VA Northwest Network

Background and Objectives:Physical activity and sleep are potential modifiable risk factors for the development of Alzheimer’s disease and related disorders (ADRD), but few studies have objectively measured both domains in participants across the cognitive continuum.Research Design and Methods:Standard clinical assessment, accelerometry, and at-home EEG sleep data were obtained from older controls (n=9) and adults who met consensus diagnostic criteria for mild cognitive impairment (MCI; n=7), Alzheimer’s disease (AD; n=10), and dementia with Lewy bodies (DLB; n=11). Given these sample sizes, descriptive statistics are presented rather than formal statistical testing.Results:The MCI group had the most surprising findings—although they were cognitively similar to the control group, they were less physically active than the AD group and had the worst sleep efficiency. The DLB group had the most severe motor and neuropsychiatric symptoms, were the least physically active, spent the least amount of time in rapid eye movement (REM) sleep, and spent the highest amount of time in non-REM sleep with hypotonia (NRH). The AD group had physical activity counts that fell between the DLB and control groups; REM sleep and NRH levels that were similar to the control and MCI groups; and autonomic activation index (AAI) and sleep spindle durations that were higher than the MCI and DLB groups.Discussion and Implications:These findings highlight interesting physical activity and sleep patterns between groups, but larger samples are needed to investigate how objectively measured physical activity and sleep might serve as disease-specific digital biomarkers of neurodegenerative disorders.

This study sought to investigate differences in physical activity and activity fragmentation between older adults with and without dementia and between older adults with dementia with Lewy bodies (DLB) and older adults with Alzheimer's disease (AD). The study also sought to investigate how these differences vary in magnitude at different ages. Accelerometry data were analyzed from individuals with dementia (n = 94) and individuals without dementia (n = 613) who participated in the National Health and Aging Trends Study (NHATS), as well as from individuals with DLB (n = 12) and AD (n = 10) who participated in a pilot study. In the NHATS cohort, individuals without dementia had more activity counts (0.325 million [95% CI 0.162 million, 0.487 million]) and a longer active bout length (0.631 minutes [95% CI 0.311, 0.952]) at the mean age of 79 than individuals with dementia at the same age. There was also suggestive evidence that individuals without dementia had a shorter resting bout length (-2.196 minutes [95% CI -4.996, 0.605]) than individuals with dementia. Differences in data collection and processing prevented direct comparisons between the cohorts, and the parallel analyses in the smaller cohort were underpowered to detect statistically significant differences between DLB and AD. This work shows that objectively measured accelerometry data differ between individuals with and without dementia; future studies with larger samples should investigate whether accelerometry data can be used to aid in the early identification of dementia and differentiation of dementia subtypes.

Objective: Cognitive impairment is a core feature of traumatic encephalopathy syndrome (TES), the putative clinical syndrome of chronic traumatic encephalopathy—a neuropathological disease associated with repetitive head impacts (RHI). Careful operationalization of cognitive impairment is essential to improving the diagnostic specificity and accuracy of TES criteria. We compared single- versus two-test criteria for cognitive impairment in their associations with CSF and imaging biomarkers in male former American football players. Method: 169 participants from the DIAGNOSE CTE Research Project completed neuropsychological tests of memory and executive functioning. Cognitive impairment was identified by single-test criteria (z≤-1.5 on one test) and two-test criteria (z<-1 on two tests within a domain). ANCOVAs adjusting for age, race, education, body mass index, word-reading score, and APOE ε4 status assessed whether single- or two-test criteria predicted CSF markers (Aβ1-42, p-tau181, p-tau181/Aβ1-42, total tau, neurofilament light [NfL], glial fibrillary acidic protein [GFAP]) and MRI markers (hippocampal volume, cortical thickness, white matter hyperintensities). Results: Ninety-nine participants met single-test criteria for cognitive impairment. Sixty-six met two-test criteria. Participants who met two-test criteria had greater exposure to RHI than those who did not (p=.04). Two-test criteria were ­associated with higher CSF p-tau181/Aβ1-42 (q=.02) and CSF NfL (q=.02). The association between two-test criteria and CSF NfL remained after excluding amyloid-positive participants (q=.04). Single-test criteria were not associated with any biomarkers (q’s>.05). Conclusions: Two-test but not single-test criteria for cognitive impairment were associated with markers of neurodegeneration. Future clinical research in TES may benefit from applying two-test criteria to operationalize cognitive impairment.

