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In 2020, the Lancet Commission identified 12 modifiable factors that increase population-level dementia risk. It is unclear if these risk factors co-occur among individuals in a clinically meaningful way. Using latent class analysis, we identified profiles of modifiable dementia risk factors in dementia-free adults aged 60-64 years from the UK Biobank. We then estimated associations between these profiles with incident dementia, cognition, and neuroimaging outcomes, and explored the differences across profiles in the effects of a polygenic risk score for Alzheimer's disease on outcomes. In 55,333 males and 63,063 females, three sex-specific latent profiles were identified: cardiometabolic risk, substance use-related risk, and low risk. The cardiometabolic risk profile in both males and females was associated with greater incidence of all-cause dementia (male: OR [95% CI] = 2.33 [2.03, 2.66]; female: OR [95% CI] = 1.44 [1.24, 1.68]), poorer cognitive performance, greater brain atrophy, and greater white matter hyperintensity volume compared to the low risk profile. The substance use-related risk profile in males was associated with poorer cognitive performance and greater white matter hyperintensities compared to the low risk profile, but no difference in all-cause dementia incidence was observed (OR [95% CI] = 1.00 [0.95, 1.06]). In females, the substance use-related risk profile demonstrated increased dementia incidence (OR [95% CI] = 1.58 [1.57, 1.58]) and greater brain atrophy but smaller white matter hyperintensity volume compared to the low risk profile. The polygenic risk score had larger effects among females, and differentially influenced outcomes across profiles; for instance, there were larger effects of the polygenic risk score on atrophy in the cardiometabolic profile vs. the low risk profile among males, and larger effects of the polygenic risk score on loss of white matter integrity in the cardiometabolic profile vs. the low risk profile among females. These results reveal three modifiable dementia risk profiles, their unique cognitive/neuroimaging outcomes, and their interactions with genetic risk for Alzheimer's disease. These differences highlight the need to consider population heterogeneity in risk prediction tools and in planning personalized prevention strategies., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

The purpose of this study was to investigate relationships between depressive symptoms, functional disability, and physical activity over time in community-dwelling older adults. The Religious Order Study and Rush Memory and Aging Project are longitudinal cohort studies based in the United States which began recruitment in 1994 and 1997, respectively. This analysis included 1611 participants (27.4% male, 92.9% White, 74.7% cognitively normal) who were included at age 80 and followed until age 90. Depressive symptoms were assessed using the modified Center for Epidemiologic Studies Depression scale. Functional disability was assessed using the Instrumental Activities of Daily Living (IADL) scale. Physical activity was self-reported hours of weekly exercise. Reciprocal temporal relationships between these variables were investigated using a random intercept cross-lagged panel model, which decomposes observed variables into stable between-person ('trait') and variable within-person ('state') components to estimate the directional effects between variables over time. Traits for depressive symptoms, IADL disability, and physical activity were correlated. IADL disability showed autoregressive effects; disability starting at age 82 strongly predicted subsequent disability. Consistent autoregressive effects were not observed for depressive symptoms nor physical activity. Several small cross-lagged effects between states were observed for IADL disability and physical activity, as well as for IADL disability and depressive symptoms. There were no direct effects between depressive symptoms and physical activity, but several paths through IADL disability were observed between ages 82 and 88. Functional disability played an important role in octogenarians, highlighting the importance of maintaining functional independence later in life., (© 2024. The Author(s), under exclusive licence to American Aging Association.)

Background: Major depressive disorder (MDD) is a leading cause of disability worldwide across domains of health and cognition, affecting overall quality of life. Approximately one third of individuals with depression do not fully respond to treatments (e.g., conventional antidepressants, psychotherapy) and alternative strategies are needed. Recent early phase trials suggest psilocybin may be a safe and efficacious intervention with rapid-acting antidepressant properties. Psilocybin is thought to exert therapeutic benefits by altering brain network connectivity and inducing neuroplastic changes that endure for weeks post-treatment. Although early clinical results are encouraging, psilocybin's acute neurobiological effects on neuroplasticity have not been fully investigated. We aim to examine for the first time how psilocybin acutely (intraday) and subacutely (weeks) alters functional brain networks implicated in depression., Methods: Fifty participants diagnosed with MDD or persistent depressive disorder (PDD) will be recruited from a tertiary mood disorders clinic and undergo 1:1 randomization into either an experimental or control arm. Participants will be given either 25 mg psilocybin or 25 mg microcrystalline cellulose (MCC) placebo for the first treatment. Three weeks later, those in the control arm will transition to receiving 25 mg psilocybin. We will investigate whether treatments are associated with changes in arterial spin labelling and blood oxygenation level-dependent contrast neuroimaging assessments at acute and subacute timepoints. Primary outcomes include testing whether psilocybin demonstrates acute changes in (1) cerebral blood flow and (2) functional brain activity in networks associated with mood regulation and depression when compared to placebo, along with changes in MADRS score over time compared to placebo. Secondary outcomes include changes across complementary clinical psychiatric, cognitive, and functional scales from baseline to final follow-up. Serum peripheral neurotrophic and inflammatory biomarkers will be collected at baseline and follow-up to examine relationships with clinical response, and neuroimaging measures., Discussion: This study will investigate the acute and additive subacute neuroplastic effects of psilocybin on brain networks affected by depression using advanced serial neuroimaging methods. Results will improve our understanding of psilocybin's antidepressant mechanisms versus placebo response and whether biological measures of brain function can provide early predictors of treatment response., Trial Registration: ClinicalTrials.gov Identifier: NCT06072898. Registered on 6 October 2023., (© 2024. The Author(s).)

The common requirement to set the time to "10 past 11" on the Clock Drawing Test is intended to elicit a stimulus bound response (SBR), in which the responder is "pulled" to the salient stimulus "10," resulting in hands set at "10 before 11." SBRs are considered markers of executive dysfunction, although this assumption has not yet been validated. We compared SBR and other time-setting errors on inhibitory control tests, hypothesizing that they represent related constructs. The role of semantic dysfunction in the formation of those errors was also investigated. We examined baseline test performance of participants with Mild Cognitive Impairment or a history of depression, and control participants, enrolled in a dementia prevention study. Among 258 participants, we identified clocks with SBRs ( n  = 16), other time errors ( n  = 22), or no errors at all ( n  = 42). Performance between the groups with SBRs and other time-setting errors did not differ on any of the executive tests, and both error groups performed significantly worse than the No Error group on the semantic tests. Control for covariates further supported semantic and executive components in time-setting errors. Both semantic and inhibitory control deficits may underlie time representation errors in general.

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., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Introduction: Agitation, psychosis, and apathy are prevalent and highly distressing neuropsychiatric symptoms (NPS) of Alzheimer's disease (AD) that have been linked to numerous negative outcomes, including increased mortality, worsened cognitive decline, and caregiver burden. Current treatments for AD-associated agitation, namely atypical antipsychotics, provide some benefits but may increase the risk of serious adverse events and death. Meanwhile, no pharmacotherapies have been approved by regulatory agencies for the treatment of psychosis or apathy in AD. Over the past decade, many new and repurposed drugs have emerged as potential therapeutic options for managing these challenging NPS., Areas Covered: This review aims to provide a comprehensive summary of pharmacotherapies that have recently been investigated in phase 2 and 3 clinical trials for the treatment of agitation, psychosis, or apathy in AD., Expert Opinion: Novel atypical antipsychotics, serotonergic antidepressants, cannabinoids, and dextromethorphan combination drugs have shown promising results for alleviating agitation. Pimavanserin appears to be the most effective emerging therapy for psychosis, while methylphenidate has demonstrated good efficacy for apathy. Further research on biomarkers of NPS severity and treatment response, as well as continued improvements in methodological approaches are needed to advance the field.

Importance: Nonsuicidal self-injury (NSSI) is a strong predictor of suicide attempts. The prevalence of NSSI has been increasing among female adolescents in North America and Europe, but less is known about trends in other geographical regions., Objective: To examine sex differences in the prevalence of NSSI among adolescents within and between geographical regions., Data Sources: MEDLINE and PsycINFO were searched using the keywords adolescents, self-injury, sex factors, and synonyms for articles published in English between January 1, 2000, and May 10, 2022., Study Selection: Studies were included if they presented original data (any study design), included adolescents aged 10 to 19 years, reported results stratified by sex, and explicitly defined self-injury as behaviors occurring without suicidal intent., Data Extraction and Synthesis: This meta-analysis was registered with PROSPERO and conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses. Articles were assessed for quality by 2 independent coders (F.M. and J.A.). A random-effects model was used to calculate prevalence. Data were analyzed from July 2022 to April 2023., Main Outcomes and Measures: The prevalence of NSSI in male and female adolescents within and between regions was the main outcome. Odds ratios (OR) with 95% CIs were calculated for community samples., Results: Eight hundred and two studies were screened, and 38 were included (266 491 participants). Across 17 countries, the pooled prevalence of NSSI was 17.7% (female:male OR, 1.60; 95% CI, 1.29-1.98). NSSI was twice as prevalent among female adolescents compared with male adolescents in North America (OR, 2.49; 95% CI, 2.16-2.86) and Europe (OR, 2.08; 95% CI, 1.69-2.58), but not in Asia (OR, 1.00; 95% CI, 0.71-1.41)., Conclusions and Relevance: In this meta-analysis of sex differences in global prevalence of NSSI, the female predominance of NSSI observed among adolescents in North America and Europe aligned with rising rates of suicide in these populations. The comparable prevalence of NSSI among male and female adolescents in Asia also aligned with the lower male-to-female suicide ratio compared with other countries. More research is needed to characterize regional (and potentially cultural) sex differences among adolescents with NSSI to prevent and treat the behavior and to understand the possible interplay with corresponding regional trends in suicide.

