Explore the vast range of titles available.

Active-duty Army personnel can be exposed to traumatic warzone events and are at increased risk for developing post-traumatic stress disorder (PTSD) compared with the general population. PTSD is associated with high individual and societal costs, but identification of predictive markers to determine deployment readiness and risk mitigation strategies is not well understood. This prospective longitudinal naturalistic cohort study—the Fort Campbell Cohort study—examined the value of using a large multidimensional dataset collected from soldiers prior to deployment to Afghanistan for predicting post-deployment PTSD status. The dataset consisted of polygenic, epigenetic, metabolomic, endocrine, inflammatory and routine clinical lab markers, computerized neurocognitive testing, and symptom self-reports. The analysis was computed on active-duty Army personnel (N = 473) of the 101st Airborne at Fort Campbell, Kentucky. Machine-learning models predicted provisional PTSD diagnosis 90–180 days post deployment (random forest: AUC = 0.78, 95% CI = 0.67–0.89, sensitivity = 0.78, specificity = 0.71; SVM: AUC = 0.88, 95% CI = 0.78–0.98, sensitivity = 0.89, specificity = 0.79) and longitudinal PTSD symptom trajectories identified with latent growth mixture modeling (random forest: AUC = 0.85, 95% CI = 0.75–0.96, sensitivity = 0.88, specificity = 0.69; SVM: AUC = 0.87, 95% CI = 0.79–0.96, sensitivity = 0.80, specificity = 0.85). Among the highest-ranked predictive features were pre-deployment sleep quality, anxiety, depression, sustained attention, and cognitive flexibility. Blood-based biomarkers including metabolites, epigenomic, immune, inflammatory, and liver function markers complemented the most important predictors. The clinical prediction of post-deployment symptom trajectories and provisional PTSD diagnosis based on pre-deployment data achieved high discriminatory power. The predictive models may be used to determine deployment readiness and to determine novel pre-deployment interventions to mitigate the risk for deployment-related PTSD.

BackgroundConverging evidence implicates the anterior hippocampus in the proximal pathophysiology of schizophrenia. Although resting state functional connectivity (FC) holds promise for characterizing anterior hippocampal circuit abnormalities and their relationship to treatment response, this technique has not yet been used in first-episode psychosis (FEP) patients in a manner that distinguishes the anterior from posterior hippocampus.MethodsWe used masked-hippocampal-group-independent component analysis with dual regression to contrast subregional hippocampal–whole brain FC between healthy controls (HCs) and antipsychotic naïve FEP patients (N = 61, 36 female). In a subsample of FEP patients (N = 27, 15 female), we repeated this analysis following 8 weeks of second-generation antipsychotic treatment and explored whether baseline FC predicted treatment response using random forest.ResultsRelative to HC, untreated FEP subjects displayed reproducibly lower FC between the left anteromedial hippocampus and cortical regions including the anterior cingulate and insular cortex (P < .05, corrected). Anteromedial hippocampal FC increased in FEP patients following treatment (P < .005), and no longer differed from HC. Random forest analysis showed baseline anteromedial hippocampal FC with four brain regions, namely the insular–opercular cortex, superior frontal gyrus, precentral gyrus, and postcentral gyrus predicted treatment response (area under the curve = 0.95).ConclusionsAntipsychotic naïve FEP is associated with lower FC between the anterior hippocampus and cortical regions previously implicated in schizophrenia. Preliminary analysis suggests that random forest models based on hippocampal FC may predict treatment response in FEP patients, and hence could be a useful biomarker for treatment development.

