Neurophysiological and other features of working memory in older adults at risk for dementia.

Theta-gamma coupling (TGC) is a neurophysiological process that supports working memory. Working memory is associated with other clinical and biological features. The extent to which TGC is associated with these other features and whether it contributes to working memory beyond these features is unknown. Two-hundred-and-three older participants at risk for Alzheimer's dementia-98 with mild cognitive impairment (MCI), 39 with major depressive disorder (MDD) in remission, and 66 with MCI and MDD (MCI + MDD)-completed a clinical assessment, N-back-EEG, and brain MRI. Among them, 190 completed genetic testing, and 121 completed [11C] Pittsburgh Compound B ([11C] PIB) PET imaging. Hierarchical linear regressions were used to assess whether TGC is associated with demographic and clinical variables; Alzheimer's disease-related features (APOE ε4 carrier status and ß-amyloid load); and structural features related to working memory. Then, linear regressions were used to assess whether TGC is associated with 2-back performance after accounting for these features. Other than age, TGC was not associated with any non-neurophysiological features. In contrast, TGC (ß = 0.27; p = 0.006), age (ß = - 0.29; p = 0.012), and parietal cortical thickness (ß = 0.24; p = 0.020) were associated with 2-back performance. We also examined two other EEG features that are linked to working memory-theta event-related synchronization and alpha event-related desynchronization-and found them not to be associated with any feature or performance after accounting for TGC. Our findings suggest that TGC is a process that is independent of other clinical, genetic, neurochemical, and structural variables, and supports working memory in older adults at risk for dementia. Supplementary Information: The online version contains supplementary material available at 10.1007/s11571-023-09938-y.

Elevated senescence-associated secretory phenotype index in late-life bipolar disorder.

BACKGROUND: The senescence-associated secretory phenotype (SASP) is a biomarker index based on the profile of 22 blood proteins associated with cellular senescence. The SASP index has not been assessed in older patients with bipolar disorder (BD). We hypothesized that older adults with BD will have elevated cellular senescence burden as measured by the SASP index. METHODS: We measured the 22 SASP proteins to calculate the SASP index in 38 older patients with BD and 34 non-psychiatric comparison individuals (HC). RESULTS: The SASP index scores were significantly higher in BD than HC after controlling for age, sex, psychopathology, and physical health (F(1,8) = 5.37, p = 0.024, η2 = 0.08). SASP index scores were also associated with higher age, more severe depressive symptoms, and physical illness burden (p < 0.05) in the whole sample. LIMITATION: Cross-sectional study and small sample size. CONCLUSION: This is the first report of increased SASP index scores in older adults with BD. Our results suggest that dysregulation of age-related biological processes may contribute to more severe depressive symptoms and worse physical health in older adults with BD.

History of traumatic brain injury is associated with increased grey-matter loss in patients with mild cognitive impairment.

OBJECTIVES: To investigate whether a history of traumatic brain injury (TBI) is associated with greater long-term grey-matter loss in patients with mild cognitive impairment (MCI). METHODS: 85 patients with MCI were identified, including 26 with a previous history of traumatic brain injury (MCI[TBI-]) and 59 without (MCI[TBI+]). Cortical thickness was evaluated by segmenting T1-weighted MRI scans acquired longitudinally over a 2-year period. Bayesian multilevel modelling was used to evaluate group differences in baseline cortical thickness and longitudinal change, as well as group differences in neuropsychological measures of executive function. RESULTS: At baseline, the MCI[TBI+] group had less grey matter within right entorhinal, left medial orbitofrontal and inferior temporal cortex areas bilaterally. Longitudinally, the MCI[TBI+] group also exhibited greater longitudinal declines in left rostral middle frontal, the left caudal middle frontal and left lateral orbitofrontal areas sover the span of 2 years (median = 1-2%, 90%HDI [-0.01%: -0.001%], probability of direction (PD) = 90-99%). The MCI[TBI+] group also displayed greater longitudinal declines in Trail-Making-Test (TMT)-derived ratio (median: 0.737%, 90%HDI: [0.229%: 1.31%], PD = 98.8%) and differences scores (median: 20.6%, 90%HDI: [-5.17%: 43.2%], PD = 91.7%). CONCLUSIONS: Our findings support the notion that patients with MCI and a history of TBI are at risk of accelerated neurodegeneration, displaying greatest evidence for cortical atrophy within the left middle frontal and lateral orbitofrontal frontal cortex. Importantly, these results suggest that long-term TBI-mediated atrophy is more pronounced in areas vulnerable to TBI-related mechanical injury, highlighting their potential relevance for diagnostic forms of intervention in TBI.

