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Association of Midlife Depressive Symptoms with Regional Amyloid-β and Tau in the Framingham Heart Study

Gonzales, Mitzi M; Samra, Jasmeet; O'Donnell, Adrienne; Mackin, R Scott; Salinas, Joel; Jacob, Mini E; Satizabal, Claudia L; Aparicio, Hugo J; Thibault, Emma G; Sanchez, Justin S; Finney, Rebecca; Rubinstein, Zoe B; Mayblyum, Danielle V; Killiany, Ron J; Decarli, Charlie S; Johnson, Keith A; Beiser, Alexa S; Seshadri, Sudha
BACKGROUND:Depressive symptoms predict increased risk for dementia decades before the emergence of cognitive symptoms. Studies in older adults provide preliminary evidence for an association between depressive symptoms and amyloid-β (Aβ) and tau accumulation. It is unknown if similar alterations are observed in midlife when preventive strategies may be most effective. OBJECTIVE:The study aim was to evaluate the association between depressive symptoms and cerebral Aβ and tau in a predominately middle-aged cohort with examination of the apolipoprotein (APOE) ɛ4 allele as a moderator. METHODS:Participants included 201 adults (mean age 53±8 years) who underwent 11C-Pittsburgh Compound B amyloid and 18F-Flortaucipir tau positron emission tomography (PET) imaging. Depressive symptoms were evaluated with the Center for Epidemiological Studies Depression Scale (CES-D) at the time of PET imaging, as well as eight years prior. Associations between depressive symptoms at both timepoints, as well as depression (CES-D≥16), with regional Aβ and tau PET retention were evaluated with linear regression adjusting for age and sex. Interactions with the APOE ɛ4 allele were explored. RESULTS:Depressive symptoms and depression were not associated with PET outcomes in the overall sample. However, among APOE ɛ4 allele carriers, there was a significant cross-sectional association between depressive symptoms and increased tau PET uptake in the entorhinal cortex (β= 0.446, SE = 0.155, p = 0.006) and amygdala (β= 0.350, SE = 0.133, p = 0.012). CONCLUSION:Although longitudinal studies are necessary, the results suggest that APOE ɛ4 carriers with depressive symptoms may present with higher susceptibility to early tau accumulation in regions integral to affective regulation and memory consolidation.
PMID: 34024836
ISSN: 1875-8908
CID: 4964742

Herpes Labialis, Chlamydophila pneumoniae, Helicobacter pylori, and Cytomegalovirus Infections and Risk of Dementia: The Framingham Heart Study

Zilli, Eduardo Marques; O'Donnell, Adrienne; Salinas, Joel; Aparicio, Hugo J; Gonzales, Mitzi Michelle; Jacob, Mini; Beiser, Alexa; Seshadri, Sudha
BACKGROUND:An association between chronic infectious diseases and development of dementia has been suspected for decades, based on the finding of pathogens in postmortem brain tissue and on serological evidence. However, questions remain regarding confounders, reverse causality, and how accurate, reproducible and generalizable those findings are. OBJECTIVE:Investigate whether exposure to Herpes simplex (manifested as herpes labialis), Chlamydophila pneumoniae (C. pneumoniae), Helicobacter pylori (H. pylori), and cytomegalovirus (CMV) modifies the risk of dementia in a populational cohort. METHODS:Questionnaires regarding incidence of herpes infections were administered to Original Framingham Study participants (n = 2,632). Serologies for C. pneumoniae, H. pylori, and CMV were obtained in Original (n = 2,351) and Offspring cohort (n = 3,687) participants. Participants are under continuous dementia surveillance. Brain MRI and neuropsychological batteries were administered to Offspring participants from 1999-2005. The association between each infection and incident dementia was tested with Cox models. Linear models were used to investigate associations between MRI or neuropsychological parameters and serologies. RESULTS:There was no association between infection serologies and dementia incidence, total brain volume, and white matter hyperintensities. Herpes labialis was associated with reduced 10-year dementia risk (HR 0.66, CI 0.46-0.97), but not for the duration of follow-up. H. pylori antibodies were associated with worse global cognition (β -0.14, CI -0.22, -0.05). CONCLUSION:We found no association between measures of chronic infection and incident dementia, except for a reduction in 10-year dementia risk for patients with herpes labialis. This unexpected result requires confirmation and further characterization, concerning antiviral treatment effects and capture of episodes.
PMID: 34057145
ISSN: 1875-8908
CID: 5003632

