The metabolic basis of Alzheimer disease (AD) is poorly understood, and the relationships between systemic abnormalities in metabolism and AD pathogenesis are unclear. Understanding how global ...perturbations in metabolism are related to severity of AD neuropathology and the eventual expression of AD symptoms in at-risk individuals is critical to developing effective disease-modifying treatments. In this study, we undertook parallel metabolomics analyses in both the brain and blood to identify systemic correlates of neuropathology and their associations with prodromal and preclinical measures of AD progression.
Quantitative and targeted metabolomics (Biocrates AbsoluteIDQ identification and quantification p180) assays were performed on brain tissue samples from the autopsy cohort of the Baltimore Longitudinal Study of Aging (BLSA) (N = 44, mean age = 81.33, % female = 36.36) from AD (N = 15), control (CN; N = 14), and "asymptomatic Alzheimer's disease" (ASYMAD, i.e., individuals with significant AD pathology but no cognitive impairment during life; N = 15) participants. Using machine-learning methods, we identified a panel of 26 metabolites from two main classes-sphingolipids and glycerophospholipids-that discriminated AD and CN samples with accuracy, sensitivity, and specificity of 83.33%, 86.67%, and 80%, respectively. We then assayed these 26 metabolites in serum samples from two well-characterized longitudinal cohorts representing prodromal (Alzheimer's Disease Neuroimaging Initiative ADNI, N = 767, mean age = 75.19, % female = 42.63) and preclinical (BLSA) (N = 207, mean age = 78.68, % female = 42.63) AD, in which we tested their associations with magnetic resonance imaging (MRI) measures of AD-related brain atrophy, cerebrospinal fluid (CSF) biomarkers of AD pathology, risk of conversion to incident AD, and trajectories of cognitive performance. We developed an integrated blood and brain endophenotype score that summarized the relative importance of each metabolite to severity of AD pathology and disease progression (Endophenotype Association Score in Early Alzheimer's Disease EASE-AD). Finally, we mapped the main metabolite classes emerging from our analyses to key biological pathways implicated in AD pathogenesis. We found that distinct sphingolipid species including sphingomyelin (SM) with acyl residue sums C16:0, C18:1, and C16:1 (SM C16:0, SM C18:1, SM C16:1) and hydroxysphingomyelin with acyl residue sum C14:1 (SM (OH) C14:1) were consistently associated with severity of AD pathology at autopsy and AD progression across prodromal and preclinical stages. Higher log-transformed blood concentrations of all four sphingolipids in cognitively normal individuals were significantly associated with increased risk of future conversion to incident AD: SM C16:0 (hazard ratio HR = 4.430, 95% confidence interval CI = 1.703-11.520, p = 0.002), SM C16:1 (HR = 3.455, 95% CI = 1.516-7.873, p = 0.003), SM (OH) C14:1 (HR = 3.539, 95% CI = 1.373-9.122, p = 0.009), and SM C18:1 (HR = 2.255, 95% CI = 1.047-4.855, p = 0.038). The sphingolipid species identified map to several biologically relevant pathways implicated in AD, including tau phosphorylation, amyloid-β (Aβ) metabolism, calcium homeostasis, acetylcholine biosynthesis, and apoptosis. Our study has limitations: the relatively small number of brain tissue samples may have limited our power to detect significant associations, control for heterogeneity between groups, and replicate our findings in independent, autopsy-derived brain samples.
We present a novel framework to identify biologically relevant brain and blood metabolites associated with disease pathology and progression during the prodromal and preclinical stages of AD. Our results show that perturbations in sphingolipid metabolism are consistently associated with endophenotypes across preclinical and prodromal AD, as well as with AD pathology at autopsy. Sphingolipids may be biologically relevant biomarkers for the early detection of AD, and correcting perturbations in sphingolipid metabolism may be a plausible and novel therapeutic strategy in AD.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
•Mental illness is a leading public health challenge and there exist large diagnostic and care gaps.•We measured opinions of physicians from 22 countries to see whether AI/ML could replace the ...average doctor on key psychiatric tasks.•Only 3.8 % of respondents felt future technology would make their jobs obsolete.•Only 17 % felt that future AI/ML could replace a human clinician for providing empathetic care.•Our findings provide compelling insights into how psychiatrists think about AI/ML.
Futurists have predicted that new autonomous technologies, embedded with artificial intelligence (AI) and machine learning (ML), will lead to substantial job losses in many sectors disrupting many aspects of healthcare. Mental health appears ripe for such disruption given the global illness burden, stigma, and shortage of care providers.
