Disentangling and quantifying the relative cognitive impact of concurrent mixed neurodegenerative pathologies.

Neurodegenerative pathologies such as Alzheimer disease neuropathologic change (ADNC), Lewy body disease (LBD), limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC), and cerebrovascular disease (CVD) frequently coexist, but little is known about the exact contribution of each pathology to cognitive decline and dementia in subjects with mixed pathologies. We explored the relative cognitive impact of concurrent common and rare neurodegenerative pathologies employing multivariate logistic regression analysis adjusted for age, gender, and level of education. We analyzed a cohort of 6,262 subjects from the National Alzheimer's Coordinating Center database, ranging from 0 to 6 comorbid neuropathologic findings per individual, where 95.7% of individuals had at least 1 neurodegenerative finding at autopsy and 75.5% had at least 2 neurodegenerative findings. We identified which neuropathologic entities correlate most frequently with one another and demonstrated that the total number of pathologies per individual was directly correlated with cognitive performance as assessed by Clinical Dementia Rating (CDR®) and Mini-Mental State Examination (MMSE). We show that ADNC, LBD, LATE-NC, CVD, hippocampal sclerosis, Pick disease, and FTLD-TDP significantly impact overall cognition as independent variables. More specifically, ADNC significantly affected all assessed cognitive domains, LBD affected attention, processing speed, and language, LATE-NC primarily affected tests related to logical memory and language, while CVD and other less common pathologies (including Pick disease, progressive supranuclear palsy, and corticobasal degeneration) had more variable neurocognitive effects. Additionally, ADNC, LBD, and higher numbers of comorbid neuropathologies were associated with the presence of at least one APOE ε4 allele, and ADNC and higher numbers of neuropathologies were inversely correlated with APOE ε2 alleles. Understanding the mechanisms by which individual and concomitant neuropathologies affect cognition and the degree to which each contributes is an imperative step in the development of biomarkers and disease-modifying therapeutics, particularly as these medical interventions become more targeted and personalized.

Impaired Kidney Function, Cerebral Small Vessel Disease and Cognitive Disorders: The Framingham Heart Study.

BACKGROUND AND HYPOTHESIS: It remains unclear if the relation of chronic kidney disease (CKD) with cognitive dysfunction is independent of blood pressure (BP). We evaluated kidney function in relation to premorbid BP measurements, cerebral small vessel disease (CSVD) and incident mild cognitive impairment (MCI) and dementia in Framingham Offspring Cohort participants. METHODS: We included Framingham Offspring participants free of dementia, attending an examination during midlife (exam cycle 6, baseline) for ascertainment of kidney function status, with brain MRI late in life (exam cycles 7-9), cognitive outcome data and available interim hypertension and blood pressure assessments. We related CKD (estimated glomerular filtration rate < 60 ml/min/1.73m2) and albuminuria (urine albumin-to-creatinine ratio ≥ 30 mg/g) to CSVD markers and cognitive outcomes using multivariable regression analyses. RESULTS: Among 2604 participants (mean age 67.4 ± 9.2, 64% women, 7% had CKD and 9% albuminuria), albuminuria was independently associated with covert infarcts (adjusted OR, 1.55 [1.00-2.38]; P = 0.049) and incident MCI and dementia (adjusted HR, 1.68 [1.18-2.41]; P = 0.005 and 1.71, [1.11-2.64]; P = 0.015, respectively). CKD was not associated with CSVD markers but was associated with higher risk of incident dementia (HR, 1.53 [1.02-2.29]; P = 0.041), While albuminuria was predictive of the Alzheimer's disease subtype (Adjusted HR = 1.68, [1.03-2.74]; P = 0.04), CKD was predictive of vascular dementia (Adjusted HR, 2.78, [1.16-6.68]; P = 0.023). CONCLUSIONS: Kidney disease was associated with CSVD and cognitive disorders in asymptomatic community dwelling participants. The relation was independent of premorbid BP, suggesting that the link between kidney and brain disease may involve additional mechanisms beyond blood pressure related injury.

Advancements in dementia research, diagnostics, and care in Latin America: Highlights from the 2023 Alzheimer's Association International conference satellite symposium in Mexico City.