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 [ 11 C] 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 β-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 (β = 0.27; p  = 0.006), age (β = - 0.29; p  = 0.012), and parietal cortical thickness (β = 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., Competing Interests: Conflict of interestRP, HB, AG, NH, MM, NRR, WW and RZ report no biomedical financial interests or potential conflicts of interest. DMB receives research support from the CIHR, NIH, Brain Canada and the Temerty Family Foundation through the CAMH Foundation and the Campbell Research Institute. He received research support and in-kind equipment support for an investigator-initiated study from Brainsway Ltd, and he was the principal site investigator for three sponsor-initiated studies for Brainsway Ltd. He receives in-kind equipment support from Magventure for investigator-initiated research. He received medication supplies for an investigator-initiated trial from Indivior. He has participated in a scientific advisory board meeting for Janssen and Welcony Inc. CEF receives grant funding from Brain Canada, Patient Centred Outcomes Research Institute (PCORI), St. Michaels Hospital Foundation, Hoffman LaRoche and Vielight Inc. AJF has received grant support from the U.S. National Institutes of Health, the Patient Centered Outcomes Research Institute, the Canadian Institutes of Health Research, Brain Canada, the Ontario Brain Institute, the Alzheimer's Association, AGE-WELL, and the Canadian Foundation for Healthcare Improvement. AGG has obtained academic grants during the last 5 years from Canadian Institute of Health Research, Centre for Aging and Brain Health Innovation, Brain Canada Foundation, Brain & Behavior Research Foundation, Ontario Ministry of Economic Development and Innovation, Ontario Mental Health Foundation, Ontario Ministry of Health and Long Term Care Alternate Funding Plan, American Foundation for Suicide Prevention, Catalyst Fund: Miner's Lamp Innovation Fund in Prevention and Early Detection of Severe Mental Illness, Northern Ontario Academic Medicine Association, Society for Nuclear Medicine and Molecular Imaging, Researcher-Clinician Partnership Program (RCP2), Spark, W. Garfield Weston Foundation, Labatt Family Network for Research on the Biology of Depression, and PSI Foundation. JLK is a member of the Scientific Advisory Board (unpaid) of Myriad Genetics, and is author on patents relating to pharmacogenetics of psychiatric disorders. SK has received grant support from Brain Canada, NIH, Brain and Behavior Foundation (NARSAD), BrightFocus Foundation, Weston Brain Institute, Canadian Centre for Aging and Brain Health Innovation, CAMH foundation and University of Toronto, and in Kind equipment support from Soterix Medical Inc. KLL has grant support from the U.S. National Institutes of Health, the Canadian Institutes of Health Research, the Weston Brain Institute, the Alzheimer's Drug Discovery Foundation, and the Alzheimer's Association, has received consultation fees from Acadia, BioXcel Therapeutics, Cerevel Therapeutics, ICG Pharma, Kondor Pharma, Otsuka, and holds stock options in Highmark Interactive. LM reports no biomedical financial interests or potential conflicts of interest. BHM holds and receives support from the Labatt Family Chair in Biology of Depression in Late-Life Adults at the University of Toronto. He currently receives research support from Brain Canada, the Canadian Institutes of Health Research, the CAMH Foundation, the Patient-Centered Outcomes Research Institute (PCORI), the US National Institute of Health (NIH), Capital Solution Design LLC (software used in a study founded by CAMH Foundation), and HAPPYneuron (software used in a study founded by Brain Canada). Within the past 5 years, he has also received research support from Eli Lilly (medications for a NIH-funded clinical trial) and Pfizer (medications for a NIH-funded clinical trial). BGP is holder of United States Provisional Patent No. 16/490,680, Canadian Provisional Patent No. 3,054,093 and of United States Provisional Patent No.17/396,030 for a cell-based assay and kits for assessing serum anticholinergic activity. AV receives funding from the National Institute of Mental Health, Canadian Institutes of Health Research, Canada Foundation for Innovation, CAMH Foundation, and the University of Toronto. TKR has received research support from Brain Canada, Brain and Behavior Research Foundation, BrightFocus Foundation, Canada Foundation for Innovation, Canada Research Chair, Canadian Institutes of Health Research, Centre for Aging and Brain Health Innovation, National Institutes of Health, Ontario Ministry of Health and Long-Term Care, Ontario Ministry of Research and Innovation, and the Weston Brain Institute. TKR also received in-kind equipment support for an investigator-initiated study from Magstim, and in-kind research accounts from Scientific Brain Training Pro. TKR participated in 2021 in an advisory board for Biogen Canada Inc. TKR is also holder of the United States Provisional Patent No. 17/396,030 that describes cell-based assays and kits for assessing serum cholinergic receptor activity., (© The Author(s), under exclusive licence to Springer Nature B.V. 2023. Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.)

Objectives: To examine clinically important adverse events (AEs) associated with methylphenidate (MPH) treatment of apathy in Alzheimer's Disease (AD) versus placebo, including weight loss, vital signs, falls, and insomnia., Methods: The Apathy in Dementia Methylphenidate Trial 2 (ADMET2) trial was a multicenter randomized, placebo-controlled trial of MPH to treat apathy in individuals with apathy and AD. Participants in ADMET2 had vital signs and weight measured at monthly visits through 6 months. AEs, including insomnia, falls, and cardiovascular events, were reported at every visit by participants and families using a symptom checklist., Results: The study included 98 participants in the MPH group and 101 in the placebo group. Participants in the MPH group experienced greater weight loss on average than the placebo through the 6-month follow-up, with a difference in change between MPH and placebo of 2.8 lb (95% confidence interval, CI: 0.7, 4.9 lb). No treatment group differences in change during the trial were found in systolic and diastolic blood pressure. More participants in the MPH group reported falls during the follow-up, 10 versus 6 in MPH and placebo groups, respectively. No differences in post-baseline insomnia were observed between the treatment groups. No participants reported instances of myocardial infarction, congestive heart failure, arrhythmia, stroke, or cardiomyopathy throughout the study period., Conclusions: MPH use in AD patients for treating apathy is relatively safe, particularly notable given the many medical comorbidities in this population. There was a statistically significant but modest weight loss associated with MPH use, and clinicians are thus advised to monitor weight during MPH treatment., (© 2024 John Wiley & Sons Ltd.)

Aims: This study examined serum cytochrome P450-soluble epoxide hydrolase (CYP450-sEH) oxylipins and depressive symptoms together in relation to cognitive performance in individuals with type 2 diabetes mellitus (T2DM)., Methods: Clinically cognitively normal T2DM individuals were recruited (NCT04455867). Depressive symptom severity was assessed using the Beck Depression Inventory-II (BDI-II; total scores ≤13 indicated minimal depressive symptoms and ≥ 14 indicated significant depressive symptoms). Executive function and verbal memory were assessed. Fasting serum oxylipins were quantified by ultra-high-performance liquid chromatography tandem mass-spectrometry., Results: The study included 85 participants with minimal depressive symptoms and 27 with significant symptoms (mean age: 63.3 ± 9.8 years, 49 % women). In all participants, higher concentrations of linoleic acid derived sEH (12,13-dihydroxyoctadecamonoenoic acid; DiHOME) and CYP450 (12(13)-epoxyoctadecamonoenoic acid; EpOME) metabolites were associated with poorer executive function (F 1,101  = 6.094, p = 0.015 and F 1,101  = 5.598, p = 0.020, respectively). Concentrations of multiple sEH substrates interacted with depressive symptoms to predict 1) poorer executive function, including 9(10)-EpOME (F 1,100  = 12.137, p < 0.001), 5(6)-epoxyeicosatrienoic acid (5(6)-EpETrE; F 1,100  = 6.481, p = 0.012) and 11(12)-EpETrE (F 1,100  = 4.409, p = 0.038), and 2) verbal memory, including 9(10)-EpOME (F 1,100  = 4.286, p = 0.041), 5(6)-EpETrE (F 1,100  = 6.845, p = 0.010), 11(12)-EpETrE (F 1,100  = 3.981, p = 0.049) and 14(15)-EpETrE (F 1,100  = 5.019, p = 0.027)., Conclusions: Associations of CYP450-sEH metabolites and depressive symptoms with cognition highlight the biomarker and therapeutic potential of the CYP450-sEH pathway in T2DM., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Neurofilament Light Chain (NfL) is a biomarker of axonal injury elevated in mild cognitive impairment (MCI) and Alzheimer's disease dementia. Blood NfL also inversely correlates with cognitive performance in those conditions. However, few studies have assessed NfL as a biomarker of global cognition in individuals demonstrating mild cognitive deficits who are at risk for vascular-related cognitive decline., Objective: To assess the relationship between blood NfL and global cognition in individuals with possible vascular MCI (vMCI) throughout cardiac rehabilitation (CR). Additionally, NfL levels were compared to age/sex-matched cognitively unimpaired (CU) controls., Method: Participants with coronary artery disease (vMCI or CU) were recruited at entry to a 24-week CR program. Global cognition was measured using the Montreal Cognitive Assessment (MoCA) and plasma NfL level (pg/ml) was quantified using a highly sensitive enzyme-linked immunosorbent assay., Results: Higher plasma NfL was correlated with worse MoCA scores at baseline ( β = -.352, P = .029) in 43 individuals with vMCI after adjusting for age, sex, and education. An increase in NfL was associated with worse global cognition ( b [SE] = -4.81[2.06], P = .023) over time, however baseline NfL did not predict a decline in global cognition. NfL levels did not differ between the vMCI (n = 39) and CU (n = 39) groups ( F (1, 76) = 1.37, P = .245)., Conclusion: Plasma NfL correlates with global cognition at baseline in individuals with vMCI, and is associated with decline in global cognition during CR. Our findings increase understanding of NfL and neurobiological mechanisms associated with cognitive decline in vMCI., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Objective: Depression in later life is associated with a two-fold increased risk of dementia. It is not clear to what extent potentially modifiable risk factors account for this association., Method: Older adults (age 50 + ) with objective health measures ( n  = 14,014) from the Canadian Longitudinal Study on Aging were followed for a mean duration of 35 months. Linear regression analyses were used to determine if clinically significant depression (Centre for Epidemiologic Studies Depression scale score (CESD) ≥ 10) was associated with global cognitive decline, assessed with a neuropsychological battery during follow-up, and if modifiable risk factors mediated this association., Results: Depression was associated with an excess of risk factors for cognitive decline including: vascular disease, hypertension, diabetes, apnoea during sleep, higher body mass index, smoking, physical inactivity and lack of social participation. In regression analyses depression remained independently associated with cognitive decline over time (beta -0.060, P  = 0.038) as did cerebrovascular disease (beta -0.197, P  < 0.001), HbA1C (beta -0.059, P  < 0.001), visual impairment (beta -0.070, P  = 0.007), hearing impairment (beta -0.098, P  < 0.001) and physical inactivity (beta -0.075, P  = 0.014). In mediation analyses, we found that cerebrovascular disease ( z  = -3.525, P  < 0.001), HbA1C ( z  = -4.976, P  < 0.001) and physical inactivity ( z  = -3.998, P  < 0.001) partially mediated the association between depression and cognitive decline., Conclusions: In this large sample of Canadian older adults incorporating several objective health measures, older adults with depression were at increased risk of cognitive decline and had an excess of potentially modifiable risk factors. Clinicians should pay particular attention to control of diabetes, physical inactivity and risk factors for cerebrovascular disease in older adults presenting with depression as they can contribute to accelerated cognitive decline and may be addressed during routine clinical care., Competing Interests: Declaration of Conflicting InterestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Introduction: Hypertension and diabetes are common cardiovascular risk factors that increase Alzheimer's disease (AD) risk. However, it is unclear whether AD risk differs in hypertensive individuals with and without diabetes., Methods: Cognitively normal individuals (N = 11,074) from the National Alzheimer's Coordinating Center (NACC) were categorized as having (1) hypertension with diabetes (HTN+/DM+), (2) hypertension without diabetes (HTN+/DM-), or (3) neither (HTN-/DM-). AD risk in HTN+/DM+ and HTN+/DM- was compared to HTN-/DM-. This risk was then investigated in those with AD neuropathology (ADNP), cerebral amyloid angiopathy (CAA), cerebrovascular neuropathology (CVNP), arteriolosclerosis, and atherosclerosis. Finally, AD risk in HTN-/DM+ was compared to HTN-/DM-., Results: Seven percent (N = 830) of individuals developed AD. HTN+/DM+ (hazard ratio [HR] = 1.31 [1.19-1.44]) and HTN+/DM- (HR = 1.24 [1.17-1.32]) increased AD risk compared to HTN-/DM-. AD risk was greater in HTN+/DM+ with ADNP (HR = 2.10 [1.16-3.79]) and CAA (HR = 1.52 [1.09-2.12]), and in HTN+/DM- with CVNP (HR = 1.54 [1.17-2.03]). HTN-/DM+ also increased AD risk (HR = 1.88 [1.30-2.72]) compared to HTN-/DM-., Discussion: HTN+/DM+ and HTN+/DM- increased AD risk compared to HTN-/DM-, but pathological differences between groups suggest targeted therapies may be warranted based on cardiovascular risk profiles., Highlights: AD risk was studied in hypertensive (HTN+) individuals with/without diabetes (DM+/-). HTN+/DM+ and HTN+/DM- both had an increased risk of AD compared to HTN-/DM-. Post mortem analysis identified neuropathological differences between HTN+/DM+ and HTN+/DM-. In HTN+/DM+, AD risk was greater in those with AD neuropathology and CAA. In HTN+/DM-, AD risk was greater in those with cerebrovascular neuropathology., (© 2024 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

