Effectiveness of Prefrontal Transcranial Magnetic Stimulation for Depression in Older US Military Veterans.

OBJECTIVE: While typical aging is associated with decreased cortical volume, major depressive disorder (MDD) and posttraumatic stress disorder (PTSD) likely exacerbates this process. Cerebral atrophy leads to increased coil-to-cortex distance and when using transcranial magnetic stimulation (TMS), potentially reducing effectiveness in older adults. METHODS: Data from a large-scale quality improvement project was used. Included veterans eligible for TMS and completed TMS treatment. Age was assessed as a predictive factor of depression outcomes after TMS treatment among veterans. Secondary analyses examined the impact of age on 1) MDD response and remission and 2) MDD change within MDD-only verses comorbid MDD and PTSD groups. RESULTS: The entire sample included 471 veterans. Primary analysis revealed age as a negative predictor of depression outcomes (p = 0.019). Secondary analyses found age to be a significant predictor of remission (p = 0.004), but not clinical response. Age was not a predictive factor in depression outcomes between those with MDD-only compared to MDD+PTSD. CONCLUSIONS: Increased age predicts greater MDD symptom reduction after TMS. Although age did not predict response rates, it did predict increased rates of remission in veterans. Age did not differentially predict depression outcomes between those with or without PTSD. The sample size was sufficient to discern a difference in efficaciousness, and limitations were those inherent to registry studies in veterans. This data indicates that TMS can be an important treatment option for older individuals.

Sleep-wake disorders in Alzheimer's disease: further genetic analyses in relation to objective sleep measures.

This paper presents updated analyses on the genetic associations of sleep disruption in individuals with Alzheimer's disease (AD). We published previously a study of the association between single nucleotide polymorphisms (SNPs) found in eight genes related to circadian rhythms and objective measures of sleep-wake disturbances in 124 individuals with AD. Here, we present new relevant analyses using polygenic risk scores (PRS) and variable number tandem repeats (VNTRs) enumerations. PRS were calculated using the genetic data from the original participants and relevant genome wide association studies (GWAS). VNTRs for the same circadian rhythm genes studied with SNPs were obtained from a separate cohort of participants using whole genome sequencing (WGS). Objectively (wrist actigraphy) determined wake after sleep onset (WASO) was used as a measure of sleep disruption. None of the PRS were associated with sleep disturbance. Computer analyses using VNTRseek software generated a total of 30 VNTRs for the circadian-related genes but none appear relevant to our objective sleep measure. In addition, of 71 neurotransmitter function-related genes, 29 genes had VNTRs that differed from the reference VNTR, but it was not clear if any of these might affect circadian function in AD patients. Although we have not found in either the current analyses or in our previous published analyses of SNPs any direct linkages between identified genetic factors and WASO, research in this area remains in its infancy.

Ubiquity of Undiagnosed Sleep Disordered Breathing in Community-Dwelling Older Male Veterans.

OBJECTIVE: To determine the point prevalence of sleep disordered breathing (SDB) in a community-based sample of older male veterans and to determine if common markers of SDB apply to this population. METHODS: Two hundred fourteen older male Veterans (age 55-89 years) were recruited for a study on post-traumatic stress disorder and cognitive decline. Questionnaires concerning anthropomorphic and psychological variables were obtained, as was an overnight polysomnographic examination of sleep. RESULTS: Only 13% of the participants lacked clinically meaningful SDB, whereas 33% had moderate SDB and 54% had severe SDB. Being overweight, self-reported snoring, and excessive daytime sleepiness all had good sensitivity (0.86-0.92) but very poor specificity (0.10-0.28) for the prediction of SDB. CONCLUSIONS: Undiagnosed SDB was more than threefold higher than expected in these community-dwelling older veterans. Traditional markers of SDB were not specific for predicting clinically relevant SDB.

Donepezil treatment in ethnically diverse patients with Alzheimer disease.

