Predictors of Improvement after Cognitive Training in Mild Cognitive Impairment: Insights from the Cognitive Training and Neuroplasticity in Mild Cognitive Impairment Trial.

OBJECTIVE: Cognitive training may benefit older adults with mild cognitive impairment (MCI), but the prognostic factors are not well-established. METHODS: This study analyzed data from a 78-week trial with 107 participants with MCI, comparing computerized cognitive training (CCT) and computerized crossword puzzle training (CPT). Outcomes were changes in cognitive and functional measures from baseline. Linear mixed-effect models were used to identify prognostic factors for each intervention. RESULTS: Baseline neuropsychological composite z-score was positively associated with cognitive and functional improvements for both interventions in univariable models, retaining significance in the final multivariable model for functional outcome in CPT ( P < 0.001). Apolipoprotein E e4 carriers had worse cognitive ( P = 0.023) and functional ( P = 0.001) outcomes than noncarriers for CPT but not CCT. African Americans showed greater functional improvements than non-African Americans in both CPT ( P = 0.001) and CCT ( P = 0.010). Better baseline odor identification was correlated with cognitive improvements in CPT ( P = 0.006) and functional improvements in CCT ( P < 0.001). CONCLUSION: Baseline cognitive test performance, African American background, and odor identification ability are potential prognostic factors for improved outcomes with cognitive interventions in older adults with MCI. Apolipoprotein E e4 is associated with poor outcomes. Replication of these findings may improve the selection of cognitive interventions for individuals with MCI.

Biomarkers of sleep-wake disturbance as predictors of cognitive decline and accelerated disease progression.

INTRODUCTION: In older adults, where sleep disturbances and cognitive impairment are common, mounting evidence suggests a potential connection between sleep and cognitive function, highlighting the significance of utilizing sleep as a biomarker for early detection of cognitive impairment to improve clinical outcomes in a noninvasive, cost-effective manner. AREAS COVERED: This review describes the relationship between sleep and cognitive function in older adults, encompassing both subjective and objective measures of sleep quality, duration, architecture, and sleep-disordered breathing. The authors consider the directionality of the associations observed in prospective and cross-sectional studies, exploring whether sleep disturbances precede cognitive decline or vice versa. Furthermore, they discuss the potential bidirectional relationships between sleep and Alzheimer's disease (AD) risks in older adults while also examining the neurodegenerative pathways of this relationship. EXPERT OPINION: Routine sleep monitoring in primary care settings has the potential to bolster early detection and treatment of sleep disturbance, and by extension, reduce the risk of dementia. Improving sleep assessment tools, such as wearables, provide scalable alternatives to traditional methods like polysomnography, potentially enabling widespread monitoring of sleep characteristics. Standardized measurement and inclusive participant recruitment are needed to enhance generalizability, while longitudinal studies are essential to understand the interaction between sleep and AD pathology.

Eligibility for Substance Use Clinical Trials Among Emergency Psychiatry Patients: The Impact of Exclusion Criteria.

Objective: The first objective was to identify common exclusion criteria used in clinical trials. The second objective was to quantify the degree to which these criteria exclude emergency psychiatry patients. Methods: Qualitative Content Analysis was used for the first objective, identifying common exclusion criteria used in recent high-impact substance use clinical trials. A retrospective record review was used for the second objective, which examined the frequency of these exclusion criteria in a 1-month sample of adults receiving psychiatric evaluation in an emergency department. Results: Most trials had exclusions for co-occurring psychiatric problems (76.6%), medical problems (74.0%), prior or current treatment (72.7%), motivation for change (61.1%), pregnancy or lactation (57.1%), or using other specified substances of abuse (54.6%). In the clinical sample, exclusions for co-occurring psychiatric problems would make 94.7% of patients ineligible. Other exclusions had a combined effect of making 76% of patients ineligible. Conclusions: Clinical trials using typical exclusion criteria exclude nearly all emergency psychiatry patients with substance use problems.

Novel measures of cognition and function for the AD spectrum in the Novel Measures for Alzheimer's Disease Prevention Trials (NoMAD) project: Psychometric properties, convergent validation, and contrasts with established measures.