Cognition in older age bipolar disorder: An analysis of archival data across the globe.

BACKGROUND: Cognitive deficits in bipolar disorder (BD) impact functioning and are main contributors to disability in older age BD (OABD). We investigated the difference between OABD and age-comparable healthy comparison (HC) participants and, among those with BD, the associations between age, global cognitive performance, symptom severity and functioning using a large, cross-sectional, archival dataset harmonized from 7 international OABD studies. METHODS: Data from the Global Aging and Geriatric Experiments in Bipolar Disorder (GAGE-BD) database, spanning various standardized measures of cognition, functioning and clinical characteristics, were analyzed. The sample included 662 euthymic to mildly symptomatic participants aged minimum 50years (509 BD, 153 HC), able to undergo extensive cognitive testing. Linear mixed models estimated associations between diagnosis and global cognitive performance (g-score, harmonized across studies), and within OABD between g-score and severity of mania and depressive symptoms, duration of illness and lithium use and of global functioning. RESULTS: After adjustment for study cohort, age, gender and employment status, there was no significant difference in g-score between OABD and HC, while a significant interaction emerged between employment status and diagnostic group (better global cognition associated with working) in BD. Within OABD, better g-scores were associated with fewer manic symptoms, higher education and better functioning. LIMITATIONS: Cross-sectional design and loss of granularity due to harmonization. CONCLUSION: More research is needed to understand heterogenous longitudinal patterns of cognitive change in BD and understand whether particular cognitive domains might be affected in OABD in order to develop new therapeutic efforts for cognitive dysfunction OABD.

Neuropsychiatric symptoms and brain morphology in patients with mild cognitive impairment, cerebrovascular disease and Parkinson disease: A cross sectional and longitudinal study.

OBJECTIVES: Neuropsychiatric symptoms (NPS) increase risk of developing dementia and are linked to various neurodegenerative conditions, including mild cognitive impairment (MCI due to Alzheimer's disease [AD]), cerebrovascular disease (CVD), and Parkinson's disease (PD). We explored the structural neural correlates of NPS cross-sectionally and longitudinally across various neurodegenerative diagnoses. METHODS: The study included individuals with MCI due to AD, (n = 74), CVD (n = 143), and PD (n = 137) at baseline, and at 2-years follow-up (MCI due to AD, n = 37, CVD n = 103, and PD n = 84). We assessed the severity of NPS using the Neuropsychiatric Inventory Questionnaire. For brain structure we included cortical thickness and subcortical volume of predefined regions of interest associated with corticolimbic and frontal-executive circuits. RESULTS: Cross-sectional analysis revealed significant negative correlations between appetite with both circuits in the MCI and CVD groups, while apathy was associated with these circuits in both the MCI and PD groups. Longitudinally, changes in apathy scores in the MCI group were negatively linked to the changes of the frontal-executive circuit. In the CVD group, changes in agitation and nighttime behavior were negatively associated with the corticolimbic and frontal-executive circuits, respectively. In the PD group, changes in disinhibition and apathy were positively associated with the corticolimbic and frontal-executive circuits, respectively. CONCLUSIONS: The observed correlations suggest that underlying pathological changes in the brain may contribute to alterations in neural activity associated with MBI. Notably, the difference between cross-sectional and longitudinal results indicates the necessity of conducting longitudinal studies for reproducible findings and drawing robust inferences.