Aggregates of hyperphosphorylated tau protein are a hallmark of Alzheimer's disease (AD) and other tauopathies. Sleep disturbances-common in AD-have been associated with altered tau phosphorylation and secretion in both animal models and humans, and insufficient sleep is recognized as a potential risk factor for AD. Moreover, sleep deprivation affects mRNA splicing, polyadenylation, and miRNA-mediated degradation. However, how tau phosphorylation, secretion, and splicing are physiologically regulated across the sleep-wake cycle remains unknown. Here, we combine in vitro, in vivo and clinical methods to investigate whether tau phosphorylation, secretion and splicing are governed by circadian rhythms linked to sleep and body temperature (BT). To elucidate underlying mechanisms, we exposed neuronal cells to the physiological temperatures observed under each condition. We found that tau phosphorylation undergoes sleep-driven circadian variations, as it is hyperphosphorylated during sleep, when BT is lower. Similar changes in tau phosphorylation were reproduced in neuronal cells exposed to temperatures recorded during the sleep-wake cycle. In addition, we reveal a novel pathway by which BT modulates tau secretion, with higher temperature increasing extracellular and circulating tau levels. Tau splicing also varied with temperature, as lower temperatures favored exon 10 exclusion. Finally, in humans, the increase in CSF tau levels observed post-wakefulness correlated with BT increase during wakefulness. Overall, these findings demonstrate that tau phosphorylation, secretion, and splicing follow a circadian pattern primarily regulated by BT and sleep. Given the prevalence of sleep disruptions and thermoregulatory deficits in AD, this study offers new insight into how tau pathology may develop and spread.

Posttraumatic stress disorder (PTSD) is common in the general population, yet there are limitations to the effectiveness, tolerability, and acceptability of available first‐line interventions. We review the extant knowledge on the effects of marijuana and other cannabinoids on PTSD. Potential therapeutic effects of these agents may largely derive from actions on the endocannabinoid system and we review major animal and human findings in this area. Preclinical and clinical studies generally support the biological plausibility for cannabinoids’ potential therapeutic effects, but underscore heterogeneity in outcomes depending on dose, chemotype, and individual variation. Treatment outcome studies of whole plant marijuana and related cannabinoids on PTSD are limited and not methodologically rigorous, precluding conclusions about their potential therapeutic effects. Reported benefits for nightmares and sleep (particularly with synthetic cannabinoid nabilone) substantiate larger controlled trials to determine effectiveness and tolerability. Of concern, marijuana use has been linked to adverse psychiatric outcomes, including conditions commonly comorbid with PTSD such as depression, anxiety, psychosis, and substance misuse. Available evidence is stronger for marijuana's harmful effects on the development of psychosis and substance misuse than for the development of depression and anxiety. Marijuana use is also associated with worse treatment outcomes in naturalistic studies, and with maladaptive coping styles that may maintain PTSD symptoms. Known risks of marijuana thus currently outweigh unknown benefits for PTSD. Although controlled research on marijuana and other cannabinoids’ effects on PTSD remains limited, rapid shifts in the legal landscape may now enable such studies, potentially opening new avenues in PTSD treatment research.

Rationale We recently introduced a new rat model of emotional hyperthermia in which a salient stimulus activates brown adipose tissue (BAT) thermogenesis and tail artery constriction. Antipsychotic drugs, both classical and second generation, act to reduce excessive assignment of salience to objects and events in the external environment. The close association between salient occurrences and increases in body temperature suggests that antipsychotic drugs may also reduce emotional hyperthermia. Objectives We determined whether chlorpromazine, clozapine, and risperidone dose dependently reduce emotionally elicited increases in BAT thermogenesis, cutaneous vasoconstriction, and body temperature in rats. Methods Rats, chronically instrumented for measurement of BAT and body temperature and tail artery blood flow, singly housed, were confronted with an intruder rat (confined within a small wire-mesh cage) after systemic pre-treatment of the resident rat with vehicle or antipsychotic agent. BAT and body temperatures, tail blood flow, and behavioral activity were continuously measured. Results Clozapine (30 μg–2 mg/kg), chlorpromazine (0.1–5 mg/kg), and risperidone (6.25 μg–1 mg/kg) robustly and dose-relatedly reduced intruder-elicited BAT thermogenesis and tail artery vasoconstriction, with consequent dose-related reduction in emotional hyperthermia. Conclusions Chlorpromazine, a first-generation antipsychotic, as well as clozapine and risperidone, second-generation agents, dose-dependently reduce emotional hyperthermia. Dopamine D 2 receptor antagonist properties of chlorpromazine do not contribute to thermoregulatory effects. Interactions with monoamine receptors are important, and these monoamine receptor interactions may also contribute to the therapeutic effects of all three antipsychotics. Thermoregulatory actions of putative antipsychotic agents may constitute a biological marker of their therapeutic properties.

