Chronic Pain and Postoperative Cognitive Function in the Elderly: a Prospective Observational Study
To assess the possible interrelation between pre-operative chronic pain and postoperative cognitive dysfunction (POCD) in the elderly, we plan to enroll patients undergoing planned surgery. To evaluate the initial pain states, pain and mood questionnaires will be used prior to surgery. To explore the potential interrelation between chronic pain and POCD, pre-, and postoperative cognitive dysfunction will be assessed using common cognitive tests. Moreover, neurocognitive biomarkers will be assessed with blood samples drawn peri- and postoperatively with optional EEG-recordings prior to and after surgery. An optional MRI will be performed in randomly assigned subjects prior to surgery.
A SINGLE-CENTER OBSERVATIONAL LONGITUDINAL STUDY ON THE EFFECT OF SLOW WAVE SLEEP (SWS) CHARACTERISTICS AND RACE AND ETHNICITY ON AMYLOID BURDEN (A MARKER OF ALZHEIMER S DISEASE RISK) AMONG COGNITIVELY NORMAL ELDERLY.
African-Americans (AAs) have an increased prevalence of both Alzheimer’s disease (AD) and vascular risk factors for AD such as diabetes and hypertension when compared to whites. This larger component of AD-dementia has traditionally been associated with vascular risk and supported by studies showing that AAs with clinical AD more frequently have mixed pathology on autopsy. However, in a recent community based study of non-demented elderly, black race was associated with higher amyloid burden after adjusting for vascular risk factors, suggesting the presence of additional physiological differences on AD-risk by race in the early stages of the disease. The purpose of this study is to test whether poor slow wave sleep (SWS) quantity (SWS duration) and quality (slow wave activity, SWA) is one of these physiological factors.
Transcranial Photobiomodulation for Alzheimer's Disease
This multi-site study will be the first to evaluate the dose-dependent effects of t-PBM in amnestic Mild Cognitive Impairment (aMCI) and early Alzheimer’s Disease (AD) (CDR of 0.5-1, FAST 1-4; age 65-85) in a randomized clinical trial of 8 weeks of t-PBM vs. sham. At baseline, all subjects will complete initial neuropsychological testing. To elucidate mechanisms of action of t-PBM, prior to treatment, subjects will undergo neuroimaging related to critical features of AD: tau 18F MK-6240 load (PET), measures of brain bioenergetics (31P-MRS), and functional connectivity (rs-fMRI). After undergoing target engagement testing (t-PBM session performed during fMRI to detect BOLD changes with active t-PBM), subjects will then be randomized to t-PBM/sham. Subjects will then complete 24 t-PBM/sham treatments, ~6 min per day, 3 days per week, for 8 weeks. t-PBM will be administered via continuous, 808 nm wavelength laser delivery to the forehead bilaterally (at standard EEG electrode positions F4, F3).
Brain Effects of Lifetime Racial/Ethnic Discrimination on the LC-NE Function and the Risk for Alzheimer's Disease
The current biomarker classification system (i.e., the ATN model) may not fully account for racial disparity and can’t explain the increased prevalence in blacks of both AD and vascular risk factors for AD such as diabetes and hypertension when compared to whites. Postmortem studies suggest that loss of LC neurons better predicts severity of AD clinical symptoms than Aß/neurofibrillary tangle pathology in any other cortical/subcortical brain region. Our decade-long studies in humans have demonstrated a special vulnerability of LC to aging and stress. Further, our preliminary data in black and white subjects reveals that the decline rate of LC neurons is much faster in blacks starting in the mid-30s, particularly in black males. We now aim to test the hypothesis that cumulative exposure to socioeconomic disadvantage and racial discrimination may cause long-lasting changes in LC function followed by LC neuronal loss, which would explain the different AD phenotypical presentation among blacks; by asking120 cognitively normal older adults (80 blacks and 40 whites) to perform clinical evaluation, cognitive measurement, biomarkers (ATN and vascular markers) assessment, stress and discrimination scale testing, and one [11C]MRB PET-MR scan to determine NET availability.