To characterize the global psychiatrist community’s opinion regarding the potential of future autonomous technology (referred to here as AI/ML) to replace key tasks carried out in mental health practice.
Cross sectional, random stratified sample of psychiatrists registered with Sermo, a global networking platform open to verified and licensed physicians.
We measured opinions about the likelihood that AI/ML tools would be able to fully replace – not just assist – the average psychiatrist in performing 10 key psychiatric tasks. Among those who considered replacement likely, we measured opinions about how many years from now such a capacity might emerge. We also measured psychiatrist’s perceptions about whether benefits of AI/ML would outweigh the risks.
Survey respondents were 791 psychiatrists from 22 countries representing North America, South America, Europe and Asia-Pacific. Only 3.8 % of respondents felt it was likely that future technology would make their jobs obsolete and only 17 % felt that future AI/ML was likely to replace a human clinician for providing empathetic care. Documenting and updating medical records (75 %) and synthesizing information (54 %) were the two tasks where a majority predicted that AI/ML could fully replace human psychiatrists. Female- and US-based doctors were more uncertain that the benefits of AI would outweigh risks than male- and non-US doctors, respectively. Around one in 2 psychiatrists did however predict that their jobs would be substantially changed by AI/ML.
Our findings provide compelling insights into how physicians think about AI/ML which in turn may help us better integrate technology and reskill doctors to enhance mental health care.
The development of plasma biomarkers could facilitate early detection, risk assessment and therapeutic monitoring in Alzheimer's disease (AD). Alterations in ceramides and sphingomyelins have been ...postulated to play a role in amyloidogensis and inflammatory stress related neuronal apoptosis; however few studies have conducted a comprehensive analysis of the sphingolipidome in AD plasma using analytical platforms with accuracy, sensitivity and reproducibility.
We prospectively analyzed plasma from 26 AD patients (mean MMSE 21) and 26 cognitively normal controls in a non-targeted approach using multi-dimensional mass spectrometry-based shotgun lipidomics to determine the levels of over 800 molecular species of lipids. These data were then correlated with diagnosis, apolipoprotein E4 genotype and cognitive performance. Plasma levels of species of sphingolipids were significantly altered in AD. Of the 33 sphingomyelin species tested, 8 molecular species, particularly those containing long aliphatic chains such as 22 and 24 carbon atoms, were significantly lower (p<0.05) in AD compared to controls. Levels of 2 ceramide species (N16:0 and N21:0) were significantly higher in AD (p<0.05) with a similar, but weaker, trend for 5 other species. Ratios of ceramide to sphingomyelin species containing identical fatty acyl chains differed significantly between AD patients and controls. MMSE scores were correlated with altered mass levels of both N20:2 SM and OH-N25:0 ceramides (p<0.004) though lipid abnormalities were observed in mild and moderate AD. Within AD subjects, there were also genotype specific differences.
In this prospective study, we used a sensitive multimodality platform to identify and characterize an essentially uniform but opposite pattern of disruption in sphingomyelin and ceramide mass levels in AD plasma. Given the role of brain sphingolipids in neuronal function, our findings provide new insights into the AD sphingolipidome and the potential use of metabolomic signatures as peripheral biomarkers.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Abstract Objective Depression is common, frequently resistant to antidepressant treatment, and associated with impairments in cognition and everyday functioning. Computerized cognitive training (CCT) ...paradigms offer potential to improve cognition, mood and everyday functioning, but their effectiveness is not well established. The goal of this article was to conduct a systematic review and meta-analysis to determine the efficacy of CCT in depressive disorders. Method A search was conducted to identify high quality randomized controlled CCT trials per PRISMA guidelines using PsycINFO and MEDLINE with the keywords “Cognitive training” or “Cognitive remediation” or “Cognitive rehabilitation” and “Depression”. 9 randomized trials for depressed adults met inclusion criteria. Effect sizes (Hedge's g) were calculated for key outcome measures of mood symptom severity, daily functioning, and cognition. A 3-level Bayesian hierarchical linear model was used to estimate effect sizes for each domain and study. Publication bias was assessed using Classic Fail Safe N's and homogeneity was evaluated using Q and I2 indexes. Results Significant small-moderate effects for Symptom Severity (0.43) and Daily Functioning (0.72), and moderate-large effects for Attention (0.67), Working Memory (0.72), and Global Functioning (1.05) were found. No significant effects were found for Executive Functioning or Verbal Memory. Moderator variable analysis revealed decreased effect of CCT with age. Gender and concurrent medication treatment did not affect the results. Limitations Small sample size, short duration, pseudo-specificity, and high heterogeneity for Verbal Memory measures. Conclusions CCT is associated with improvement in depressive symptoms and everyday functioning, though produces inconsistent effects on cognition.