OBJECTIVE: To compare the outcome of donepezil treatment in ethnically diverse Alzheimer disease (AD) patients with ethnically diverse AD patients who did not receive donepezil. METHODS: Patients meeting NINCDS-ADRA criteria for probable or possible AD from a consortium of California sites were systematically followed for at least 1 year in this prospective, observational study. Their treatment regimens, including prescription of donepezil, were determined by their individual physician according to his or her usual criteria. Patients self-identified their ethnicity. RESULTS: The 64 ethnically diverse AD patients who completed the study and received donepezil treatment had an average 1-year decline of 2.30 points (standard deviation: 3.9) on the 30-point Mini-Mental State Exam compared with a 1.70-point (standard deviation: 4.2) decline in the 74 ethnically diverse completers who received no donepezil or other anti-AD drugs during the study period. This difference was not statistically significant. The overall Cohen effect size of this treatment-associated difference was estimated at -0.15. After using propensity analyses and other techniques to assess factors that could bias prescribing decisions, the lack of benefits associated with donepezil treatment remained. The lack of donepezil benefits also remained when more traditional analyses were applied to these data. CONCLUSION: Ethnically diverse AD patients in this study apparently did not benefit from 1 year of donepezil treatment. These unpromising results are in contrast to modest benefits of donepezil treatment measured in a directly comparable California study involving white non-Latino AD patients.

Classification and prediction of clinical Alzheimer's diagnosis based on plasma signaling proteins.

A molecular test for Alzheimer's disease could lead to better treatment and therapies. We found 18 signaling proteins in blood plasma that can be used to classify blinded samples from Alzheimer's and control subjects with close to 90% accuracy and to identify patients who had mild cognitive impairment that progressed to Alzheimer's disease 2-6 years later. Biological analysis of the 18 proteins points to systemic dysregulation of hematopoiesis, immune responses, apoptosis and neuronal support in presymptomatic Alzheimer's disease.

Phenotyping apathy in individuals with Alzheimer disease using functional principal component analysis.

OBJECTIVES: To determine if there is a specific pattern of gross motor activity associated with apathy in individuals with Alzheimer disease (AD). DESIGN: Examination of ad libitum 24-hour ambulatory gross motor activity patterns. SETTING: Community-dwelling, outpatient. PARTICIPANTS: Ninety-two individuals with AD, 35 of whom had apathy. MEASUREMENTS: Wrist actigraphy data were collected and examined using functional principal component analysis (fPCA). RESULTS: Individuals with apathy have a different pattern of gross motor activity than those without apathy (first fPCA component, p <0.0001, t = 5.73, df = 90, t test) such that there is a pronounced decline in early afternoon activity in those with apathy. This change in activity is independent of depression (p = 0.68, F[1, 89] = 0.05, analysis of variance). The decline in activity is consistent with an increase in napping. Those with apathy also have an early wake and bedtime (second fPCA component, t = 2.53, df = 90, p <0.05, t test). CONCLUSIONS: There is a signature activity pattern in individuals with apathy and AD that is distinct from those without apathy and those with depression. Actigraphy may be a useful adjunctive measurement in the clinical diagnosis of apathy in the context of AD.

The Benton Visual Form Discrimination Test as a Predictor of Neurocognitive Disorder in Older Veterans.

OBJECTIVE: The Benton Visual Form Discrimination Test (VFDT) is a commonly used measure of visual discrimination and visual recognition memory and has shown promise in distinguishing between different levels of cognitive impairment. We assess the predictive diagnostic utility of the VFDT in a sample of older Veterans with cognitive concerns. METHOD: Subjects included a total of 172 mostly male Veterans over the age of 64 (mean = 76.0; SD = 7.6) recruited from a VA clinic specializing in neuropsychological assessment of older Veterans. The clinical sample included 56 subjects diagnosed with Major Neurocognitive Disorder, 74 diagnosed with Mild Neurocognitive Disorder, and 42 with No Neurocognitive Impairment. Impairment categories were modeled in separate multinomial logistic regressions with two versions of the VFDT as predictors: the Visual Form Discrimination Test-Recognition Subtest (VFDT-Rec) test (visual recognition memory) and the Visual Form Discrimination Test-Matching Subtest VFDT-Mat test (visual form discrimination). Years of education were included as a covariate. RESULTS: After adjusting for education, higher VFDT-Rec total scores were associated with lower odds of being categorized with a greater degree of cognitive/functional impairment (OR 0.66-0.83, p < .001). VFDT-Mat scores showed a similar pattern, but only reached statistical significance for the Major versus No Neurocognitive Impairment (OR = 0.77, p = .0010) and Major versus Mild comparisons (OR = 0.89, p = .0233). CONCLUSIONS: The VFDT may enhance the confidence of differential diagnosis of dementia in older adult Veterans. Formal education-adjusted norms need to be established for clinical use.