Depression treatment and A dynamics: A study of Alzheimer s disease risk (ABD Study)
The study will use a randomized 8-week double-blind placebo controlled parallel trial using escitalopram to test the associations between depressive symptoms (captured by the MADRS and other depression scales), and AD biomarkers in both CSF and plasma as well as changes in vascular dysfunction (VD)-associated biomarkers(MMP2, MMP9, homocysteine, and platelet activation markers P-selectin and GP IIa/IIIb). The primary endpoints are the severity of depression symptoms at baseline, the change in depression scores after treatment with escitalopram, and the associated changes in AD and VD markers peptide levels. Secondary endpoints are depression severity at baseline, which will be tested in regression models in relation to the AD biomarkers (Aß peptides in CSF) cross-sectionally at baseline and after antidepressant treatment to test that Aß peptides are correlated with symptoms. The study will also examine if decreased levels of VD-associated biomarkers will (at least partially) mediate the effect of depression treatment response on increases in CSF Aß levels. This proposal will be the first to explore the relationships between CSF AD and VD biomarker levels and MDD symptom severity in cognitively normal MDD patients and the direction of causation between changes in Aß and VD biomarkers and changes in MDD symptom severity. The results of this study, if successful, may provide a rationale for reducing AD risk through a more effective treatment of depression in the elderly.
Race-spEcific regional Tau deposition and role of Obstructive Sleep Apnea (RETOSA)
This proposal will generate pilot data for an R01 application that aims to determine whether Blacks/African Americans (‘blacks’) generally exhibit lower tau-PET signal compared to non-Hispanic whites (‘whites’) for a given level of global Aß burden, and further determine the effect of obstructive sleep apnea (OSA) as a possible race-related biologic mechanism on this signal. To do this, we will leverage data and resources from NYU Alzheimer’s Disease Research Center (ADRC NYULH STUDY ID#: s20-00427) and two affiliated ongoing NIH supported R01 studies (2R01AG056031 NYULH STUDY ID#: s17-01005 and 1R01AG056531 NYULH STUDY ID#: s18-01302). All studies have neuroimaging measures of vascular burden, and amyloid. NYULH STUDY ID#: s17-01005 and NYULH STUDY ID#: s20-00427 have tau-PET neuroimaging using 18F-PI2620 or 18F-MK6240 MR scans. NYULH STUDY ID#: s17-01005 and NYULH STUDY ID#: s18-01302 have nocturnal polysomnography (NPSG) recordings. This study adds tau-PET neuroimaging using 18F-PI2620 or 18F-MK6240 MR scan to 24 black subjects in 1R01AG056531 NYULH STUDY ID#: s18-01302. Altogether, subjects will include 120 cognitively normal (60 controls [30 blacks & 30 whites recruited from both NYULH STUDY ID#: s18-01302 & NYULH STUDY ID#: s20-00427) and 60 newly diagnosed OSA subjects with complaints of EDS [30 blacks & 30 whites]), ages 60-75 (recruited from NYULH STUDY ID#: s17-01005) relatively matched on or similar in age (60-75 range), sex, BMI, education and income.
Mechanisms of rAcial dIfferences in the relatioNship between Obstructive Sleep Apnea and in vivo Tau deposition in the context of AmYloid burden
African-Americans (blacks) have two times the risk of developing Alzheimer’s disease (AD) compared to non-Hispanic whites.1-6 Neuropathological studies show blacks with more mixed pathology1-6. Recent evidence demonstrate differences in AD biomarkers with blacks having decreased cortical thickness, and lower cerebrospinal fluid (CSF) P-tau, and T-tau.7-10. Notably, area-based socio-economic status (SES) partly explain racial differences in cortical thickness.11 This suggests the possible existence of additional physiologic differences on AD-risk by race, mediated by SES and resulting to greater neuronal loss, similar or less CSF-tau for similar levels of amyloid. Recent studies suggest that obstructive sleep apnea (OSA) increases AD-risk,12-14 is associated with higher brain amyloid and tau in cognitive normal (CN) participants.15-22. Notably, blacks have a higher burden of symptomatic OSA, particularly with excessive daytime sleepiness (EDS),23 which is associated with longitudinal amyloid-PET uptake.24. Potential intermediate mechanisms linking OSA and AD, such as decreased non rapid eye movement (NREM) slow wave activity (SWA) and increased inflammation affect amyloid and tau pathology,25,26 are associated with changes in cognition in late-life,27 and are more burdensome in blacks.28 OSA effects changes in circulating levels of CRP, TNFa, IL-6, and IL-17A.29,30 . More importantly, inflammation arising from cumulative stress exposure placed blacks at a greater risk for developing vascular risk factors,31-33 that increase AD-risk. In addition, SES and psychosocial factors11,34-36 may contribute to increase OSA and AD-risk in blacks. This highlights the need to utilize OSA as a unique disease model to explore racial differences in AD biomarkers.
