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Introduction: Progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD), are the most common four‐repeat tauopathies (4RT), and both frequently occur with varying degree of Alzheimer's disease (AD) copathology. Intriguingly, patients with 4RT and patients with AD are at opposite ends of the wakefulness spectrum—AD showing reduced wakefulness and excessive sleepiness whereas 4RT showing decreased homeostatic sleep. The neural mechanisms underlying these distinct phenotypes in the comorbid condition of 4RT and AD are unknown. The objective of the current study was to define the alpha oscillatory spectrum, which is prominent in the awake resting‐state in the human brain, in patients with primary 4RT, and how it is modified in comorbid AD‐pathology. Method: In an autopsy‐confirmed case series of 4R‐tauopathy patients (n = 10), whose primary neuropathological diagnosis was either PSP (n = 7) or CBD (n = 3), using high spatiotemporal resolution magnetoencephalography (MEG), we quantified the spectral power density within alpha‐band (8–12 Hz) and examined how this pattern was modified in increasing AD‐copathology. For each patient, their regional alpha power was compared to an age‐matched normative control cohort (n = 35). Result: Patients with 4RT showed increased alpha power but in the presence of AD‐copathology alpha power was reduced. Conclusions: Alpha power increase in PSP‐tauopathy and reduction in the presence of AD‐tauopathy is consistent with the observation that neurons activating wakefulness‐promoting systems are preserved in PSP but degenerated in AD. These results highlight the selectively vulnerable impacts in 4RT versus AD‐tauopathy that may have translational significance on disease‐modifying therapies for specific proteinopathies. [ABSTRACT FROM AUTHOR]

Background: Sleep/wake disturbance is a common and debilitating symptom of Alzheimer's disease (AD) that precedes cognitive loss. The lateral hypothalamic area (LHA) is critical in orchestrating the sleep/wake cycle through the neuropeptide orexin and melanin‐concentrating hormone. We previously demonstrated that LHA neurons accumulate AD‐tau from Braak stage (BB) 0 and losses ∼72% of neurons by BB6. Little is known about the molecular changes underlying LHA vulnerability during AD progression. We investigated RNA expression changes in LHA across Braak stages to close this gap. Method: We dissected LHA from 30um‐thick sections of the brain from healthy control (HC) and subjects at progressive AD stages and extracted RNA using conventional techniques. We ran RNA transcriptomic assay using customized and neuropathology nCounter® (Nanostring) panels. The Wald statistical test was used to compare the groups, and the genes were considered differentially expressed when log2 fold‐change was > = |1| and the p‐value was <0.05. Result: We found an upregulation of HCRTR1, LDHC, NKX6, and SLC11A1 from early stages (BB2‐3), whereas HCRTR2 RNA levels remained stable. Circadian gene PER2 was downregulated from the intermediate stages (BB4). Gene Ontology analyses detected dysregulation of neuropeptide‐ligand interaction pathways from early AD. Linoleic acid metabolism, fat digestion and absorption, and immune pathways became dysregulated at intermediate stages, while glycolysis and gluconeogenesis pathways were in late stages (BB5‐6). Of note, it is critical to consider that the massive LHA neuronal loss during AD progression may confound the interpretation of changes in late stages because of the few remaining neurons. Conclusion: nCounter® is suitable for identifying transcriptome changes in LHA, even at early AD stages. Molecular profiling of LHA across the Braak stage revealed that the earliest changes are associated with an imbalance in neurotransmitter receptors, while the decline in metabolism and increased inflammation marked the intermediate stage. The late‐stage AD is characterized by hypoglycemia and energy deficit. Notably, discrepancies in receptor behavior can inform more effective symptomatic treatment for sleep dysfunction in AD. [ABSTRACT FROM AUTHOR]

Study objective: This proof-of-concept study aimed to determine whether the combined features of two non-rapid eye movement (NREM) sleep biomarkers acquired predominantly in-home could characterize different neurodegenerative disorders. Methods: Sleep spindle duration and non-REM hypertonia (NRH) were evaluated in seven groups including a control group (CG = 61), and participants with isolated REM sleep behavior disorder (iRBD = 19), mild cognitive impairment (MCI = 41), Parkinson disease (PD = 16), Alzheimer disease dementia (ADem = 29), dementia with Lewy Bodies or Parkinson disease dementia (LBD = 19) and progressive supranuclear palsy (PSP = 13). One-way analysis of variance (ANOVA), Mann-Whitney U, intra-class (ICC) and Spearman ranked correlations, Bland-Altman plots and Kappa scores, Chi-square and Fisher exact probability test, and multiple-logistic regression were focused primarily on spindle duration and NRH and the frequencies assigned to the four normal/abnormal spindle duration/NRH combinations. Results: ANOVA identified group differences in age, sleep efficiency, REM, NRH (p < 0.0001) and sleep time (p = 0.015), Spindle duration and NRH each demonstrated good night-to-night reliabilities (ICC = 0.95 and 0.75, Kappa = 0.93 and 0.66, respectively) and together exhibited an association in the PD and LBD groups only (p < 0.01). Abnormal spindle duration was greater in records of PSP (85%) and LBD (84%) patients compared to CG, MCI, PD and ADem (p < 0.025). Abnormal NRH was greater in PSP = 92%, LBD = 79%, and iRBD = 74% compared to MCI = 32%, ADem = 17%, and CG = 16% (p < 0.005). The combination biomarker normal spindle duration/normal NRH was observed most frequently in CG (56%) and MCI (41%). ADem most frequently demonstrated normal spindle duration/normal NRH (45%) and abnormal spindle duration/normal NRH (38%). Normal spindle duration/abnormal NRH was greatest in iRBD = 47%, while abnormal spindle duration/abnormal NRH was predominant in PSP = 85% and LBD = 74%. Conclusion: The NREM sleep biomarkers spindle duration and NRH may be useful in distinguishing patients with different neurodegenerative disorders. Larger prospective cohort studies are needed to determine whether spindle duration and NRH can be combined for prodromal assessment and/or monitoring disease progression. [ABSTRACT FROM AUTHOR]