INTRODUCTION: While Latin America (LatAm) is facing an increasing burden of dementia due to the rapid aging of the population, it remains underrepresented in dementia research, diagnostics, and care. METHODS: In 2023, the Alzheimer's Association hosted its eighth satellite symposium in Mexico, highlighting emerging dementia research, priorities, and challenges within LatAm. RESULTS: Significant initiatives in the region, including intracountry support, showcased their efforts in fostering national and international collaborations; genetic studies unveiled the unique genetic admixture in LatAm; researchers conducting emerging clinical trials discussed ongoing culturally specific interventions; and the urgent need to harmonize practices and studies, improve diagnosis and care, and use affordable biomarkers in the region was highlighted. DISCUSSION: The myriad of topics discussed at the 2023 AAIC satellite symposium highlighted the growing research efforts in LatAm, providing valuable insights into dementia biology, genetics, epidemiology, treatment, and care.

A Novel Method for Establishing Functional Change in Older Adults With Cognitive Impairment.

OBJECTIVE: The aim was to set syndrome stage-specific (eg, cognitively unimpaired, severe dementia) metrics for functional change. METHODS: We selected 18,097 individuals who participated in 2 National Alzheimer's Coordinating Center visits between June 2005 and May 2020, with completed collateral rating of functioning on activities of daily living assessed by the Functional Activities Questionnaire.Both distribution-based (ie, regression-based reliable change indices) and anchor-based (ie, typical change associated with advancing a syndromal stage for clinically meaningful difference) methods were applied for individuals classified as: unimpaired cognition, mild cognitive impairment, mild dementia, moderate dementia, or severe dementia. RESULTS: There were marked differences in the distribution of functional ratings depending on their syndromal stage. There were also differences in the functional change associated with advancing across different syndromal stages. These informed stage-specific metrics for reliable change indices and clinically meaningful differences. CONCLUSIONS: Our indices provide a hitherto unavailable method that allows clinicians to determine whether observed functional change is reliable or meaningful based on syndromal stage.

Insomnia symptom severity and cognitive performance: Moderating role of APOE genotype.

INTRODUCTION: We evaluated whether insomnia symptom severity was associated with cognitive function, and whether this relationship was modified by biomarkers associated with Alzheimer's disease risk. METHODS: We examined insomnia symptoms and neuropsychological performance 3.4 years later in 511 dementia-free Framingham Heart Study participants (62.65 ± 8.7 years, 50.9% male). Additionally, we explored insomnia symptoms combined with self-reported short habitual sleep duration and effect modification by apolipoprotein E (APOE) ε4 allele status. RESULTS: More severe insomnia symptoms were associated with lower performance on global cognition, and immediate and delayed Logical Memory recall, especially when insomnia symptoms were combined with short sleep duration. The association between insomnia symptoms and poorer memory recall was more pronounced in APOE ε4 allele carriers. DISCUSSION: Insomnia symptom severity was associated with worse subsequent global cognitive and memory performance, which was especially apparent in APOE ε4 allele carriers, suggesting that poor sleep might be particularly detrimental when the brain is already vulnerable to neurodegeneration.

Joint trajectories of cognition and gait speed in Mexican American and European American older adults: The San Antonio longitudinal study of aging.

OBJECTIVES: Cognitive decline and gait speed slowing are independent predictors of disability and mortality. While both factors increase in prevalence with advancing age, little is known about their combined patterns of change. The study goal was to identify joint trajectories of cognition and gait speed within an aging bi-ethnic cohort of Mexican Americans and European Americans. METHODS/DESIGN: Participants included 182 Mexican Americans and 188 European Americans, ages 65 to 74, who were followed over a mean of 9.5 years. Cognition was assessed with the mini-mental state examination and gait speed was examined with a timed 10-ft walk. Joint trajectory classes of cognition and gait speed were identified with latent growth mixture modeling. Odd-ratios assessed predictors for trajectory classes. RESULTS: Three latent trajectory classes were identified: (a) relatively stable cognition and gait (termed stable cognition and gait class, 65.4%); (b) deteriorating cognition and gait (termed cognitive and physical vulnerability class, 22.2%); (c) stable cognition and deteriorating gait (termed physical vulnerability class, 12.4%). The odds of classification in the cognitive and physical vulnerability class vs stable cognition and gait class was associated with Mexican American ethnicity (OR = 3.771, P = .016), age (OR = 1.186, P = .017), income (OR = 0.828, P = .029), education (OR = 0.703, P < .001), and diabetes (OR = 4.547, P = .010). The odds of classification in the physical vulnerability class was associated with female sex (OR = 6.481, P = .004) and body mass index (OR = 1.118, P = .025). CONCLUSIONS: The trajectories of cognition and gait speed were generally parallel, suggesting the two domains may act synergistically to shape important health outcomes. Socioeconomic disparities and Mexican American ethnicity independently conferred risk for accelerated decline.