We investigated whether the cerebellum develops neuropathology that correlates with well-accepted Alzheimer's disease (AD) neuropathological markers and cognitive status. We studied cerebellar cytoarchitecture in a cohort (N=30) of brain donors. In a larger cohort (N=605), we queried whether the weight of the contents of the posterior fossa (PF), which contains primarily cerebellum, correlated with dementia status. Although there was no granular layer (GL) cell loss, GL area was lower in AD cases, particularly in the lateral cerebellum. Lower numbers of mossy fiber synaptic terminals in the cerebellar GL of AD cases correlated with Braak stages IV-VI. PF content weight correlated with dementia independently of age, neuropathology, and education. In addition, we found that a measure of the relative size of the PF content weight to total brain weight correlated with less dementia. These results confirm that the cerebellum is not spared neuropathological damage in AD. Novel evidence of cerebellar atrophy in the granule cell layer of the lateral cerebellar cortex (or 'cognitive cerebellum'), and loss of a specific cerebellar synapse type in this region, the cerebellar glomerulus. Both correlated with dementia status and Braak stages IV through VI, in a cohort with complete neuropathological characterization. Although there have been recent brain imaging studies suggesting a role for cerebellum in Alzheimer's disease, we believe our study constitutes some of the most concrete neuropathological evidence to date of anatomic and synaptic substrates that are disrupted in AD. These changes in this cerebellar region may even play a role in the etiology of cognitive symptoms. Novel evidence that individuals with lower postmortem cerebellar weights showed more cognitive decline, independent of classical neuropathology markers such as Braak stage, Thal phase, or Corsortium to Establish a Registry for Alzheimer's Disease (CERAD) score, suggesting a role for this brain region in dementia, using advanced statistical analysis of a large unbiased population cohort (n=605), the Adult Changes in Thought (ACT) study. Conversely, a measure of how intact the cerebellum was correlated with less dementia, independent of classical neuropathology markers and cerebral cortical weight, again, in the ACT cohort of 605 brain donors. We believe that this novel finding has relevance and implications for the identification of resilience factors, which may protect against the development of dementia.

Suicide rates in the military are a significant public health concern. The suicide prevention safety planning intervention is a brief and effective intervention in which a provider and patient work collaboratively to recognize warning signs of a suicidal crisis and create a defined list of coping strategies and supports for use during future crises (Stanley & Brown, 2012). Implementation of safety planning has been supported by the Department of Defense (DoD), yet readily available training and continuing education for healthcare providers in this intervention is limited and passive in nature. Existing safety planning training experiences and needs of DoD behavioral health providers are unknown. The present study is an exploratory qualitative assessment of current safety planning in DoD to inform the design and development of an interactive virtual standardized training patient. Ten military behavioral health providers completed semi-structured interviews. Thematic content analysis was conducted, and three themes are described in this paper: variety of training received, barriers to receiving suicide safety planning training, and desires for future training. Lack of protected time for training and a lack of access to training resources were identified as key barriers. Rich data obtained can help inform the key design features and relevance of new safety planning intervention training approaches.