Background: A majority of women with multiple sclerosis (MS) are diagnosed prior to menopause, yet their experiences during this transition are not well characterized. Objectives: To explore associations between mental health, sleep, and other quality of life metrics, and vasomotor symptoms (VMSs) in ambulatory, menopausal women with MS. Methods: A secondary analysis was performed of baseline data from two trials enrolling ambulatory peri/postmenopausal women with MS: NCT02710214 (N = 24, bothersome VMS) and NCT04002934 (ongoing, N = 35, myelin repair). Measures analyzed were 36-Item Short-Form Survey (SF-36) (primary scale: general mental health), subjective sleep quality (Pittsburg Sleep Quality Index), VMS (daily diary, interference), mood (Center for Epidemiologist Studies—Depression Scale (CES-D)), walking impairment (timed 25-foot walk (T25FW)), and global disability (Expanded Disability Status Scale (EDSS)). Results: Participants' characteristics (N = 59) were: mean age 51.8 years (SD = 3.4), mean disease duration 11.3 years (SD = 7.6), median EDSS 3.0 (IQR = 2.0–4.0). Mental health was associated with better sleep quality (rho = −0.41, p = 0.019) and better mood (rho = −0.75, p < 0.001), but not with EDSS or T25FW (rho < 0.20, p > 0.10). Worse sleep quality also correlated with more frequent VMS (rho = 0.41, p = 0.02) and VMS interference (rho = 0.59, p < 0.001). Conclusions: Findings suggest that optimizing sleep quality, mood, and hot flash quantity/interference could substantially improve mental health in menopausal women with MS—and highlight an important care gap in this population. [ABSTRACT FROM AUTHOR]

INTRODUCTION: Sleep–wake disturbances are a prominent feature of Alzheimer's disease (AD). Atypical (non‐amnestic) AD syndromes have different patterns of cortical vulnerability to AD. We hypothesized that atypical AD also shows differential vulnerability in subcortical nuclei that will manifest as different patterns of sleep dysfunction. METHODS: Overnight electroencephalography monitoring was performed on 48 subjects, including 15 amnestic, 19 atypical AD, and 14 controls. AD was defined based on neuropathological or biomarker confirmation. We compared sleep architecture by visual scoring and spectral power analysis in each group. RESULTS: Overall, AD cases showed increased sleep fragmentation and N1 sleep compared to controls. Compared to atypical AD groups, typical AD showed worse N3 sleep dysfunction and relatively preserved rapid eye movement (REM) sleep. DISCUSSION: Results suggest differing effects of amnestic and atypical AD variants on slow wave versus REM sleep, respectively, corroborating the hypothesis of differential selective vulnerability patterns of the subcortical nuclei within variants. Optimal symptomatic treatment for sleep dysfunction in clinical phenotypes may differ. Highlights: Alzheimer's disease (AD) variants show distinct patterns of sleep impairment.Amnestic/typical AD has worse N3 slow wave sleep (SWS) impairment compared to atypical AD.Atypical AD shows more rapid eye movement deficits than typical AD.Selective vulnerability patterns in subcortical areas may underlie sleep differences.Relatively preserved SWS may explain better memory scores in atypical versus typical AD. [ABSTRACT FROM AUTHOR]

This first test of the role of REM (rapid eye movement) sleep in reversal spatial learning is also the first attempt to replicate a much cited pair of papers reporting that REM sleep deprivation impairs the consolidation of initial spatial learning in the Morris water maze. We hypothesized that REM sleep deprivation following training would impair both hippocampus-dependent spatial learning and learning a new target location within a familiar environment: reversal learning. A 6-d protocol was divided into the initial spatial learning phase (3.5 d) immediately followed by the reversal phase (2.5 d). During the 6 h following four or 12 training trials/day of initial or reversal learning phases, REM sleep was eliminated and non-REM sleep left intact using the multiple inverted flowerpot method. Contrary to our hypotheses, REM sleep deprivation during four or 12 trials/day of initial spatial or reversal learning did not affect training performance. However, some probe trial measures indicated REM sleep-deprivation-associated impairment in initial spatial learning with four trials/day and enhancement of subsequent reversal learning. In naive animals, REM sleep deprivation during normal initial spatial learning was followed by a lack of preference for the subsequent reversal platform location during the probe. Our findings contradict reports that REM sleep is essential for spatial learning in the Morris water maze and newly reveal that short periods of REM sleep deprivation do not impair concurrent reversal learning. Effects on subsequent reversal learning are consistent with the idea that REM sleep serves the consolidation of incompletely learned items.

Background: Neuropsychiatric symptoms, including sleep‐wake disturbances, are more common in Early‐onset Alzheimer's disease (EOAD) than in Late‐onset AD (LOAD)(Falgàs, EurJNeurol2022). The pattern of tau‐related degeneration of wake and sleep‐promoting neurons determine sleep‐wake profiles in neurodegenerative disorders (Oh, JAMANeurol2022). We hypothesize that distinct patterns of noradrenergic (locus coeruleus‐LC) and orexigenic (hypothalamus‐HT) degeneration contribute for the differential sleep‐wake patterns between EOAD and LOAD. Method: A group of 21 participants (7 EOAD, 18 LOAD) with a diagnosis of AD confirmed by cerebrospinal fluid biomarkers (CSF) were recruited from Hospital Clínic de Barcelona. Participants underwent sleep questionnaires (Pittsburg Sleep Quality Inventory‐PSQI and Epworth Sleepiness Scale‐ESS), 2‐week actigraphy (MotionWatch8, CamnTech) and 3T‐neuromelanin‐sensitive MRI to measure locus coeruleus (LC) and hypothalamus (HT) volumes. Sleep, napping, and circadian parameters were obtained (MotionWare). Result: The preliminary results showed no differences in sex (71vs.61% women) or disease stage (CDR 0.5: 85% vs.72%). The amnestic phenotype was prevalent (100 vs.78%). EOAD had longer daytime napping (93.2±74 vs. 58.2±28min, p<0.05), later fell asleep times (0:42am vs. 11:30pm, p<0.05) and higher central phase measure (4.4±0.5 vs. 3.5±1 h, p<0.05, midpoint between fell asleep and wake‐up) than LOAD. Daytime napping correlated with ESS (r = 0.53, p<0.01). Other parameters such as actual sleep time, sleep efficiency, sleep latency, or fragmentation index showed no differences. PSQI did not correlate to any measures. LC‐volumes were lower in EOAD than in LOAD (24.4±7mm3 vs. 33.3±6 p<0.01). In contrast, HT‐ trended towards higher volumes in EOAD (416.8±38 vs. 392.9±36, p = 0.09), being inversely correlated to the age at onset (r = ‐0.47, p<0.05). The central phase measure was inversely correlated to LC‐volumes (r = ‐0.47, p<0.05) but not to HT. Further analyses with increased sample size, CSF noradrenaline and orexin will be performed. Conclusion: Greater daytime sleepiness and circadian dysfunction could be main differing traits regarding sleep‐wake patterns between EOAD and LOAD. An opposite pattern of degeneration within wake‐promoting systems consisting of higher degeneration of the LC‐noradrenergic system and relative preservation of the HT‐orexigenic in EOAD in contrast to LOAD might underlie differing sleep‐wake phenotypes. Age‐related hypothalamic volume loss can be adding to AD driven loss resulting in higher volumes in EOAD. [ABSTRACT FROM AUTHOR]