Impaired Financial Capacity in Late-Life Depression: Revisiting Associations with Cognitive Functioning.

OBJECTIVES: Impairment in financial capacity is an early sign of cognitive decline and functional impairment in late life. Cognitive impairments such as executive dysfunction are well documented in late-life major depression; however, little progress has been made in assessing associations of these impairments with financial incapacity. METHODS: Participants included 95 clinically depressed and 41 nondepressed older adults without dementia. Financial capacity (assessed with the Managing Money scale of the Independent Living Scale), cognitive functioning (comprehensive neuropsychological evaluation), and depression severity (Hamilton Depression Rating Scale - 24) were assessed. T tests were used to assess group differences. Linear regression was used to analyze data. RESULTS: Depressed participants performed significantly lower on financial capacity (t = 2.98, p < .01). Among depressed participants, executive functioning (B = .24, p < .05) was associated with reduced financial capacity, controlling for age, gender, education, depression severity, and other cognitive domains. CONCLUSIONS: Our results underscore the importance of assessing financial capacity in older depressed adults as they are likely vulnerable to financial abuse even in the absence of dementia. It will be valuable to assess whether treatment for depression is an effective intervention to improve outcomes.

Chronic depressive symptomatology and CSF amyloid beta and tau levels in mild cognitive impairment.

OBJECTIVES: To investigate the association between chronic subsyndromal symptoms of depression (SSD), cerebrospinal fluid (CSF) biomarkers, and neuropsychological performance in individuals with mild cognitive impairment (MCI). METHODS: Participants included 238 older adults diagnosed with MCI from the Alzheimer's Disease Neuroimaging Initiative repository with cognitive and CSF amyloid beta (Aß1-42 ), total tau (t-tau), and phosphorylated tau (p-tau) data. The Neuropsychiatric Inventory identified individuals with chronic endorsement (SSD group N = 80) or no endorsement (non-SSD group N = 158) of depressive symptoms across timepoints. CSF biomarker and cognitive performance were evaluated with linear regression models adjusting for age, education, gender, APOE genotype, global cognitive status, and SSD group. RESULTS: As compared to the non-SSD group, the SSD group displayed lower CSF Aß1-42 levels (ß = -24.293, S.E. = 6.345, P < 0.001). No group differences were observed for CSF t-tau (P = 0.497) or p-tau levels (P = 0.392). Lower CSF Aß1-42 levels were associated with poorer performance on learning (ß = 0.041, S.E. = 0.018, P = 0.021) and memory (ß = -0.012, S.E. = 0.005, P = 0.031) measures, whereas higher CSF t-tau levels were associated with poorer performance on measures of global cognition (ß = 0.022, S.E = 0.008, P = 0.007) and language (ß = -0.010, S.E = 0.004, P = 0.019). SSD was independently associated with diminished global cognition, learning and memory, language, and executive function performance over and above the effects of CSF biomarkers (all P < 0.05). CONCLUSIONS: MCI participants with SSD displayed diminished CSF Aß1-42 levels but did not differ from non-SSD controls in CSF tau levels. Additionally, CSF biomarkers and SSD independently accounted for variance in cognitive performance, suggesting that these factors may uniquely confer cognitive risk in MCI.

Divergent Influences of Cardiovascular Disease Risk Factor Domains on Cognition and Gray and White Matter Morphology.