ABSTRACT Poor sleep is implicated in the development of Alzheimer’s disease (AD) pathology and cognitive impairment. Dysfunction of the glymphatic system has been proposed as a mechanistic link between sleep disruption and AD, and in animal models glymphatic impairment is sufficient to drive the development of AD pathology. It remains unknown whether the glymphatic system clears amyloid beta (Aβ) and tau from the brain in humans. This study directly tested the hypothesis that sleep-active glymphatic clearance increases morning plasma AD biomarker levels. In a multi-site randomized crossover clinical trial, participants (N=39) underwent overnight in-laboratory conditions of normal sleep and sleep deprivation following instrumentation that included a novel device to measure sleep features by electroencephalography (EEG), cerebrovascular compliance by measurement of pulse transit time (PTT), and brain parenchymal resistance to glymphatic flow (RP) by transcranial multifrequency impedance spectroscopy. We evaluated whether RP, sleep EEG features, PTT, and heart rate variability (HRV) predicted overnight changes in plasma AD biomarker (Aβ40, Aβ42, np-tau181, np-tau217 and p-tau181) levels. We found that changes in RP, PTT, HRV and EEG delta power in a multivariate linear mixed model predicted sleep-associated overnight changes in Aβ40 (p=0.013), Aβ42 (p&lt;0.001), np-tau181 (p&lt;0.001), np-tau217 (p&lt;0.001) and p-tau181 (p&lt;0.001). The predicted changes replicated those from a multicompartment model based on published data on synaptic-metabolic release and clearance of Aβ and tau to the plasma. Sensitivity analysis demonstrated that while morning biomarker levels were altered by both the synaptic-metabolic release and clearance of Aβ and tau, during sleep glymphatic clearance was the dominant influence. In contrast, during sleep deprivation (waking) while glymphatic clearance was a contributor, Aβ and tau release was the dominant factor explaining variance in morning plasma Aβ and tau levels. Our findings show that elements of sleep-active physiology, in particular decreased brain parenchymal resistance, facilitates the overnight clearance of AD biomarkers to plasma, supporting a role for glymphatic clearance in these processes, and suggesting the enhancement of glymphatic function as a therapeutic target to reduce the development and progression of AD pathology in at-risk populations.

Experiments to study the biology of addiction have historically focused on the mechanisms through which drugs of abuse drive changes in the functioning of neurons and neural circuits. Glia have often been ignored in these studies, however, and this has left many questions in the field unanswered, particularly, surrounding how glia contribute to changes in synaptic plasticity, regulation of neuroinflammation, and functioning of neural ensembles given massive changes in signaling across the CNS. Omics methods (transcriptomics, translatomics, epigenomics, proteomics, metabolomics, and others) have expanded researchers' abilities to generate hypotheses and carry out mechanistic studies of glial cells during acquisition of drug taking, intoxication, withdrawal, and relapse to drug seeking. Here, we present a survey of how omics technological advances are revising our understanding of astrocytes, microglia, oligodendrocytes, and ependymal cells in addiction biology.

Migraine is a prevalent and debilitating condition that substantially impacts quality of life. Investigating migraine prevalence, associated comorbidities, and potential military service exposures in veterans, focusing on gender differences, is crucial for targeted interventions and management strategies. To determine the prevalence of migraine, associated health comorbidities, and potential military service and environmental exposures among men and women US veterans using a large-scale epidemiological sample from the Million Veteran Program (MVP). This cross-sectional study analyzed self-report survey data from the MVP, a large epidemiological sample of US veterans that was started in 2011 and has ongoing enrollment. Eligible participants were selected from the MVP database in 2023. The study included 491 604 veterans to examine migraine prevalence, health comorbidities, demographic characteristics, military service history, and environmental exposures. Data were analyzed from December 2022 to July 2023. Military service and environmental factors, such as chemical or biological warfare exposure, were considered. The primary outcome was migraine prevalence among men and women veterans, assessed through self-reported diagnoses. Secondary outcomes included the association between migraine and health comorbidities, demographic characteristics, military service history, and environmental exposures. Of the 491 604 veterans included in this study, 450 625 (91.8%) were men and 40 979 (8.2%) were women. The lifetime prevalence of migraine was significantly higher in women (12 324 of 40 979 [30.1%]) than in men (36 816 of 450 625 [8.2%]). Migraine prevalence varied by race and ethnicity, with the highest prevalence in Hispanic or Latinx women (1213 of 3495 [34.7%]). Veterans with migraine reported worse general health, higher levels of pain, increased pain interference with work, a higher likelihood of psychiatric and neurological health conditions, and greater lifetime opioid use. Specific aspects of military service, including service post-September 2001 and deployment in Operation Enduring Freedom and Operation Iraqi Freedom, and environmental factors, including Agent Orange, chemical and biological welfare, and antinerve agent pills history, were significantly associated with migraine prevalence. In this cross-sectional study of migraine, the results highlighted gender differences in migraine prevalence and associated health comorbidities among US veterans. The findings emphasized the need for interdisciplinary approaches to migraine management, increased awareness and education efforts, and population-based screening strategies, particularly for women and Hispanic veterans who are at greater risk. Our findings encourage further research into tailored interventions for specific subpopulations and the impact of military service and environmental exposures on migraine and related health conditions.