Violent victimization disrupts lives and has the potential to undermine socioeconomic well-being. Intimate partner violence (IPV) is a particular concern because rates rise during adolescence to high rates in early adulthood. Prior literature has been hampered by specialized samples, short time-periods, and limited theoretical development. We draw from theorizing on victimization in the life course and the stress process model to analyze the Add Health data covering a twelve-year period. We find pathways from adolescent and early adult IPV are associated with reduced adult socioeconomic well-being. This provides evidence for the enduring effects of adversity on life course inequality. [ABSTRACT FROM AUTHOR]

Modeling and predicting of mental workload are among the most important issues in studying human performance in complex systems. Ample research has shown that the amplitude of the P300 component of event-related potential (ERP) is an effective real-time index of mental workload, yet no computational model exists that is able to account for the change of P300 amplitude in dual-task conditions compared with that in single-task situations. We describe the successful extension and application of a new computational modeling approach in modeling P300 and mental workload--a queuing network approach based on the queuing network theory of human performance and neuroscience discoveries. Based on the neurophysiological mechanisms underlying the generation of P300, the current modeling approach accurately accounts for P300 amplitude both in temporal and intensity dimensions. This approach not only has a basis in its biological plausibility but also has the ability to model and predict workload in real time and can be applied to other applied domains. Further model developments in simulating other dimensions of mental workload and its potential applications in adaptive system design are discussed. Index Terms--Computational modeling, dual task, event-related potential (ERP), mental workload, P300, queuing network.

Objectives: To investigate the objective sleep influencers behind older adult responses to subjective sleep measures, in this case, the Pittsburgh Sleep Quality Index (PSQI). Based on previous literature, we hypothesized that SE would be associated with PSQI reported sleep disruption. Furthermore, because SOL increases progressively with age and it tends to be easily remembered by the patients, we also expected it to be one of the main predictors of the perceived sleep quality in the elderly. Methods: We studied 32 cognitively healthy community-dwelling older adults (age 74 ± 0.3 years) who completed an at-home sleep assessment (Zeo, Inc.) and the PSQI. Linear mixed models were used to analyze the association of the objective sleep parameters (measured by the Zeo) with the PSQI total score and sub-scores, adjusting for age, gender, years of education and likelihood of sleep apnea. Results: Objective sleep parameters did not show any association with the PSQI total score. We found that objective measures of Wake after sleep onset (WASO, % and min) were positively associated with the PSQI sleep disturbance component, while SE and Total Sleep Time (TST) were negatively associated with PSQI sleep disturbance. Lastly, objective SE was positively associated with PSQI SE. Conclusions: Our findings showed that WASO, SE and TST, are associated with PSQI sleep disturbance, where the greater WASO, overall lower SE and less TST, were associated with increased subjective report of sleep disturbance. As expected, subjective (PSQI) and objective measures of SE were related. However, PSQI total score did not relate to any of the objective measures. These results suggest that by focusing on the PSQI total score we may miss the insight this easily administered self-report tool can provide. If interpreted in the right way, the PSQI can provide further insight into cognitively healthy older adults that have the likelihood of objective sleep disturbance. [ABSTRACT FROM AUTHOR]

Background and purpose: The faster rates of cognitive decline and predominance of atypical forms in early‐onset Alzheimer's disease (EOAD) suggest that neuropsychiatric symptoms could be different in EOAD compared to late‐onset AD (LOAD); however, prior studies based on non‐biomarker‐diagnosed cohorts show discordant results. Our goal was to determine the profile of neuropsychiatric symptoms in EOAD and LOAD, in a cohort with biomarker/postmortem‐confirmed diagnoses. Additionally, the contribution of co‐pathologies was explored. Methods: In all, 219 participants (135 EOAD, 84 LOAD) meeting National Institute on Aging and Alzheimer's Association criteria for AD (115 amyloid positron emission tomography/cerebrospinal fluid biomarkers, 104 postmortem diagnosis) at the University of California San Francisco were evaluated. The Neuropsychiatric Inventory—Questionnaire (NPI‐Q) was assessed at baseline and during follow‐up. The NPI‐Q mean comparisons and regression models adjusted by cognitive (Mini‐Mental State Examination) and functional status (Clinical Dementia Rating Sum of Boxes) were performed to determine the effect of EOAD/LOAD and amnestic/non‐amnestic diagnosis on NPI‐Q. Regression models assessing the effect of co‐pathologies on NPI‐Q were performed. Results: At baseline, the NPI‐Q scores were higher in EOAD compared to LOAD (p < 0.05). Longitudinally, regression models showed a significant effect of diagnosis, where EOAD had higher NPI‐Q total, anxiety, motor disturbances and night‐time behavior scores (p < 0.05). No differences between amnestics/non‐amnestics were found. Argyrophilic grain disease co‐pathology predicted a higher severity of NPI‐Q scores in LOAD. Conclusions: Anxiety, night‐time behaviors and motor disturbances are more severe in EOAD than LOAD across the disease course. The differential patterns of neuropsychiatric symptoms observed between EOAD/LOAD could suggest a pattern of selective vulnerability extending to the brain's subcortical structures. Further, co‐pathologies such as argyrophilic grain disease in LOAD may also play a role in increasing neuropsychiatric symptoms. [ABSTRACT FROM AUTHOR]