OBJECTIVE: Hypertension, diabetes, dyslipidemia, and obesity are associated with preclinical alterations in cognition and brain structure; however, this often comes from studies of comprehensive risk scores or single isolated factors. We examined associations of empirically derived cardiovascular disease risk factor domains with cognition and brain structure. METHODS: A total of 124 adults (age, 59.8 [13.1] years; 41% African American; 50% women) underwent neuropsychological and cardiovascular assessments and structural magnetic resonance imaging. Principal component analysis of nine cardiovascular disease risk factors resulted in a four-component solution representing 1, cholesterol; 2, glucose dysregulation; 3, metabolic dysregulation; and 4, blood pressure. Separate linear regression models for learning, memory, executive functioning, and attention/information processing were performed, with all components entered at once, adjusting for age, sex, and education. MRI analyses included whole-brain cortical thickness and tract-based fractional anisotropy adjusted for age and sex. RESULTS: Higher blood pressure was associated with poorer learning (B = -0.19; p = .019), memory (B = -0.22; p = .005), and executive functioning performance (B = -0.14; p = .031), and lower cortical thickness within the right lateral occipital lobe. Elevated glucose dysregulation was associated with poorer attention/information processing performance (B = -0.21; p = .006) and lower fractional anisotropy in the right inferior and bilateral superior longitudinal fasciculi. Cholesterol was associated with higher cortical thickness within left caudal middle frontal cortex. Metabolic dysfunction was positively associated with right superior parietal lobe, left inferior parietal lobe, and left precuneus cortical thickness. CONCLUSIONS: Cardiovascular domains were associated with distinct cognitive, gray, and white matter alterations and distinct age groups. Future longitudinal studies may assist in identifying vulnerability profiles that may be most important for individuals with multiple cardiovascular disease risk factors.

Cortical Atrophy is Associated with Accelerated Cognitive Decline in Mild Cognitive Impairment with Subsyndromal Depression.

OBJECTIVES: To investigate the association between cognitive decline and cortical atrophy in individuals with mild cognitive impairment (MCI) and chronic subsyndromal symptoms of depression (SSD) over a 4-year period. DESIGN: Prospective cohort study. SETTING: Multicenter, clinic-based. PARTICIPANTS: Within the Alzheimer's Disease Neuroimaging Initiative repository, the Neuropsychiatric Inventory was used to identify individuals with MCI and stable endorsement (SSD group N = 32) or no endorsement (non-SSD group N = 69) of depressive symptoms across time points. MEASUREMENTS: Repeated measures of cognitive outcomes, cortical atrophy, and their associations were evaluated with mixed effects models adjusting for age, education, sex, and APOE genotype. RESULTS: The SSD group demonstrated accelerated decline on measures of global cognition (Alzheimer Disease Assessment Scale; df = 421, t = 2.242, p = 0.025), memory (Wechsler Memory Scale-Revised Logical Memory II; df = 244, t = -2.525, p = 0.011), information processing speed (Trail Making Test Parts A [df = 421, t = 2.376, p = 0.018] and B [df = 421, t = 2.533, p = 0.012]), and semantic fluency (Category Fluency; df = 424, t = -2.418, p = 0.016), as well as accelerated frontal lobe (df = 341, t = -2.648, p = 0.008) and anterior cingulate (df = 341, t = -3.786, p < 0.001) atrophy. No group differences were observed for rate of decline on measures of attention, learning, and confrontation naming or for rate of atrophy in any other regions. Accelerated frontal lobe and anterior cingulate atrophy was associated with cognitive decline on measures of global cognition, information processing speed, and semantic fluency (all p < 0.05), but not memory. CONCLUSIONS: Individuals with chronic SSD may represent an MCI subgroup that is highly vulnerable to accelerated cognitive decline, an effect that may be governed by frontal lobe and anterior cingulate atrophy.

Nutrient intake and cerebral metabolism in healthy middle-aged adults: Implications for cognitive aging.

