draw associations from observational studies in clinical populations. Lastly, we highlight areas of research (including therapeutic approaches) in which further investigation is needed to better understand asymptomatic CSVD.
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http://dx.doi.org/10.5853/jos.2018.03608DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6549070PMC
May 2019

The relation of telomere length at midlife to subsequent 20-year depression trajectories among women.

Depress Anxiety 2019 06 8;36(6):565-575. Epub 2019 Apr 8.

Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts.

Background: Telomeres cap and protect DNA but shorten with each somatic cell division. Aging and environmental and lifestyle factors contribute to the speed of telomere attrition. Current evidence suggests a link between relative telomere length (RTL) and depression but the directionality of the relationship remains unclear. We prospectively examined associations between RTL and subsequent depressive symptom trajectories.

Methods: Among 8,801 women of the Nurses' Health Study, depressive symptoms were measured every 4 years from 1992 to 2012; group-based trajectories of symptoms were identified using latent class growth-curve analysis. Multinomial logistic models were used to relate midlife RTLs to the probabilities of assignment to subsequent depressive symptom trajectory groups.

Results: We identified four depressive symptom trajectory groups: minimal depressive symptoms (62%), worsening depressive symptoms (14%), improving depressive symptoms (19%), and persistent-severe depressive symptoms (5%). Longer midlife RTLs were related to significantly lower odds of being in the worsening symptoms trajectory versus minimal trajectory but not to other trajectories. In comparison with being in the minimal symptoms group, the multivariable-adjusted odds ratio of being in the worsening depressive symptoms group was 0.78 (95% confidence interval, 0.62-0.97; p = 0.02), for every standard deviation increase in baseline RTL.

Conclusions: In this large prospective study of generally healthy women, longer telomeres at midlife were associated with significantly lower risk of a subsequent trajectory of worsening mood symptoms over 20 years. The results raise the possibility of telomere shortening as a novel contributing factor to late-life depression.
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http://dx.doi.org/10.1002/da.22892DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6548605PMC
June 2019

Genetic meta-analysis of diagnosed Alzheimer's disease identifies new risk loci and implicates Aβ, tau, immunity and lipid processing.

Nat Genet 2019 03 28;51(3):414-430. Epub 2019 Feb 28.

Research Center and Memory Clinic of Fundació ACE, Institut Català de Neurociències Aplicades-Universitat Internacional de Catalunya, Barcelona, Spain.

Risk for late-onset Alzheimer's disease (LOAD), the most prevalent dementia, is partially driven by genetics. To identify LOAD risk loci, we performed a large genome-wide association meta-analysis of clinically diagnosed LOAD (94,437 individuals). We confirm 20 previous LOAD risk loci and identify five new genome-wide loci (IQCK, ACE, ADAM10, ADAMTS1, and WWOX), two of which (ADAM10, ACE) were identified in a recent genome-wide association (GWAS)-by-familial-proxy of Alzheimer's or dementia. Fine-mapping of the human leukocyte antigen (HLA) region confirms the neurological and immune-mediated disease haplotype HLA-DR15 as a risk factor for LOAD. Pathway analysis implicates immunity, lipid metabolism, tau binding proteins, and amyloid precursor protein (APP) metabolism, showing that genetic variants affecting APP and Aβ processing are associated not only with early-onset autosomal dominant Alzheimer's disease but also with LOAD. Analyses of risk genes and pathways show enrichment for rare variants (P = 1.32 × 10), indicating that additional rare variants remain to be identified. We also identify important genetic correlations between LOAD and traits such as family history of dementia and education.
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http://dx.doi.org/10.1038/s41588-019-0358-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6463297PMC
March 2019

Medicare claims can identify post-stroke epilepsy.

Epilepsy Res 2019 03 8;151:40-47. Epub 2019 Feb 8.

Mongan Institute, Department of Medicine, Massachusetts General Hospital, 100 Cambridge Street, Boston, MA, 02114, USA; Department of Health Care Policy, Harvard Medical School, 677 Huntington Avenue, Boston, MA, 02115, USA. Electronic address:

Objective: There have been no validated Medicare claims-based algorithms available to identify epilepsy by discrete etiology of stroke (e.g., post-stroke epilepsy, PSE) in community-dwelling elderly individuals, despite the increasing availability of large datasets. Our objective was to validate algorithms that detect which patients have true PSE.