INTRODUCTION: This study derived composite scores for two novel cognitive measures, the No Practice Effect (NPE) battery and the Miami Computerized Functional Skills Assessment and Training system for use in early-stage Alzheimer's disease (AD) clinical trials. Their psychometric properties and associations with AD risk markers were compared to those of well-established measures. METHODS: For 291 older adults with healthy cognition or early mild cognitive impairment, Exploratory factor analyses were used to identify the factor structure of the NPE. Factor and total scores were examined for their psychometric properties and associations with AD risk biomarkers. RESULTS: Composite scores from the novel cognitive and functional measures demonstrated better psychometric properties (distribution and test-retest reliability) and stronger associations with AD-related demographic, genetic, and brain risk markers than well-established measures, DISCUSSION: These novel measures have potential for use as primary cognitive and functional outcomes in early-stage AD clinical trials. HIGHLIGHTS: Well-established cognitive tests may not accurately detect subtle cognitive changes. No Practice Effect (NPE) and Computerized Functional Skills Assessment and Training are novel measures designed to have improved psychometric properties. NPE had Executive Function, Cognitive Control/Speed, and Episodic Memory domains. Novel measures had better psychometric properties compared to established measures. Significant associations with Alzheimer's disease biomarkers were found with novel measures.

Recovery rates of persistent post-COVID-19 olfactory dysfunction using psychophysical assessment: A longitudinal cohort study.

Objectives: Persistent olfactory dysfunction (OD) following loss of smell associated with SARS-CoV-2 infection is a major feature of long COVID. Perspectives on the prevalence of persistent OD predominantly rely on self-reported olfactory function. Few studies have tracked longitudinal rates of recovery using psychophysical assessment among patients presenting for evaluation of persistent OD beyond a window of acute recovery. Data anchored in standardized testing methods are needed to counsel patients who fail to acutely regain their sense of smell. This study aims to quantify the degree of persistent OD in post-COVID-19 patients who experience subjective and psychophysical OD. Methods: We grouped participants presenting for OD evaluation into cohorts based on both subjective and psychophysical olfactory status at a baseline assessment and assessed their olfactory abilities with a visual analogue scale and the Sniffin' Sticks extended test at baseline and 1-year time points. Participants had confirmed a history of COVID-19 by lab evaluation or clinical diagnosis if lab evaluation was not available. Results: Baseline olfactory evaluation was completed by 122 participants, 53 of whom completed the 1-year follow-up assessment. Among participants presenting with perceived OD, 74.5% had confirmed psychophysical OD at baseline, with 55.1% at 1-year follow-up. Participants had reliable trends in self-rated versus psychophysically tested olfactory function at both time points. The total threshold, discrimination, and identification (TDI) score improved by +3.25 points in the cohort with psychophysical OD (p = 0.0005), with this improvement largely attributable to an increase in median threshold scores (+2.75 points; p = 0.0004). Conclusions: OD persists in a significant number of patients who fail to acutely recovery their sense of smell after COVID-19, with many demonstrating lingering deficits at 1-year. Improvements in threshold, but not discrimination or identification, most significantly mediate improvement of total TDI score at follow-up.

Sleep-wake behavior, perceived fatigability, and cognitive reserve in older adults.

INTRODUCTION: The effects of sleep-wake behavior on perceived fatigability and cognitive abilities when performing daily activities have not been investigated across levels of cognitive reserve (CR). METHODS: CR Index Questionnaire (CRIq) data were collected and subjected to moderated mediation analysis. RESULTS: In amnestic mild cognitive impairment (aMCI; n = 41), CR moderated sleep-related impairments (SRIs), and fatigability at low CR (CRIq < 105.8, p = 0.004) and mean CR (CRIq = 126.9, p = 0.03) but not high CR (CRIq > 145.9, p = 0.65) levels. SRI affected cognitive abilities mediated by fatigability at low CR (p < 0.001) and mean CR (p = 0.003) levels. In healthy controls (n = 13), SRI in fatigability did not alter cognitive abilities across CR levels; controls had higher leisure scores than patients with aMCI (p = 0.003, effect size = 0.93). DISCUSSION: SRI can amplify impaired cognitive abilities through exacerbation of fatigability in patients with aMCI with below-mean CR. Therefore, improving sleep-wake regulation and leisure activities may protect against fatigability and cognitive decline. HIGHLIGHTS: Clinical fatigue and fatigability cannot be alleviated by rest. Clinical fatigability disrupts daily activities during preclinical Alzheimer's. High cognitive reserve mitigates sleep-wake disturbance effects. High cognitive reserve attenuates clinical fatigability effects on daily functioning. Untreated obstructive sleep apnea potentiates Alzheimer's pathology in the brain.