OBJECTIVES: Growing evidence suggests dietary factors influence cognition, but the effects of nutrient intake on cerebral metabolism in adults are currently unknown. The present study investigated the relationship between major macronutrient intake (fat, carbohydrate, and protein) and cerebral neurochemical profiles in middle-aged adults. METHODS: Thirty-six adults recorded dietary intake for 3 days prior to completing cognitive testing and a proton magnetic resonance spectroscopy (1H-MRS) scan. 1H-MRS of occipitoparietal gray matter was used to assess glutamate (Glu), N-acetyl-aspartate (NAA), choline (Cho), and myo-inositol (mI) relative to creatine (Cr) levels. RESULTS: Regression analyses revealed that high intake of polyunsaturated fatty acids (PUFAs) was associated with lower cerebral Glu/Cr (P = 0.005), and high intake of saturated fat (SFA) was associated with poorer memory function (P = 0.030) independent of age, sex, education, estimated intelligence, total caloric intake, and body mass index. DISCUSSION: In midlife, greater PUFA intake (ω-3 and ω-6) may be associated with lower cerebral glutamate, potentially indicating more efficient cellular reuptake of glutamate. SFA intake, on the other hand, was linked with poorer memory performance. These results suggest that dietary fat intake modification may be an important intervention target for the prevention of cognitive decline.

Serum Brain-Derived Neurotrophic Factor Mediates the Relationship between Abdominal Adiposity and Executive Function in Middle Age.

OBJECTIVES: Excessive adipose tissue, especially in the abdominal area, is associated with increased risk of dementia in older adults. However, the mechanisms underlying this relationship are poorly understood. As increased adiposity is also associated with lower circulating levels of brain-derived neurotrophic factor (BDNF), a key molecule modulating brain plasticity and neuronal regeneration, we hypothesized that the changes in cognition that occur as a result of excessive abdominal adiposity would be driven by lower levels of circulating BDNF. METHODS: Fasting blood samples were obtained from 60 participants aged 40-60 years (mean±SD=52.3±5.6) and BDNF levels were assessed with an enzyme linked immunosorbent assay. Abdominal adiposity was measured using a ratio of waist circumference to hip circumference (WHR). Participants also completed a neuropsychological assessment battery to assess executive function. Statistical mediation was assessed using traditional causal steps and nonparametric bootstrapping. RESULTS: Higher WHR was significantly associated with poorer performance on the Controlled Oral Word Association (COWA) letter fluency test (ß=-0.489; p=.003) and lower levels of circulating BDNF (ß=-0.345; p=.006). Linear regression and bootstrapping methods indicated that BDNF fully mediated the relationship between WHR and performance on the COWA (ß=0.60; 95% confidence interval [-3.79, -0.26]). CONCLUSIONS: The relationship between higher WHR and verbal fluency was fully statistically mediated by circulating BDNF levels. The BDNF pathway is thus a useful probable mechanism through which executive function decline occurs in individuals with high abdominal adiposity. BDNF enhancing interventions (physical exercise and dietary restriction) could thus be used to improve executive function in these individuals.

Central Adiposity and Cortical Thickness in Midlife.

OBJECTIVES: Excessive visceral fat is associated with greater metabolic fluctuation and increased risk for dementia in older adults. The aim of the current study is to directly determine the impact of central adiposity on brain structure at midlife by examining the thickness of the cerebral cortex. METHODS: High-resolution magnetization-prepared rapid acquisition gradient-echo images were obtained from 103 participants aged 40 to 60 years (mean [standard deviation] = 49.63 [6.47] years) on a 3-T Siemens Skyra scanner. Visceral fat was measured using dual-energy x-ray absorptiometry. RESULTS: Individuals with higher visceral fat mass and volume had significantly thicker cortex in the right posterior cingulate gyrus (ß = 0.29 [p = .019] and ß = 0.31 [p = .011], respectively), controlling for age, systolic blood pressure, total cholesterol level, and blood glucose level. CONCLUSIONS: Visceral fat was significantly associated with thicker cortex in the posterior cingulate gyrus. Although future studies are necessary, these results indicate that central adiposity is associated with significant metabolic changes that impinge upon the central nervous system in middle age.

Association between cardiovagal baroreflex sensitivity and baseline cerebral perfusion of the hippocampus.