A Cognitive Biotype of Depression and Symptoms, Behavior Measures, Neural Circuits, and Differential Treatment Outcomes: A Prespecified Secondary Analysis of a Randomized Clinical Trial.

Importance: Cognitive deficits in depression have been associated with poor functional capacity, frontal neural circuit dysfunction, and worse response to conventional antidepressants. However, it is not known whether these impairments combine together to identify a specific cognitive subgroup (or "biotype") of individuals with major depressive disorder (MDD), and the extent to which these impairments mediate antidepressant outcomes. Objective: To undertake a systematic test of the validity of a proposed cognitive biotype of MDD across neural circuit, symptom, social occupational function, and treatment outcome modalities. Design, Setting, and Participants: This secondary analysis of a randomized clinical trial implemented data-driven clustering in findings from the International Study to Predict Optimized Treatment in Depression, a pragmatic biomarker trial in which patients with MDD were randomized in a 1:1:1 ratio to antidepressant treatment with escitalopram, sertraline, or venlafaxine extended-release and assessed at baseline and 8 weeks on multimodal outcomes between December 1, 2008, and September 30, 2013. Eligible patients were medication-free outpatients with nonpsychotic MDD in at least the moderate range, and were recruited from 17 clinical and academic practices; a subset of these patients underwent functional magnetic resonance imaging. This prespecified secondary analysis was performed between June 10, 2022, and April 21, 2023. Main Outcomes and Measures: Pretreatment and posttreatment behavioral measures of cognitive performance across 9 domains, depression symptoms assessed using 2 standard depression scales, and psychosocial function assessed using the Social and Occupational Functioning Assessment Scale and World Health Organization Quality of Life scale were analyzed. Neural circuit function engaged during a cognitive control task was measured using functional magnetic resonance imaging. Results: A total of 1008 patients (571 [56.6%] female; mean [SD] age, 37.8 [12.6] years) participated in the overall trial and 96 patients participated in the imaging substudy (45 [46.7%] female; mean [SD] age, 34.5 [13.5] years). Cluster analysis identified what may be referred to as a cognitive biotype of 27% of depressed patients with prominent behavioral impairment in executive function and response inhibition domains of cognitive control. This biotype was characterized by a specific profile of pretreatment depressive symptoms, worse psychosocial functioning (d = -0.25; 95% CI, -0.39 to -0.11; P < .001), and reduced activation of the cognitive control circuit (right dorsolateral prefrontal cortex: d = -0.78; 95% CI, -1.28 to -0.27; P = .003). Remission was comparatively lower in the cognitive biotype positive subgroup (73 of 188 [38.8%] vs 250 of 524 [47.7%]; P = .04) and cognitive impairments persisted regardless of symptom change (executive function: ηp2 = 0.241; P < .001; response inhibition: ηp2 = 0.750; P < .001). The extent of symptom and functional change was specifically mediated by change in cognition but not the reverse. Conclusions and Relevance: Our findings suggest the presence of a cognitive biotype of depression with distinct neural correlates, and a functional clinical profile that responds poorly to standard antidepressants and instead may benefit from therapies specifically targeting cognitive dysfunction. Trial Registration: ClinicalTrials.gov Identifier: NCT00693849.

Ketamine's acute effects on negative brain states are mediated through distinct altered states of consciousness in humans.

Ketamine commonly and rapidly induces dissociative and other altered states of consciousness (ASCs) in humans. However, the neural mechanisms that contribute to these experiences remain unknown. We used functional neuroimaging to engage key regions of the brain's affective circuits during acute ketamine-induced ASCs within a randomized, multi-modal, placebo-controlled design examining placebo, 0.05 mg/kg ketamine, and 0.5 mg/kg ketamine in nonclinical adult participants (NCT03475277). Licensed clinicians monitored infusions for safety. Linear mixed effects models, analysis of variance, t-tests, and mediation models were used for statistical analyses. Our design enabled us to test our pre-specified primary and secondary endpoints, which were met: effects of ketamine across dose conditions on (1) emotional task-evoked brain activity, and (2) sub-components of dissociation and other ASCs. With this design, we also could disentangle which ketamine-induced affective brain states are dependent upon specific aspects of ASCs. Differently valenced ketamine-induced ASCs mediated opposing effects on right anterior insula activity. Participants experiencing relatively higher depersonalization induced by 0.5 mg/kg of ketamine showed relief from negative brain states (reduced task-evoked right anterior insula activity, 0.39 SD). In contrast, participants experiencing dissociative amnesia showed an exacerbation of insula activity (0.32 SD). These results in nonclinical participants may shed light on the mechanisms by which specific dissociative states predict response to ketamine in depressed individuals.