Cognitive function based on theta-gamma coupling vs. clinical diagnosis in older adults with mild cognitive impairment with or without major depressive disorder.

Whether individuals with mild cognitive impairment (MCI) and a history of major depressive disorder (MDD) are at a higher risk for cognitive decline than those with MCI alone is still not clear. Previous work suggests that a reduction in prefrontal cortical theta phase-gamma amplitude coupling (TGC) is an early marker of cognitive impairment. This study aimed to determine whether using a TGC cutoff is better at separating individuals with MCI or MCI with remitted MDD (MCI+rMDD) on cognitive performance than their clinical diagnosis. Our hypothesis was that global cognition would differ more between TGC-based groups than diagnostic groups. We analyzed data from 128 MCI (mean age: 71.8, SD: 7.3) and 85 MCI+rMDD (mean age: 70.9, SD: 4.7) participants. Participants completed a comprehensive neuropsychological battery; TGC was measured during the N-back task. An optimal TGC cutoff was determined during the performance of the 2-back. This TGC cutoff was used to classify participants into low vs. high-TGC groups. We then compared Cohen's d of the difference in global cognition between the high and low TGC groups to Cohen's d between the MCI and MCI+rMDD groups. We used bootstrapping to determine 95% confidence intervals for Cohen's d values using the whole sample. As hypothesized, Cohen's d for the difference in global cognition between the TGC groups was larger (0.64 [0.32, 0.88]) than between the diagnostic groups (0.10 [0.004, 0.37]) with a difference between these two Cohen's d's of 0.54 [0.10, 0.80]. Our findings suggest that TGC is a useful marker to identify individuals at high risk for cognitive decline, beyond clinical diagnosis. This could be due to TGC being a sensitive marker of prefrontal cortical dysfunction that would lead to an accelerated cognitive decline.

Predictors of remission after repetitive transcranial magnetic stimulation for the treatment of late-life depression.

Repetitive transcranial magnetic stimulation (rTMS) is an effective treatment in patients with depression, yet treatment response remains variable. While previous work has identified predictors of remission in younger adults, relatively little data exists in late-life depression (LLD). To address this gap, data from 164 participants with LLD from a randomized non-inferiority treatment trial comparing standard bilateral rTMS to bilateral theta burst stimulation (TBS) (ClinicalTrials.gov identifier: NCT02998580) were analyzed using binary logistic regression and conditional inference tree (CIT) modeling. Lower baseline depression symptom severity, fewer prior antidepressant treatment failures, and higher global cognition predicted remission following rTMS treatment. The CIT predicted a higher likelihood of achieving remission for patients with a total score of 19 or lower on the Montgomery-Åsberg Depression Rating Scale, 1 or fewer prior antidepressant treatment failures, and a total score of 23 or higher on the Montreal Cognitive Assessment. Our results indicate that older adults with lower severity of depression, fewer antidepressant treatment failures, and higher global cognition benefit more from current forms of rTMS. The results suggest that there is potentially higher value in using rTMS earlier in the treatment pathway for depression in older adults.

Age-Related Alterations in Gray Matter Microstructure in Older People With Remitted Major Depression at Risk for Dementia.

Background: Major depressive disorder (MDD) in late life is a risk factor for mild cognitive impairment (MCI) and Alzheimer's disease. However, studies of gray matter changes have produced varied estimates of which structures are implicated in MDD and dementia. Changes in gray matter volume and cortical thickness are macrostructural measures for the microstructural processes of free water accumulation and dendritic spine loss. Methods: We conducted multishell diffusion imaging to assess gray matter microstructure in 244 older adults with remitted MDD (n = 44), MCI (n = 115), remitted MDD+MCI (n = 61), or without psychiatric disorders or cognitive impairment (healthy control participants; n = 24). We estimated measures related to neurite density, orientation dispersion, and free water (isotropic volume fraction) using a biophysically plausible model (neurite orientation dispersion and density imaging). Results: Results showed that increasing age was correlated with an increase in isotropic volume fraction and a decrease in orientation dispersion index, which is consistent with neuropathology dendritic loss. In addition, this relationship between age and increased isotropic volume fraction was more disrupted in the MCI group than in the remitted MDD or healthy control groups. However, the association between age and orientation dispersion index was similar for all 3 groups. Conclusions: The findings suggest that the neurite orientation dispersion and density imaging measures could be used to identify biological risk factors for Alzheimer's disease, signifying both conventional neurodegeneration observed with MCI and dendritic loss seen in MDD.