The Neutrophil to Lymphocyte Ratio Is Associated With the Risk of Subsequent Dementia in the Framingham Heart Study

Ramos-Cejudo, Jaime; Johnson, Andrew D; Beiser, Alexa; Seshadri, Sudha; Salinas, Joel; Berger, Jeffrey S; Fillmore, Nathanael R; Do, Nhan; Zheng, Chunlei; Kovbasyuk, Zanetta; Ardekani, Babak A; Bubu, Omonigho M; Parekh, Ankit; Convit, Antonio; Betensky, Rebecca A; Wisniewski, Thomas M; Osorio, Ricardo S
PMID: 34916927
ISSN: 1663-4365
CID: 5080232

Particulate matter and episodic memory decline mediated by early neuroanatomic biomarkers of Alzheimer's disease

Younan, Diana; Petkus, Andrew J; Widaman, Keith F; Wang, Xinhui; Casanova, Ramon; Espeland, Mark A; Gatz, Margaret; Henderson, Victor W; Manson, JoAnn E; Rapp, Stephen R; Sachs, Bonnie C; Serre, Marc L; Gaussoin, Sarah A; Barnard, Ryan; Saldana, Santiago; Vizuete, William; Beavers, Daniel P; Salinas, Joel A; Chui, Helena C; Resnick, Susan M; Shumaker, Sally A; Chen, Jiu-Chiuan
Evidence suggests exposure to particulate matter with aerodynamic diameter <2.5 μm (PM2.5) may increase the risk for Alzheimer's disease and related dementias. Whether PM2.5 alters brain structure and accelerates the preclinical neuropsychological processes remains unknown. Early decline of episodic memory is detectable in preclinical Alzheimer's disease. Therefore, we conducted a longitudinal study to examine whether PM2.5 affects the episodic memory decline, and also explored the potential mediating role of increased neuroanatomic risk of Alzheimer's disease associated with exposure. Participants included older females (n = 998; aged 73-87) enrolled in both the Women's Health Initiative Study of Cognitive Aging and the Women's Health Initiative Memory Study of Magnetic Resonance Imaging, with annual (1999-2010) episodic memory assessment by the California Verbal Learning Test, including measures of immediate free recall/new learning (List A Trials 1-3; List B) and delayed free recall (short- and long-delay), and up to two brain scans (MRI-1: 2005-06; MRI-2: 2009-10). Subjects were assigned Alzheimer's disease pattern similarity scores (a brain-MRI measured neuroanatomical risk for Alzheimer's disease), developed by supervised machine learning and validated with data from the Alzheimer's Disease Neuroimaging Initiative. Based on residential histories and environmental data on air monitoring and simulated atmospheric chemistry, we used a spatiotemporal model to estimate 3-year average PM2.5 exposure preceding MRI-1. In multilevel structural equation models, PM2.5 was associated with greater declines in immediate recall and new learning, but no association was found with decline in delayed-recall or composite scores. For each interquartile increment (2.81 μg/m3) of PM2.5, the annual decline rate was significantly accelerated by 19.3% [95% confidence interval (CI) = 1.9% to 36.2%] for Trials 1-3 and 14.8% (4.4% to 24.9%) for List B performance, adjusting for multiple potential confounders. Long-term PM2.5 exposure was associated with increased Alzheimer's disease pattern similarity scores, which accounted for 22.6% (95% CI: 1% to 68.9%) and 10.7% (95% CI: 1.0% to 30.3%) of the total adverse PM2.5 effects on Trials 1-3 and List B, respectively. The observed associations remained after excluding incident cases of dementia and stroke during the follow-up, or further adjusting for small-vessel ischaemic disease volumes. Our findings illustrate the continuum of PM2.5 neurotoxicity that contributes to early decline of immediate free recall/new learning at the preclinical stage, which is mediated by progressive atrophy of grey matter indicative of increased Alzheimer's disease risk, independent of cerebrovascular damage.
PMID: 31746986
ISSN: 1460-2156
CID: 4347372

Design and results of a smartphone-based digital phenotyping study to quantify ALS progression