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., (© 2024. The Author(s).)

Impaired angiogenesis is associated with cognitive decline in older adults. While exercise has been broadly associated with increased angiogenesis, the relevant mechanisms in older adults are not clear. Here, we present a systematic review and meta-analysis on the relationship between exercise and specific blood angiogenesis markers in older adults to better understand the relevant mechanisms. MEDLINE, Embase, and Cochrane CENTRAL were searched for original reports of angiogenesis markers' concentrations in blood before and after exercise in older adults (≥50 years). Heterogeneity was investigated using sub-group analyses and meta-regressions. Of the 44 articles included in the review, 38 were included in the meta-analyses for five markers: vascular endothelial growth factor (VEGF), e-selectin (CD62E), endostatin, fibroblast growth factor 2, and matrix metallopeptidase-9. VEGF levels were higher (SMD[95%CI]= 0.18[0.03, 0.34], and CD62E levels were lower (SMD[95%CI]= -0.72[-1.42, -0.03], p = 0.04) after exercise. No other markers were altered. Although more studies are needed, changes in angiogenesis markers may help explain the beneficial effects of exercise on angiogenesis in older adults., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Apathy and depression are common neuropsychiatric symptoms across neurodegenerative disorders and are associated with impairment in several cognitive domains, yet little is known about the influence of sex on these relationships., Objectives: We examined the relationship between these symptoms with neuropsychological performance across a combined cohort with mild or major neurodegenerative disorders, then evaluated the impact of sex., Design, Setting and Participants: We conducted a cohort analysis of participants in the COMPASS-ND study with mild cognitive impairment (MCI), vascular MCI, Alzheimer's disease, mixed dementia, Parkinson's disease, frontotemporal dementia, and cognitively unimpaired (CU) controls., Measurements: Participants with neurodegenerative disease and CU controls were stratified by the presence (severity ≥1 on Neuropsychiatric Inventory Questionnaire) of either depressive symptoms alone, apathy symptoms alone, both symptoms, or neither. A neuropsychological battery evaluated executive function, verbal fluency, verbal learning, working memory, and visuospatial reasoning. Analysis of covariance was used to assess group differences with age, sex, and education as covariates., Results: Groups included depressive symptoms only (n = 70), apathy symptoms only (n = 52), both (n = 68), or neither (n = 262). The apathy and depression + apathy groups performed worse than the neither group on tests of working memory (t (312)  = -2.4, p = 0.02 and t (328)  = -3.8, p = 0.001, respectively) and visuospatial reasoning (t (301)  = -2.3, p = 0.02 and t (321)  = -2.6, p = 0.01, respectively). The depression, apathy, and depression + apathy groups demonstrated a similar degree of impairment on tests of executive function, processing speed, verbal fluency, and verbal learning when compared to participants without apathy or depression. Sex-stratified analyses revealed that compared to the male neither group, the male apathy and depression + apathy groups were impaired broadly across all cognitive domains except for working memory. Females with depression alone showed deficits on tests of executive function (t (166)  = 2.4, p = 0.01) and verbal learning (t (167)  = -4.3, p = 0.001) compared to the female neither group., Conclusions: This study demonstrated that in neurodegenerative diseases, apathy with or without depression in males was associated with broad cognitive impairments. In females, depression was associated with deficits in executive function and verbal learning. These findings highlight the importance of effectively treating apathy and depression across the spectrum of neurodegenerative disorders with the goal of optimizing neuropsychological outcomes., (© 2024 The Authors. International Journal of Geriatric Psychiatry published by John Wiley & Sons Ltd.)

Background: Understanding the relationship among changes in Clinical Dementia Rating (CDR), patient outcomes, and probability of progression is crucial for evaluating the long-term benefits of disease-modifying treatments. We examined associations among changes in Alzheimer's disease (AD) stages and outcomes that are important to patients and their care partners including activities of daily living (ADLs), geriatric depression, neuropsychiatric features, cognitive impairment, and the probabilities of being transitioned to a long-term care facility (i.e., institutionalization). We also estimated the total time spent at each stage and annual transition probabilities in AD., Methods: The study included participants with unimpaired cognition, mild cognitive impairment (MCI) due to AD, and mild, moderate, and severe AD dementia in the National Alzheimer's Coordinating Center (NACC) Uniform Data Set (UDS) database. The associations among change in AD stages and change in relevant outcomes were estimated using linear mixed models with random intercepts. The probability of transitioning to long-term care facilities was modeled using generalized estimating equations. The total length of time spent at AD stages and annual transition probabilities were estimated with multistate Markov models., Results: The estimated average time spent in each stage was 3.2 years in MCI due to AD and 2.2, 2.0, and 2.8 years for mild, moderate, and severe AD dementia, respectively. The annual probabilities of progressing from MCI to mild, moderate, and severe AD dementia were 20, 4, and 0.7%, respectively. The incremental change to the next stage of participants with unimpaired cognition, MCI, and mild, moderate, and severe AD dementia (to death) was 3.2, 20, 26.6, 31, and 25.3%, respectively. Changes in ADLs, neuropsychiatric features, and cognitive measures were greatest among participants who transitioned from MCI and mild AD dementia to more advanced stages. Participants with MCI and mild and moderate AD dementia had increasing odds of being transitioned to long-term care facilities over time during the follow-up period., Conclusions: The findings demonstrated that participants with early stages AD (MCI or mild dementia) were associated with the largest changes in clinical scale scores. Early detection, diagnosis, and intervention by disease-modifying therapies are required for delaying AD progression. Additionally, estimates of transition probabilities can inform future studies and health economic modeling., (© 2024. The Author(s).)