Atypical alpha band microstates produced during eyes-closed resting state EEG in autism.

Electroencephalogram (EEG) microstates, which represent quasi-stable patterns of scalp topography, are a promising tool that has the temporal resolution to study atypical spatial and temporal networks in autism spectrum disorder (ASD). While current literature suggests microstates are atypical in ASD, their clinical utility, i.e., relationship with the core behavioural characteristics of ASD, is not fully understood. The aim of this study was to examine microstate parameters in ASD, and examine the relationship between these parameters and core behavioural characteristics in ASD. We compared duration, occurrence, coverage, global explained variance percentage, global field power and spatial correlation of EEG microstates between autistic and neurotypical (NT) adults. Modified k-means cluster analysis was used on eyes-closed, resting state EEG from 30 ASD (10 females, 28.97 ± 9.34 years) and 30 age-equated NT (13 females, 29.33 ± 8.88 years) adults. Five optimal microstates, A to E, were selected to best represent the data. Five microstate maps explaining 80.44% of the NT and 78.44% of the ASD data were found. The ASD group was found to have atypical parameters of microstate A, C, D, and E. Of note, all parameters of microstate C in the ASD group were found to be significantly less than NT. While parameters of microstate D, and E were also found to significantly correlate with subscales of the Ritvo Autism Asperger Diagnostic Scale - Revised (RAADS-R), these findings did not survive a Bonferroni Correction. These findings, in combination with previous findings, highlight the potential clinical utility of EEG microstates and indicate their potential value as a neurophysiologic marker that can be further studied.

Heterogeneity of Cognition in Older Adults with Remitted Major Depressive Disorder: A Latent Profile Analysis.

OBJECTIVES: To identify data-driven cognitive profiles in older adults with remitted major depressive disorder (rMDD) with or without mild cognitive impairment (MCI) and examine how the profiles differ regarding demographic, clinical, and neuroimaging measures. DESIGN: Secondary cross-sectional analysis using latent profile analysis. SETTING: Multisite clinical trial in Toronto, Canada. PARTICIPANTS: One hundred seventy-eight participants who met DSM-5 criteria for rMDD without MCI (rMDD-MCI; n = 60) or with MCI (rMDD + MCI; n = 118). MEASUREMENTS: Demographic, clinical, neuroimaging measures, and domain scores from a neuropsychological battery assessing verbal memory, visuospatial memory, processing speed, working memory, language, and executive function. RESULTS: We identified three latent profiles: Profile 1 (poor cognition; n = 75, 42.1%), Profile 2 (intermediate cognition; n = 75, 42.1%), and Profile 3 (normal cognition; n = 28, 15.7%). Compared to participants with Profile 3, those with Profile 1 or 2 were older, had lower education, experienced a greater burden of medical comorbidities, and were more likely to have MCI. The profiles did not differ on the severity of residual symptoms, age of onset of rMDD, number of depressive episodes, psychotropic medication, cerebrovascular risk, ApoE4 carrier status, or family history of depression, dementia, or Alzheimer's disease. The profiles differed in cortical thickness of 15 regions, with the most prominent effects for left precentral and pars opercularis, and right inferior parietal and supramarginal. CONCLUSION: Older patients with rMDD can be grouped cross-sectionally based on data-driven cognitive profiles that differ from the absence or presence of a diagnosis of MCI. Future research should determine the differential risk for dementia of these data-driven subgroups.