Methods: We linked electronic health records (EHR) to Medicare claims from a Medicare Pioneer Accountable Care Organization (ACO) to identify PSE. A neurologist reviewed 01/2012-12/2014 EHR data from a stratified sample of Medicare patients aged 65+ years to adjudicate a reference-standard to develop an algorithm for identifying patients with PSE. Patient sampling strata included those with: A) epilepsy-related claims diagnosis (n = 534 [all]); B) no diagnosis but neurologist visit (n = 500 [randomly sampled from 4346]); C) all others (n = 500 [randomly sampled from 16,065]). We reconstructed the full sample using inverse probability sampling weights; then used half to derive algorithms and assess performance, and the remainder to confirm performance. We evaluated predictive performance across several measures, e.g., specificity, sensitivity, negative and positive predictive values (NPV, PPV). We selected our best performing algorithms based on the greatest specificity and sensitivity.

Results: Of 20,943 patients in the reconstructed sample, 13.6% of patients with epilepsy had reference-standard PSE diagnosis, which represents a 3-year overall prevalence of 0.28% or 28/10,000, and a prevalence within the subpopulation with stroke of 3%. The best algorithm included three conditions: (a) at least one cerebrovascular claim AND one epilepsy-specific anticonvulsant OR (b) at least one cerebrovascular claim AND one electroencephalography claim (specificity 100.0% [95% CI 99.9%-100.0%], NPV 98.8% [98.6%-99.0%], sensitivity 20.6% [95% CI 14.6%-27.9%], PPV 86.5% [95% CI 71.2%-95.5%]).

Conclusion: Medicare claims can identify elderly Medicare beneficiaries with PSE with high accuracy. Future epidemiological surveillance of epilepsy could incorporate similar algorithms to accurately identify epilepsy by varying etiologies.
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http://dx.doi.org/10.1016/j.eplepsyres.2019.02.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6640134PMC
March 2019

Epilepsy Among Elderly Medicare Beneficiaries: A Validated Approach to Identify Prevalent and Incident Epilepsy.

Med Care 2019 04;57(4):318-324

Department of Medicine, Mongan Institute, Massachusetts General Hospital.

Background: Uncertain validity of epilepsy diagnoses within health insurance claims and other large datasets have hindered efforts to study and monitor care at the population level.

Objectives: To develop and validate prediction models using longitudinal Medicare administrative data to identify patients with actual epilepsy among those with the diagnosis.

Research Design, Subjects, Measures: We used linked electronic health records and Medicare administrative data including claims to predict epilepsy status. A neurologist reviewed electronic health record data to assess epilepsy status in a stratified random sample of Medicare beneficiaries aged 65+ years between January 2012 and December 2014. We then reconstructed the full sample using inverse probability sampling weights. We developed prediction models using longitudinal Medicare data, then in a separate sample evaluated the predictive performance of each model, for example, area under the receiver operating characteristic curve (AUROC), sensitivity, and specificity.

Results: Of 20,945 patients in the reconstructed sample, 2.1% had confirmed epilepsy. The best-performing prediction model to identify prevalent epilepsy required epilepsy diagnoses with multiple claims at least 60 days apart, and epilepsy-specific drug claims: AUROC=0.93 [95% confidence interval (CI), 0.90-0.96], and with an 80% diagnostic threshold, sensitivity=87.8% (95% CI, 80.4%-93.2%), specificity=98.4% (95% CI, 98.2%-98.5%). A similar model also performed well in predicting incident epilepsy (k=0.79; 95% CI, 0.66-0.92).

Conclusions: Prediction models using longitudinal Medicare data perform well in predicting incident and prevalent epilepsy status accurately.
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http://dx.doi.org/10.1097/MLR.0000000000001072DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6417929PMC
April 2019

Genetic overlap between vascular pathologies and Alzheimer's dementia and potential causal mechanisms.

Alzheimers Dement 2019 01 19;15(1):65-75. Epub 2018 Sep 19.

Department of Epidemiology, Harvard T. H. Chan School of Public Health, Boston, MA, USA; Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA; Gerontology Research Unit, Massachusetts General Hospital, Boston, MA, USA. Electronic address:

Introduction: We sought to examine the genetic overlap between vascular pathologies and Alzheimer's disease (AD) dementia, and the potential mediating role of vascular pathologies between AD-related genetic variants and late-life cognition.

Methods: For 2907 stroke-free older individuals, we examined the association of polygenic risk scores for AD dementia (ADPRSs) with vascular pathologies and with cognition. Mediation analyses addressed whether association between ADPRSs and cognition was mediated by a vascular pathology.

Results: ADPRSs were associated with lobar cerebral microbleeds, white matter lesion load, and coronary artery calcification, mostly explained by single nucleotide polymorphisms in the 19q13 region. The effect of ADPRSs on cognition was partially but significantly mediated by cerebral microbleeds, white matter lesions, and coronary artery calcification.

