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, 53.0Â years; 57.5% women). During follow-up (median, 20.5Â 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 1.0Â Âµmol/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 0.1Â Âµmol/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.
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
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 (nâ€Š=â€Š882), the Xgboost model achieved a concordance index (C-index) of 84.5%. When the model was used for MCI risk prediction in CN (nâ€Š=â€Š100) 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.
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.
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.
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.
Obstructive Sleep Apnea and Hypertension with Longitudinal Î²-Amyloid Burden and Cognitive Changes
Bubu, Omonigho M; Kaur, Sonya S; Mbah, Alfred K; Umasabor-Bubu, Ogie Q; Ramos-Cejudo, Jaime; Debure, Ludovic; Mullins, Anna E; Parekh, Ankit; Kam, Korey; Osakwe, Zainab T; Williams, Ellita T; Turner, Arlener D; Glodzik, Lidia; Rapoport, David M; Ogedegbe, Gbenga; Fieremans, Els; de Leon, Mony J; Ayappa, Indu; Jean-Louis, Girardin; Masurkar, Arjun V; Varga, Andrew W; Osorio, Ricardo S
Plasma Amyloid-Î² dynamics in late-life major depression: a longitudinal study
Pomara, Nunzio; Bruno, Davide; Plaska, Chelsea Reichert; Ramos-Cejudo, Jaime; Osorio, Ricardo S; Pillai, Anilkumar; Imbimbo, Bruno P; Zetterberg, Henrik; Blennow, Kaj
Depressed individuals are twice as likely to develop Alzheimer's disease (AD) as compared to controls. Brain amyloid-Î² (AÎ²) deposition is believed to have a major role in AD pathogenesis but studies also suggest associations of AÎ² dynamics and depression. The aim of this study was to test if plasma AÎ² levels are longitudinally associated to late-life depression. We measured plasma levels of amyloid-Î²1-40 (AÎ²40) and amyloid-Î²1-42 (AÎ²42) peptides longitudinally for three consecutive years in 48 cognitively intact elderly subjects with late-life major depressive disorder (LLMD) and 45 age-matched cognitively healthy controls. We found that the AÎ²42/AÎ²40 plasma ratio was significantly and steadily lower in depressed subjects compared to controls (pâ€‰<â€‰0.001). At screening, AÎ²42/AÎ²40 plasma did not correlate with depression severity (as measured with Hamilton Depression Scale) or cognitive performance (as measured with Mini-Mental State Examination) but was associated to depression severity at 3â€‰years after adjustment for age, education, cognitive performance, and antidepressants use. This study showed that reduced plasma AÎ²42/AÎ²40 ratio is consistently associated with LLMD diagnosis and that increased severity of depression at baseline predicted low AÎ²42/AÎ²40 ratio at 3â€‰years. Future studies are needed to confirm these findings and examine if the consistently lower plasma AÎ²42/AÎ²40 ratio in LLMD reflects increased brain amyloid deposition, as observed in AD subjects, and an increased risk for progressive cognitive decline and AD.
Endotyping Sleep Apnea One Breath at a Time: An Automated Approach for Separating Obstructive from Central Sleep-disordered Breathing
Parekh, Ankit; Tolbert, Thomas M; Mooney, Anne M; Ramos-Cejudo, Jaime; Osorio, Ricardo S; Treml, Marcel; Herkenrath, Simon-Dominik; Randerath, Winfried J; Ayappa, Indu; Rapoport, David M
Longitudinal increase in CSF strem2 is associated with increased markers of CSF ad pathology in late-life major depression potentially reflecting a compensatory mechanism [Meeting Abstract]
Pomara, N; Plaska, C R; Ramos-Cejudo, J; Bruno, D; Osorio, R; Heslegrave, A; Pillai, A; Zetterberg, H; Blennow, K
Background: Triggering receptor expressed on myeloid cells 2 (TREM2) is a transmembrane innate immune receptor of the immunoglobulin family. In the brain, TREM2 is found exclusively on microglia and its stimulation has been associated with antiinflammatory and protective effects. Activation of TREM2 also results in the formation of a proteolytic soluble product (sTREM2). Higher baseline CSF sTREM2 concentrations have been associated with a slower rate of cognitive decline and decreased longitudinal brain amyloid deposition in Alzheimer's disease (AD). Thus, it has been proposed that CSF sTREM2 might reflect an antiinflammatory state. In a previous study by our group (ACNP presentation 2017), cognitively unimpaired individuals with latelife major depression (LLMD) which is associated with increased risk for AD, showed significant reductions in CSF sTREM2 levels and a lack of significant correlations with CSF AD biomarkers compared to controls, consistent with the aforementioned hypothesis and that TREM2- mediated anti-inflammatory microglia activation might be impaired in this disorder. In the current report, we examined the relationship between longitudinal changes in CSF sTREM2 during a 3-year period and their relationship to LLMD diagnosis and changes in AD and inflammatory markers.