Introduction: We examined associations between the Clinical Dementia Rating Scale (CDR) and function (Functional Assessment Scale [FAS]), neuropsychiatric symptoms (Neuropsychiatric Inventory Questionnaire [NPI-Q]), and cognitive impairment in Alzheimer's disease (AD)., Methods: We used data from the National Alzheimer's Coordinating Center Uniform Data Set and defined cognitively unimpaired and AD stages using CDR-global., Results: Functional and neuropsychiatric symptoms occur as early as the mild cognitive impairment (MCI) phase. The adjusted lest square mean FAS (95% confidence interval [CI]) was lowest in cognitively unimpaired (3.88 [3.66, 4.11] to 5.01 [4.76, 5.26]) and higher with more advanced AD (MCI: 8.17 [6.92, 9.43] to 20.87 [19.53, 22.20]; mild: 18.54 [17.57, 19.50] to 28.13 [27.14, 29.12]; moderate: 26.01 [25.31, 26.70] to 29.42 [28.73, 30.10]). FAS and NPI-Q scores increased steeply with MCI (NPI-Q: 5.55 [4.89, 6.20] to 7.11 [6.43, 7.78]) and mild AD dementia (NPI-Q: 6.66 [5.72, 7.60] to 8.32 [7.32, 9.33])., Discussion: CDR-global staged AD by capturing differences in relevant outcomes along AD progression., Highlights: There were strong associations among CDR and the various outcomes relevant to healthcare providers, patients, and their care givers, such as activities of daily living.Overall, activities of daily living, neuropsychiatric symptoms, and cognitive function outcomes deteriorated over time and can be observed in early stages of AD (MCI or mild dementia).Our findings directly inform the current understanding of AD progression and can aid in care planning and benefit assessments of early AD interventions to delay the progression of AD to more advanced stages., Competing Interests: Author disclosures are available in the Supporting Information., (© 2024 Novo Nordisk A/S and The Authors. Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Background: Metformin has been suggested to reduce dementia risk; however, most epidemiologic studies have been limited by immortal time bias or confounding due to disease severity., Objectives: To investigate the association of metformin initiation with incident dementia using strategies that mitigate these important sources of bias., Methods: Residents of Ontario, Canada ≥66 years newly diagnosed with diabetes from January 1, 2008 to December 31, 2017 entered this retrospective population-based cohort. To consider the indication for metformin monotherapy initiation, people with hemoglobin A1c of 6.5%-8.0% and estimated glomerular filtration rate ≥45 mL/min/1.73 m 2 were selected. Using the landmark method to address immortal time bias, exposure was grouped into "metformin monotherapy initiation within 180 days after new diabetes diagnosis" or "no glucose-lowering medications within 180 days." To address disease latency, 1-year lag time was applied to the end of the 180-day landmark period. Incident dementia was defined using a validated algorithm for Alzheimer's disease and related dementias. Adjusted hazard ratios (aHR) and confidence intervals (CIs) were estimated from propensity-score weighted Cox proportional hazard models., Results: Over mean follow-up of 6.77 years from cohort entry, metformin initiation within 180 days after new diabetes diagnosis (N = 12,331; 978 events; 65,762 person-years) showed no association with dementia risk (aHR [95% CI] = 1.05 [0.96-1.15]), compared to delayed or no glucose-lowering medication initiation (N = 22,369; 1768 events; 117,415 person-years)., Conclusion: Early metformin initiation was not associated with incident dementia in older adults newly diagnosed with diabetes. The utility of metformin to prevent dementia was not supported., (© 2023 The Authors. Journal of Internal Medicine published by John Wiley & Sons Ltd on behalf of Association for Publication of The Journal of Internal Medicine.)

Objective: The Apathy in Dementia Methylphenidate Trial 2 (ADMET 2) found that methylphenidate was effective in treating apathy with a small-to-medium effect size but showed heterogeneity in response. We assessed clinical predictors of response to help determine individual likelihood of treatment benefit from methylphenidate., Design: Univariate and multivariate analyses of 22 clinical predictors of response chosen a priori., Setting: Data from the ADMET 2 randomized, placebo controlled multi-center clinical trial., Participants: Alzheimer's disease patients with clinically significant apathy., Measurements: Apathy assessed with the Neuropsychiatric Inventory apathy domain (NPI-A)., Results: In total, 177 participants (67% male, mean [SD] age 76.4 [7.9], mini-mental state examination 19.3 [4.8]) had 6-months follow up data. Six potential predictors met criteria for inclusion in multivariate modeling. Methylphenidate was more efficacious in participants without NPI anxiety (change in NPI-A -2.21, standard error [SE]:0.60) or agitation (-2.63, SE:0.68), prescribed cholinesterase inhibitors (ChEI) (-2.44, SE:0.62), between 52 and 72 years of age (-2.93, SE:1.05), had 73-80 mm Hg diastolic blood pressure (-2.43, SE: 1.03), and more functional impairment (-2.56, SE:1.16) as measured by the Alzheimer's Disease Cooperative Study Activities of Daily Living scale., Conclusion: Individuals who were not anxious or agitated, younger, prescribed a ChEI, with optimal (73-80 mm Hg) diastolic blood pressure, or having more impaired function were more likely to benefit from methylphenidate compared to placebo. Clinicians may preferentially consider methylphenidate for apathetic AD participants already prescribed a ChEI and without baseline anxiety or agitation., (Copyright © 2023 American Association for Geriatric Psychiatry. Published by Elsevier Inc. All rights reserved.)

Mild cognitive impairment (MCI) is a well-established prodromal stage of dementia (e.g., Alzheimer's disease) that is often accompanied by early signs of neurodegeneration. To facilitate a better characterization of the underlying pathophysiology, we assessed the available literature to evaluate potential fluid biomarkers in MCI. Peer-reviewed articles that measured cerebrospinal fluid (CSF) and/or peripheral biomarkers of neuronal injury (total-tau [T-tau], neurofilament light chain [NfL], heart-type fatty acid binding protein [HFABP], neuron-specific enolase, ubiquitin C-terminal hydrolase L1) and/or astroglial pathology (glial fibrillary acidic protein [GFAP], S100 calcium-binding protein B) in MCI and healthy controls were assessed. Group differences were summarized by standardized mean differences (SMDs) and 95% confidence intervals calculated using a random-effects model. Heterogeneity was quantified using I 2 . A total of 107 studies were included in the meta-analysis and 10 studies were qualitatively reviewed. In CSF, concentrations of NfL (SMD = 0.69 [0.56, 0.83]), GFAP (SMD = 0.41 [0.07, 0.75]), and HFABP (SMD = 0.57 [0.26, 0.89]) were elevated in MCI. In blood, increased concentrations of T-tau (SMD = 0.19 [0.09, 0.29]), NfL (SMD = 0.41 [0.32, 0.49]), and GFAP (SMD = 0.39 [0.23, 0.55]) were found in MCI. Heterogeneity that was identified in all comparisons was explored using meta-regression and subgroup analysis. Elevated NfL and GFAP can be detected in both CSF and peripheral blood. Monitoring these biomarkers in clinical settings may provide important insight into underlying neurodegenerative processes in MCI., Competing Interests: Declaration of Competing Interest KL declares no competing financial interests related to the present article. She is supported by the Bernick Chair in Geriatric Psychopharmacology and has received grants from the Canadian Institutes of Health Research [PJT 183584; PJT153079; PJ2 179753; CNA 163902], Alzheimer's Association Part the Cloud (PTC18-543823), the Alzheimer's Drug Discovery Foundation [GC-201808–2016354], and Weston Brain Institute [CT190002], as well as consulting fees from BioXcel Therapeutics, Bright Minds, Cerevel Therapeutics, Eisai Co. Ltd, Exciva, ICG Pharma, Jazz Pharmaceuticals, Kondor Pharma, H Lundbeck A/S, Merck, Novo Nordisk, Praxis Therapeutics, Sumitomo Pharma Co. Ltd and has stock options for Highmark Interactive. AG, LR, EM, KB, DG, and NH declare that they have no conflict of interest., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: This paper used data from the Apathy in Dementia Methylphenidate Trial 2 (NCT02346201) to conduct a planned cost consequence analysis to investigate whether treatment of apathy with methylphenidate is economically attractive., Methods: A total of 167 patients with clinically significant apathy randomized to either methylphenidate or placebo were included. The Resource Utilization in Dementia Lite instrument assessed resource utilization for the past 30 days and the EuroQol five dimension five level questionnaire assessed health utility at baseline, 3 months, and 6 months. Resources were converted to costs using standard sources and reported in 2021 USD. A repeated measures analysis of variance compared change in costs and utility over time between the treatment and placebo groups. A binary logistic regression was used to assess cost predictors., Results: Costs were not significantly different between groups whether the cost of methylphenidate was excluded ( F (2,330) = 0.626, η p 2 = 0.004, p = 0.535) or included ( F (2,330) = 0.629, η p 2 = 0.004, p = 0.534). Utility improved with methylphenidate treatment as there was a group by time interaction ( F (2,330) = 7.525, η p 2 = 0.044, p < 0.001)., Discussion: Results from this study indicated that there was no evidence for a difference in resource utilization costs between methylphenidate and placebo treatment. However, utility improved significantly over the 6-month follow-up period. These results can aid in decision-making to improve quality of life in patients with Alzheimer's disease while considering the burden on the healthcare system.

