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Platelet Function Is Associated With Dementia Risk 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; Nunzio, Pomara; Bubu, Omonigho M; Parekh, Ankit; Convit, Antonio; Betensky, Rebecca A; Wisniewski, Thomas M; Osorio, Ricardo S
Background Vascular function is compromised in Alzheimer disease (AD) years before amyloid and tau pathology are detected and a substantial body of work shows abnormal platelet activation states in patients with AD. The aim of our study was to investigate whether platelet function in middle age is independently associated with future risk of AD. Methods and Results We examined associations of baseline platelet function with incident dementia risk in the community-based FHS (Framingham Heart Study) longitudinal cohorts. The association between platelet function and risk of dementia was evaluated using the cumulative incidence function and inverse probability weighted Cox proportional cause-specific hazards regression models, with adjustment for demographic and clinical covariates. Platelet aggregation response was measured by light transmission aggregometry. The final study sample included 1847 FHS participants (average age, 53.0 years; 57.5% women). During follow-up (median, 20.5 years), we observed 154 cases of incident dementia, of which 121 were AD cases. Results from weighted models indicated that platelet aggregation response to adenosine diphosphate 1.0 µmol/L was independently and positively associated with dementia risk, and it was preceded in importance only by age and hypertension. Sensitivity analyses showed associations with the same directionality for participants defined as adenosine diphosphate hyper-responders, as well as the platelet response to 0.1 µmol/L epinephrine. Conclusions Our study shows individuals free of antiplatelet therapy with a higher platelet response are at higher risk of dementia in late life during a 20-year follow-up, reinforcing the role of platelet function in AD risk. This suggests that platelet phenotypes may be associated with the rate of dementia and potentially have prognostic value.
PMID: 35470685
ISSN: 2047-9980
CID: 5215632

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
PMCID:8670436
PMID: 34916927
ISSN: 1663-4365
CID: 5080232

Survival Analysis in Cognitively Normal Subjects and in Patients with Mild Cognitive Impairment Using a Proportional Hazards Model with Extreme Gradient Boosting Regression

Khajehpiri, Boshra; Moghaddam, Hamid Abrishami; Forouzanfar, Mohamad; Lashgari, Reza; Ramos-Cejudo, Jaime; Osorio, Ricardo S; Ardekani, Babak A
BACKGROUND:Evaluating the risk of Alzheimer's disease (AD) in cognitively normal (CN) and patients with mild cognitive impairment (MCI) is extremely important. While MCI-to-AD progression risk has been studied extensively, few studies estimate CN-to-MCI conversion risk. The Cox proportional hazards (PH), a widely used survival analysis model, assumes a linear predictor-risk relationship. Generalizing the PH model to more complex predictor-risk relationships may increase risk estimation accuracy. OBJECTIVE:The aim of this study was to develop a PH model using an Xgboost regressor, based on demographic, genetic, neuropsychiatric, and neuroimaging predictors to estimate risk of AD in patients with MCI, and the risk of MCI in CN subjects. METHODS:We replaced the Cox PH linear model with an Xgboost regressor to capture complex interactions between predictors, and non-linear predictor-risk associations. We endeavored to limit model inputs to noninvasive and more widely available predictors in order to facilitate future applicability in a wider setting. RESULTS:In MCI-to-AD (n = 882), the Xgboost model achieved a concordance index (C-index) of 84.5%. When the model was used for MCI risk prediction in CN (n = 100) individuals, the C-index was 73.3%. In both applications, the C-index was statistically significantly higher in the Xgboost in comparison to the Cox PH model. CONCLUSION/CONCLUSIONS:Using non-linear regressors such as Xgboost improves AD dementia risk assessment in CN and MCI. It is possible to achieve reasonable risk stratification using predictors that are relatively low-cost in terms of time, invasiveness, and availability. Future strategies for improving AD dementia risk estimation are discussed.
PMID: 34864679
ISSN: 1875-8908
CID: 5110022

Potential long-term effect of tumor necrosis factor inhibitors on dementia risk: A propensity score matched retrospective cohort study in US veterans