Investigating the Temperature Dependence of Age-related Tau Pathology Relevant to Early Alzheimer's Disease
This is a cross-sectional study in 100 older adults (n = 100, 50 female, 60–80 years) who are cognitively normal (n = 70) or have mild cognitive impairment (n = 30). The purpose is to test whether features of body temperature (Tb), measured with ingestible telemetry, are associated with tau pathology, measured with [18-F]-MK-6240 tau PET-MR and plasma P-tau. Participant involvement includes 6 study visits over a period of 4 months. The duration of the project is 5 years. Briefly, subjects who express interest and are eligible for screening based on a pre-screening call will undergo in-person medical screening and complete several intake questionnaires at Visit 1, followed by a blood draw at CTSI, a clinical interview and neuropsychological testing at Visit 2. A 7-day at-home sleep assessment and actigraphy data, after Visit 2, will help us determine sleep-wake cycles and screen for Obstructive Sleep Apnea which is exclusionary for our study, if severe. At Visits 3 & 4, subjects will undergo body temperature measurements with ingestible telemetric thermometry over 48 hours, commencing on Night 1 of a 48 hour visit to the MSCIC sleep lab. Sleep EEG characteristics will be assessed with polysomnography on Nights 1 and 2 of this 48 hour period. During the day between these nights, subjects will be free to return home. After sleep study data is analyzed, the Eligibility Checklist can be completed. At Visit 5 which will take place at least 7 days after the sleep study completion, subjects will undergo a Tau PET/MR scan at the Center for Biomedical Imaging. At Visit 6, at least 7 days after the sleep study (but not on the same day as the Tau PET/MR) subjects will undergo an amyloid PET/MR scan. The purpose of the PET/MR scans is to control for tau and amyloid burden in the central nervous system.This cross-sectional study will lay the ground work for future prospective studies to determine whether Tb based interventions can prevent the progression of NFT pathology toward reducing Alzheimer’s Disease burden.
Using a Health Disparity Research Framework to examine mechanisms linking Obstructive Sleep Apnea with higher Alzheimer s disease risk in older Blacks/African-Americans
Blacks/African-Americans (blacks) have two times the risk of developing Alzheimer’s disease (AD) compared to non-Hispanic whites (whites), in part attributable to the higher prevalence of vascular risk factors such as diabetes and hypertension. Obstructive sleep apnea (OSA) is one such risk factor. Notably, blacks have a higher burden of OSA with excessive daytime sleepiness (EDS), which is associated with longitudinal amyloid-PET uptake. OSA is associated with decreased non rapid eye movement (NREM) slow wave sleep/activity (SWS/SWA) and increased inflammation, both of which affect amyloid and tau pathology. Reduced NREM SWS/SWA and inflammation are also associated with changes in cognition in late-life, and are more burdensome in blacks. Our central hypothesis is that black OSA participants will exhibit higher tau and greater neurodegeneration, as well as reduced NREM SWS/SWA and increased inflammation compared to their white counterparts, in the context of amyloid burden. Furthermore, we hypothesize structural/social determinants of health (SDOH; i.e., environmental, socio-structural, and behavioral factors) and vascular risk will mediate racial/ethnic heterogeneity in OSA-AD outcomes. We will test our central hypothesis in a sample of 300 community-dwelling cognitively normal (CN) subjects, ages 55-85 matched on race (2:1), age and sex, and balanced by education, income and BMI. Subjects will include 150 controls (100 blacks & 50 whites), and 150 newly diagnosed OSA subjects with complaints of EDS (100 blacks & 50 whites). Subjects will be recruited primarily from the community, guided by principles of stakeholder-engaged research, and undergo 2 nights of at-home sleep monitoring for OSA, followed by 5 days of actigraphy and sleep logs. Clinical visits will include: full clinical evaluation, neuropsychological tests and clinical labs on visit 1; one night of nocturnal polysomnography (NPSG) recording on visit 2; obtaining neuroimaging measures of vascular burden and amyloid on visit 3, and tau on visit 4, using 18F-florbetaben (FBB) and MK 6240 (with PI2620 as a backup) PET-MRI respectively, at baseline and at 2.5 years follow-up. More importantly, we will prioritize acquisition of SDOH data to elucidate disease mechanisms to aid future discovery of disease prevention targets.