Discussion: Our findings provide evidence for genetic overlap, mostly due to apolipoprotein E (APOE) gene, between vascular pathologies and AD dementia. The association between AD polygenic risk and late-life cognition is mediated in part via effects on vascular pathologies.
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http://dx.doi.org/10.1016/j.jalz.2018.08.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6435328PMC
January 2019

Brain Exercise and Brain Outcomes: Does Cognitive Activity Really Work to Maintain Your Brain?

JAMA Psychiatry 2018 07;75(7):703-704

Department of Epidemiology, Boston University School of Public Health, Boston, Massachusetts.

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http://dx.doi.org/10.1001/jamapsychiatry.2018.0656DOI Listing
July 2018

Polygenic pleiotropy and potential causal relationships between educational attainment, neurobiological profile, and positive psychotic symptoms.

Transl Psychiatry 2018 05 16;8(1):97. Epub 2018 May 16.

Department of Psychiatry, Harvard Medical School, Boston, MA, USA.

Event-related potential (ERP) components have been used to assess cognitive functions in patients with psychotic illness. Evidence suggests that among patients with psychosis there is a distinct heritable neurophysiologic phenotypic subtype captured by impairments across a range of ERP measures. In this study, we investigated the genetic basis of this "globally impaired" ERP cluster and its relationship to psychosis and cognitive abilities. We applied K-means clustering to six ERP measures to re-derive the globally impaired (n = 60) and the non-globally impaired ERP clusters (n = 323) in a sample of cases with schizophrenia (SCZ = 136) or bipolar disorder (BPD = 121) and healthy controls (n = 126). We used genome-wide association study (GWAS) results for SCZ, BPD, college completion, and childhood intelligence as the discovery datasets to derive polygenic risk scores (PRS) in our study sample and tested their associations with globally impaired ERP. We conducted mediation analyses to estimate the proportion of each PRS effect on severity of psychotic symptoms that is mediated through membership in the globally impaired ERP. Individuals with globally impaired ERP had significantly higher PANSS-positive scores (β = 3.95, P = 0.005). The SCZ-PRS was nominally associated with globally impaired ERP (unadjusted P = 0.01; R = 3.07%). We also found a significant positive association between the college-PRS and globally impaired ERP (FDR-corrected P = 0.004; R = 6.15%). The effect of college-PRS on PANSS positivity was almost entirely (97.1%) mediated through globally impaired ERP. These results suggest that the globally impaired ERP phenotype may represent some aspects of brain physiology on the path between genetic influences on educational attainment and psychotic symptoms.
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http://dx.doi.org/10.1038/s41398-018-0144-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5954124PMC
May 2018

Impaired memory is more closely associated with brain beta-amyloid than leukoaraiosis in hypertensive patients with cognitive symptoms.

PLoS One 2018 30;13(1):e0191345. Epub 2018 Jan 30.

Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, United States of America.

Background: Hypertension is the strongest modifiable risk factor for subcortical ischemic changes and is also a risk factor for Alzheimer's dementia. We used neuroimaging to investigate the pathological basis of early cognitive symptoms in patients with hypertension.

Methods: In this cross-sectional cohort study 67 patients age >60 years with hypertension and Clinical Dementia Rating scale score of 0.5 without dementia, and without history of symptomatic stroke, underwent MRI for measurement of subcortical vascular changes and positron emission tomography (PET) scan with Pittsburgh Compound B (PiB-PET) to detect beta-amyloid deposition. These imaging measures were related to neuropsychological tests of memory, executive function and processing speed.

Results: Mean age was 75.0 (standard deviation, SD, 7.3). Mean neuropsychological Z scores were: episodic memory -0.63 (SD 1.23), executive function -0.40 (SD 1.10), processing speed -0.24 (SD 0.88); 22 of the 67 subjects met criteria for mild cognitive impairment (MCI) and the remaining 45 subjects had subjective cognitive concerns only. In multivariable models adjusting for age and years of education, each 0.1 unit increase in mean cortical PiB-PET binding was associated with 0.14 lower mean Z score for episodic memory (95% CI -0.28 to -0.01). This means that for every 0.1 unit increase in mean cortical PiB-PET, episodic memory was 0.14 standard deviations lower. White matter hyperintensity volume, silent brain infarcts and microbleeds were not associated with neuropsychological test scores.

Conclusions: Episodic memory was prominently affected in hypertensive participants with MCI or subjective cognitive concerns, and was associated with PiB-PET binding. This suggests a prominent role for Alzheimer pathology in cognitive impairment even in hypertensive participants at elevated risk for vascular cognitive impairment.
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Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0191345PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5790236PMC
February 2018
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