Background: Sleep‐wake disturbance precedes the prodromal stage of Alzheimer's disease (AD) and is characterized by excessive daytime sleepiness and sundowning. In contrast, hyper‐insomnia is seen in progressive supranuclear palsy (PSP), a pure 4‐repeat tauopathy. The wake‐promoting histaminergic (HA) neurons of the tuberomamillary nucleus (TMN) together with the orexinergic (OX) neurons of the lateral hypothalamic area (LHA) modulate the sleep‐wake cycle. Previously, we reported wake‐promoting nucleus (WPNs) are selectively vulnerable to AD‐tau toxicity than PSP, and neuronal loss in TMN is specific to AD. In the present study, we investigated changes in RNA expression in the TMN and LHA to understand the selective vulnerability of WPNs in AD at the molecular level. Method: LHA and TMN were dissected from serial histological sections from the postmortem brains of AD, PSP, and healthy control (HC) subjects. 50ng total RNA was extracted using RNeasy Micro Kit, and RNA integrity was accessed using Nanodrop. Cases with RIN > 5 were included for RNA sequencing. The nCounter Neuropathology panel and nSolver software (NanoString Technologies) was employed to obtain and analyze the data. Result: Molecular profiling of TMN in AD demonstrated 13 upregulated genes associated with angiogenesis, apoptosis, chromatin modification, disease‐association, and transcription factor, and 12 genes in PSP. The proto‐oncogene RELA, RNA binding protein FUS and oligodendrocyte specific NKX6‐2 genes were upregulated in AD and PSP. Further, in the LHA, we identified 17 differentially expressed genes associated with circadian rhythm, inflammatory cytokines, apoptosis, autophagy, and angiogenesis in AD over HC and 72 genes in PSP over HC. Both IL4 and CRY2 genes demonstrated downregulation in the AD and PSP. Conclusion: Differential gene expression in the WPNs revealed a significant upregulation of genes associated with pro‐inflammatory cytokines, activated microglia, apoptosis, oxidative stress, and autophagy in AD over PSP. The neuromodulatory subcortical system shows different vulnerability patterns in AD vs. PSP making it an excellent candidate to interrogate the molecular bases of vulnerability. [ABSTRACT FROM AUTHOR]

Although, the clinical variants of Alzheimer's disease (AD) show distinct patterns of cognitive and behavioral decline, disease progression, and neuropathological features, it is unclear if this clinical heterogeneity extends to sleep‐wake patterns. Sleep and wake disturbances are frequent in typical AD, often preceding memory loss and negatively impacting the quality of life of patients and caregivers alike. Still, sleep and wake disorders are often misdiagnosed and undertreated in typical AD. Better characterization of sleep‐wake features in AD clinical variants is an unmet gap of high importance because these differing patterns may require tailored treatment strategies. Moreover, as wake‐promoting neurons are located in subcortical nuclei and degenerate early in typical AD, contrasting the profiles of sleep‐wake patterns in typical and atypical AD aids diagnosis and brings a unique opportunity to uncover the mechanisms underlying AD clinical variants at the subcortical level and mechanisms for selective neuronal vulnerability. [ABSTRACT FROM AUTHOR]

Background: There is an increasing awareness that sleep disturbances are a risk factor for dementia. Prior case-control studies suggested that brain grey matter (GM) changes involving cortical (i.e, prefrontal areas) and subcortical structures (i.e, putamen, thalamus) could be associated with insomnia status. However, it remains unclear whether there is a gradient association between these regions and the severity of insomnia in older adults who could be at risk for dementia. Since depressive symptoms and sleep apnea can both feature insomnia-related factors, can impact brain health and are frequently present in older populations, it is important to include them when studying insomnia. Therefore, our goal was to investigate GM changes associated with insomnia severity in a cohort of healthy older adults, taking into account the potential effect of depression and sleep apnea as well. We hypothesized that insomnia severity is correlated with 1) cortical regions responsible for regulation of sleep and emotion, such as the orbitofrontal cortex and, 2) subcortical regions, such as the putamen. Methods: 120 healthy subjects (age 74.8±5.7 years old, 55.7% female) were recruited from the Hillblom Healthy Aging Network at the Memory and Aging Center, UCSF. All participants were determined to be cognitively healthy following a neurological evaluation, neuropsychological assessment and informant interview. Participants had a 3T brain MRI and completed the Insomnia Severity Index (ISI), Geriatric Depression Scale (GDS) and Berlin Sleep Questionnaire (BA) to assess sleep apnea. Cortical thickness (CTh) and subcortical volumes were obtained by the CAT12 toolbox within SPM12. We studied the correlation of CTh and subcortical volumes with ISI using multiple regressions adjusted by age, sex, handedness and MRI scan type. Additional models adjusting by GDS and BA were also performed. Results: ISI and GDS were predominantly mild (4.9±4.2 and 2.5±2.9, respectively) and BA was mostly low risk (80%). Higher ISI correlated with lower CTh of the right orbitofrontal, right superior and caudal middle frontal areas, right temporo-parietal junction and left anterior cingulate cortex (p<0.001, uncorrected FWE). When adjusting by GDS, right ventral orbitofrontal and temporo-parietal junction remained significant, and left insula became significant (p<0.001, uncorrected FWE). Conversely, BA showed no effect. The results were no longer significant following FWE multiple comparisons. Regarding subcortical areas, higher putamen volumes were associated with higher ISI (p<0.01). Conclusions: Our findings highlight a relationship between insomnia severity and brain health, even with relatively mild insomnia, and independent of depression and likelihood of sleep apnea. The results extend the previous literature showing the association of specific GM areas (i.e, orbitofrontal, insular and temporo-parietal junction) not just with the presence of insomnia, but across the spectrum of severity itself. Moreover, our results suggest subcortical structures (i.e., putamen) are involved as well. Longitudinal studies are needed to clarify how these insomnia-related brain changes in healthy subjects align with an increased risk of dementia. [ABSTRACT FROM AUTHOR]

There is increasing awareness that self-reported sleep abnormalities are negatively associated with brain structure and function in older adults. Less is known, however, about how objectively measured sleep associates with brain structure. We objectively measured at-home sleep to investigate how sleep architecture and sleep quality related to white matter microstructure in older adults. 43 cognitively normal, older adults underwent diffusion tensor imaging (DTI) and a sleep assessment within a six-month period. Participants completed the PSQI, a subjective measure of sleep quality, and used an at-home sleep recorder (Zeo, Inc.) to measure total sleep time (TST), sleep efficiency (SE), and percent time in light sleep (LS), deep sleep (DS), and REM sleep (RS). Multiple regressions predicted fractional anisotropy (FA) and mean diffusivity (MD) of the corpus callosum as a function of total PSQI score, TST, SE, and percent of time spent in each sleep stage, controlling for age and sex. Greater percent time spent in RS was significantly associated with higher FA (β = 0.41, p = 0.007) and lower MD (β = -0.30, p = 0.03). Total PSQI score, TST, SE, and time spent in LS or DS were not significantly associated with FA or MD (p>0.13). Percent time spent in REM sleep, but not quantity of light and deep sleep or subjective/objective measures of sleep quality, positively predicted white matter microstructure integrity. Our results highlight an important link between REM sleep and brain health that has the potential to improve sleep interventions in the elderly. [ABSTRACT FROM AUTHOR]