PURPOSE: A failure to control perfusion pressure due to impaired baroreflex sensitivity (BRS) could potentially cause chronic brain hypoperfusion, leading to cognitive dysfunction. The primary aim of this study was to determine whether BRS was associated with regional cerebral blood flow as measured by MRI arterial spin labeling (ASL) technique. METHODS: Baroreflex sensitivity was measured using the Valsalva maneuver technique in 52 middle-aged normotensive adults (49 ± 1 years), and phase IV of the Valsalva maneuver was used for analyses. Cerebral perfusion was measured using the ASL MRI technique in 10 pre-determined brain regions of interest. RESULTS: Hippocampal perfusion was correlated with BRS (R (2) = 0.17, P = 0.01). No association was observed between BRS and cerebral perfusion in the other brain regions of interest. Partial correlational analyses revealed that BRS was an important predictor of hippocampal perfusion, explaining 11 % of the variability independent of other covariates. When participants were divided into tertiles of BRS (11.8 ± 1.9 and 3.5 ± 0.1 ms/mmHg for the highest and lowest tertiles), regional cerebral perfusion of the hippocampus was significantly lower in the lowest BRS tertile than in the highest tertile (39.1 ± 4.3 and 60.5 ± 8.4 ml/100 g/min). CONCLUSIONS: Baroreflex sensitivity in midlife is positively associated with regional cerebral perfusion of the hippocampus, and impaired BRS appears to be related to brain hypoperfusion even in apparently healthy middle-aged adults. Future longitudinal studies based on the present cross-sectional findings may help to further define the relationship between BRS to cognitive dysfunction.

Greater BOLD response to working memory in endurance-trained adults revealed by breath-hold calibration.

BACKGROUND: Cardiorespiratory fitness is associated with increased frontal and parietal activation during executive function tasks. While these findings suggest fitness-related enhancement of neuronal response, the utility of functional magnetic resonance imaging (fMRI) may be limited by potential fitness-related differences in global vascular reactivity. The aim of this study was to determine if highly fit adults display differential activation during working memory after calibration for vascular reactivity relative to their sedentary counterparts. METHODS: Thirty-two endurance-trained and 24 sedentary adults, aged 40-65 years, completed a 2-Back verbal working memory task and a breath-hold challenge during fMRI. Group differences in blood oxygen level-dependent (BOLD) response during working memory were examined across the whole brain and in a priori regions of interest (ROI) before and after breath-hold calibration using non-parametric permutation testing. Multiple regression was used to explore the association between cardiorespiratory fitness (VO2 max), age, and calibrated 2-Back-related activation within the one a priori ROI with significant group effects. RESULTS: In comparison to the endurance-trained group, the sedentary group exhibited greater BOLD signal changes in response to the breath-hold task. After, but not before calibration, the endurance-trained group displayed significantly higher 2-Back-related activation in the right middle frontal gyrus (P = 0.049). Older age predicted lower 2-Back-related activation (ß = -0.308, P = 0.031), whereas fitness predicted higher activation (ß = 0.372, P = 0.021) in this region. CONCLUSIONS: Breath-hold calibration increased detection of working memory-related BOLD response differences between sedentary and endurance-trained adults. Moreover, cardiorespiratory fitness appeared to mitigate age-related changes in BOLD during working memory in this region.

Blood Markers in Relation to a History of Traumatic Brain Injury Across Stages of Cognitive Impairment in a Diverse Cohort.

BACKGROUND: Traumatic brain injury (TBI) has been linked to multiple pathophysiological processes that could increase risk for Alzheimer's disease and related dementias (ADRD). However, the impact of prior TBI on blood biomarkers for ADRD remains unknown. OBJECTIVE: Using cross-sectional data, we assessed whether a history of TBI influences serum biomarkers in a diverse cohort (approximately 50% Hispanic) with normal cognition, mild cognitive impairment, or dementia. METHODS: Levels of glial fibrillary acidic protein (GFAP), neurofilament light (NFL), total tau (T-tau), and ubiquitin carboxy-terminal hydrolase-L1 (UCHL1) were measured for participants across the cognitive spectrum. Participants were categorized based on presence and absence of a history of TBI with loss of consciousness, and study samples were derived through case-control matching. Multivariable general linear models compared concentrations of biomarkers in relation to a history of TBI and smoothing splines modelled biomarkers non-linearly in the cognitively impaired groups as a function of time since symptom onset. RESULTS: Each biomarker was higher across stages of cognitive impairment, characterized by clinical diagnosis and Mini-Mental State Examination performance, but these associations were not influenced by a history of TBI. However, modelling biomarkers in relation to duration of cognitive symptoms for ADRD showed differences by history of TBI, with only GFAP and UCHL1 being elevated. CONCLUSIONS: Serum GFAP, NFL, T-tau, and UCHL1 were higher across stages of cognitive impairment in this diverse clinical cohort, regardless of TBI history, though longitudinal investigation of the timing, order, and trajectory of the biomarkers in relation to prior TBI is warranted.