Objective: Debate continues regarding the use of self- versus informant-report to diagnose mild cognitive impairment (MCI) with studies reporting patients both overestimating and underestimating their abilities relative to informants. We assessed concordance of self- versus informant-report of cognitive decline with objective cognitive and functional performance in the participants of the preventing Alzheimer's dementia with cognitive remediation plus transcranial direct current stimulation in mild cognitive impairment and depression randomized controlled trial (PACt-MD)., Method: Three hundred six participants with MCI, and their informants, reported on cognitive decline; the participants also completed a comprehensive assessment of objective cognitive and functional performance. Based on the discrepancy between self- versus informant-report of cognitive decline, we grouped participants into categories of underestimators, congruent estimators, and overestimators., Results: Informant- but not self-reported cognitive decline significantly correlated with objective cognitive performance. There were 68 underestimators, 94 congruent estimators, and 144 overestimators. Underestimators had significantly lower objective cognitive performance and functional performance than congruent estimators and overestimators. Cognitive performance significantly predicted functional performance in all three groups, and the relationship between cognitive and functional performance was moderated by the discrepancy between self- and informant-report., Conclusions: We showed a poor concordance among self-report of cognitive decline and both informant-report of cognitive decline and cognitive performance in patients with MCI. Our findings highlight clinical and research value in the assessment and consideration of degree of discrepancy between self- and informant-reports of cognitive decline in MCI. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Background: Sulfonylureas are oral glucose-lowering medications positioned as a second-line therapy for type 2 diabetes. Evidence relating them to cognitive decline has been mixed. The objective was to determine whether sulfonylurea use was associated with a differential risk of dementia compared with dipeptidyl peptidase-4 (DPP4) inhibitor use., Methods: Using administrative data from residents in Ontario, Canada, adults aged ≥66 years who were new users of a sulfonylurea or a DPP4 inhibitor from June 14, 2011, to March 31, 2021 entered this population-based retrospective cohort study. Dementia was ascertained using a validated algorithm for Alzheimer's disease and related dementias. Propensity-score weighted Cox proportional hazards models were used to obtain adjusted hazard ratios (aHR) and confidence intervals (CI) for time to incident dementia. The observation window started at 1 year after cohort entry to mitigate protopathic bias due to delayed diagnosis. The primary analysis used an intention-to-treat exposure definition. A separate propensity-score weighted analysis was conducted to explore within-class differences in dementia risk among sulfonylurea new users selected from the primary cohort., Results: Among 107,806 DPP4 inhibitor new users and 37,030 sulfonylurea new users, sulfonylureas compared with DPP4 inhibitors were associated with a higher risk of dementia (18.4/1000 person-years; aHR [95% CI] = 1.09 [1.04-1.15]) over a mean follow-up of 4.82 years from cohort entry. Glyburide compared to gliclazide exhibited a higher dementia risk (aHR [95% CI] = 1.17 [1.03-1.32])., Conclusion: New use of a sulfonylurea especially glyburide was associated with a higher dementia risk compared with new use of a DPP4 inhibitor in older adults with diabetes., (© 2023 The Authors. Journal of the American Geriatrics Society published by Wiley Periodicals LLC on behalf of The American Geriatrics Society.)

Introduction: Methylphenidate has been shown to improve apathy in patients with Alzheimer's disease (AD). The authors evaluated the impact of methylphenidate on neuropsychiatric symptoms (NPS) of AD, excluding apathy, using data from the Apathy in Dementia Methylphenidate Trial 2 (ADMET 2) study., Methods: A secondary analysis was conducted on data from the ADMET 2 study to determine the effect of methylphenidate on Neuropsychiatric Inventory (NPI) scores outside of apathy. Caregiver scores were compared from baseline to month 6 in 199 participants receiving methylphenidate (20 mg/day) or placebo regarding the presence or absence of individual neuropsychiatric symptoms, emergence of new symptoms, and individual domain scores., Results: No clinically meaningful improvement was observed in any NPI domain, excluding apathy, in participants treated with methylphenidate compared to placebo after 6 months. A statistical difference between groups was appreciated in the domains of elation/euphoria ( P = 0.044) and appetite/eating disorders ( P = 0.014); however, these findings were not considered significant., Discussion: Methylphenidate is a selective agent for symptoms of apathy in patients with AD with no meaningful impact on other NPS. Findings from this secondary analysis are considered exploratory and multiple limitations should be considered when interpreting these results, including small sample size and use of a single questionnaire. HIGHLIGHTS: Methylphenidate was not associated with significant improvement on the Neuropsychiatric Inventory in domains outside of apathy.Methylphenidate did not show a statistically significant emergence of new neuropsychiatric symptoms (NPS) throughout the 6-month treatment period compared to placebo.Methylphenidate appears to be a highly selective agent for apathy in Alzheimer's disease, potentially supporting catecholaminergic dysfunction as the driving force behind this presentation of symptoms., Competing Interests: Dr. Brawman‐Mintzer receives grant funding from the National Institute on Aging, Merck, Alzheimer's Trials Research Institute and Alzheimer's Cooperative Trials Consortium, and the Department of Defense. Dr. Brawman‐Mintzer has served as a steering committee member for the Alzheimer's Disease Cooperative Study and as an associate steering committee member with the Alzheimer's Clinical Trials Consortium. Dr. Brawman‐Mintzer has received payment or honoraria from Medscape. Dr. Clark reports grants to her institution for clinical trials from Alzheon and Biogen. Dr. Lanctôt reports grants from Alzheimer's Association (PTC‐18‐543823, PTCG‐20‐ 700751), Alzheimer Society of Canada, Alzheimer's Drug Discovery Foundation (Grant No: 2016354), Canadian Institutes Health Research (PJ2‐179752, PJT‐183584), National Institute on Aging (R01AG046543), and Weston Brain Institute; consulting fees from BioXcel Therapeutics, Bright Minds, Cerevel Therapeutics, Eisai Co. Ltd, Exciva, ICG Pharma, Jazz Pharmaceuticals, Kondor Pharma, H Lundbeck A/S, Merck, Novo Nordisk, Praxis Therapeutics, Sumitomo Pharma Co. Ltd; stock options from Highmark Interactive outside the submitted work. Krista Lanctôt is the Bernick Chair in Geriatric Psychopharmacology of Sunnybrook Health Sciences Centre and University of Toronto's Temerty Faculty of Medicine. Dr. Lerner receives research grant support from the National Institutes of Health and National Institute on Aging (P30AG072959), Alzheimer's Clinical Trials Consortium, the Elisabeth S. Prentiss Foundation. He receives honoraria for consulting from Premier Inc (PINC AI Applied Sciences). He has received book royalties from Elsevier. He is a steering committee member of the Alzheimer's Clinical Trials Consortium. Dr. Jacobo Mintzer is a consultant and Governance Committee Member for AARP's Global Council on Brain Health and a consultant and Scientific Advisor for AARP's Staying Sharp Scientific Advisory Committee. He is a consultant for ACADIA, AiOmed, Corium, Exciva, Genentech (affiliate of F. Hoffmann‐La Roche Ltd), Ironshore Pharmaceuticals, Lundbeck, Praxis Bioresearch, and Sygnature Discovery. Dr. Mintzer is a Steering Committee Member for the Alzheimer's Clinical Trials Consortium, Alzheimer's Disease Cooperative Study, and the Elder Court. He is a Board Member for the Alzheimer's Association, SC Chapter and the Technology Accelerator Company as well as an Association Member of the International Psychogeriatric Association. He is a Scientific Advisory Board Member for Exciva and Advisory Board Member for ACADIA. Dr. Mintzer is a stockholder and the VP for Clinical Affairs for NeuroQuest, a majority owner of Biopharma Connex, and a majority partner for Recruitment Partners. Dr. Mintzer has received payment or honoraria from ACADIA. He is receiving support for specific clinical trials from Cerevel Therapeutics, LLC, Eisai Inc., Eli Lilly and Company, the Alzheimer's Association, the Alzheimer's Drug Discovery Foundation, the National Institute on Aging, the National Institutes of Health, and the National Endowment for the Arts. Dr. Mintzer has received support for attending meetings and/or travel from AARP Global Council on Brain Health (GCBH), AiOmed, and Alzheimer's Clinical Trials Consortium. Finally, he has served as a DSMB member for NAB‐It: Nabilone for Agitation Blinded Intervention Trial. Dr. Padala receives support for his time from the Department of Veterans Affairs and the National Institutes of Health. Dr. Perin received grant support for the present manuscript from the National Institutes of Health (Grant R01AG046543). Dr. Rosenberg has received research grants from the National Institute on Aging, Alzheimer's Association, Alzheimer's Clinical Trials Consortium, Alzheimer's Trials Research Institute and Alzheimer's Cooperative Trials Consortium, Richman Family Precision Medicine Center of Excellence on Alzheimer's Disease, Eisai, Functional Neuromodulation, and Lilly; honoraria from consulting for GLG, Leerink, Cerevel, Cerevance, Bioxcel, Sunovion, Acadia, Medalink, Novo Nordisk, Noble Insights, TwoLabs, Otsuka, Lundbeck, Biogen, MedaCorp, ExpertConnect, and HMP Global. He participates on an advisory board for Synaptogenix. He has received honoraria for presentations from Medscape and Neurology Week, and has received support for travel for a consultation meeting from Lundbeck. Dr. David Shade received grant support for the present manuscript from the National Institutes of Health. Dr. van Dyck serves as a scientific advisor for Eisai, Roche, Ono, and Cerevel and reports grant support for clinical trials from Biogen, Biohaven, Cerevel, Eisai, Eli Lilly, Genentech, Janssen, Roche, and UCB. He also participates as a member of the Medical and Scientific Advisory Group for the Alzheimer's Association. Dr. Porsteinsson reports DSMB membership fees from Acadia, Cadent, Cognitive Research Corp, Functional Neuromodulation, Neurim, Novartis, and Tetra Discovery Partners; consulting fees from Athira, Avanir, Biogen, BioXcel, Eisai, Grifols, IQVIA, Lundbeck, Maplight Therapeutics, Merck, ONO Pharmaceuticals, Pfizer, and Toyama; grants for clinical trials from the National Institute on Aging, National Institute on Mental Health, the Department of Defense, Alector, AstraZeneca, Athira, Avanir, Biogen, Biohaven, Cassava, Eisai, Eli Lilly, Genentech/Roche, Janssen, Merck, Novartis, Toyama, and Vaccinex outside the submitted work. Dr. Herrmann declares no conflicts of interest. Susie Sami declares no conflicts of interest. This research did not receive any specific grant from funding agencies in the public, commercial, or not‐for‐profit sectors. Author disclosures are available in the supporting information., (© 2023 The Authors. Alzheimer's & Dementia: Translational Research & Clinical Interventions published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Type 2 diabetes mellitus (T2DM) increases the risk of cognitive decline and dementia. Disruptions in the cytochrome P450-soluble epoxide hydrolase (CYP450-sEH) pathway have been reported in T2DM, obesity and cognitive impairment. We examine linoleic acid (LA)-derived CYP450-sEH oxylipins and cognition in T2DM and explore potential differences between obese and nonobese individuals. The study included 51 obese and 57 nonobese participants (mean age 63.0 ± 9.9, 49% women) with T2DM. Executive function was assessed using the Stroop Color-Word Interference Test, FAS-Verbal Fluency Test, Digit Symbol Substitution Test, and Trails Making Test-Part B. Verbal memory was assessed using the California Verbal Learning Test, second Edition. Four LA-derived oxylipins were analyzed by ultra-high-pressure-LC/MS, and the 12,13-dihydroxyoctadecamonoenoic acid (12,13-DiHOME) considered the main species of interest. Models controlled for age, sex, BMI, glycosylated hemoglobin A1c, diabetes duration, depression, hypertension, and education. The sEH-derived 12,13-DiHOME was associated with poorer executive function scores (F 1,98  = 7.513, P = 0.007). The CYP450-derived 12(13)-epoxyoctadecamonoenoic acid (12(13)-EpOME) was associated with poorer executive function and verbal memory scores (F 1,98  = 7.222, P = 0.008 and F 1,98  = 4.621, P = 0.034, respectively). There were interactions between obesity and the 12,13-DiHOME/12(13)-EpOME ratio (F 1,97  = 5.498, P = 0.021) and between obesity and 9(10)-epoxyoctadecamonoenoic acid (9(10)-EpOME) concentrations (F 1,97  = 4.126, P = 0.045), predicting executive function such that relationships were stronger in obese individuals. These findings suggest that the CYP450-sEH pathway as a potential therapeutic target for cognitive decline in T2DM. For some markers, relationships may be obesity dependent., Competing Interests: Conflict of interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests. B. R. S. of Sunnybrook Health Sciences Centre is funded by the University of Toronto as the Novo Nordisk Research Chair in Equitable Care of Diabetes and Related Conditions. J. G. of Sunnybrook Health Sciences Centre received speaker honoraria from Abbott, Ascencia, Amgen, Astra Zeneca, Boehringer, Dexcom, Eli Lilly, HLS, Insulet, Janssen, Merck, Novo Nordisk, and Sanofi. J. G. also performs advisory services to Abbott, Amgen, Astra Zeneca, Boehringer, Dexcom, Eli Lilly, Janssen, Merck, Novo Nordisk, and Sanofi. A. A. of Sunnybrook Health Sciences Centre received speaker honoraria from Solutions Event Management. I. J. H. of Sunnybrook Health Sciences Centre received speaker honoraria from Dexcom, Abbott, Sanofi, and Boehringer Ingelheim. These roles are unrelated to the present work. The other authors declare no conflicts of interest., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Agitation is a disabling neuropsychiatric symptom of dementia. Pro re nata (PRN) injections of psychotropics can be administered for severe acute agitation, but little is known about the frequency of their actual use., Objective: Characterize actual use of injectable PRN psychotropics for severe acute agitation in Canadian long-term care (LTC) residents with dementia and compare use before and during the COVID-19 pandemic., Methods: Residents from two Canadian LTC facilities with orders for PRN haloperidol, olanzapine, or lorazepam between January 1, 2018- May 1, 2019 (i.e., pre-COVID-19) and January 1, 2020- May 1, 2021 (i.e., COVID-19) were identified. Electronic medical records were reviewed to document PRN injections of psychotropic medications and collect data on reason and demographic characteristics. Descriptive statistics were used to characterize frequency, dose, and indications of use, and multivariate regression models were used to compare use between time periods., Results: Of the 250 residents, 45 of 103 (44%) people in the pre-COVID-19 period and 85 of 147 (58%) people in the COVID-19 period with standing orders for PRN psychotropics received ≥1 injections. Haloperidol was the most frequently used agent in both time periods (74% (155/209 injections) pre-COVID-19; 81% (323/398 injections) during COVID-19). Residents in the COVID-19 period were almost two times more likely to receive injections compared with those in the pre-COVID-19 period (odds ratio = 1.96; 95% CI = 1.15-3.34; p  = 0.01)., Conclusion: Our results suggest that use of PRN injections increased in LTC during the pandemic and contribute to the mounting evidence that agitation worsened during that time., Competing Interests: Krista L. Lanctôt reports consulting fees from BioXcel Therapeutics, Inc., Bright Minds, Cerevel Therapeutics, Eisai Co. Ltd, Exciva, ICG Pharma, Jazz Pharmaceuticals, Kondor Pharma, H Lundbeck A/S, Merck, Novo Nordisk, Praxis Therapeutics, and Sumitomo Pharma Co. Ltd; stock options from Highmark Interactive., (© 2023 –The authors. Published by IOS Press.)