New tools are needed to match cancer patients with effective treatments. Patient-derived organoids offer a high-throughput platform to personalize treatments and discover novel therapies. Currently, methods to evaluate drug response in organoids are limited because they overlook cellular heterogeneity. In this study, non-invasive optical metabolic imaging (OMI) of cellular heterogeneity was characterized in breast cancer (BC) and pancreatic cancer (PC) patient-derived organoids. Baseline heterogeneity was analyzed for each patient, demonstrating that single-cell techniques, such as OMI, are required to capture the complete picture of heterogeneity present in a sample. Treatment-induced changes in heterogeneity were also analyzed, further demonstrating that these measurements greatly complement current techniques that only gauge average cellular response. Finally, OMI of cellular heterogeneity in organoids was evaluated as a predictor of clinical treatment response for the first time. Organoids were treated with the same drugs as the patient's prescribed regimen, and OMI measurements of heterogeneity were compared to patient outcome. OMI distinguished subpopulations of cells with divergent and dynamic responses to treatment in living organoids without the use of labels or dyes. OMI of organoids agreed with long-term therapeutic response in patients. With these capabilities, OMI could serve as a sensitive high-throughput tool to identify optimal therapies for individual patients, and to develop new effective therapies that address cellular heterogeneity in cancer. [ABSTRACT FROM AUTHOR]

Background: Recent studies reveal an association between slow-wave sleep (SWS), amyloid-β aggregation, and cognition.Objective: This retrospective study examines whether long-term use of trazodone, an SWS enhancer, is associated with delayed cognitive decline.Methods: We identified 25 regular trazodone users (mean age 75.4±7.5; 9 women, 16 men) who carried a diagnosis of Alzheimer's dementia, mild cognitive impairment, or normal cognition, and 25 propensity-matched trazodone non-users (mean age 74.5±8.0; 13 women, 12 men), accounting for age, sex, education, type of sleep deficit (hypersomnia, insomnia, parasomnia), diagnosis, and baseline Mini-Mental State Examination (MMSE). Longitudinal group differences in cognitive testing were evaluated through repeated measures tests over an average inter-evaluation interval of four years.Results: Trazodone non-users had 2.6-fold faster decline MMSE (primary outcome) compared to trazodone users, 0.27 (95% confidence interval [CI]: 0.07-0.48) versus 0.70 (95% CI: 0.50-0.90) points per year (p = 0.023). The observed effects were especially associated with subjective improvement of sleep complaints in post-hoc analyses (p = 0.0006). Secondary outcomes of other cognitive and functional scores had variable worsening in non-users and varied in significance when accounting for co-administered medications and multiple comparisons. Trazodone effects on MMSE remained significant within participants with AD-predicted pathology, with 2.4-fold faster decline in non-users (p = 0.038).Conclusions: These results suggest an association between trazodone use and delayed cognitive decline, adding support for a potentially attractive and cost-effective intervention in dementia. Whether the observed relationship of trazodone to cognitive function is causal or an indirect marker of other effects, such as treated sleep disruption, and if such effects are mediated through SWS enhancement requires confirmation through prospective studies. [ABSTRACT FROM AUTHOR]

Background: Early‐onset Alzheimer's Disease presentations (EOAD, under 65) frequently present with atypical phenotypes and a more aggressive disease course with a higher burden of neuropsychiatric symptoms than late‐onset AD (LOAD). Current treatments for sleep and behavioral disturbances are still non‐specific, causing side effects (e.g., sedation, falls). Identifying the underlying changes driving behavioral differences between EOAD and LOAD is crucial to developing tailored treatment avenues. The noradrenergic locus coeruleus (LC), one of the first sites of tau deposition in AD, has been implicated in sleep‐wake patterns and mood regulation. We aim to test the hypothesis that the LC is more affected in EOAD than LOAD by comparing LC volume (neuromelanin‐sensitive MRI) and sleep‐behavioral symptoms in biomarker‐confirmed EOAD and LOAD cohorts. Method: Fifty‐four subjects with AD biomarker‐based diagnosis (20 EOAD, 34 LOAD) were recruited at the Hospital Clínic de Barcelona. All participants and informants completed the Epworth Sleepiness Scale (ESS), Pittsburgh Sleep Quality Index (PSQI), and Neuropsychiatric Inventory (NPI) questionnaires to assess the severity of sleep‐wake alterations and neuropsychiatric symptoms. In addition, they underwent a 3T turbospin‐echo MRI to measure LC volume. We compared mean values of LC volume, ESS, PSQI, and NPI between EOAD and LOAD. Furthermore, linear regression models controlling by cognitive status (MMSE) were performed. Result: EOAD and LOAD had similar cognition (MMSE 21.3±5 vs. 22.6±4, respectively), functional status (CDR 0.92±0.1 vs. 0.68±0.1), and prevalence of amnestic phenotype (57 vs. 70%). EOAD compared to LOAD, trended towards higher scores for ESS (7.4±1 vs. 5.1±1, respectively), PSQI (7.3±2 vs. 5.6±1), NPI (21.6±8 vs. 14.6±8), and caregiver distress (9.4±3 vs. 4.7±3). LC volume was lower in EOAD according to preliminary MRI data [n=18, 9 EOAD (21.8±3 mm3), 9 LOAD (29.5±3 mm3)]. Linear regression models showed that MMSE did not influence the EOAD/LOAD effect on LC volume (coef. 7.7, p=0.032). Conclusion: The current preliminary study suggests that LC degeneration is greater in EOAD than LOAD. This difference may explain the EOAD‐associated worse sleep‐wake dysfunction and neuropsychiatric symptoms. Deep phenotyping/comparison of EOAD and LOAD can inform tailored treatment strategies for these behavioral symptoms. [ABSTRACT FROM AUTHOR]