Association of Loneliness with Functional Connectivity MRI, Amyloid-ß PET, and Tau PET Neuroimaging Markers of Vulnerability for Alzheimer's Disease.

Background: Loneliness has been declared an "epidemic" associated with negative physical, mental, and cognitive health outcomes such as increased dementia risk. Less is known about the relationship between loneliness and advanced neuroimaging correlates of Alzheimer's disease (AD). Objective: To assess whether loneliness was associated with advanced neuroimaging markers of AD using neuroimaging data from Framingham Heart Study (FHS) participants without dementia. Methods: In this cross-sectional observational analysis, we used functional connectivity MRI (fcMRI), amyloid-ß (Aß) PET, and tau PET imaging data collected between 2016 and 2019 on eligible FHS cohort participants. Loneliness was defined as feeling lonely at least one day in the past week. The primary fcMRI marker was Default Mode Network intra-network connectivity. The primary PET imaging markers were Aß deposition in precuneal and FLR (frontal, lateral parietal and lateral temporal, retrosplenial) regions, and tau deposition in the amygdala, entorhinal, and rhinal regions. Results: Of 381 participants (mean age 58 [SD 10]) who met inclusion criteria for fcMRI analysis, 5% were classified as lonely (17/381). No association was observed between loneliness status and network changes. Of 424 participants (mean age 58 [SD = 10]) meeting inclusion criteria for PET analyses, 5% (21/424) were lonely; no associations were observed between loneliness and either Aß or tau deposition in primary regions of interest. Conclusions: In this cross-sectional study, there were no observable associations between loneliness and select fcMRI, Aß PET, and tau PET neuroimaging markers of AD risk. These findings merit further investigation in prospective studies of community-based cohorts.

Performance of the Dreem 2 EEG headband, relative to polysomnography, for assessing sleep in Parkinson's disease.

GOAL AND AIMS: To pilot the feasibility and evaluate the performance of an EEG wearable for measuring sleep in individuals with Parkinson's disease. FOCUS TECHNOLOGY: Dreem Headband, Version 2. REFERENCE TECHNOLOGY: Polysomnography. SAMPLE: Ten individuals with Parkinson's disease. DESIGN: Individuals wore Dreem Headband during a single night of polysomnography. CORE ANALYTICS: Comparison of summary metrics, bias, and epoch-by-epoch analysis. ADDITIONAL ANALYTICS AND EXPLORATORY ANALYSES: Correlation of summary metrics with demographic and Parkinson's disease characteristics. CORE OUTCOMES: Summary statistics showed Dreem Headband overestimated several sleep metrics, including total sleep, efficiency, deep sleep, and rapid eye movement sleep, with an exception in light sleep. Epoch-by-epoch analysis showed greater specificity than sensitivity, with adequate accuracy across sleep stages (0.55-0.82). IMPORTANT SUPPLEMENTAL OUTCOMES: Greater Parkinson's disease duration and rapid eye movement behavior were associated with more wakefulness, and worse Parkinson's disease motor symptoms were associated with less deep sleep. CORE CONCLUSION: The Dreem Headband performs similarly in Parkinson's disease as it did in non-Parkinson's disease samples and shows promise for improving access to sleep assessment in people with Parkinson's disease.

Association of Plasma YKL-40 With MRI, CSF, and Cognitive Markers of Brain Health and Dementia.