Zheng, Chunlei; Fillmore, Nathanael R; Ramos-Cejudo, Jaime; Brophy, Mary; Osorio, Ricardo; Gurney, Mark E; Qiu, Wei Qiao; Au, Rhoda; Perry, George; Dubreuil, Maureen; Chen, Shu G; Qi, Xin; Davis, Pamela B; Do, Nhan; Xu, Rong
INTRODUCTION/BACKGROUND:Tumor necrosis factor (TNF) inhibitors are widely used to treat rheumatoid arthritis (RA) and their potential to retard Alzheimer's disease (AD) progression has been reported. However, their long-term effects on the dementia/AD risk remain unknown. METHODS:A propensity scored matched retrospective cohort study was conducted among 40,207 patients with RA within the US Veterans Affairs health-care system from 2000 to 2020. RESULTS:A total of 2510 patients with RA prescribed TNF inhibitors were 1:2 matched to control patients. TNF inhibitor use was associated with reduced dementia risk (hazard ratio [HR]: 0.64, 95% confidence interval [CI]: 0.52-0.80), which was consistent as the study period increased from 5 to 20 years after RA diagnosis. TNF inhibitor use also showed a long-term effect in reducing the risk of AD (HR: 0.57, 95% CI: 0.39-0.83) during the 20 years of follow-up. CONCLUSION/CONCLUSIONS:TNF inhibitor use is associated with lower long-term risk of dementia/AD among US veterans with RA.
PMID: 34569707
ISSN: 1552-5279
CID: 5067402

Association of CSF sTREM2, a marker of microglia activation, with cholinergic basal forebrain volume in major depressive disorder

Teipel, Stefan; Bruno, Davide; Plaska, Chelsea Reichert; Heslegrave, Amanda; Ramos-Cejudo, Jaime; Osorio, Ricardo S; Zetterberg, Henrik; Blennow, Kaj; Pomara, Nunzio
BACKGROUND:Inflammatory mechanisms are believed to contribute to the manifestation of major depressive disorder (MDD). Central cholinergic activity may moderate this effect. Here, we tested if volume of the cholinergic basal forebrain is associated with cerebrospinal fluid (CSF) levels of sTREM2 as a marker of microglial activation in people with late life MDD. METHODS:Basal forebrain volume was determined from structural MRI scans and levels of CSF sTREM2 with immunoassay in 29 people with late-life MDD and 20 healthy older controls at baseline and 3 years follow-up. Associations were determined using Bayesian analysis of covariance. RESULTS:and total tau. Evidence was in favor of absence of an effect for baseline levels of CSF sTREM2 in MDD cases and for baseline and follow up data in controls. LIMITATIONS/CONCLUSIONS:The sample size of repeated CSF examinations was relatively small. Therefore, we used Bayesian sequential analysis to assess if effects were affected by sample size. Still, the number of cases was too small to stratify effects for different antidepressive treatments. CONCLUSIONS:Our data agree with the assumption that central cholinergic system integrity may contribute to regulation of microglia activity in late-life MDD.
PMID: 34246952
ISSN: 1573-2517
CID: 4936262

Evidence of upregulation of the cholinergic anti-inflammatory pathway in late-life depression

Pomara, Nunzio; Bruno, Davide; Plaska, Chelsea Reichert; Pillai, Anilkumar; Ramos-Cejudo, Jaime; Osorio, Ricardo; Imbimbo, Bruno P; Heslegrave, Amanda; Zetterberg, Henrik; Blennow, Kaj
BACKGROUND:Decreased cholinergic tone associated with increased proinflammatory cytokines has been observed in several human diseases associated with low-grade inflammation. We examined if this attenuated cholinergic anti-inflammatory pathway (CAP) mechanism contributed to increased neuroinflammation observed in depression. METHODS:We measured cerebrospinal fluid (CSF) cholinergic markers (AChE and BChE activities) in 28 individuals with longstanding late-life major depression (LLMD) and 19 controls and their relationship to central and peripheral levels of pro-inflammatory cytokines (IL-6 and IL-8). Additionally, we examined if these cholinergic indices were related to CSF markers of microglial activation and neuroinflammation (sTREM2 and complement C3). RESULTS:Compared with controls, LLMD patients had a significant reduction in CSF BChE levels. Lower CSF BChE and AChE activities were associated with lower CSF markers of microglial and neuroinflammation (sTREM2 and C3). In addition, in LLMD patients we found an inverse relationship between peripheral marker of inflammation (plasma IL-6) and CSF BChE and AChE levels. CONCLUSIONS:Our results suggest an upregulation of the CAP mechanism in LLMD with an elevation in peripheral markers of inflammation and concomitant reduction in markers of glial activation associated with a higher cholinergic tone. Future studies should confirm these findings in a larger sample including individuals with acute and more severe depressive episodes and across all ages.
PMID: 33756305
ISSN: 1573-2517
CID: 4822602