The advent of tau-targeted PET tracers such as flortaucipir (18F) (flortaucipir, also known as 18F-AV-1451 or 18F-T807) have made it possible to investigate the sequence of development of tau in ...relationship to age, amyloid-β, and to the development of cognitive impairment due to Alzheimer's disease. Here we report a multicentre longitudinal evaluation of the relationships between baseline tau, tau change and cognitive change, using flortaucipir PET imaging. A total of 202 participants 50 years old or older, including 57 cognitively normal subjects, 97 clinically defined mild cognitive impairment and 48 possible or probable Alzheimer's disease dementia patients, received flortaucipir PET scans of 20 min in duration beginning 80 min after intravenous administration of 370 MBq flortaucipir (18F). On separate days, subjects also received florbetapir amyloid PET imaging, and underwent a neuropsychological test battery. Follow-up flortaucipir scans and neuropsychological battery assessments were also performed at 9 and 18 months. Fifty-five amyloid-β+ and 90 amyloid-β- subjects completed the baseline and 18-month study visits and had valid quantifiable flortaucipir scans at both time points. There was a statistically significant increase in the global estimate of cortical tau burden as measured by standardized uptake value ratio (SUVr) from baseline to 18 months in amyloid-β+ but not amyloid-β- subjects (least squared mean change in flortaucipir SUVr : 0.0524 ± 0.0085, P < 0.0001 and 0.0007 ± 0.0024 P = 0.7850, respectively), and a significant association between magnitude of SUVr increase and baseline tau burden. Voxel-wise evaluations further suggested that the regional pattern of change in flortaucipir PET SUVr over the 18-month study period (i.e. which regions exhibited the greatest change) also varied as a function of baseline global estimate of tau burden. In subjects with lower global SUVr, temporal lobe regions showed the greatest flortaucipir retention, whereas in subjects with higher baseline SUVr, parietal and frontal regions were increasingly affected. Finally, baseline flortaucipir and change in flortaucipir SUVr were both significantly (P < 0.0001) associated with changes in cognitive performance. Taken together, these results provide a preliminary characterization of the longitudinal spread of tau in Alzheimer's disease and suggest that the amount and location of tau may have implications both for the spread of tau and the cognitive deterioration that may occur over an 18-month period.
The demand for clinically efficacious, safe, patient acceptable, and cost-effective forms of treatment for mental illness is growing. Several studies have demonstrated benefit from yoga in specific ...psychiatric symptoms and a general sense of well-being.
To systematically examine the evidence for efficacy of yoga in the treatment of selected major psychiatric disorders.
Electronic searches of The Cochrane Central Register of Controlled Trials and the standard bibliographic databases, MEDLINE, EMBASE, and PsycINFO, were performed through April 2011 and an updated in June 2011 using the keywords yoga AND psychiatry OR depression OR anxiety OR schizophrenia OR cognition OR memory OR attention AND randomized controlled trial (RCT). Studies with yoga as the independent variable and one of the above mentioned terms as the dependent variable were included and exclusion criteria were applied.
The search yielded a total of 124 trials, of which 16 met rigorous criteria for the final review. Grade B evidence supporting a potential acute benefit for yoga exists in depression (four RCTs), as an adjunct to pharmacotherapy in schizophrenia (three RCTs), in children with ADHD (two RCTs), and Grade C evidence in sleep complaints (three RCTs). RCTs in cognitive disorders and eating disorders yielded conflicting results. No studies looked at primary prevention, relapse prevention, or comparative effectiveness versus pharmacotherapy.
There is emerging evidence from randomized trials to support popular beliefs about yoga for depression, sleep disorders, and as an augmentation therapy. Limitations of literature include inability to do double-blind studies, multiplicity of comparisons within small studies, and lack of replication. Biomarker and neuroimaging studies, those comparing yoga with standard pharmaco- and psychotherapies, and studies of long-term efficacy are needed to fully translate the promise of yoga for enhancing mental health.
To assess whether patients receiving aerobic exercise training performed either at home or in a supervised group setting achieve reductions in depression comparable to standard antidepressant ...medication (sertraline) and greater reductions in depression compared to placebo controls.