24 h Rest/Activity Rhythms in Older Adults with Memory Impairment: Associations with Cognitive Performance and Depressive Symptomatology.

Little is known about links of circadian rhythm alterations with neuropsychiatric symptoms and cognition in memory impaired older adults. Associations of actigraphic rest/activity rhythms (RAR) with depressive symptoms and cognition are examined using function-on-scalar regression (FOSR). Forty-four older adults with memory impairment (mean: 76.84 ± 8.15 years; 40.9% female) completed 6.37 ± 0.93 days of actigraphy, the Beck depression inventory-II (BDI-II), mini-mental state examination (MMSE) and consortium to establish a registry for Alzheimer's disease (CERAD) delayed word recall. FOSR models with BDI-II, MMSE, or CERAD as individual predictors adjusted for demographics (Models A1-A3) and all three predictors and demographics (Model B). In Model B, higher BDI-II scores are associated with greater activity from 12:00-11:50 a.m., 2:10-5:50 p.m., 8:40-9:40 p.m., 11:20-12:00 a.m., higher CERAD scores with greater activity from 9:20-10:00 p.m., and higher MMSE scores with greater activity from 5:50-10:50 a.m. and 12:40-5:00 p.m. Greater depressive symptomatology is associated with greater activity in midafternoon, evening, and overnight into midday; better delayed recall with greater late evening activity; and higher global cognitive performance with greater morning and afternoon activity (Model B). Time-of-day specific RAR alterations may affect mood and cognitive performance in this population.

Sleep-disordered breathing in Vietnam veterans with posttraumatic stress disorder.

OBJECTIVE: : To study the prevalence of sleep-disordered breathing (SDB) in Vietnam- era veterans. METHODS: : This was an observational study of Vietnam-era veterans using unattended, overnight polysomnography, cognitive testing, and genetic measures. RESULTS: : A sample of 105 Vietnam-era veterans with posttraumatic stress disorder: 69% had an Apnea Hypopnea Index >10. Their mean body mass index was 31, "obese" by Centers for Disease Control and Prevention criteria, and body mass index was significantly associated with Apnea Hypopnea Index (Spearman r = 0.41, N = 97, p < 0.0001). No significant effects of sleep-disordered breathing or apolipoprotein status were found on an extensive battery of cognitive tests. CONCLUSION: : There is a relatively high prevalence of SDB in these patients which raises the question of to what degree excess cognitive loss in older PTSD patients may be due to a high prevalence of SDB.

Decreased daytime motor activity associated with apathy in Alzheimer disease: an actigraphic study.

OBJECTIVE: Across all stages of Alzheimer disease (AD), apathy is the most common neuropsychiatric symptom. Studies using the Neuropsychiatric Inventory (NPI) have found that apathy is present in up to 70% of individuals with Alzheimer disease. One of the main difficulties in assessing apathy and other neuropsychiatric symptoms is the absence of reliable, objective measures. Motor activity assessment using ambulatory actigraphy could provide an indirect, objective evaluation of apathy. The aim of our study was to assess the relationship between apathy and daytime motor activity in AD, using ambulatory actigraphy. METHODS: One hundred seven AD outpatients wore a wrist actigraph (Motionlogger) during seven consecutive 24-hour periods to evaluate motor activity. Participants were divided into two subgroups according to their apathy subscores on the NPI: individuals with apathy (NPI-apathy subscores >4) and those without. Daytime mean motor activity scores were compared between the two subgroups. RESULTS: Individuals with AD who had symptoms of apathy (n = 43; age = 79 ± 4.7 years; Mini-Mental State Examination = 20.9 ± 4.8) had significantly lower daytime mean motor activity than AD patients without apathy (n = 64; age = 76.3 ± 7.7; Mini-Mental State Examination = 21.5 ± 4.7), while nighttime mean motor activity did not significantly differ between the two subgroups. CONCLUSIONS: Ambulatory actigraphy could be added to currently used questionnaires as a simple, objective technique for assessing apathy in the routine assessment of AD patients.