Berry, James D; Paganoni, Sabrina; Carlson, Kenzie; Burke, Katherine; Weber, Harli; Staples, Patrick; Salinas, Joel; Chan, James; Green, Jordan R; Connaghan, Kathryn; Barback, Josh; Onnela, Jukka Pekka
Objective/UNASSIGNED:The amyotrophic lateral sclerosis (ALS) trial outcome measures are clinic based. Active and passive smartphone data can provide important longitudinal information about ALS progression outside the clinic. Methods/UNASSIGNED:We used Beiwe, a research platform for smartphone-based digital phenotyping, to collect active (self-report ALSFRS-R surveys and speech recordings) and passive (phone sensors and logs) data from patients with ALS for approximately 24 weeks. In clinics, at baseline and every 3 months, we collected vital capacity, ALSFRS-R, and ALS-CBS at enrollment, week 12, and week 24. We also collected ALSFRS-R by telephone at week 6. Results/UNASSIGNED: < 0.001). ALSFRS-R slopes were equivalent and within-subject standard deviation was smaller for smartphone-based self-report (0.26 vs. 0.56). Use of Beiwe afforded weekly collection of speech samples amenable to a variety of analyses, and we found mean pause time to increase by 0.02 sec per month across the sample. Interpretation/UNASSIGNED:Smartphone-based digital phenotyping in people with ALS is feasible and informative. Self-administered smartphone ALSFRS-R scores correlate highly with clinic-based ALSFRS-R scores, have low variability, and could be used in clinical trials. More research is required to fully analyze speech recordings and passive data, and to identify optimal digital markers for use in future ALS clinical trials.
PMID: 31139685
ISSN: 2328-9503
CID: 4347342

Whole blood microRNA expression associated with stroke: Results from the Framingham Heart Study

Salinas, Joel; Lin, Honghuang; Aparico, Hugo J; Huan, Tianxiao; Liu, Chunyu; Rong, Jian; Beiser, Alexa; Himali, Jayandra J; Freedman, Jane E; Larson, Martin G; Rosand, Jonathan; Soreq, Hermona; Levy, Daniel; Seshadri, Sudha
Emerging evidence suggests microRNAs (miRNAs) may play an important role in explaining variation in stroke risk and recovery in humans, yet there are still few longitudinal studies examining the association between whole blood miRNAs and stroke. Accounting for multiple testing and adjusting for potentially confounding technical and clinical variables, here we show that whole blood miR-574-3p expression was significantly lower in participants with chronic stroke compared to non-cases. To explore the functional relevance of our findings, we analyzed miRNA-mRNA whole blood co-expression, pathway enrichment, and brain tissue gene expression. Results suggest miR-574-3p is involved in neurometabolic and chronic neuronal injury response pathways, including brain gene expression of DBNDD2 and ELOVL1. These results suggest miR-574-3p plays a role in regulating chronic brain and systemic cellular response to stroke and thus may implicate miR-574-3p as a partial mediator of long-term stroke outcomes.
PMID: 31393881
ISSN: 1932-6203
CID: 4347352

Polygenic Risk for Depression Increases Risk of Ischemic Stroke: From the Stroke Genetics Network Study

Wassertheil-Smoller, Sylvia; Qi, Qibin; Dave, Tushar; Mitchell, Braxton D; Jackson, Rebecca D; Liu, Simin; Park, Ki; Salinas, Joel; Dunn, Erin C; Leira, Enrique C; Xu, Huichun; Ryan, Kathleen; Smoller, Jordan W
BACKGROUND AND PURPOSE:Although depression is a risk factor for stroke in large prospective studies, it is unknown whether these conditions have a shared genetic basis. METHODS:We applied a polygenic risk score (PRS) for major depressive disorder derived from European ancestry analyses by the Psychiatric Genomics Consortium to a genome-wide association study of ischemic stroke in the Stroke Genetics Network of National Institute of Neurological Disorders and Stroke. Included in separate analyses were 12 577 stroke cases and 25 643 controls of European ancestry and 1353 cases and 2383 controls of African ancestry. We examined the association between depression PRS and ischemic stroke overall and with pathogenic subtypes using logistic regression analyses. RESULTS:=0.011) samples from the Stroke Genetics Network. Ischemic stroke risk increased by 3.0% (odds ratio, 1.03; 95% confidence interval, 1.00-1.05) for every 1 SD increase in PRS for those of European ancestry and by 8% (odds ratio, 1.08; 95% confidence interval, 1.04-1.13) for those of African ancestry. Among stroke subtypes, elevated risk of small artery occlusion was observed in both European and African ancestry samples. Depression PRS was also associated with higher risk of cardioembolic stroke in European ancestry and large artery atherosclerosis in African ancestry persons. CONCLUSIONS:Higher polygenic risk for major depressive disorder is associated with increased risk of ischemic stroke overall and with small artery occlusion. Additional associations with ischemic stroke subtypes differed by ancestry.
PMID: 29438084
ISSN: 1524-4628
CID: 4347322