Post-traumatic stress disorder (PTSD) is a mental disorder diagnosed by clinical interviews, self-report measures and neuropsychological testing. Traumatic brain injury (TBI) can have neuropsychiatric symptoms similar to PTSD. Diagnosing PTSD and TBI is challenging and more so for providers lacking specialized training facing time pressures in primary care and other general medical settings. Diagnosis relies heavily on patient self-report and patients frequently under-report or over-report their symptoms due to stigma or seeking compensation. We aimed to create objective diagnostic screening tests utilizing Clinical Laboratory Improvement Amendments (CLIA) blood tests available in most clinical settings. CLIA blood test results were ascertained in 475 male veterans with and without PTSD and TBI following warzone exposure in Iraq or Afghanistan. Using random forest (RF) methods, four classification models were derived to predict PTSD and TBI status. CLIA features were selected utilizing a stepwise forward variable selection RF procedure. The AUC, accuracy, sensitivity, and specificity were 0.730, 0.706, 0.659, and 0.715, respectively for differentiating PTSD and healthy controls (HC), 0.704, 0.677, 0.671, and 0.681 for TBI vs. HC, 0.739, 0.742, 0.635, and 0.766 for PTSD comorbid with TBI vs HC, and 0.726, 0.723, 0.636, and 0.747 for PTSD vs. TBI. Comorbid alcohol abuse, major depressive disorder, and BMI are not confounders in these RF models. Markers of glucose metabolism and inflammation are among the most significant CLIA features in our models. Routine CLIA blood tests have the potential for discriminating PTSD and TBI cases from healthy controls and from each other. These findings hold promise for the development of accessible and low-cost biomarker tests as screening measures for PTSD and TBI in primary care and specialty settings.

Nocturnal melatonin secretion may contribute to the nocturnal core body temperature (Tc) drop (Tdrop) and benefit cognitive function, which itself is affected by Tc. Prior research has not examined sex differences in melatonin's associations with Tc or cognition, impeding understanding of melatonin's potential pro-cognitive actions. We tested sex differences in associations of melatonin area under the curve (AUC) and dim light melatonin onset (DLMO) with Tdrop and cognitive function in older adults. Participants-65 cognitively unimpaired retired adults (32 postmenopausal females, 33 males; mean age: 68.4 +/-5.6 years) -completed a 60-hour laboratory study, including one night of baseline sleep followed by a 24-hour circadian unmasking protocol including one night of sleep deprivation (SD), followed by a recovery night sleep (Recovery). Tc was continuously assessed with ingestible telemetry. Salivary melatonin values obtained hourly during the unmasking protocol (AUC, DLMO) were correlated with Tdrop (Tc - Tc ) and neurocognitive outcomes (n = 29) obtained ∼6 months later. Greater melatonin AUC correlated with greater Tdrop during SD in males and females, however, correlations peaked at an earlier and more narrow range of Tdrop times in females (5-7pm, r = 0.40-0.46, p < 0.01) than males (5-10pm, r = 0.34-0.60, p < 0.001). In both sexes, earlier DLMO correlated with greater Tdrop (p < 0.05). During Recovery, AUC did not correlate with Tdrop in either sex, whereas DLMO still inversely correlated with Tdrop in males only (p < 0.01). Greater melatonin AUC correlated with immediate (β = .72, p = .003) and delayed recall memory (β = .71, p = .020) and visuospatial function (β = .67, p = .009) in females only. Greater Tdrop during SD was associated with executive function (r = 0.59-0.66) and attention (r = 0.57-0.67) in females and language in males (r = 0.51-0.67), all p <0.01. Melatonin release is strongly coupled to nocturnal Tdrop, however the timing and strength of this coupling exhibit sex differences. Greater melatonin and Tdrop may be protective for cognition particularly among female older adults. Future research in younger adults should determine whether aging-related changes (e.g., menopause) influence observed sex differences.