Modeling the effects of obstructive sleep apnea and hypertension in Vietnam veterans with PTSD.

PURPOSE: The present work aimed to extend models suggesting that obstructive sleep apnea (OSA) is associated with worse cognitive performance in community-dwelling older adults. We hypothesized that in addition to indices of OSA severity, hypertension is associated with worse cognitive performance in such adults. METHODS: The PTSD Apnea Clinical Study recruited 120 community-dwelling, male veterans diagnosed with PTSD, ages 55 and older. The Rey Auditory Verbal Learning Test (RAVLT) and Color-Word Interference Test (CWIT) were measures of auditory verbal memory and executive function, respectively. Apnea-hypopnea index (AHI), minimum and mean pulse oximeter oxygen saturation (min SpO(2), mean SpO(2)) indicators were determined during standard overnight polysomnography. Multivariate linear regression and receiver operating characteristic (ROC) curve analyses were performed. RESULTS: In regression models, AHI (ß = -4.099; p < 0.01) and hypertension (ß = -4.500; p < 0.05) predicted RAVLT; hypertension alone (ß = 9.146; p < 0.01) predicted CWIT. ROC analyses selected min SpO(2) cut-points of 85% for RAVLT (κ = 0.27; χ² = 8.23, p < 0.01) and 80% for CWIT (κ = 0.25; χ² = 12.65, p < 0.01). Min SpO(2) cut-points and hypertension were significant when added simultaneously in a regression model for RAVLT (min SpO(2), ß = 4.452; p < 0.05; hypertension, ß = -4.332; p < 0.05), and in separate models for CWIT (min SpO(2), ß = -8.286; p < 0.05; hypertension, ß = -8.993; p < 0.01). CONCLUSIONS: OSA severity and presence of self-reported hypertension are associated with poor auditory verbal memory and executive function in older adults.

Pilot expertise and hippocampal size: associations with longitudinal flight simulator performance.

BACKGROUND: Previous research suggests that the size of the hippocampus can vary in response to intensive training (e.g., during the acquisition of expert knowledge). However, the role of the hippocampus in maintenance of skilled performance is not well understood. The Stanford/Veterans Affairs Aviation MRI Study offers a unique opportunity to observe the interaction of brain structure and multiple levels of expertise on longitudinal flight simulator performance. METHODS: The current study examined the relationship between hippocampal volume and three levels of aviation expertise, defined by pilot proficiency ratings issued by the U.S. Federal Aviation Administration (11). At 3 annual time points, 60 pilots who varied in their level of aviation expertise (ages ranging from 45 to 69 yr) were tested. RESULTS: At baseline, higher expertise was associated with better flight simulator performance, but not with hippocampal volume. Longitudinally, there was an Expertise x Hippocampal volume interaction, in the direction that a larger hippocampus was associated with better performance at higher levels of expertise. DISCUSSION: These results are consistent with the notion that expertise in a cognitively demanding domain involves the interplay of acquired knowledge ('mental schemas') and basic hippocampal-dependent processes.

Targeting the Salience Network: A Mini-Review on a Novel Neuromodulation Approach for Treating Alcohol Use Disorder.

Alcohol use disorder (AUD) continues to be challenging to treat despite the best available interventions, with two-thirds of individuals going on to relapse by 1 year after treatment. Recent advances in the brain-based conceptual framework of addiction have allowed the field to pivot into a neuromodulation approach to intervention for these devastative disorders. Small trials of repetitive transcranial magnetic stimulation (rTMS) have used protocols developed for other psychiatric conditions and applied them to those with addiction with modest efficacy. Recent evidence suggests that a TMS approach focused on modulating the salience network (SN), a circuit at the crossroads of large-scale networks associated with AUD, may be a fruitful therapeutic strategy. The anterior insula or dorsal anterior cingulate cortex may be particularly effective stimulation sites given emerging evidence of their roles in processes associated with relapse.