Cognitive Outcomes After Antidepressant Pharmacotherapy for Late-Life Depression: A Systematic Review and Meta-Analysis.

OBJECTIVE: The authors evaluated whether treatment of late-life depression (LLD) with antidepressants leads to changes in cognitive function. METHODS: A systematic review and meta-analysis of prospective studies of antidepressant pharmacotherapy for adults age 50 or older (or mean age of 65 or older) with LLD was conducted. MEDLINE, EMBASE, and PsycInfo were searched through December 31, 2022. The primary outcome was a change on cognitive test scores from baseline to after treatment. Secondary outcomes included the effects of specific medications and the associations between changes in depressive symptoms and cognitive test scores. Participants with bipolar disorder, psychotic depression, dementia, or neurological disease were excluded. Findings from all eligible studies were synthesized at a descriptive level, and a random-effects model was used to pool the results for meta-analysis. RESULTS: Twenty-two studies were included. Thirteen of 19 studies showed an improvement on at least one cognitive test after antidepressant pharmacotherapy, with the most robust evidence for the memory and learning (nine of 16 studies) and processing speed (seven of 10 studies) domains and for sertraline (all five studies). Improvements in depressive symptoms were associated with improvement in cognitive test scores in six of seven relevant studies. The meta-analysis (eight studies; N=493) revealed a statistically significant overall improvement in memory and learning (five studies: effect size=0.254, 95% CI=0.103-0.404, SE=0.077); no statistically significant changes were seen in other cognitive domains. The evaluated risk of publication bias was low. CONCLUSION: Antidepressant pharmacotherapy of LLD appears to improve certain domains of cognitive function, particularly memory and learning. This effect may be mediated by an improvement in depressive symptoms. Studies comparing individuals receiving pharmacotherapy with untreated control participants are needed.

Cannabis and Driving in Older Adults.

Importance: Epidemiological studies have found that cannabis increases the risk of a motor vehicle collision. Cannabis use is increasing in older adults, but laboratory studies of the association between cannabis and driving in people aged older than 65 years are lacking. Objective: To investigate the association between cannabis, simulated driving, and concurrent blood tetrahydrocannabinol (THC) levels in older adults. Design, Setting, and Participants: Using an ecologically valid counterbalanced design, in this cohort study, regular cannabis users operated a driving simulator before, 30 minutes after, and 180 minutes after smoking their preferred legal cannabis or after resting. This study was conducted in Toronto, Canada, between March and November 2022 with no follow-up period. Data were analyzed from December 2022 to February 2023. Exposures: Most participants chose THC-dominant cannabis with a mean (SD) content of 18.74% (6.12%) THC and 1.46% (3.37%) cannabidiol (CBD). Main outcomes and measures: The primary end point was SD of lateral position (SDLP, or weaving). Secondary outcomes were mean speed (MS), maximum speed, SD of speed, and reaction time. Driving was assessed under both single-task and dual-task (distracted) conditions. Blood THC and metabolites of THC and CBD were also measured at the time of the drives. Results: A total of 31 participants (21 male [68%]; 29 White [94%], 1 Latin American [3%], and 1 mixed race [3%]; mean [SD] age, 68.7 [3.5] years), completed all study procedures. SDLP was increased and MS was decreased at 30 but not 180 minutes after smoking cannabis compared with the control condition in both the single-task (SDLP effect size [ES], 0.30; b = 1.65; 95% CI, 0.37 to 2.93; MS ES, -0.58; b = -2.46; 95% CI, -3.56 to -1.36) and dual-task (SDLP ES, 0.27; b = 1.75; 95% CI, 0.21 to 3.28; MS ES, -0.47; b = -3.15; 95% CI, -5.05 to -1.24) conditions. Blood THC levels were significantly increased at 30 minutes but not 180 minutes. Blood THC was not correlated with SDLP or MS at 30 minutes, and SDLP was not correlated with MS. Subjective ratings remained elevated for 5 hours and participants reported that they were less willing to drive at 3 hours after smoking. Conclusions and relevance: In this cohort study, the findings suggested that older drivers should exercise caution after smoking cannabis.