Background: The Alzheimer's Disease Assessment Scale Cognitive Subscale (ADAS-Cog) is used to assess decline in memory, language, and praxis in Alzheimer's disease (AD)., Methods: A latent state-trait model with autoregressive effects was used to determine how much of the ADAS-Cog item measurement was reliable, and of that, how much of the information was occasion specific (state) versus consistent (trait or accumulated from one visit to the next)., Results: Participants with mild AD ( n = 341) were assessed four times over 24 months. Praxis items were generally unreliable as were some memory items. Language items were generally the most reliable, and this increased over time. Only two ADAS-Cog items showed reliability >0.70 at all four assessments, word recall (memory) and naming (language). Of the reliable information, language items exhibited greater consistency (63.4% to 88.2%) than occasion specificity, and of the consistent information, language items tended to reflect effects of AD progression that accumulated from one visit to the next (35.5% to 45.3%). In contrast, reliable information from praxis items tended to come from trait information. The reliable information in the memory items reflected more consistent than occasion-specific information, but they varied between items in the relative amounts of trait versus accumulated effects., Conclusions: Although the ADAS-Cog was designed to track cognitive decline, most items were unreliable, and each item captured different amounts of information related to occasion-specific, trait, and accumulated effects of AD over time. These latent properties complicate the interpretation of trends seen in ordinary statistical analyses of trials and other clinical studies with repeated ADAS-Cog item measures., Highlights: Studies have described unfavorable psychometric properties of the Alzheimer's Disease Assessment Scale Cognitive Subscale (ADAS-Cog), bringing into question its ability to track changes in cognition uniformly over time. There remains a need to estimate how much of the ADAS-Cog measurement is reliable, of that how much is occasion specific versus consistent, and of the consistent information, how much represents enduring traits versus autoregressive effects (i.e., effects of Alzheimer's disease [AD] progression carried over from one assessment to the next).A latent state-trait model with autoregressive effects in mild AD found most items to be unreliable, and each item to capture different amounts of occasion-specific, trait, and autoregressive information. Language items, specifically, naming and the memory item word recall, were the most reliable.Psychometric idiosyncrasies of individual items complicate the interpretation of their summed score, biasing ordinary statistical analyses of repeated measures in mild AD. Future studies should consider item trajectories individually., Competing Interests: All authors have no actual or potential competing of interests to declares. Author disclosures are available in the supporting information., (© 2023 The Authors. Alzheimer's & Dementia: Translational Research & Clinical Interventions published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Anodal transcranial direct current stimulation (tDCS) can improve cognition in healthy older adults, those with Alzheimer's disease (AD) and mild cognitive impairment (MCI), albeit with considerable variability in response. This systematic review identifies interindividual factors that may influence tDCS outcomes in older individuals with or without cognitive impairment. Peer-reviewed articles were included if they assessed whether cognitive outcomes (memory or global cognition) after tDCS were associated with pre-intervention factors in healthy older adults or individuals with AD/MCI. We identified eight factors that may affect cognitive outcomes after tDCS. Improved tDCS outcomes were predicted by lower baseline cognitive function when tDCS was combined with a co-intervention (but not when used alone). Preserved brain structure and better baseline functional connectivity, genetic polymorphisms, and the use of concomitant medications may predict better tDCS outcomes, but further research is warranted. tDCS outcomes were not consistently associated with age, cognitive reserve, sex, and AD risk factors. Accounting for individual differences in baseline cognition, particularly for combined interventions, may thus maximize the therapeutic potential of tDCS., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Limited studies have investigated the effects of cannabis use on driving among older adults, who represent the fastest growing segment of drivers globally. We conducted a systematic review and meta-analysis to evaluate the effects of delta-9-tetrahydrocannabinol (THC) exposure on risks of (1) motor vehicle collisions (MVC) and (2) culpability for MVCs among adults 50 years and older. Three reviewers screened 7022 studies identified through MEDLINE, EMBASE, CENTRAL, and PsycINFO. Odds Ratios (OR) were calculated using the Mantel-Haenszel method in Review Manager 5.4.1. Heterogeneity was assessed using I 2 . The National Heart, Lung, and Blood Institute tool was used to assess the quality of each study. Seven cross-sectional studies were included. Three studies evaluated culpability while four evaluated MVC. The pooled risk of MVC was not significantly different between THC-positive and THC-negative older drivers (OR, 95% CI 1.15 [0.40, 3.31]; I 2 = 72%). In culpability studies, THC exposure was not significantly associated with an increased risk of being culpable for MVC among adults over the age of 50 (OR, 95% CI 1.24 [0.95, 1.61]; I 2 = 0%). Inspection of funnel plots did not indicate publication bias. Our review found that THC exposure was not associated with MVC involvement nor with culpability for MVCs.