Subjective versus Psychophysical Measures of Chemosensory Alterations following COVID-19.

INTRODUCTION: Olfactory dysfunction is a common symptom of COVID-19. However, subjective perception of olfactory function does not always correlate well with more objective measures. This study seeks to clarify associations between subjective and psychophysical measures of olfaction and gustation in patients with subjective chemosensory dysfunction following COVID-19. METHODS: Adults with persistent COVID-19-associated chemosensory disturbance were recruited for a prospective, longitudinal cohort study at a tertiary care institution. Participants provided subjective measures of olfactory and gustatory function and underwent psychophysical assessment using Sniffin' Sticks olfactory and Monell gustatory tests. RESULTS: Data analysis (n = 65) showed a statistically significant association between subjective and psychophysical measures of olfaction (p < 0.001). For each one-point increase in subjectively-reported olfactory ability, there is, on average, a 0.11 (95% CI: 0.06, 0.16; p < 0.001) point increase in TDI score while adjusting for age at baseline assessment, sex, and follow-up time. For each one-point increase in subjectively-reported olfactory ability, there is, on average, a 0.04 (95% CI: 0.02, 0.06; p < 0.001) point and 0.05 (95% CI: 0.03, 0.07; p < 0.001) point increase in discrimination and identification scores, respectively, when adjusting for age at baseline assessment, sex, and follow-up time. CONCLUSION: Subjective olfaction shows a mild to moderate association with psychophysical measures, but it fails to comprehensively assess persistent COVID-19-associated chemosensory deficits. The lack of significant association between subjective olfaction and threshold limits the utility of subjective olfaction in tracking recovery. These findings support the push for more widespread psychophysical chemosensory testing.

Altered Hierarchical Gradients of Intrinsic Neural Timescales in Mild Cognitive Impairment and Alzheimer's Disease.

Alzheimer's disease (AD) is a devastating neurodegenerative disease that affects millions of seniors in the United States. Resting-state functional magnetic resonance imaging (rs-fMRI) is widely used to study neurophysiology in AD and its prodromal condition, mild cognitive impairment (MCI). The intrinsic neural timescale (INT), which can be estimated through the magnitude of the autocorrelation of neural signals from rs-fMRI, is thought to quantify the duration that neural information is stored in a local circuit. Such heterogeneity of the timescales forms a basis of the brain functional hierarchy and captures an aspect of circuit dynamics relevant to excitation/inhibition balance, which is broadly relevant for cognitive functions. Given that, we applied rs-fMRI to test whether distinct changes of INT at different hierarchies are present in people with MCI, those progressing to AD (called Converter), and AD patients of both sexes. Linear mixed-effect model was implemented to detect altered hierarchical gradients across populations followed by pairwise comparisons to identify regional differences. High similarities between AD and Converter were observed. Specifically, the inferior temporal, caudate, and pallidum areas exhibit significant alterations in both AD and Converter. Distinct INT-related pathological changes in MCI and AD were found. For AD/Converter, neural information is stored for a longer time in lower hierarchical areas, while higher levels of hierarchy seem to be preferentially impaired in MCI leading to a less pronounced hierarchical gradient. These results inform that the INT holds great potential as an additional measure for AD prediction, even a stable biomarker for clinical diagnosis.

Assessing harmonized intelligence measures in a multinational study.

Studies examining the neurocognitive and circuit-based etiology of psychiatric illness are moving toward inclusive, global designs. A potential confounding effect of these associations is general intelligence; however, an internationally validated, harmonized intelligence quotient (IQ) measure is not available. We describe the procedures used to measure IQ across a five-site, multinational study and demonstrate the harmonized measure's cross-site validity. Culturally appropriate intelligence measures were selected: four short-form Wechsler intelligence tests (Brazil, Netherlands, South Africa, United States) and the Binet Kamat (India). Analyses included IQ scores from 255 healthy participants (age 18-50; 42% male). Regression analyses tested between-site differences in IQ scores, as well as expected associations with sociodemographic factors (sex, socioeconomic status, education) to assess validity. Harmonization (e.g., a priori selection of tests) yielded the compatibility of IQ measures. Higher IQ was associated with higher socioeconomic status, suggesting good convergent validity. No association was found between sex and IQ at any site, suggesting good discriminant validity. Associations between higher IQ and higher years of education were found at all sites except the United States. Harmonized IQ scores provide a measure of IQ with evidence of good validity that can be used in neurocognitive and circuit-based studies to control for intelligence across global sites.