Association of plasma biomarkers with cognition, cognitive decline, and daily function across and within neurodegenerative diseases: Results from the Ontario Neurodegenerative Disease Research Initiative.

INTRODUCTION: We investigated whether novel plasma biomarkers are associated with cognition, cognitive decline, and functional independence in activities of daily living across and within neurodegenerative diseases. METHODS: Glial fibrillary acidic protein (GFAP), neurofilament light chain (NfL), phosphorylated tau (p-tau)181 and amyloid beta (Aß)42/40 were measured using ultra-sensitive Simoa immunoassays in 44 healthy controls and 480 participants diagnosed with Alzheimer's disease/mild cognitive impairment (AD/MCI), Parkinson's disease (PD), frontotemporal dementia (FTD) spectrum disorders, or cerebrovascular disease (CVD). RESULTS: GFAP, NfL, and/or p-tau181 were elevated among all diseases compared to controls, and were broadly associated with worse baseline cognitive performance, greater cognitive decline, and/or lower functional independence. While GFAP, NfL, and p-tau181 were highly predictive across diseases, p-tau181 was more specific to the AD/MCI cohort. Sparse associations were found in the FTD and CVD cohorts and for Aß42/40 . DISCUSSION: GFAP, NfL, and p-tau181 are valuable predictors of cognition and function across common neurodegenerative diseases, and may be useful in specialized clinics and clinical trials.

Stress-related cellular pathophysiology as a crosstalk risk factor for neurocognitive and psychiatric disorders.

In this narrative review, we examine biological processes linking psychological stress and cognition, with a focus on how psychological stress can activate multiple neurobiological mechanisms that drive cognitive decline and behavioral change. First, we describe the general neurobiology of the stress response to define neurocognitive stress reactivity. Second, we review aspects of epigenetic regulation, synaptic transmission, sex hormones, photoperiodic plasticity, and psychoneuroimmunological processes that can contribute to cognitive decline and neuropsychiatric conditions. Third, we explain mechanistic processes linking the stress response and neuropathology. Fourth, we discuss molecular nuances such as an interplay between kinases and proteins, as well as differential role of sex hormones, that can increase vulnerability to cognitive and emotional dysregulation following stress. Finally, we explicate several testable hypotheses for stress, neurocognitive, and neuropsychiatric research. Together, this work highlights how stress processes alter neurophysiology on multiple levels to increase individuals' risk for neurocognitive and psychiatric disorders, and points toward novel therapeutic targets for mitigating these effects. The resulting models can thus advance dementia and mental health research, and translational neuroscience, with an eye toward clinical application in cognitive and behavioral neurology, and psychiatry.

About time: neurocognitive correlates of stimulus-bound and other time setting errors in the Clock Drawing Test.

OBJECTIVE: Previous findings suggest that time setting errors (TSEs) in the Clock Drawing Test (CDT) may be related mainly to impairments in semantic and executive function. Recent attempts to dissociate the classic stimulus-bound error (setting the time to "10 to 11" instead of "10 past 11") from other TSEs, did not support hypotheses regarding this error being primarily executive in nature or different from other time setting errors in terms of neurocognitive correlates. This study aimed to further investigate the cognitive correlates of stimulus-bound errors and other TSEs, in order to trace possible underlying cognitive deficits. METHODS: We examined cognitive test performance of participants with preliminary diagnoses associated with mild cognitive impairment. Among 490 participants, we identified clocks with stimulus-bound errors (n = 78), other TSEs (n = 41), other errors not related to time settings (n = 176), or errorless clocks (n = 195). RESULTS: No differences were found on any dependent measure between the stimulus-bound and the other TSErs groups. Group comparisons suggested TSEs in general, to be associated with lower performance on various cognitive measures, especially on semantic and working memory measures. Regression analysis further highlighted semantic and verbal working memory difficulties as being the most prominent deficits associated with these errors. CONCLUSION: TSEs in the CDT may indicate underlying deficits in semantic function and working memory. In addition, results support previous findings related to the diagnostic value of TSEs in detecting cognitive impairment.