Carbonic anhydrase inhibitors prevent presymptomatic capillary flow disturbances in a model of cerebral amyloidosis

Gutiérrez-Jiménez, Eugenio; Rasmussen, Peter Mondrup; Mikkelsen, Irene Klærke; Kura, Sreekanth; Fruekilde, Signe K; Hansen, Brian; Bordoni, Luca; Carlsen, Jasper; Palmfeldt, Johan; Boas, David A; Sakadžić, Sava; Vinogradov, Sergei; Khatib, Mirna El; Ramos-Cejudo, Jaime; Wied, Boris; Leduc-Galindo, Desiree; Canepa, Elisa; Mar, Adam C; Gamallo-Lana, Begona; Fossati, Silvia; Østergaard, Leif
INTRODUCTION/BACKGROUND:Disturbances in microvascular flow dynamics are hypothesized to precede the symptomatic phase of Alzheimer's disease (AD). However, evidence in presymptomatic AD remains elusive, underscoring the need for therapies targeting these early vascular changes. METHODS:We employed a multimodal approach, combining in vivo optical imaging, molecular techniques, and ex vivo magnetic resonance imaging, to investigate early capillary dysfunction in C57BL/6-Tg(Thy1-APPSwDutIowa)BWevn/Mmjax (Tg-SwDI) mice without memory impairment. We also assessed the efficacy of carbonic anhydrase inhibitors (CAIs) in preventing capillary flow disturbances. RESULTS:Our study revealed capillary flow disturbances associated with alterations in capillary morphology, adhesion molecule expression, and amyloid beta (Aβ) load in 9- to 10-month-old Tg-SwDI mice without memory impairment. CAI treatment ameliorated these capillary flow disturbances, enhanced oxygen availability, and reduced Aβ load. DISCUSSION/CONCLUSIONS:These findings underscore the importance of capillary flow disturbances as early biomarkers in presymptomatic AD and highlight the potential of CAIs for preserving vascular integrity in the early stages of AD. HIGHLIGHTS/CONCLUSIONS:Uncovered early capillary dysfunction in a presymptomatic Alzheimer's disease (AD) mouse model. Evidence linking capillary stalls and capillary dysfunction with oxygen delivery issues in AD. Novel use of carbonic anhydrase inhibitors to prevent early capillary flow disturbances in AD.
PMCID:11936728
PMID: 40133235
ISSN: 1552-5279
CID: 5815312

Obstructive Sleep Apnea, Platelet Aggregation, and Cardiovascular Risk

Kovbasyuk, Zanetta; Ramos-Cejudo, Jaime; Parekh, Ankit; Bubu, Omonigho M; Ayappa, Indu A; Varga, Andrew W; Chen, Ming-Huei; Johnson, Andrew D; Gutierrez-Jimenez, Eugenio; Rapoport, David M; Osorio, Ricardo S
BACKGROUND:Although related, the precise mechanisms linking obstructive sleep apnea (OSA) and cardiovascular disease (CVD) are unclear. Platelets are mediators of CVD risk and thrombosis and prior studies suggested associations of OSA and platelet activity. The aim of this study is to assess the link between OSA, platelet activity, and CVD-related risk factors. METHODS AND RESULTS/RESULTS:=0.002). No associations were detected in nonaspirin users (n=417). CONCLUSIONS:No associations were detected between OSA and platelet aggregation in a community sample. Our finding that OSA associates with increased platelet aggregation in the aspirin group, most of whom use it for primary prevention of CVD, suggests that platelet aggregation may mediate the adverse impact of OSA on vascular health in individuals with existing CVD risk, supporting further investigation.
PMID: 39056328
ISSN: 2047-9980
CID: 5696172