Prefrontal transcranial magnetic stimulation for depression in US military veterans - A naturalistic cohort study in the veterans health administration.

BACKGROUND: Repetitive transcranial magnetic stimulation (TMS) is an evidence-based treatment for pharmacoresistant major depressive disorder (MDD), however, the evidence in veterans has been mixed. To this end, VA implemented a nationwide TMS program that included evaluating clinical outcomes within a naturalistic design. TMS was hypothesized to be safe and provide clinically meaningful reductions in MDD and posttraumatic stress disorder (PTSD) symptoms. METHODS: Inclusion criteria were MDD diagnosis and standard clinical TMS eligibility. Of the 770 patients enrolled between October 2017 and March 2020, 68.4% (n = 521) met threshold-level PTSD symptom criteria. Treatments generally used standard parameters (e.g., left dorsolateral prefrontal cortex, 120% motor threshold, 10 Hz, 3000 pulses/treatment). Adequate dose was operationally defined as 30 sessions. MDD and PTSD symptoms were measured using the 9-item patient health questionnaire (PHQ-9) and PTSD checklist for DSM-5 (PCL-5), respectively. RESULTS: Of the 770 who received at least one session, TMS was associated with clinically meaningful (Cohen's d>1.0) and statistically significant (all p<.001) reductions in MDD and PTSD. Of the 340 veterans who received an adequate dose, MDD response and remission rates were 41.4% and 20%, respectively. In veterans with comorbid PTSD, 65.3% demonstrated clinically meaningful reduction and 46.1% no longer met PTSD threshold criteria after TMS. Side effects were consistent with the known safety profile of TMS. LIMITATIONS: Include those inherent to retrospective observational cohort study in Veterans. CONCLUSIONS: These multisite, large-scale data supports the effectiveness and safety of TMS for veterans with MDD and PTSD using standard clinical approaches.

Ruminative reflection is associated with anticorrelations between the orbitofrontal cortex and the default mode network in depression: implications for repetitive transcranial magnetic stimulation.

Patients with depression who ruminate repeatedly focus on depressive thoughts; however, there are two cognitive subtypes of rumination, reflection and brooding, each associated with different prognoses. Reflection involves problem-solving and is associated with positive outcomes, whereas brooding involves passive, negative, comparison with other people and is associated with poor outcomes. Rumination has also been related to atypical functional hyperconnectivity between the default mode network and subgenual prefrontal cortex. Repetitive pulse transcranial magnetic stimulation of the prefrontal cortex has been shown to alter functional connectivity, suggesting that the abnormal connectivity associated with rumination could potentially be altered. This study examined potential repetitive pulse transcranial magnetic stimulation prefrontal cortical targets that could modulate one or both of these rumination subtypes. Forty-three patients who took part in a trial of repetitive pulse transcranial magnetic stimulation completed the Rumination Response Scale questionnaire and resting-state functional magnetic resonance imaging. Seed to voxel functional connectivity analyses identified an anticorrelation between the left lateral orbitofrontal cortex (-44, 26, -8; k = 172) with the default mode network-subgenual region in relation to higher levels of reflection. Parallel analyses were not significant for brooding or the RRS total score. These findings extend previous studies of rumination and identify a potential mechanistic model for symptom-based neuromodulation of rumination.

Circadian clock gene polymorphisms and sleep-wake disturbance in Alzheimer disease.

OBJECTIVES: One of the hypothesized causes of the breakdown in sleep-wake consolidation often occurring in individuals with Alzheimer disease (AD) is the dysfunction of the circadian clock. The goal of this study is to report indices of sleep-wake function collected from individuals with AD in relation to relevant polymorphisms in circadian clock-related genes. DESIGN: One week of ad libitum ambulatory sleep data collection. SETTING: At-home collection of sleep data and in-laboratory questionnaire. PARTICIPANTS: Two cohorts of AD participants. Cohort 1 (N = 124): individuals with probable AD recruited from the Stanford/Veterans Affairs, National Institute on Aging Alzheimer's Disease Core Center (N = 81), and the Memory Disorders Clinic at the University of Nice School of Medicine (N = 43). Cohort 2 (N = 176): individuals with probable AD derived from the Alzheimer's Disease Neuroimaging Initiative data set. MEASUREMENTS: Determination of sleep-wake state was obtained by wrist actigraphy data for 7 days in Cohort 1 and by the Neuropsychiatric Inventory questionnaire for Cohort 2. Both cohorts were genotyped by using an Illumina Beadstation (Illumina, San Diego, CA), and 122 circadian-related single-nucleotide polymorphisms (SNPs) were examined. In Cohort 1, an additional polymorphism (variable-number tandem repeat in per3) was also determined. RESULTS: Adjusting for multiple tests, none of the candidate gene SNPs were significantly associated with the amount of wake time after sleep onset (WASO), a marker of sleep consolidation. Although the study was powered sufficiently to identify moderate-sized correlations, we found no relationships likely to be of clinical relevance. CONCLUSIONS: It is unlikely that a relationship with a clinically meaningful correlation exists between the circadian rhythm-associated SNPs and WASO in individuals with AD.