Assessment and Comparison of Nonlinear Measures in Resting-State Magnetoencephalograms in Alzheimer's Disease and Mild Cognitive Impairment.

BACKGROUND: Nonlinear dynamical measures, such as fractal dimension (FD), entropy, and Lempel-Ziv complexity (LZC), have been extensively investigated individually for detecting information content in magnetoencephalograms (MEGs) from patients with Alzheimer's disease (AD). OBJECTIVE: To compare systematically the performance of twenty conventional and recently introduced nonlinear dynamical measures in studying AD versus mild cognitive impairment (MCI) and healthy control (HC) subjects using MEG. METHODS: We compared twenty nonlinear measures to distinguish MEG recordings from 36 AD (mean age = 74.06±6.95 years), 18 MCI (mean age = 74.89±5.57 years), and 26 HC subjects (mean age = 71.77±6.38 years) in different brain regions and also evaluated the effect of the length of MEG epochs on their performance. We also studied the correlation between these measures and cognitive performance based on the Mini-Mental State Examination (MMSE). RESULTS: The results obtained by LZC, zero-crossing rate (ZCR), FD, and dispersion entropy (DispEn) measures showed significant differences among the three groups. There was no significant difference between HC and MCI. The highest Hedge's g effect sizes for HC versus AD and MCI versus AD were respectively obtained by Higuchi's FD (HFD) and fuzzy DispEn (FuzDispEn) in the whole brain and was most prominent in left lateral. The results obtained by HFD and FuzDispEn had a significant correlation with the MMSE scores. DispEn-based techniques, LZC, and ZCR, compared with HFD, were less sensitive to epoch length in distinguishing HC form AD. CONCLUSIONS: FuzDispEn was the most consistent technique to distinguish MEG dynamical patterns in AD compared with HC and MCI.

Impact of psychotropic medications on cognition among older adults: a systematic review.

OBJECTIVES: The aim of this systematic review is to examine the cognitive impact of psychotropic medications including benzodiazepines, antidepressants, mood stabilizers, antipsychotics, or a combination of these drugs on older adults. DESIGN: Systematic review. SETTING: We searched Medline, PsycINFO, and Embase through the Ovid platform, CINAHL through EBSCO, and Web of Science. PARTICIPANTS AND INTERVENTIONS: Randomized control trials (RCTs) and cohort studies that used a validated scale to measure cognition with a follow-up period of at least six months were included. MEASUREMENT: The primary outcome of interest was cognitive change associated with psychotropic medication use. RESULTS: A total of 7551 articles were identified from the primary electronic literature search across the five databases after eliminating duplicates. Based on full-text analysis, 27 articles (two RCTs, 25 cohorts) met the inclusion criteria. Of these, nine each examined the impact of benzodiazepines and antidepressants, five examined psychotropic combinations, three on antipsychotic drugs, and one on the effects of mood stabilizers. CONCLUSIONS: This is the first systematic review to examine the cognitive impact of multiple psychotropic drug classes in older adults over an extended follow-up period (six months or more) using robust sample sizes, drug-free control groups, and validated cognitive instruments. We found evidence to indicate cognitive decline with the cumulative use of benzodiazepines and the use of antidepressants, especially those with anticholinergic properties among older adults without cognitive impairment at baseline. Further, the use of antipsychotics and psychotropic combinations is also associated with cognitive decline in older adults.

The use of theta burst stimulation in patients with schizophrenia - A systematic review.