Effects of Successful OSA TreatmENT on Memory and AD BIomarkers in Older AduLts (ESSENTIAL)
The prevalence of Alzheimer disease (AD) is high and projected to increase. Further, epidemiological data suggests that ~15% of AD risk may be attributed to sleep problems. Obstructive sleep apnea (OSA) is common among the elderly (30-55%), and our prior work has established that cognitively normal older women with OSA have nearly double the 5-year risk of developing mild cognitive impairment (MCI) or dementia. Further, we showed that: i. OSA patients treated with positive airway pressure (PAP) experienced significant overnight increases in plasma neurofilament light (NfL), a marker of neural injury, with trends for AD-specific biomarkers (i.e. Aß40 and Tau) after PAP withdrawal; ii. OSA predicted longitudinal increases in AD biomarkers; and, iii. PAP treatment delayed the onset of MCI in subjects with reported OSA. There is therefore strong evidence suggesting that OSA treatment could be an important prevention strategy for AD. However, OSA trials to slow progression to AD face a number of challenges. First, the most effective therapy (i.e. PAP) has poor adherence. Second is defining the target population, prior trials targeted OSA patients with MCI/AD, who have advanced disease and could be less amenable to treatment. A third challenge is identifying cognitive testing that is sensitive to both sleep disruption and predictive of AD risk. (To better capture effects of OSA on the offline memory processing phase requires sleep-dependent memory paradigms, in which the encoding and recall are separated by a period of sleep with/without OSA). Finally, a randomized trial of sufficient duration to test the effects of treatment of OSA on risk of incident AD is currently not feasible. Our proposed trial, Effects of Successful OSA TreatmENT on Memory and AD BIomarkers in Older AduLts (ESSENTIAL), addresses these challenges. ESSENTIAL is a 5-year study of cognitively normal older adults with newly diagnosed OSA, ages 55-75, recruited from 4 well-established sleep clinics. OSA patients (n=200) will be randomized to either: i) a 3-month OSA treatment by any combination of PAP, OAT, and positional therapy that results in an “effective” improvement in the apnea-hypopnea index (AHI); ii) a waitlist control group to receive treatment at the conclusion of the 3-month intervention period. Effectively treated individuals (~150) and untreated individuals (~50 previously randomized +50 additionally-recruited untreated patients from the sleep clinic) will then be followed for up to 24 months to compare whether sustained improvements in AHI are associated with better cognitive function and AD biomarker change profiles as compared to untreated controls. Participants will undergo PSG, actigraphy, cognitive tests, and blood draws at baseline, 3 and 24 months. Our aims are to: 1) test 3-month differences in plasma AD biomarkers (NfL, p-tau, Aß) between those randomized to treatment and wait-list control groups; 2) test 3-month differences in cognition between the OSA treatment and wait-list control groups; 3) examine if sustained reduction in AHI over 24 months among effectively treated participants versus untreated controls is associated with better 24-month change profiles for AD biomarkers and cognition.