Method(s): Our baseline sample consisted of 51 subjects aged 60 years and older who completed a longitudinal observational study over three years and an optional lumbar puncture (LP). 38 of these individuals completed the LP at year 3 (20 with LLMD and 18 controls). We evaluated the effects of time on CSF TREM2 with related-samples Wilcoxon Signed Rank Test and the effect diagnosis on change in CSF sTREM2 with Mann Whitney U test. Correlations between change in CSF sTREM2 and CSF markers of AD (Abeta42, Abeta40, total-tau, p-tau181), inflammation (Il-6, Il-8), and Complement component 3 (C3) markers were run with Spearman's Rank test.
Result(s): Baseline CSF sTREM2 was significantly lower in the LLMD group vs controls (p = 0.03). There were no group differences in CSF sTREM2 from baseline to Year 3 (LLMD p = 0.82, Controls p = 0.18), nor did Year 3 differ between the LLMD and control group (p = 0.35). No differences were observed between controls and LLMD for the longitudinal change in CSF sTREM2, AD biomarkers and inflammatory markers. In the whole group, change in sTREM2 was significantly moderately correlated with change in CSF Abeta40 (rho = 0.54, p < 0.001), Abeta42 (rho = 0.48, p = 0.003), and PTau181 (rho = 0.34, p = 0.04). In the control group, change in sTREM2 was significantly correlated with change in CSF Abeta40 (rho = 0.58, p = 0.01) and Abeta42 (rho = 0.56, p = 0.02). In the LLMD group, change in sTREM2 was significantly correlated with change in CSF Abeta40 (rho = 0.50, p = 0.03), Tau (rho = 0.44, p = 0.05) and P-Tau181 (rho = 0.52, p = 0.02) but not with change in CSF Abeta42, a more specific marker of cerebral amyloidosis. Change in inflammatory markers (i.e., IL-6, IL-8) were not significantly correlated with change in sTREM2 (p > 0.05) for LLMD or controls, or the whole group. Change in sTREM2 was significantly correlated with C3 (rho = 0.35, p = 0.04) in the whole group.
Conclusion(s): There were no group differences in change in CSF sTREM2 during a 3-year period, nor any difference between baseline and year 3. The longitudinal increase in CSF sTREM2 during a 3-year period and its association with CSF AD biomarkers may reflect increased anti-inflammatory microglia activation and phagocytosis in response to pathological forms of AD biomarkers Abeta, tau, and p-tau 181. Interestingly, the CSF sTREM2 increase was associated with the increase CSF Abeta42 in controls, but not in LLMD. This finding suggests that upregulation of anti-inflammatory microglia and phagocytosis of brain amyloid deposits may be less efficient in LLMD. Similarly, the positive correlation between the longitudinal increase in CSF sTREM2 and the increase in CSF T-tau and Ptau181, which we found in the LLMD group but not in controls is also consistent with an upregulation of anti-inflammatory microglia in response to increased tau and neurofibrillary tangles, markers of neurodegeneration and AD, respectively. However, the change in CSF sTREM2 was correlated with the change in CSF C3 in the whole cohort; our group and others have also found positive correlations between CSF sTREM2 and CSF neurofilament light (NFL) protein, a biomarker of neuroaxonal damage. Taken together these results suggest that higher CSF sTREM2 concentrations may reflect not only upregulation of antiinflammatory microglia and phagocytosis in response to increased brain amyloid and tau pathology, but also increased neurotoxic effects which are possibly related to its reported intrinsic proinflammatory effects