Effects of APOE e4 and Neuropathological Diagnoses on Neuropsychiatric Symptoms: Mediation Analyses and Likely Causation in an Integrated NACC Database.

Background: Our goal in this study was to identify paths from APOE e4 to neurobehaviors itemized on a neuropsychiatric inventory that involved neuropathologies associated with e4 (amyloid, tau, cerebral amyloid angiopathy, and Lewy bodies) or cognition mediators (memory or global cognitive status), as well as direct paths from e4 to cognition or neurobehaviors. Methods: A total of 1199 cases with available neurobehavioral, cognition and neuropathological data were included. We then conducted a series of causal mediation analyses in R in which e4 always served as the independent variable and Neuropsychiatric Inventory (NPI) neurobehavioral items, when included in the mediation, the outcome. Neuropathologies or cognition served as mediators. Results: Multiple significant indirect paths from e4 through neuropathologies to neurobehaviors were identified. More refined analyses indicated that neuritic plaques and Braak stage, but not extent of diffuse amyloid plaques, drove the findings. A significant direct effect of e4 to memory was also identified. Additionally, Lewy body disease, when treated as an exposure, had a direct effect on hallucinations in keeping with known features of the disease. Conclusions: We found strong evidence for partial mediation of NPI symptoms by cognition, suggesting that cognitive limitations that may have influenced understanding (or misunderstanding) the environment with impacts on maladaptive behavior. In addition, neuritic amyloid plaque levels and Braak stage, but not diffuse amyloid plaque extent, were key in NPI mediated associations suggesting the possibility that synaptic failure play an important role in multiple neurobehavioral symptoms in dementia, including psychosis. Last, we found strong evidence that e4 may have direct effects on cognition when we used verbal episodic memory as an outcome, suggesting that medial temporal regions that support memory may be sensitive to non-amyloidogenic and non-tau related pathophysiological processes.

Effects of APOE ε4 and Neuropathological Diagnoses on Neuropsychiatric Symptoms: Mediation Analyses and Likely Causation in an Integrated National Alzheimer's Coordinating Center Database.

BACKGROUND: In this study, we sought to identify paths from APOE ε4 to neurobehaviors itemized on a neuropsychiatric inventory (Neuropsychiatric Inventory-Questionnaire [NPI-Q]) that involved neuropathologies associated with APOE ε4 (amyloid, tau, cerebral amyloid angiopathy, and Lewy bodies) or cognition mediators (memory or global cognitive status) as well as direct paths from APOE ε4 to neurobehaviors. METHODS: A total of 1199 cases with available neurobehavioral, cognition, and neuropathological data were included. We conducted a series of causal mediation analyses in which APOE ε4 always served as the independent variable, and NPI-Q neurobehavioral items, when included in the mediation analysis, served as the outcome. Neuropathologies or cognition served as mediators. RESULTS: Multiple significant indirect paths from APOE ε4 through neuropathologies to neurobehaviors were identified. More refined analyses indicated that neuritic plaques and Braak stage drove the findings. A significant direct effect of APOE ε4 on memory was also identified. Additionally, Lewy body disease, when treated as an exposure, had a direct effect on hallucinations consistent with features of the disease. CONCLUSIONS: We found strong evidence for partial mediation of NPI-Q symptoms by cognition, suggesting that cognitive limitations may have promoted maladaptive behavior. In addition, neuritic amyloid plaque levels and Braak stage, but not diffuse amyloid plaque extent, were key in NPI-Q-mediated associations, suggesting the possibility that synaptic failure plays an important role in multiple neurobehavioral symptoms in dementia, including psychosis. Finally, we found strong evidence that APOE ε4 may have direct effects on cognition when we used verbal episodic memory but not global cognitive status as an outcome.

Clinical Trials Studying Suicide Risk Reduction: Who is Excluded From Participation.