•Hippocampal Glx correlated with CSF p-tau181, but not after covariate adjustment.•Hippocampal NAA correlated with volume, even after covariate adjustment.•Both correlations were driven by APOE4 carriers.•There were no correlations in regions affected at later Braak stages (IV-VI). The pathological hallmarks of Alzheimer's disease (AD), amyloid, tau, and associated neurodegeneration, are present in the cortical gray matter (GM) years before symptom onset, and at significantly greater levels in carriers of the apolipoprotein E4 (APOE4) allele. Their respective biomarkers, A/T/N, have been found to correlate with aspects of brain biochemistry, measured with magnetic resonance spectroscopy (MRS), indicating a potential for MRS to augment the A/T/N framework for staging and prediction of AD. Unfortunately, the relationships between MRS and A/T/N biomarkers are unclear, largely due to a lack of studies examining them in the context of the spatial and temporal model of T/N progression. Advanced MRS acquisition and post-processing approaches have enabled us to address this knowledge gap and test the hypotheses, that glutamate-plus-glutamine (Glx) and N-acetyl-aspartate (NAA), metabolites reflecting synaptic and neuronal health, respectively, measured from regions on the Braak stage continuum, correlate with: (i) cerebrospinal fluid (CSF) p-tau181 level (T), and (ii) hippocampal volume or cortical thickness of parietal lobe GM (N). We hypothesized that these correlations will be moderated by Braak stage and APOE4 genotype. We conducted a retrospective imaging study of 34 cognitively unimpaired elderly individuals who received APOE4 genotyping and lumbar puncture from pre-existing prospective studies at the NYU Grossman School of Medicine between October 2014 and January 2019. Subjects returned for their imaging exam between April 2018 and February 2020. Metabolites were measured from the left hippocampus (Braak II) using a single-voxel semi-adiabatic localization by adiabatic selective refocusing sequence; and from the bilateral posterior cingulate cortex (PCC; Braak IV), bilateral precuneus (Braak V), and bilateral precentral gyrus (Braak VI) using a multi-voxel echo-planar spectroscopic imaging sequence. Pearson and Spearman correlations were used to examine the relationships between absolute levels of choline, creatine, myo-inositol, Glx, and NAA and CSF p-tau181, and between these metabolites and hippocampal volume or parietal cortical thicknesses. Covariates included age, sex, years of education, Fazekas score, and months between CSF collection and MRI exam. There was a direct correlation between hippocampal Glx and CSF p-tau181 in APOE4 carriers (Pearson's r = 0.76, p = 0.02), but not after adjusting for covariates. In the entire cohort, there was a direct correlation between hippocampal NAA and hippocampal volume (Spearman's r = 0.55, p = 0.001), even after adjusting for age and Fazekas score (Spearman's r = 0.48, p = 0.006). This relationship was observed only in APOE4 carriers (Pearson's r = 0.66, p = 0.017), and was also retained after adjustment (Pearson's r = 0.76, p = 0.008; metabolite-by-carrier interaction p = 0.03). There were no findings in the PCC, nor in the negative control (late Braak stage) regions of the precuneus and precentral gyrus. Our findings are in line with the spatially- and temporally-resolved Braak staging model of pathological severity in which the hippocampus is affected earlier than the PCC. The correlations, between MRS markers of synaptic and neuronal health and, respectively, T and N pathology, were found exclusively within APOE4 carriers, suggesting a connection with AD pathological change, rather than with normal aging. We therefore conclude that MRS has the potential to augment early A/T/N staging, with the hippocampus serving as a more sensitive MRS target compared to the PCC. [Display omitted]