The Hachinski ischemic score (HIS) scale is used to exclude as much as possible, individuals with dominant cerebrovascular pathology from those with dominant AD pathology. White matter hyperintensities (WMH) are the gold-standard for evaluating cerebrovascular pathology and linked to worsening cognitive impairment. HIS ≤ 4 are used to minimize non-AD pathology in ADNI participants. Here we sought to understand whether HIS scores for hypertension (HMHYPERT) in ADNI3 were associated with greater WMH burden (and hence cerebrovascular pathology) even within individuals with HIS ≤ 4. We compared HMHYPERT scores between individuals with normal cognition (CN) and with mild cognitive impairment (MCI), and participants and correlated with percent WMH burden. A total of 263 subjects screened for ADNI3 (92 MCI [38 F], age = 73 ± 6; 146 CN [94 F], age = 74 ± 7) who had HIS scores and FLAIR MRI acquisitions within a year of each other. 25 All AD participants were excluded. WMH burden was calculated by segmenting them using the Lesion Segmentation Toolbox and normalizing their volume by total intracranial volume. We used the HMHYPERT as a vascular risk factor, excluding those with any focal neurological symptoms. For analysis, we dichotomized participants into those with HMHYPERT = 0 and HMHYPERT>0. To examine whether a non-zero HMHYPERT score corresponds to greater WMH burden, we examined the prevalence of WMH in between these 2 groups and within the MCI and CN groups. Although not significant, HMHYPERT scores were higher in MCI. (Fig. 1A, MCI = 0.48±0.50, CN = 0.39±0.49). We found a greater proportion of MCI subjects had HMHYPERT>0 than CN subjects (Fig. 1B, HMHYPERT = 0: CN = 61.0% and MCI = 52.2%; HMHYPERT > 0: CN = 40.0% and MCI = 48.1%). WMH burden was greater in MCI (0.33±0.53) than CN (0.20±0.32) (Fig. 2A). MCI participants with HMHYPERT>0 had the highest WMH burden followed by MCI participants with HMHYPERT = 0, CN with HMHYPERT >0, and CN with HMHYPERT = 0 had the lowest WMH burden. (Fig. 2B). Cerebrovascular pathology increases significantly with diagnosis, but its severity increases further with findings of hypertension even when total HIS ≤ 4.

Direct oral anticoagulant (DOAC) medications are frequently associated with inappropriate prescribing and adverse events. To improve the safe use of DOACs, health systems are implementing population health tools within their electronic health record (EHR). While EHR informatics tools can help increase awareness of inappropriate prescribing of medications, a lack of empowerment (or insufficient empowerment) of nonphysicians to implement change is a key barrier. This study examined how the individual authority of clinical pharmacists and anticoagulation nurses is impacted by and changes the implementation success of an EHR DOAC Dashboard for safe DOAC medication prescribing. We conducted semistructured interviews with pharmacists and nurses following the implementation of the EHR DOAC Dashboard at 3 clinical sites. Interview transcripts were coded according to the key determinants of implementation success. The intersections between individual clinician authority and other determinants were examined to identify themes. A high level of individual clinician authority was associated with high levels of key facilitators for effective use of the DOAC Dashboard (communication, staffing and work schedule, job satisfaction, and EHR integration). Conversely, a lack of individual authority was often associated with key barriers to effective DOAC Dashboard use. Positive individual authority was sometimes present with a negative example of another determinant, but no evidence was found of individual authority co-occurring with a positive instance of another determinant. Increased individual clinician authority is a necessary antecedent to the effective implementation of an EHR DOAC Population Management Dashboard and positively affects other aspects of implementation. RR2-10.1186/s13012-020-01044-5.