BACKGROUND AND OBJECTIVES: Higher YKL-40 levels in the CSF are a known biomarker of brain inflammation. We explored the utility of plasma YKL-40 as a biomarker for accelerated brain aging and dementia risk. METHODS: We performed cross-sectional and prospective analyses of 4 community-based cohorts in the United States or Europe: the Age, Gene/Environment Susceptibility-Reykjavik Study, Atherosclerosis Risk in the Communities study, Coronary Artery Risk Development in Young Adults study, and Framingham Heart Study (FHS). YKL-40 was measured from stored plasma by a single laboratory using Mesoscale Discovery with levels log transformed and standardized within each cohort. Outcomes included MRI total brain volume, hippocampal volume, and white matter hyperintensity volume (WMHV) as a percentage of intracranial volume, a general cognitive composite derived from neuropsychological testing (SD units [SDU]), and the risk of incident dementia. We sought to replicate associations with dementia in the clinic-based ACE csf cohort, which also had YKL-40 measured from the CSF. RESULTS: Meta-analyses of MRI outcomes included 6,558 dementia-free participants, and for analysis of cognition, 6,670. The blood draw preceded MRI/cognitive assessment by up to 10.6 years across cohorts. The mean ages ranged from 50 to 76 years, with 39%-48% male individuals. In random-effects meta-analysis of study estimates, each SDU increase in log-transformed YKL-40 levels was associated with smaller total brain volume (ß = -0.33; 95% CI -0.45 to -0.22; p < 0.0001) and poorer cognition (ß = -0.04; 95% CI -0.07 to -0.02; p < 0.01), following adjustments for demographic variables. YKL-40 levels did not associate with hippocampal volume or WMHV. In the FHS, each SDU increase in log YKL-40 levels was associated with a 64% increase in incident dementia risk over a median of 5.8 years of follow-up, following adjustments for demographic variables (hazard ratio 1.64; 95% CI 1.25-2.16; p < 0.001). In the ACE csf cohort, plasma and CSF YKL-40 were correlated (r = 0.31), and both were associated with conversion from mild cognitive impairment to dementia, independent of amyloid, tau, and neurodegeneration status. DISCUSSION: Higher plasma YKL-40 levels were associated with lower brain volume, poorer cognition, and incident dementia. Plasma YKL-40 may be useful for studying the association of inflammation and its treatment on dementia risk.

Evaluation of Exploratory Fluid Biomarker Results from a Phase 1 Senolytic Trial in Mild Alzheimer's Disease.

Senescent cell accumulation contributes to the progression of age-related disorders including Alzheimer's disease (AD). Clinical trials evaluating senolytics, drugs that clear senescent cells, are underway, but lack standardized outcome measures. Our team recently published data from the first open-label trial to evaluate senolytics (dasatinib plus quercetin) in AD. After 12-weeks of intermittent treatment, we reported brain exposure to dasatinib, favorable safety and tolerability, and modest post-treatment changes in cerebrospinal fluid (CSF) inflammatory and AD biomarkers using commercially available assays. Herein, we present more comprehensive exploratory analyses of senolytic associated changes in AD relevant proteins, metabolites, lipids, and transcripts measured across blood, CSF, and urine. These analyses included mass spectrometry for precise quantification of amyloid beta (Aß) and tau in CSF; immunoassays to assess senescence associated secretory factors in plasma, CSF, and urine; mass spectrometry analysis of urinary metabolites and lipids in blood and CSF; and transcriptomic analyses relevant to chronic stress measured in peripheral blood cells. Levels of Aß and tau species remained stable. Targeted cytokine and chemokine analyses revealed treatment-associated increases in inflammatory plasma fractalkine and MMP-7 and CSF IL-6. Urinary metabolites remained unchanged. Modest treatment-associated lipid profile changes suggestive of decreased inflammation were observed both peripherally and centrally. Blood transcriptomic analysis indicated downregulation of inflammatory genes including FOS, FOSB, IL1ß, IL8, JUN, JUNB, PTGS2. These data provide a foundation for developing standardized outcome measures across senolytic studies and indicate distinct biofluid-specific signatures that will require validation in future studies. ClinicalTrials.gov: NCT04063124.