Background: Neurodegenerative disease (NDD) is associated with sleep disturbances, including decreased stage N3 and REM sleep and reduced spindle activity. Further, supine sleep position may impact NDD risk by altering glymphatic clearance. This study evaluated conventional and exploratory sleep metrics in the differentiation of subjects with normal cognition (NC) and patients with Alzheimer's disease dementia (AD) and alpha‐synucleinopathies (α‐Syn). Method: Home sleep data were acquired across multiple study sites using the self‐applied Sleep ProfilerTM, including 44 NC subjects (age=69+5.0), 22 patients diagnosed with AD (age=75+7.1) and 25 with α‐Syn (Parkinson's disease=14, Parkinson's disease with Dementia or Dementia with Lewy Bodies=11; age=69+6.9). Recordings were auto‐staged and technically reviewed, with 86% of the records having two‐night averages. Logistic regression and Mann‐Whitney U tests were used to characterize group differences based on age, conventional sleep metrics (i.e., sleep efficiency, sleep onset (SO), awakenings, percent of sleep time (%) in REM,N1, N2 and N3, and sleep spindles) and exploratory sleep measures [i.e., % supine, % Light N2 (L2=N2 epochs absent of spindles with K‐complexes and/or alpha or EMG (>40 Hz) intrusion), % NREM sleep with hypertonia (NRSH=>4 consecutive epochs with persistently elevated EMG power relative to delta and theta power) and % atypical N3 (AN3=epochs staged N3 with low theta and sigma power relative to delta, alpha, beta and EMG)]. Result: AD were older than both NC and α‐Syn patients (p<0.005). Both AD and α‐Syn had lower %REM and greater %supine than NC (p<0.005), and %NRSH was greater in α‐Syn than NC or AD (p<0.005). Based on logistic regression, AD was differentiated from NC based on age, %REM, %L2 (p<0.05) and %supine (p=0.06). α‐Syn was distinguished from NC using both conventional (%N3 and SO, p<0.05) and exploratory sleep metric (%AN3 and %NRSH, p<0.05; %supine, p=0.06). Age (p=0.05) and %NRSH (p<0.01) were the only metrics that differentiated α‐Syn from AD. Conclusion: Objective home sleep profiles hold promise for differentiating NDD patients from NC. The sleep metrics that provided the greatest distinction between NDD and NC were %REM, %supine and NRSH, while only NRSH distinguished AD from α‐Syn patients. Further confirmatory studies are underway. [ABSTRACT FROM AUTHOR]

Background: Sleep plays a key role in the origination and progression of neurodegenerative diseases. We have recently shown that the key areas that regulate sleep and wakefulness in the subcortical nuclei are particularly vulnerable to tau‐inclusion and neuronal loss even in the early stages in AD. Nevertheless, it remains uncertain whether the pathological lesion of specific nuclei directly contributes to the patient's clinical sleep impairment. Here, we correlate quantitative sleep measurements with post‐mortem stereological neuronal analysis in neurodegenerative diseases. Method: Twenty‐two patients (50% female; mean age: 70.65 ± 1.54) completed overnight polysomnography and/or MEG at the Memory and Aging Center at UCSF. Of 22 patients, 12 were neuropathologically diagnosed with AD, and 10 were PSP (progressive supranuclear palsy)(Table 1). Locus coeruleus (LC), lateral hypothalamus (LHA), and tuberomammillary nuclei (TMN) were immunostained for their respective primary neurotransmitter (TH, orexin, or histamine) and tau inclusions, followed by stereological neuronal count and Spearman correlation analysis. Result: The number of orexinergic and histaminergic neurons showed a significant correlation with the objective sleep measurements, including total sleep time (TST), wake‐after sleep onset (WASO), sleep maintenance, NREM2 sleep, and REM sleep (Figure 1). Conclusion: Loss of neurons involved in the sleep‐wake network may play a direct role in impairing sleep architecture and function in neurodegenerative disease. This is the first study to use a quantitative, systematic approach to correlate pathological lesions and sleep parameters in AD and PSP. Understanding the neuronal basis of sleep impairment in neurodegenerative diseases is crucial in designing the next generation of sleep medications and even slowing down the progress of neurodegenerative diseases through early inventions. [ABSTRACT FROM AUTHOR]

Background: Sleep‐wake disturbances are a prominent feature in Alzheimer's Disease (AD), negatively impacting patients and caregivers' quality of life. Growing evidence suggests that sleep‐wake dysregulation happens early in AD due to the AD‐tau degeneration of the arousal system (i.e., locus coeruleus). However, whether the pattern of sleep‐wake dysfunction is different among AD clinical variants and how it is different remains unclear. It is an unmet gap of high importance because these differing patterns may require tailored treatment strategies. Since AD phenotypes with different clinical profiles have distinct regional patterns of cortical tau, we hypothesized that AD variants may also have differential sleep patterns. Therefore, we aim to contrast the behavioral sleep features within AD variants. Method: A cohort of 24 patients, including 8 amnestic AD and 16 non‐amnestic AD (7 lvPPA, 9 PCA), with a neuropathological or biomarker based diagnosis of AD, underwent an overnight EEG monitoring. Sleep stages were evaluated by PRANA software and confirmed by REM Logic spectral analyses. We performed nonparametric analyses to study group differences in the amount of each sleep stage as a percent of total sleep time. Additionally, we performed linear regression models adjusting by the age of onset, MMSE, and CDR Total. Results: There were no differences between amnestic AD, lvPPA, and PCA groups in gender, age of onset (59±11, 55±6, 59±8, respectively), global cognition (MMSE 21±7, 23±3, 21±5), or functional performance (CDR Total 0.9±0.5, 0.7±0.3, 1±0.4). Compared to non‐amnestic AD, amnestic AD had more REM sleep (p<0.05) and a trend toward lower NREM sleep stages 1 and 3. In the same line, this pattern was still observed when comparing the three clinical variants (amnestic AD, lvPPA, and PCA) (p<0.05). Regression models confirmed that clinical AD variants accounted for differences in REM sleep (p<0.01). We are continuing to evaluate additional AD participants and age‐matched healthy controls. Conclusion: Preliminary results suggest that sleep profiles might differ between AD variants. The existence of specific sleep‐wake profiles would suggest differential degeneration patterns of the arousal system within AD phenotypes, which would open the door to uncover the selective vulnerability of subcortical structures for the first time. [ABSTRACT FROM AUTHOR]

Background: Sleep disturbances are common precognitive symptoms of Alzheimer's disease (AD). Wake‐promoting orexinergic neurons (Oxe) in the lateral hypothalamic area (LHA) are key regulators of sleep‐wake states. We recently reported a major loss of Oxe in the terminal stages of AD. This was unexpected, because clinical research shows elevated orexin levels in the cerebrospinal fluid (CSF) of AD patients. In line with this finding, suvorexant, an orexin receptor antagonist, was recently the first drug approved for insomnia in patients with mild‐to‐moderate AD. The aim of our current study was to understand the biological basis of these findings and elucidate the still unknown pattern of orexinergic neuron degeneration in the course of AD. Methods: We performed a postmortem study of 15 subjects with different AD stages and controls. Patients with contributing pathologies other than AD were excluded from the study. Using double immunohistochemistry and unbiased stereology, we estimated the number of total neurons, Oxe and tau‐inclusions in the LHA along the Braak stages of AD. Results: Examined participants' mean age was 70± 12 years, 47% female. Along AD progression, there was an increase of tau inclusions in Oxe, with 0.1% of tau‐positive neurons at Braak stage 0 and 23% at stage 6 (Fig. 1). Further, we observed a substantial decrease of ONs from Braak stage 0 to stage 6 (Fig. 2). Along other Braak stages the decrease of orexinergic neuronal number was slower. Conclusion: We provide evidence of tau‐accumulation in Oxe as early as Braak stage 0 and significant orexinergic neuronal loss from Braak 1. This correlates well with clinical data showing that in many patients sleep‐wake disorders precede the cognitive symptoms, which typically emerge with Braak 3‐4 stages. Further, we conclude that elevated orexin levels in the CSF of AD patients may represent a compensatory mechanism for the loss of Oxe in the early and middle disease stages, whereas in the terminal stage the compensatory capacity may be lost. The practical consequence is that during treatment, disease stages should be considered and symptomatic therapy should be adjusted accordingly. Further studies are necessary to develop better targeting / therapeutics for sleep disturbances in AD. [ABSTRACT FROM AUTHOR]