Brain health registry GenePool study: A novel approach to online genetics research.

INTRODUCTION: Remote data collection, including the establishment of online registries, is a novel approach to efficiently identify risk for cognitive decline and Alzheimer's disease (AD) in older adults, with growing evidence for feasibility and validity. Addition of genetic data to online registries has the potential to facilitate identification of older adults at risk and to advance the understanding of genetic contributions to AD. METHODS: 573 older adult participants with longitudinal online Brain Health Registry (BHR) data underwent apolipoprotein E (APOE) genotyping using remotely collected saliva samples and a novel, automated Biofluid Collection Management Portal. We evaluated acceptability of genetic sample collection and estimated associations between (1) sociodemographic variables and willingness to participate in genetics research and (2) APOE results and online cognitive and functional assessments. We also assessed acceptance of hypothetical genetics research participation by surveying a larger sample of 25,888 BHR participants. RESULTS: 51% of invited participants enrolled in the BHR genetics study, BHR-GenePool Study (BHR-GPS); 27% of participants had at least one APOE ε4 allele. Older participants and those with higher educational attainment were more likely to participate. In the remotely administered Cogstate Brief Battery, APOE ε4/ε4 homozygotes (HM) had worse online learning scores, and greater decline in processing speed and attention, compared to ε3/ε4 heterozygotes (HT) and ε4 non-carriers (NC). DISCUSSION: APOE genotyping of more than 500 older adults enrolled in BHR supports the feasibility and validity of a novel, remote biofluids collection approach from a large cohort of older adults, with data linkage to longitudinal online cognitive data. This approach can be expanded for efficient collection of genetic data and other information from biofluids in the future.

Brainstem damage is associated with poorer sleep quality and increased pain in gulf war illness veterans.

AIMS: Gulf War Illness (GWI) is manifested as multiple chronic symptoms, including chronic pain, chronic fatigue, sleep problems, neuropsychiatric disorders, respiratory, gastrointestinal, and skin problems. No single target tissue or unifying pathogenic process has been identified that accounts for this variety of symptoms. The brainstem has been suspected to contribute to this multiple symptomatology. The aim of this study was to assess the role of the brainstem in chronic sleep problems and pain in GWI veterans. MATERIALS AND METHODS: We enrolled 90 veterans (Age = 50 ± 5, 87% Male) who were deployed to the 1990-91 Gulf War and presented with GWI symptoms. Sleep quality was evaluated using the global Pittsburgh Sleep Quality Index. Pain intensities were obtained with the Brief Pain Inventory sum score. Volumes in cortical, subcortical, brainstem, and brainstem subregions and diffusion tensor metrics in 10 bilateral brainstem tracts were tested for correlations with symptom measures. KEY FINDINGS: Poorer sleep quality was significantly correlated with atrophy of the whole brainstem and brainstem subregions (including midbrain, pons, medulla). Poorer sleep quality also significantly correlated with lower fractional anisotropy in the nigrostriatal tract, medial forebrain tract, and the dorsal longitudinal fasciculus. There was a significant correlation between increased pain intensity and decreased fractional anisotropy in the dorsal longitudinal fasciculus. These correlations were not altered after controlling for age, sex, total intracranial volumes, or additional factors, e.g., depression and neurological conditions. SIGNIFICANCE: These findings suggest that the brainstem plays an important role in the aberrant neuromodulation of sleep and pain symptoms in GWI.