Behavioral Interventions for Stroke Prevention: The Need for a New Conceptual Model

Salinas, Joel; Schwamm, Lee H
PMID: 28487341
ISSN: 1524-4628
CID: 4347302

Associations between social relationship measures, serum brain-derived neurotrophic factor, and risk of stroke and dementia

Salinas, Joel; Beiser, Alexa; Himali, Jayandra J; Satizabal, Claudia L; Aparicio, Hugo J; Weinstein, Galit; Mateen, Farrah J; Berkman, Lisa F; Rosand, Jonathan; Seshadri, Sudha
INTRODUCTION/BACKGROUND:Mechanisms underlying social determinants of stroke and dementia are unclear and brain-derived neurotrophic factor (BDNF) may contribute as a molecular link. METHODS:Using the Framingham Study, we examined social relationship measures as predictors of higher serum BDNF level and cumulative incidence of stroke and dementia. RESULTS:Among 3294 participants, controlling for age and sex, isolation trended with lower BDNF (odds ratio = 0.69 [0.47-1.00]). Participants with more companionship had reduced risk for stroke (hazard ratio [HR] = 0.59 [0.41-0.83]) and dementia (HR = 0.67 [0.49-0.92]). Greater emotional support was associated with higher BDNF (odds ratio = 1.27 [1.04-1.54]), reduced dementia risk (HR = 0.69 [0.51-0.94], and among smokers, reduced stroke risk (HR = 0.23 [0.10-0.57]). Associations persisted after additional adjustments. BDNF partly mediated the total effect between emotional support and dementia risk. CONCLUSIONS:Availability of social support appears to be associated with increased BDNF levels and, in certain subsets, reduce risk of subsequent dementia and stroke, thus warranting study of these pathways to understand their role in neuroprotection.
PMID: 29067329
ISSN: 2352-8737
CID: 4347312

Factors Associated With New-Onset Depression Following Ischemic Stroke: The Women's Health Initiative

Salinas, Joel; Ray, Roberta M; Nassir, Rami; Lakshminarayan, Kamakshi; Dording, Christina; Smoller, Jordan; Wassertheil-Smoller, Sylvia; Rosand, Jonathan; Dunn, Erin C
BACKGROUND:Psychosocial characteristics have a strong effect on risk of depression, and their direct treatment with behavioral interventions reduces rates of depression. Because new-onset poststroke depression (NPSD) is frequent, devastating, and often treatment-resistant, novel preventive efforts are needed. As a first step toward developing behavioral interventions for NPSD, we investigated whether prestroke psychosocial factors influenced rates of NPSD in a manner similar to the general population. METHODS AND RESULTS:Using the Women's Health Initiative, we analyzed 1424 respondents who were stroke-free at enrollment and had no self-reported history of depression from enrollment to their nonfatal ischemic stroke based on initiation of treatment for depression or the Burnam screening instrument for detecting depressive disorders. NPSD was assessed using the same method during the 5-year poststroke period. Logistic regression provided odds ratios of NPSD controlling for multiple covariates. NPSD occurred in 21.4% (305/1424) of the analytic cohort and varied by stroke severity as measured by the Glasgow scale, ranging from 16.7% of those with good recovery to 31.6% of those severely disabled. Women with total anterior circulation infarction had the highest level (31.4%) of NPSD while those with lacunar infarction had the lowest (16.1%). Prestroke psychosocial measures had different associations with NPSD depending on functional recovery of the individual. CONCLUSIONS:There is a difference in the relationship of prestroke psychosocial status and risk of NPSD depending on stroke severity; thus it may be that the same preventive interventions might not work for all stroke patients. One size does not fit all.
PMID: 28151400
ISSN: 2047-9980
CID: 4347292