An elevated neutrophil-lymphocyte ratio (NLR) has been associated with Alzheimer's disease (AD). However, an elevated NLR has also been implicated in many other conditions that are risk factors for AD, prompting investigation into whether the NLR is directly linked with AD pathology or a result of underlying comorbidities. We explored the relationship between the NLR and AD biomarkers in the cerebrospinal fluid (CSF) of cognitively unimpaired (CU) subjects. Adjusting for sociodemographics, APOE4, and common comorbidities, we investigated these associations in two cohorts: the Alzheimer's Disease Neuroimaging Initiative (ADNI) and NYU Center for Brain Health (CBH). Specifically, we examined associations between the NLR and cross-sectional measures of amyloid-β42 (Aβ42), total tau (t-tau), and phosphorylated tau (p-tau ), as well as the trajectories of these CSF measures obtained longitudinally. A total of 111 ADNI and 190 NYU participants classified as CU with available NLR, CSF, and covariate data were included. Compared to NYU, ADNI participants were older (73.79 vs. 61.53, p<0.001), had a higher proportion of males (49.5% vs. 36.8%, p = 0.042), higher BMIs (27.94 vs. 25.79, p<0.001), higher prevalence of hypertensive history (47.7% vs. 16.3%, p<0.001), and a greater percentage of Aβ-positivity (34.2% vs. 20.0%, p = 0.009) (Table 1). In the ADNI cohort, we found cross-sectional associations between the NLR and CSF Aβ42 (β = -12.193, p = 0.021), but not t-tau or p-tau . In the NYU cohort, we found cross-sectional associations between the NLR and CSF t-tau (β = 26.812, p = 0.019) and p-tau (β = 3.441, p<0.001), but not Aβ42. In the NYU cohort alone, subjects classified as Aβ+ (n = 38) displayed a stronger association between the NLR and t-tau (β = 100.476, p = 0.037) compared to Aβ- subjects or the non-stratified cohort (Figure 1). In both cohorts, the same associations observed in the cross-sectional analyses were observed after incoporating longitudinal CSF data (Figure 2). We report associations between the NLR and Aβ42 in the older ADNI cohort, and between the NLR and t-tau and p-tau in the younger NYU cohort. Associations persisted after adjusting for comorbidities, suggesting a direct link between the NLR and AD. However, changes in associations between the NLR and specific AD-biomarkers may occur as part of immunosenescence.

Obstructive sleep apnea (OSA) is a complex condition characterized by repeated episodes of upper airway collapse during sleep, leading to chronic intermittent hypoxia. Diffusion magnetic resonance imaging (dMRI) techniques offer sensitivity to white matter (WM) microstructure changes. 150 individuals from a community-based study underwent one-night nocturnal polysomnography (NPSG), cognitive assessments, and brain structural MRI. Gaussian and non-Gaussian diffusion signal changes in WM tracts were quantified with diffusion tensor metrics as (DTI) and Diffusion Kurtosis Imaging (DKI), respectively. While changes in WM microstructure were assessed in terms of Standard Model metrics. The genu of the corpus callosum (GCC) demonstrated negative correlations between AHI3A and FA ( p  < 0.01), AD ( p  < 0.05), f (SMI-based axonal water fraction) ( p  < 0.05), and p 2 (p < 0.05) (SMI-based extra-axonal water), alongside positive correlations with RD ( p  < 0.05). The right cingulum showed negative associations with FA ( p  < 0.01), RK ( p  < 0.01), f ( p  < 0.01) and ( p  < 0.01). Subjects without OSA showed higher values in FA ( p  = 0.001), AD (p = 0.01), f ( p  = 0.03), and ( p  = 0.0006) in the GCC and cingulum. The strongest differences between severity groups were observed between AHI3A(0–5/h) and AHI3A(> 30/h), particularly in the GCC FA ( p  = 0.001), RD ( p  = 0.008), and RK ( p  = 0.02), and the cingulum f ( p  ≤ 0.01). Decreases in AD, RK, and FA, and increased RD with increasing OSA severity suggest demyelination and axonal loss. This contrasts with f, a direct measurement for axonal density, which was lower in the OSA group, demonstrating that OSA affects the WM microstructure. Future studies should include longitudinal evaluations to assess the effects of disease duration, and the clinical significance of changes in dMRI metrics over time.