Transcranial magnetic stimulation (TMS) can offer therapeutic benefits and provide value in neurophysiological research. One of the newer TMS paradigms is theta burst stimulation (TBS) which can be delivered in two patterns: continuous (cTBS - inducing LTD-like effects) and intermittent (iTBS - inducing LTP-like effects). This review paper aims to explore studies that have utilized TBS protocols over different areas of the cortex to study the neurophysiological functions and treatment of patients with schizophrenia. PubMed was searched using the following keywords "schizophrenia", "schizoaffective", or "psychosis", and "theta burst stimulation". Out of the 90 articles which were found, thirty met review inclusion criteria. The inclusion criteria included studying the reported effect (clinical, physiological, or both) of at least one session of TBS on human subjects, and abstracts (at minimum) must have been in English. The main target areas included prefrontal cortex (12 studies - 10 dorsolateral prefrontal cortex (DLPFC), 2 dorsomedial prefrontal cortex (DMPFC)) vermal cerebellum (5), and temporo-parietal cortex (8). Other target areas included inferior parietal lobe (2), and motor cortex (3). TBS neurophysiological effect was explored in 5 studies using functional magnetic resonance image (fMRI), magnetic resonance spectroscopy (MRS), electroencephalography (EEG), electromyography (EMG) and positron emission topography (PET) scan. Overall, TBS can offer great therapeutic potential as it is well-tolerated, feasible, and has few, if any, adverse effects. TBS may be targeted to treat specific symptomatology, as an augmenting intervention to pharmacotherapy, or even improving patient's insight into their diagnosis.

Landscape of Phase II Trials in Alzheimer's Disease.

BACKGROUND: Drug development in Alzheimer's disease (AD) over the past two decades has had high rates of failure. Novel trial designs, such as adaptive designs, have the potential to improve the efficiency of drug development in AD. OBJECTIVE: To evaluate the design characteristics, temporal trends, and differences in design between sponsor types in phase II trials of investigational agents in AD. METHODS: Phase I/II, II, and II/III trials for AD with drug or other biological interventions registered from December 1996 to December 2021 in ClinicalTrials.gov were included. Descriptive statistics were used to summarize trial characteristics. Linear, logistic, and multinomial regression models assessed temporal trends and differences between sponsor types in design characteristics. RESULTS: Of N = 474 trials identified, randomized parallel group design was the most common design (72%). Only 12 trials (2.5%) used an adaptive design; adaptive features included early stopping rules, model-based dose-finding, adaptive treatment arm selection, and response adaptive randomization. The use of non-randomized parallel-group and open-label single arm designs increased over time. No temporal trend in the use of adaptive design was identified. Trials sponsored by industry only were more likely to use a randomized parallel-group design and have a larger estimated sample size than trials with other sponsor types. CONCLUSION: Our systematic review showed that very few phase II trials in AD used an adaptive trial design. Innovation and implementation of novel trial designs in AD trials can accelerate the drug development process.

Walking Alongside: Views of Family Members on Medical Assistance in Dying for Mental Illness as the Sole Underlying Medical Condition.

Medical assistance in dying (MAiD) was introduced into Canadian federal legislation in 2016. Mental illness as the sole underlying medical condition (MI-SUMC) is currently excluded from eligibility; such exclusion is scheduled to expire on March 17, 2024. Irremediability, capacity, quality of life, autonomy, family involvement, and healthcare system constraints have been debated intensively. Recent studies have not explored the views of family members of persons with mental illness on MAiD MI-SUMC. This study aimed to fill this knowledge gap. Twenty-five Ontario residents who had a loved one with mental illness participated. A persona-scenario exercise was designed to explore participants' views on MAiD MI-SUMC in hypothetical situations. Reflexive thematic analysis was used to analyze the data. A lived experience-advisory panel was engaged throughout the study. Seven themes were developed: Witnessing suffering; A road with barriers and limitations; Societal barriers; The unknowns of mental illness; Individual choices: the life or death that a person wants; MAiD MI-SUMC as an acceptable choice when suffering cannot be relieved with available treatments and supports; and The emotional outcome. Participants constructed their views based on their experience of supporting a loved one with mental illness. MAiD MI-SUMC was perceived as a multifaceted issue, whose acceptability and potential introduction required a concurrent exploration and discussion of the challenges arising due to limitations of the healthcare system, the opportunities and limits to family involvement, and the value of patient autonomy.