OBJECTIVE: The use of exclusion criteria in clinical trials can cause research participants to differ markedly from clinical populations, which negatively impacts generalizability of results. This study identifies and quantifies common and recurring exclusion criteria in clinical trials studying suicide risk reduction, and estimates their impact on eligibility among a clinical sample of adults in an emergency department with high suicide risk. METHOD: Recent trials were identified by searching PubMed (terms suicide, efficacy, effectiveness, limited to clinical trials in prior 5 years). Common exclusion criteria were identified using Qualitative Content Analysis. A retrospective chart review examined a one-month sample of all adults receiving psychiatric evaluation in a large urban academic emergency department. RESULTS: The search yielded 27 unique clinical trials studying suicide risk reduction as a primary or secondary outcome. After research fundamentals (e.g. informed consent, language fluency), the most common exclusion criteria involved psychosis (77.8%), cognitive problems (66.7%), and substance use (63.0%). In the clinical sample of adults with high suicide risk (N = 232), psychosis exclusions would exclude 53.0% of patients and substance use exclusions would exclude 67.2% of patients. Overall, 5.6% of emergency psychiatry patients would be eligible for clinical trials that use common exclusion criteria. CONCLUSIONS: Recent clinical trials studying suicide risk reduction have low generalizability to emergency psychiatry patients with high suicide risk. Trials enrolling persons with psychosis and substance use in particular are needed to improve generalizability to this clinical population.

Exclusion criteria limit who can enroll in trials studying suicide risk reduction.Trials most frequently exclude psychosis, cognitive problems, and substance use.Trials have poor generalizability to emergency psychiatry patients.

Associations between olfactory dysfunction and cognition: a scoping review.

INTRODUCTION: Strong evidence suggests that olfactory dysfunction (OD) can predict additional neurocognitive decline in neurodegenerative conditions such as Alzheimer's and Parkinson's diseases. However, research exploring olfaction and cognition in younger populations is limited. The aim of this review is to evaluate cognitive changes among non-elderly adults with non-COVID-19-related OD. METHODS: We performed a structured comprehensive literature search of PubMed, Ovid Embase, Web of Science, and Cochrane Library in developing this scoping review. The primary outcome of interest was the association between OD and cognitive functioning in adults less than 60 years of age. RESULTS: We identified 2878 studies for title and abstract review, with 167 undergoing full text review, and 54 selected for data extraction. Of these, 34 studies reported on populations of individuals restricted to the ages of 18-60, whereas the remaining 20 studies included a more heterogeneous population with the majority of individuals in this target age range in addition to some above the age of 60. The etiologies for smell loss among the included studies were neuropsychiatric disorders (37%), idiopathic cause (25%), type 2 diabetes (7%), trauma (5%), infection (4%), intellectual disability (4%), and other (18%). Some studies reported numerous associations and at times mixed, resulting in a total number of associations greater than the included number of 54 studies. Overall, 21/54 studies demonstrated a positive association between olfaction and cognition, 7/54 demonstrated no association, 25/54 reported mixed results, and only 1/54 demonstrated a negative association. CONCLUSION: Most studies demonstrate a positive correlation between OD and cognition, but the data are mixed with associations less robust in this young adult population compared to elderly adults. Despite the heterogeneity in study populations and outcomes, this scoping review serves as a starting point for further investigation on this topic. Notably, as many studies in this review involved disorders that may have confounding effects on both olfaction and cognition, future research should control for these confounders and incorporate non-elderly individuals with non-psychiatric causes of smell loss.

Overview of late-onset psychoses.

BACKGROUND: Several etiologies can underlie the development of late-onset psychosis, defined by first psychotic episode after age 40 years. Late-onset psychosis is distressing to patients and caregivers, often difficult to diagnose and treat effectively, and associated with increased morbidity and mortality. METHODS: The literature was reviewed with searches in Pubmed, MEDLINE, and the Cochrane library. Search terms included "psychosis," "delusions," hallucinations," "late onset," "secondary psychoses," "schizophrenia," bipolar disorder," "psychotic depression," "delirium," "dementia," "Alzheimer's," "Lewy body," "Parkinson's, "vascular dementia," and "frontotemporal dementia." This overview covers the epidemiology, clinical features, neurobiology, and therapeutics of late-onset psychoses. RESULTS: Late-onset schizophrenia, delusional disorder, and psychotic depression have unique clinical characteristics. The presentation of late-onset psychosis requires investigation for underlying etiologies of "secondary" psychosis, which include neurodegenerative, metabolic, infectious, inflammatory, nutritional, endocrine, and medication toxicity. In delirium, psychosis is common but controlled evidence is lacking to support psychotropic medication use. Delusions and hallucinations are common in Alzheimer's disease, and hallucinations are common in Parkinson's disease and Lewy body dementia. Psychosis in dementia is associated with increased agitation and a poor prognosis. Although commonly used, no medications are currently approved for treating psychosis in dementia patients in the USA and nonpharmacological interventions need consideration. CONCLUSION: The plethora of possible causes of late-onset psychosis requires accurate diagnosis, estimation of prognosis, and cautious clinical management because older adults have greater susceptibility to the adverse effects of psychotropic medications, particularly antipsychotics. Research is warranted on developing and testing efficacious and safe treatments for late-onset psychotic disorders.