Background: Cognitive deficits are presumed to be the primary driver of functional impairment in Alzheimer's disease (AD); however, functional impairment is likely multifactorially determined.Objective: Our objective was to determine the relative contribution of neuropsychiatric symptoms in predicting ratings of functional status.Methods: A total of 223 patients received routine neurological and neuropsychological evaluations and met criteria of probable AD dementia based on the McKhann criteria. Demographic, cognitive, and neuropsychiatric variables were entered in a hierarchical linear regression analysis to predict functional status as measured by the Functional Activities Questionnaire (FAQ).Results: The total model explained 29.7% of the variance (p <  0.001) in FAQ. Importantly, neuropsychiatric variables explained 12.7% of the unique variance, with apathy and sleep as significant contributors.Conclusion: Two neuropsychiatric variables, apathy and changes in sleep/nighttime behaviors, predicted ratings of functional status in AD patients independent of age, global cognition, memory and executive function measures, and depressive symptoms. These results highlight the importance of neuropsychiatric symptoms in understanding and potentially treating the functional limitations so prevalent in AD. [ABSTRACT FROM AUTHOR]

The contribution of inflammation to deleterious aging outcomes is increasingly recognized; however, little is known about the complex relationship between interleukin-6 (IL-6) and brain structure, or how this association might change with increasing age. We examined the association between IL-6, white matter integrity, and cognition in 151 community dwelling older adults, and tested whether age moderated these associations. Blood levels of IL-6 and vascular risk (e.g., homocysteine), as well as health history information, were collected. Processing speed assessments were administered to assess cognitive functioning, and we employed tract-based spatial statistics to examine whole brain white matter and regions of interest. Given the association between inflammation, vascular risk, and corpus callosum (CC) integrity, fractional anisotropy (FA) of the genu, body, and splenium represented our primary dependent variables. Whole brain analysis revealed an inverse association between IL-6 and CC fractional anisotropy. Subsequent ROI linear regression and ridge regression analyses indicated that the magnitude of this effect increased with age; thus, older individuals with higher IL-6 levels displayed lower white matter integrity. Finally, higher IL-6 levels were related to worse processing speed; this association was moderated by age, and was not fully accounted for by CC volume. This study highlights that at older ages, the association between higher IL-6 levels and lower white matter integrity is more pronounced; furthermore, it underscores the important, albeit burgeoning role of inflammatory processes in cognitive aging trajectories. [ABSTRACT FROM AUTHOR]

Abstract: Manual state scoring of physiological recordings in sleep studies is time-consuming, resulting in a data backlog, research delays and increased personnel costs. We developed MATLAB-based software to automate scoring of sleep/waking states in rats, potentially extendable to other animals, from a variety of recording systems. The software contains two programs, Sleep Scorer and Auto-Scorer, for manual and automated scoring. Auto-Scorer is a logic-based program that displays power spectral densities of an electromyographic (EMG) signal and σ, δ, and θ frequency bands of an electroencephalographic (EEG) signal, along with the δ/θ ratio and σ × θ, for every epoch. The user defines thresholds from the training file state definitions which the Auto-Scorer uses with logic to discriminate the state of every epoch in the file. Auto-Scorer was evaluated by comparing its output to manually scored files from 6 rats under 2 experimental conditions by 3 users. Each user generated a training file, set thresholds, and auto-scored the 12 files into 4 states (waking, non-REM, transition-to-REM, and REM sleep) in 1/4 the time required to manually score the file. Overall performance comparisons between Auto-Scorer and manual scoring resulted in a mean agreement of 80.24±7.87%, comparable to the average agreement among 3 manual scorers (83.03±4.00%). There was no significant difference between user–user and user–Auto-Scorer agreement ratios. These results support the use of our open-source Auto-Scorer, coupled with user review, to rapidly and accurately score sleep/waking states from rat recordings. [Copyright &y& Elsevier]

Modeling and predicting of mental workload are among the most important issues in studying human performance in complex systems. Ample research has shown that the amplitude of the P300 component of event-related potential (ERP) is an effective real-time index of mental workload, yet no computational model exists that is able to account for the change of P300 amplitude in dual-task conditions compared with that in single-task situations. We describe the successful extension and application of a new computational modeling approach in modeling P300 and mental workload—a queuing network approach based on the queuing network theory of human performance and neuroscience discoveries. Based on the neurophysiological mechanisms underlying the generation of P300, the current modeling approach accurately accounts for P300 amplitude both in temporal and intensity dimensions. This approach not only has a basis in its biological plausibility but also has the ability to model and predict workload in real time and can be applied to other applied domains. Further model developments in simulating other dimensions of mental workload and its potential applications in adaptive system design are discussed. [ABSTRACT FROM AUTHOR]

Background: There is an increasing awareness that sleep disturbances are a risk factor for dementia (Sindi, 2018). Prior case‐control studies have suggested that certain alterations in brain structure could be associated with insomnia status (Sexton, 2014; Grau‐Rivera, 2019). Specifically, they mainly described smaller cortical volumes in orbitofrontal and cingulate areas. However, it remains unclear whether there is a gradient association between these regions and the severity of insomnia. Therefore, our goal was to investigate the association between gray matter (GM) and white matter (WM) regions with insomnia severity. We hypothesized that a smaller orbitofrontal and cingulate cortex is associated with greater insomnia severity. Method: 122 healthy subjects (age 74.7±5.7 years old, 55.7% female) were recruited from the Healthy Aging Study at Memory and Aging Center, UCSF. All participants were determined to be cognitively healthy following a neurological evaluation, neuropsychological assessment and informant interview. Participants had a 3T brain MRI and completed the Insomnia Severity Index (ISI), a subjective measure of insomnia (Bastien, 2001). FreeSurfer was used to obtain GM and WM volumes. We used linear regression models to evaluate the relevance of regional GM and WM volumes to ISI, controlling for age and total intracranial volume. Result: Distribution of ISI scores ranged from 0 to 16 (4.8±4.2). Regression models showed that smaller pars orbitalis (β=‐0.29, p=0.008), supramarginal (β=‐0.26, p=0.019), transverse temporal (β=‐0.24, p=0.018), postcentral (β=‐0.24, p=0.027), rostral anterior cingulate (β=‐0.23, p=0.044) and isthmus cingulate (β=‐0.23, p=0.045) GM regions were associated with higher ISI scores. White matter regions were not associated with ISI. Conclusion: Lower volumes in certain cortical regions contributed to a higher degree of perceived insomnia severity. Conversely, white matter regions had no effect. Our results not only reinforce the involvement of orbitofrontal and cingulate regions with the presence of insomnia (Sexton, 2014; Grau‐Rivera, 2019) but furthermore, extend this showing that insomnia severity is associated with volumetric values in these areas. Further studies are needed to clarify how these insomnia‐related brain changes in healthy subjects align with an increased risk of dementia. [ABSTRACT FROM AUTHOR]