Evidence for reduced anti-inflammatory microglial phagocytic response in late-life major depression

Reichert Plaska, Chelsea; Heslegrave, Amanda; Bruno, Davide; Ramos-Cejudo, Jaime; Han Lee, Sang; Osorio, Ricardo; Imbimbo, Bruno P; Zetterberg, Henrik; Blennow, Kaj; Pomara, Nunzio
Major depressive disorder (MDD) is associated with Alzheimer's disease (AD) but the precise mechanisms underlying this relationship are not understood. While it is well established that cerebrospinal fluid (CSF) soluble levels of triggering receptor expressed on myeloid cells 2 (sTREM2) increase during early stages of AD, how sTREM2 levels behave in subjects with MDD is not known. In a longitudinal study, we measured CSF sTREM2 levels in 27 elderly cognitively intact individuals with late-life major depression (LLMD) and in 19 healthy controls. We tested the hypothesis that, similarly to what happens in early stages of AD, CSF sTREM2 would be elevated in MDD. In addition, we compared the associations of CSF sTREM2, pro- and anti- inflammatory, and AD biomarkers in LLMD and control subjects. Surprisingly, we found that mean CSF sTREM2 levels were significantly reduced in LLMD compared to controls. This reduction was no longer significant at the 3-year follow-up visit when depression severity improved. In addition, we found that CSF sTREM2 was associated with AD biomarkers and proinflammatory cytokines in controls but not in LLMD. These findings suggest that impaired microglia phagocytic response to AD pathology may be a novel link between MDD and AD.
PMID: 38795783
ISSN: 1090-2139
CID: 5663152

Antidepressant exposure and long-term dementia risk in a nationwide retrospective study on US veterans with midlife major depressive disorder

Ramos-Cejudo, Jaime; Corrigan, June K; Zheng, Chunlei; Swinnerton, Kaitlin N; Jacobson, Sean R; La, Jennifer; Betensky, Rebecca A; Osorio, Ricardo S; Madanes, Sharon; Pomara, Nunzio; Iosifescu, Dan; Brophy, Mary; Do, Nhan V; Fillmore, Nathanael R
INTRODUCTION/BACKGROUND:The use of antidepressants in major depressive disorder (MDD) has been reported to influence long-term risk of Alzheimer's disease (AD) and AD-related dementias (AD/ADRD), but studies are conflicting. METHODS:We used inverse probability weighted (IPW) Cox models with time-varying covariates in a retrospective cohort study among midlife veterans with MDD within the US Veterans Affairs healthcare system from January 1, 2000 to June 1, 2022. RESULTS:A total of 35,200 patients with MDD were identified. No associations were seen regarding the effect of being exposed to any antidepressant versus no exposure on AD/ADRD risk (events = 1,056, hazard ratio = 0.94, 95% confidence interval: 0.81 to 1.09) or the exposure to specific antidepressant classes versus no exposure. A risk reduction was observed for female patients in a stratified analysis; however, the number of cases was small. DISCUSSION/CONCLUSIONS:Our study suggests that antidepressant exposure has no effect on AD/ADRD risk. The association in female patients should be interpreted with caution and requires further attention. HIGHLIGHTS/CONCLUSIONS:We studied whether antidepressant use was associated with future dementia risk. We specifically focused on patients after their first-ever diagnosis of depression. We used IPW Cox models with time-varying covariates and a large observation window. Our study did not identify an effect of antidepressant use on dementia risk. A risk reduction was observed in female patients, but the number of cases was small.
PMCID:11180845
PMID: 38717046
ISSN: 1552-5279
CID: 5671562