Between October 2000 and November 2005, we performed a prospective, randomized controlled trial (SMILE study) with allocation concealment and blinded outcome assessment in a tertiary care teaching hospital. A total of 202 adults (153 women; 49 men) diagnosed with major depression were assigned randomly to one of four conditions: supervised exercise in a group setting; home-based exercise; antidepressant medication (sertraline, 50-200 mg daily); or placebo pill for 16 weeks. Patients underwent the structured clinical interview for depression and completed the Hamilton Depression Rating Scale (HAM-D).
After 4 months of treatment, 41% of the participants achieved remission, defined as no longer meeting the criteria for major depressive disorder (MDD) and a HAM-D score of <8. Patients receiving active treatments tended to have higher remission rates than the placebo controls: supervised exercise = 45%; home-based exercise = 40%; medication = 47%; placebo = 31% (p = .057). All treatment groups had lower HAM-D scores after treatment; scores for the active treatment groups were not significantly different from the placebo group (p = .23).
The efficacy of exercise in patients seems generally comparable with patients receiving antidepressant medication and both tend to be better than the placebo in patients with MDD. Placebo response rates were high, suggesting that a considerable portion of the therapeutic response is determined by patient expectations, ongoing symptom monitoring, attention, and other nonspecific factors.
To assess the extent to which multiple Alzheimer disease (AD) biomarkers improve the ability to predict future decline in subjects with mild cognitive impairment (MCI) compared with predictions based ...on clinical parameters alone.
All protocols were approved by the institutional review board at each site, and written informed consent was obtained from all subjects. The study was HIPAA compliant. Alzheimer's Disease Neuroimaging Initiative (ADNI) baseline magnetic resonance (MR) imaging and fluorine 18 fluorodeoxyglucose (FDG) positron emission tomography (PET) studies for 97 subjects with MCI were used. MR imaging-derived gray matter probability maps and FDG PET images were analyzed by using independent component analysis, an unbiased data-driven method to extract independent sources of information from whole-brain data. The loading parameters for all MR imaging and FDG components, along with cerebrospinal fluid (CSF) proteins, were entered into logistic regression models (dependent variable: conversion to AD within 4 years). Eight models were considered, including all combinations of MR imaging, PET, and CSF markers with the covariates (age, education, apolipoprotein E genotype, Alzheimer's Disease Assessment Scale-Cognitive subscale score).
Combining MR imaging, FDG PET, and CSF data with routine clinical tests significantly increased the accuracy of predicting conversion to AD compared with clinical testing alone. The misclassification rate decreased from 41.3% to 28.4% (P < .00001). FDG PET contributed more information to routine tests (P < .00001) than CSF (P = .32) or MR imaging (P = .08).
Imaging and CSF biomarkers can improve prediction of conversion from MCI to AD compared with baseline clinical testing. FDG PET appears to add the greatest prognostic information.
Sex differences in Alzheimer's disease (AD) biology and progression are not yet fully characterized. The goal of this study is to examine the effect of sex on cognitive progression in subjects with ...high likelihood of mild cognitive impairment (MCI) due to Alzheimer's and followed up to 10 years in the Alzheimer's Disease Neuroimaging Initiative (ADNI). Cerebrospinal fluid total-tau and amyloid-beta (Aβ42) ratio values were used to sub-classify 559 MCI subjects (216 females, 343 males) as having "high" or "low" likelihood for MCI due to Alzheimer's. Data were analyzed using mixed-effects models incorporating all follow-ups. The worsening from baseline in Alzheimer's Disease Assessment Scale-Cognitive score (mean, SD) (9 ± 12) in subjects with high likelihood of MCI due to Alzheimer's was markedly greater than that in subjects with low likelihood (1 ± 6, p < 0.0001). Among MCI due to AD subjects, the mean worsening in cognitive score was significantly greater in females (11.58 ± 14) than in males (6.87 ± 11, p = 0.006). Our findings highlight the need to further investigate these findings in other populations and develop sex specific timelines for Alzheimer's disease progression.
The heterogeneity of Alzheimer's disease contributes to the high failure rate of prior clinical trials. We analyzed 5-year longitudinal outcomes and biomarker data from 562 subjects with mild ...cognitive impairment (MCI) from two national studies (ADNI) using a novel multilayer clustering algorithm. The algorithm identified homogenous clusters of MCI subjects with markedly different prognostic cognitive trajectories. A cluster of 240 rapid decliners had 2-fold greater atrophy and progressed to dementia at almost 5 times the rate of a cluster of 184 slow decliners. A classifier for identifying rapid decliners in one study showed high sensitivity and specificity in the second study. Characterizing subgroups of at risk subjects, with diverse prognostic outcomes, may provide novel mechanistic insights and facilitate clinical trials of drugs to delay the onset of AD.
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