Background: Individuals with progressive supranuclear palsy (PSP), a form of 4‐repeat tauopathy, show an extreme sleep phenotype featuring a short sleep duration. This is likely due to tau‐associated lesions in the subcortical sleep‐wake network. Nevertheless, it is unknown how the pathological lesions in the brainstem and hypothalamus relate to sleep phenotypes in PSP because detailed clinicopathological studies focusing on sleep are lacking. To elucidate this mechanism, here we correlate objective sleep‐wake measurements with quantitative pathological findings in the key sleep‐wake network in PSP for the first time. Method: Participants with a diagnosis of probable PSP based on the Litvan criteria were recruited at the Memory and Aging Center, UCSF from 2013 to 2019. Twenty participants (68% male; mean age: 70.95 ± 5.3) were asked to complete overnight polysomnography (PSG) and multiple sleep latency tests (MSLT) the subsequent day. Measures of interest on the PSG and MSLT are indicated in Figure 1. Of these individuals, 13 have undergone an autopsy, neurotransmitter and tau immunohistochemistry staining, and neuronal quantification using unbiased stereology in the following nuclei: noradrenergic Locus Coeruleus (LC), orexinergic lateral hypothalamic area (LHA), and histaminergic tuberomammillary nuclei (TMN). Result: Sleep parameters and pathological parameters (nuclei neuronal number, neurotransmitter expression, and tau burden), show significant and variable correlations (Figure 1). Conclusion: Neuronal loss and tau burden in the key neuromodulatory systems may explain clinical sleep signatures in PSP. For instance, shorter MSLT correlated with fewer histaminergic neurons which suggest that impaired histaminergic wake‐promoting system may lead to a higher tendency to fall asleep. Altogether, our preliminary data highlights the importance of clinicopathological study combining objective sleep measurements with unbiased postmortem evaluation in clarifying the contribution of subcortical tau pathology to sleep‐wake disturbances in tauopathies. [ABSTRACT FROM AUTHOR]

Autonomic dysfunction is common in α-synucleinopathies such as Lewy Body dementias (LBD), Parkinson's disease (PD), and isolated REM Sleep Behavior Disorder (iRBD). We analyzed pulse-rate changes during sleep to index autonomic nervous system (ANS) dysfunction in patients with α-synucleinopathies vs. non-synucleinopathy groups expected to have normal ANS function. Patients with LBD (n = 16), PD (PD, n = 14) or iRBD (n = 12) were compared to the non-synucleinopathy groups Alzheimers disease dementia (ADem, n = 26), mild cognitive impairment (MCI, n = 34) or controls (CG, n = 54). Sleep Profiler was used to derive a sleep autonomic activation index (AAI), i.e., ≥6 beat-per-minute increase/decrease, pulse rate coefficient of variation (PR-CV), and automated sleep staging with sleep-spindles and non-REM hypertonia (NRH). Analysis included statistical group comparisons and receiver operating characteristics curves to determine optimal classification of groups. AAI and PR-CV were moderately correlated across all recordings (r s = 0.58, P < 0.0001), except in the LBD and PD groups. AAI but not PR-CV differentiated the LBD, PD and iRBD from non-Parkinsonian groups. AAI was decreased in LBD and PD patients compared to the CG (p < 0.003) and MCI (p < 0.03). AAI decreased based on age and its receiver operating characteristic area under the curve ranged from 0.63 to 0.75. AAI had a weak negative correlation to NRH (r s ≤ −0.26) but not sleep-spindles. Synucleinopathy-related ANS dysfunction can reasonably discriminate prodromal and manifest PD/LBD diseased groups from non-synucleinopathies. Further studies incorporating AAI into a multivariate classifier of neurodegenerative disorders based on sleep characteristics acquired in the patient's home are planned. • The autonomic activation index (AAI) detects sharp changes in pulse rate. • The AAI is generally blunted in patients with Parkinsonian spectrum disorders. • The proportion with blunted AAI is consistent with disease progression. • AAI during sleep is unrelated to sleep spindles. • AAI is weakly negatively correlated with non-REM hypertonia (NRH). [ABSTRACT FROM AUTHOR]

High adiposity is deleteriously associated with brain health, and may disproportionately affect white matter integrity; however, limited information exists regarding the mechanisms underlying the association between body mass (BMI) and white matter integrity. The present study evaluated whether vascular and inflammatory markers influence the relationship between BMI and white matter in healthy aging. We conducted a cross-sectional evaluation of white matter integrity, BMI, and vascular/inflammatory factors in a cohort of 138 healthy older adults (mean age: 71.3 years). Participants underwent diffusion tensor imaging, provided blood samples, and participated in a health evaluation. Vascular risk factors and vascular/inflammatory blood markers were assessed. The primary outcome measure was fractional anisotropy (FA) of the genu, body, and splenium (corpus callosum); exploratory measures included additional white matter regions, based on significant associations with BMI. Regression analyses indicated that higher BMI was associated with lower FA in the corpus callosum, cingulate, and fornix (p<.001). Vascular and inflammatory factors influenced the association between BMI and FA. Specifically, BMI was independently associated with the genu [β=-.21; B=-.0024; 95% CI, -.0048 to -.0000; p=.05] and cingulate fibers [β=-.39; B=-.0035; 95% CI,-.0056 to -.0015; p<.001], even after controlling for vascular/inflammatory risk factors and blood markers. In contrast, BMI was no longer significantly associated with the fornix and middle/posterior regions of the corpus callosum after controlling for these markers. Results partially support a vascular/inflammatory hypothesis, but also suggest a more complex relationship between BMI and white matter characterized by potentially different neuroanatomic vulnerability. [ABSTRACT FROM AUTHOR]