Objective: Type 2 diabetes (T2D) increases dementia risk, but clear evidence to recommend interventions that can mitigate that risk remains lacking. This population-based retrospective cohort study aimed to determine whether new use of sodium-glucose cotransporter 2 (SGLT2) inhibitors compared with dipeptidyl peptidase 4 (DPP-4) inhibitors was associated with lower dementia risk., Research Design and Methods: Ontario residents aged ≥66 years who were new users of an SGLT2 inhibitor or a DPP-4 inhibitor from 1 July 2016 to 31 March 2021 entered the cohort. Incident dementia was identified using a validated algorithm for Alzheimer's disease and related dementias. Propensity score-weighted Cox proportional hazards models were used to obtain adjusted hazard ratios (aHR) and CIs for time to incident dementia. To address reverse causality and disease latency, the observation window started at 1-year lag time from cohort entry. The primary analysis followed intention-to-treat exposure definition, and a secondary as-treated analysis was performed., Results: Among 106,903 individuals, SGLT2 inhibitors compared with DPP-4 inhibitors were associated with lower risk of dementia (14.2/1,000 person-years; aHR 0.80 [95% CI 0.71-0.89]) over a mean follow-up of 2.80 years from cohort entry. When stratified by different SGLT2 inhibitors, dapagliflozin exhibited the lowest risk (aHR 0.67 [95% CI 0.53-0.84]), followed by empagliflozin (aHR 0.78 [95% CI 0.69-0.89]), whereas canagliflozin showed no association (aHR 0.96 [95% CI 0.80-1.16]). The as-treated analysis observed a larger association (aHR 0.66 [95% CI 0.57-0.76]) than the intention-to-treat analysis., Conclusions: SGLT2 inhibitors showed an association with lower dementia risk in older people with T2D. Randomized controlled trials are warranted., (© 2023 by the American Diabetes Association.)

Objectives: This narrative review describes the clinical features of apathy and depression in individuals with neurocognitive disorders (NCDs), with the goal of differentiating the two syndromes on the basis of clinical presentation, diagnostic criteria, neuropathological features, and contrasting responses to treatments., Methods: Literature was identified using PubMed, with search terms to capture medical conditions of interest; additional references were also included based on our collective experience and knowledge of the literature., Results: Evidence from current literature supports the distinction between the two disorders; apathy and depression occur with varying prevalence in individuals with NCDs, pose different risks of progression to dementia, and have distinct, if overlapping, neurobiological underpinnings. Although apathy is a distinct neuropsychiatric syndrome, distinguishing apathy from depression can be challenging, as both conditions may occur concurrently and share several overlapping features. Apathy is associated with unfavorable outcomes, especially those with neurodegenerative etiologies (e.g., Alzheimer's disease) and is associated with an increased burden for both patients and caregivers. Diagnosing apathy is important not only to serve as the basis for appropriate treatment, but also for the development of novel targeted interventions for this condition. Although there are currently no approved pharmacologic treatments for apathy, the research described in this review supports apathy as a distinct neuropsychiatric condition that warrants specific treatments aimed at alleviating patient disability., Conclusions: Despite differences between these disorders, both apathy and depression pose significant challenges to patients, their families, and caregivers; better diagnostics are needed to develop more tailored treatment and support., (© 2023 The Authors. International Journal of Geriatric Psychiatry published by John Wiley & Sons Ltd.)

Background Cerebral small vessel disease is associated with higher ratios of soluble-epoxide hydrolase derived linoleic acid diols (12,13-dihydroxyoctadecenoic acid [DiHOME] and 9,10-DiHOME) to their parent epoxides (12(13)-epoxyoctadecenoic acid [EpOME] and 9(10)-EpOME); however, the relationship has not yet been examined in stroke. Methods and Results Participants with mild to moderate small vessel stroke or large vessel stroke were selected based on clinical and imaging criteria. Metabolites were quantified by ultra-high-performance liquid chromatography-mass spectrometry. Volumes of stroke, lacunes, white matter hyperintensities, magnetic resonance imaging visible perivascular spaces, and free water diffusion were quantified from structural and diffusion magnetic resonance imaging (3 Tesla). Adjusted linear regression models were used for analysis. Compared with participants with large vessel stroke (n=30), participants with small vessel stroke (n=50) had a higher 12,13-DiHOME/12(13)-EpOME ratio (β=0.251, P =0.023). The 12,13-DiHOME/12(13)-EpOME ratio was associated with more lacunes (β=0.266, P =0.028) but not with large vessel stroke volumes. Ratios of 12,13-DiHOME/12(13)-EpOME and 9,10-DiHOME/9(10)-EpOME were associated with greater volumes of white matter hyperintensities (β=0.364, P <0.001; β=0.362, P <0.001) and white matter MRI-visible perivascular spaces (β=0.302, P =0.011; β=0.314, P =0.006). In small vessel stroke, the 12,13-DiHOME/12(13)-EpOME ratio was associated with higher white matter free water diffusion (β=0.439, P =0.016), which was specific to the temporal lobe in exploratory regional analyses. The 9,10-DiHOME/9(10)-EpOME ratio was associated with temporal lobe atrophy (β=-0.277, P =0.031). Conclusions Linoleic acid markers of cytochrome P450/soluble-epoxide hydrolase activity were associated with small versus large vessel stroke, with small vessel disease markers consistent with blood brain barrier and neurovascular-glial disruption, and temporal lobe atrophy. The findings may indicate a novel modifiable risk factor for small vessel disease and related neurodegeneration.

Background: Recent therapeutic approaches for Alzheimer's disease (AD) have had limited success. Considering the association of neuroinflammation with AD symptoms as demonstrated in multiple studies, assessment of the clinical efficacy of molecules that reduce systemic or brain inflammation is warranted., Objective: This clinical trial assessed whether boswellic acids can improve cognitive and neuropsychiatric symptoms while reducing inflammation in AD patients., Methods: A double-blind, placebo-controlled, study was conducted on 85 AD patients randomized to boswellic acids (K-Vie™ as the main ingredient in Memowell™) or placebo for 6 months. Clinical Dementia Rating-Sum of Boxes (CDR-SOB) and Mini-Mental State Examination (MMSE) scores were compared to baseline and between groups and constituted the co-primary clinical efficacy endpoints. Secondary outcomes included neuropsychiatric assessment (Neuropsychiatric Inventory-Questionnaire, NPI-Q) and assessment of AD and inflammation biomarkers., Results: Patients on K-Vie™ showed a 3.1- and 1.6-unit improvement in MMSE and CDR-SOB scores, respectively, when compared to patients on placebo. NPI-Q analysis revealed significant improvement in the K-Vie™ but not in the placebo group. Only mild gastrointestinal side effects were reported in a few patients. Patients on K-Vie™ showed improvement in plasma AD biomarkers and reduction of key inflammatory cytokines including IL-6 and TNF., Conclusion: Our results support the positive cognitive effects of boswellic acids by reducing the systemic inflammation.

Background: Many individuals with Alzheimer's disease (AD) are dependent on nonprofessional care partners. Providing informal care can result in emotional, physical, and financial burdens; however, there is a need for a better understanding of the impact of AD on care partners to support the clinical and economic assessment of potential new treatments., Objective: We conducted a literature review to evaluate the burden experienced by care partners of individuals with AD., Methods: Electronic screening and supplementary searches identified studies published from 2011 to 2022 describing the association between AD and the quality of life (QoL) and physical health of care partners, and the economic or financial burden of AD., Results: Following electronic screening, 62, 25, and 39 studies were included on care partner burden, cost, and healthcare resource use in AD, respectively. Supplementary searches identified an additional 32 studies, resulting in 149 unique studies. These studies showed that care partners of individuals with AD report moderate to severe burden. Higher burden and lower QoL were observed in those caring for individuals with more severe AD. Care partners of individuals with AD experience higher burden, lower QoL, and higher levels of stress, depression, and anxiety than those without caring responsibilities. Informal care costs increased with AD severity and accounted for the greatest proportion of overall societal cost., Conclusions: Care partners of individuals with AD experience emotional and economic burden, which increases with AD severity. These impacts should be quantified comprehensively in future studies and captured in economic evaluations of AD interventions.

Introduction: Mild behavioral impairment (MBI) is characterized by later-life emergence of neuropsychiatric symptoms. Investigating its relationship with progression to Alzheimer's disease (AD) would provide insight on its importance as a predictor of AD., Methods: Cognitively normal participants (N = 11,372) from the National Alzheimer's Coordinating Center were stratified by MBI status, using the Neuropsychiatric Inventory-Questionnaire. We investigated whether MBI and its domains were predictors of progression to clinically-diagnosed AD. MBI as a predictor of progression to neuropathology-confirmed AD was also investigated in those with neuropathological data., Results: Six percent (N = 671) of participants progressed to AD. MBI (N = 2765) was a significant predictor of progression to clinically-diagnosed (hazard ratio [HR] = 1.75) and neuropathology-confirmed AD (HR = 1.59). MBI domains were also associated with clinically-diagnosed AD, with psychosis having the greatest effect (HR = 6.49)., Discussion: These findings support the biological underpinnings of MBI, emphasizing the importance of later life behavioral changes in dementia detection and prognostication., (© 2021 the Alzheimer's Association.)

Objectives: Previous studies regarding the relationship between depression and Alzheimer's neuropathology in older adults without dementia have reported conflicting findings. This study examined whether depression is associated with Alzheimer's neuropathology and whether sex moderates these relationships., Methods: This is a cross-sectional study of older adults without dementia (normal cognition or mild cognitive impairment, age 50+; CDR ≤ 0.5) who had autopsy within 1 year of their last clinic visit in the National Alzheimer's Coordinating Center database (2005-2020). Logistic regression models were fitted to determine if a recent or remote history of depression was associated with amyloid spread beyond the neocortex measured by modified Thal phase score, density of amyloid plaques measured by CERAD score or tau neuropathology measured by modified Braak score. A moderator analysis was performed to determine if any of these associations were moderated by sex., Results: This study included 407 participants (96 Thal, 405 Braak, and 406 CERAD). Those who had recently active depression (within previous 2 years) but not remote depression only were more likely to have higher Thal phase score compared to those without a history of depression (OR = 3.74; 95% CI, 1.15-12.17; p = 0.028). Sex did not moderate this association. No significant associations between recent depression and Braak or CERAD scores were observed., Conclusion: Our findings indicate that the association between late life depression and Alzheimer's neuropathology is associated with spread of amyloid pathology beyond the neocortex to include allocortical and subcortical regions critical for regulation of mood and motivated behavior., (© 2022 John Wiley & Sons Ltd.)