Effects of age on the relationship between sleep quality and cognitive performance: Findings from the Human Connectome Project-Aging cohort.

BACKGROUND: The association between sleep quality and cognition is widely established, but the role of aging in this relationship is largely unknown. OBJECTIVE: To examine how age impacts the sleep-cognition relationship and determine whether there are sensitive ranges when the relationship between sleep and cognition is modified. This investigation could help identify individuals at risk for sleep-related cognitive impairment. SUBJECTS: Sample included 711 individuals (ages 36.00-89.8359.66 ± 14.9155.7 % female) from the Human Connectome Project-Aging (HCP-A). METHODS: The association between sleep quality (Pittsburgh Sleep Quality Index, PSQI) and cognition (Crystallized Cognition Composite and Fluid Cognition Composite from the NIH Toolbox, the Trail Making Test, TMT, and the Rey Auditory Verbal Learning Test, RAVLT) was measured using linear regression models, with sex, race, use of sleep medication, hypertension, and years of education as covariates. The interaction between sleep and age on cognition was tested using the moderation analysis, with age as both continuous linear and nonlinear (quadratic) terms. RESULTS: There was a significant interaction term between the PSQI and nonlinear age term (age2) on TMT-B (p = 0.02) and NIH Toolbox crystallized cognition (p = 0.02), indicating that poor sleep quality was associated with worse performance on these measures (sensitive age ranges 50-75 years for TMT-B and 66-70 years for crystallized cognition). CONCLUSIONS: The sleep-cognition relationship may be modified by age. Individuals in the middle age to early older adulthood age band may be most vulnerable to sleep-related cognitive impairment.

BMI Increases in Individuals with COVID-19-Associated Olfactory Dysfunction.

(1) Background: Reports suggest COVID-19-associated olfactory dysfunction (OD) may result in alterations in dietary behaviors and perceived weight change, but few studies using psychophysical evaluation of post-COVID-19-associated chemosensory dysfunction and body mass index (BMI) exist. The purpose of this study is to assess the impact of both quantitative and qualitative features of COVID-19-associated OD on BMI; (2) Methods: Recruitment of thirty-one participants with self-reported OD in the form of quantitative loss with and without qualitative features. Surveys with questions specific to qualitative olfactory function, Sniffin' Sticks tests, and BMI measures were completed at two visits, one year apart. Group differences were assessed with Wilcoxon signed-rank tests and the Holm-Bonferroni method; (3) Results: Individuals with persistent quantitative OD (n = 15) and self-reported parosmia (n = 19) showed statistically significant increases in BMI after 1 year (p = 0.004, adjusted α = 0.0125; p = 0.011, adjusted α = 0.0167). Controls with transient quantitative OD (n = 16) and participants without self-reported parosmia (n = 12) showed no statistically significant changes in BMI over the same time period (p = 0.079, adjusted α = 0.05; p = 0.028, adjusted α = 0.025); (4) Conclusions: This study shows an association between COVID-19-associated OD and BMI, suggesting olfaction may play a role in altering dietary habits and nutrition in this population. Larger study cohorts are needed to further evaluate this relationship.

Comparison of relative change with effect size metrics in Alzheimer's disease clinical trials.

BACKGROUND: Per cent slowing of decline is frequently used as a metric of outcome in Alzheimer's disease (AD) clinical trials, but it may be misleading. Our objective was to determine whether per cent slowing of decline or Cohen's d is the more valid and informative measure of efficacy. METHODS: Outcome measures of interest were per cent slowing of decline; Cohen's d effect size and number-needed-to-treat (NNT). Data from a graphic were used to model the inter-relationships among Cohen's d, placebo decline in raw score units and per cent slowing of decline with active treatment. NNTs were computed based on different magnitudes of d. Last, we tabulated recent AD anti-amyloid clinical trials that reported per cent slowing and for which we computed their respective d's and NNTs. RESULTS: We demonstrated that d and per cent slowing were potentially independent. While per cent slowing of decline was dependent on placebo decline and did not include variance in its computation, d was dependent on both group mean difference and pooled SD. We next showed that d was a critical determinant of NNT, such that NNT was uniformly smaller when d was larger. In recent AD associated trials including those focused on anti-amyloid biologics, d's were below 0.23 and thus considered small, while per cent slowing was in the 22-29% range and NNTs ranged from 14 to 18. CONCLUSIONS: Standardised effect size is a more meaningful outcome than per cent slowing of decline because it determines group overlap, which can directly influence NNT computations, and yield information on the likelihood of minimum clinically important differences. In AD, greater use of effect sizes, NNTs, rather than relative per cent slowing, will improve the ability to interpret clinical trial results and evaluate the clinical meaningfulness of statistically significant results.

Altered hierarchical gradients of intrinsic neural timescales in mild cognitive impairment and Alzheimer's disease.

Alzheimer's disease (AD) is a devastating neurodegenerative disease that affects millions of older adults in the US and worldwide. Resting-state functional magnetic resonance imaging (rs-fMRI) has become a widely used neuroimaging tool to study neurophysiology in AD and its prodromal condition, mild cognitive impairment (MCI). The intrinsic neural timescale (INT), which can be estimated through the magnitude of the autocorrelation of intrinsic neural signals using rs-fMRI, is thought to quantify the duration that neural information is stored in a local cortical circuit. The heterogeneity of the timescales is considered to be a basis of the functional hierarchy in the brain. In addition, INT captures an aspect of circuit dynamics relevant to excitation/inhibition (E/I) balance, which is thought to be broadly relevant for cognitive functions. Here we examined its relevance to AD. We used rs-fMRI data of 904 individuals from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database. The subjects were divided into 4 groups based on their baseline and end-visit clinical status, which were cognitively normal (CN), stable MCI, Converter, and AD groups. Linear mixed effect model and pairwise comparison were implemented to investigate the large-scale hierarchical organization and local differences. We observed high similarities between AD and Converter groups. Specifically, among the eight identified ROIs with distinct INT alterations in AD, three ROIs (inferior temporal, caudate, pallidum areas) exhibit stable and significant alteration in AD converter. In addition, distinct INT related pathological changes in stable MCI and AD/Converter were found. For AD and Converter groups, neural information is stored for a longer time in lower hierarchical order areas, while higher levels of hierarchy seem to be preferentially impaired in stable MCI leading to a less pronounced hierarchical gradient effect. These results inform that the INT holds great potential as an additional measure for AD prediction, a stable biomarker for clinical diagnosis and an important therapeutic target in AD.

Eligibility of emergency psychiatry patients for clinical trials studying depression.

BACKGROUND: Differences often exist between people with depression who are eligible for clinical trials and those seen in clinical practice. The impact of exclusion criteria on eligibility has been previously reported for inpatients and outpatients, but has not been assessed for emergency psychiatry patients; a group that overlaps with inpatients and outpatients but also has important distinctives. Understanding the frequencies of commonly used exclusion criteria in this population could inform interpretation of existing data (generalizability) and highlight opportunities/needs for future trials. METHODS: We reviewed 67 clinical trials studying depression using Qualitative Content Analysis to identify common and recurring exclusion criteria. We examined the frequency of these exclusion criteria among a clinical sample of emergency psychiatry patients. RESULTS: Most clinical trials had exclusions for basic research requirements, age, symptom severity, psychosis, and substance use. Applying 9 commonly used exclusion criteria to the clinical population resulted in a 3.3 % eligibility rate (95 % CI 1.2 %-7.0 %). Exclusions for psychosis (85.1 % of trials), substance use (83.6 % of trials), and suicide risk (65.7 % of trials) would likely exclude 93 % of emergency psychiatry patients. The prevalence of psychosis, substance use, and suicide risk was much higher among emergency psychiatry patients than among previously studied populations. LIMITATIONS: Some eligibility criteria could not be measured. The Qualitative Content Analysis consolidated similar exclusion criteria, losing potentially important nuances in wordings. CONCLUSIONS: Exclusion criteria commonly used in contemporary clinical trials of depression limit generalizability to emergency psychiatry patients, due in large part to exclusions for psychosis, substance use, and suicide risk.