Introduction: At present, no pharmacological interventions have been approved for the treatment of agitation in Alzheimer's disease (AD), an important neuropsychiatric symptom that has been linked to increased mortality and greater caregiver burden. Antipsychotics offer some benefit, but increase the risk of adverse events such as falls, extrapyramidal symptoms, stroke, and mortality. Over the past 10 years, several new and repurposed medications have shown promise for treating AD-associated agitation., Areas Covered: We review the risks and benefits of emerging therapies for agitation in AD, which include newer atypical antipsychotics, selective serotonin reuptake inhibitors, cannabinoids, and dextromethorphan combination products. Other drugs such as mirtazapine, prazosin, and lithium are also discussed. Clinicaltrials.gov, PubMed/MEDLINE, EMBASE and Cochrane Central databases were searched for relevant studies from 1 January 2012 to 1 May 2022., Expert Opinion: At the present time, there are no pharmacological interventions for the treatment of agitation in AD whose benefits clearly outweigh their potential safety concerns. Therefore, management of agitation in AD should primarily be based on non-pharmacological approaches. When medications are considered necessary, they should only be initiated with the caregiver's appreciation of their risks and benefits and with careful and ongoing assessment of their safety.

Background: (1) Sleep disorders are prevalent in coronary artery disease (CAD) patients and predict cardiac events and prognosis. While increased oxidative stress (OS) has been associated with sleep disorders, less is known about its relationship with sleep quality. Similarly, little is known of how this relationship might change with exercise, which can improve sleep quality. Factors of sleep quality, such as sleep duration and disturbances, are also important as they predict cardiovascular diseases better than a global score alone. This study investigated whether OS was associated with self-rated sleep quality and its factors before and after completing a 24-week exercise intervention. (2) Methods: CAD patients undergoing an exercise program were recruited. OS was measured at baseline by the concentrations of early- (lipid hydroperoxides, LPH) and late-stage (8-isoprostane, 8-ISO) lipid peroxidation products and their ratio. Sleep quality was measured by the self-reported Pittsburgh Sleep Quality Index (PSQI) instrument at baseline and termination. Three sleep factors-perceived sleep quality, sleep efficiency, and daily disturbances-were derived from the PSQI. (3) Results: Among CAD patients ( n = 113, 85.0% male, age = 63.7 ± 6.4 years, global PSQI = 5.8 ± 4.0), those with poor sleep (PSQI ≥ 5) had higher baseline 8-ISO levels (F(1, 111) = 6.212, p = 0.014, η p 2 = 0.053) compared to those with normal sleep. Concentrations of LPH (F(1, 105) = 0.569, p = 0.453, η p 2 = 0.005) and 8-ISO/LPH ratios (F(1, 105) = 2.173, p = 0.143, η p 2 = 0.020) did not differ between those with poor sleep and normal sleep. Among factors, perceived sleep quality was associated with 8-ISO and 8-ISO/LPH, and daily disturbances were associated with 8-ISO. (4) Conclusions: A marker of late-stage lipid peroxidation is elevated in CAD patients with poor sleep and associated with daily disturbances, but not with other factors or with sleep quality and its factors after exercise intervention., Competing Interests: Krista L. Lanctôt is a consultant or advisory board member for BioXcel Therapeutics, Bright Minds, Cerevel Therapeutics, Eisai Co., Ltd., Exciva, ICG Pharma, Jazz Pharmaceuticals, Kondor Pharma, H Lundbeck A/S, Merck Sharp Dohme, Novo Nordisk, Praxis Therapeutics, and Sumitomo Pharma Co. Ltd. and has stock options for Highmark Interactive.

Investigating effects of aging on neurophysiological mechanisms underlying working memory provides a better understanding of potential targets for brain intervention to prevent cognitive decline. Theta-gamma coupling (TGC) indexes the ability to order information processed during working memory tasks. Frontal theta event-related synchronization (ERS) and parietal alpha event-related desynchronization (ERD) index cognitive control and interference inhibition, respectively. Relative contributions of TGC, theta ERS, and alpha ERD in relation to stimulus presentation are not characterized. Further, differential effect of normal aging on pre- or post-stimulus processes is unknown. Electroencephalography was recorded in 66 younger and 41 older healthy participants while performing 3-back working memory task. We assessed relationships between 3-back task performance and each of post-stimulus TGC, pre-stimulus parietal alpha ERD, and pre-stimulus frontal theta ERS in each age group. While older adults performed worse on 3-back task than younger adults, TGC, alpha ERD, or theta ERS did not differ between the two groups. TGC was positively associated with 3-back performance in both age groups; pre-stimulus alpha ERD was associated with performance among younger adults; and pre-stimulus theta ERS was not associated with performance in either group. Our findings suggest that both pre-stimulus interference inhibition and post-stimulus ordering of information are important for working memory in younger adults. In contrast, performance in older adults appears to depend only on post-stimulus ordering of information. These specific contributions of neurophysiological resources may explain the poorer performance of older adults and suggest different targets to enhance working memory in age groups., (© 2022. The Author(s), under exclusive licence to American Aging Association.)

Objectives: To compare the prevalence of select cardiovascular risk factors (CVRFs) in patients with mild cognitive impairment (MCI) versus lifetime history of major depression disorder (MDD) and a normal comparison group using baseline data from the Prevention of Alzheimer's Dementia with Cognitive Remediation plus Transcranial Direct Current Stimulation (PACt-MD) study., Design: Baseline data from a multi-centered intervention study of older adults with MCI, history of MDD, or combined MCI and history of MDD (PACt-MD) were analyzed., Setting: Community-based multi-centered study based in Toronto across 5 academic sites., Participants: Older adults with MCI, history of MDD, or combined MCI and history of MDD and healthy controls., Measurements: We examined the baseline distribution of smoking, hypertension and diabetes in three groups of participants aged 60+ years in the PACt-MD cohort study: MCI (n = 278), MDD (n = 95), and healthy older controls (n = 81). Generalized linear models were fitted to study the effect of CVRFs on MCI and MDD as well as neuropsychological composite scores., Results: A higher odds of hypertension among the MCI cohort compared to healthy controls (p < .05) was noted in unadjusted analysis. Statistical significance level was lost on adjusting for age, sex and education (p > .05). A history of hypertension was associated with lower performance in composite executive function (p < .05) and overall composite neuropsychological test score (p < .05) among a pooled cohort with MCI or MDD., Conclusions: This study reinforces the importance of treating modifiable CVRFs, specifically hypertension, as a means of mitigating cognitive decline in patients with at-risk cognitive conditions.

Theta-gamma coupling (TGC) is a neurophysiologic mechanism that supports working memory (WM). TGC is associated with N-back performance, a WM task. Similar to TGC, theta and alpha event-related synchronization (ERS) and desynchronization (ERD) are also associated with WM. Few studies have examined the longitudinal relationship between WM performance and TGC, ERS, or ERD. This study aimed to determine if changes in WM performance are associated with changes in TGC (primary aim), as well as theta and alpha ERS or ERD over 6 to 12 weeks. Participants included 62 individuals aged 60 and older with no neuropsychiatric conditions or with remitted Major Depressive Disorder (MDD) and no cognitive disorders. TGC, ERS, and ERD were assessed using electroencephalography (EEG) during the N-back task (3-back condition). There was an association between changes in 3-back performance and changes in TGC, alpha ERD and ERS, and theta ERS in the control group. In contrast, there was only a significant association between changes in 3-back performance and changes in TGC in the subgroup with remitted MDD. Our results suggest that the relationship between WM performance and TGC is stable over time, while this is not the case for changes in theta and alpha ERS and ERD., (© The Author(s) 2021. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Neuropsychiatric symptoms (NPS) are common in individuals with Alzheimer's disease (AD) dementia, but substantial heterogeneity exists in the manifestation of NPS. Sex differences may explain this clinical variability. We aimed to investigate the sex differences in the prevalence and severity of NPS in AD dementia., Methods: Literature searches were conducted in Embase, MEDLINE/PubMed, Web of Science Core Collection, Cochrane Central Register of Controlled Trials, PsycINFO, and Google Scholar from inception to February 2021. Study selection, data extraction, and quality assessment were conducted in duplicate. Effect sizes were calculated as odds ratios (OR) for NPS prevalence and Hedges' g for NPS severity. Data were pooled using random-effects models. Sources of heterogeneity were examined using meta-regression analyses., Results: Sixty-two studies were eligible representing 21,554 patients (61.2% females). The majority of the included studies had an overall rating of fair quality (71.0%), with ten studies of good quality (16.1%) and eight studies of poor quality (12.9%). There was no sex difference in the presence of any NPS (k = 4, OR = 1.35 [95% confidence interval 0.78, 2.35]) and overall NPS severity (k = 13, g = 0.04 [- 0.04, 0.12]). Regarding specific symptoms, female sex was associated with more prevalent depressive symptoms (k = 20, OR = 1.60 [1.28, 1.98]), psychotic symptoms (general psychosis k = 4, OR = 1.62 [1.12, 2.33]; delusions k = 12, OR = 1.56 [1.28, 1.89]), and aberrant motor behavior (k = 6, OR = 1.47 [1.09, 1.98]). In addition, female sex was related to more severe depressive symptoms (k = 16, g = 0.24 [0.14, 0.34]), delusions (k = 10, g = 0.19 [0.04, 0.34]), and aberrant motor behavior (k = 9, g = 0.17 [0.08, 0.26]), while apathy was more severe among males compared to females (k = 11, g = - 0.10 [- 0.18, - 0.01]). There was no association between sex and the prevalence and severity of agitation, anxiety, disinhibition, eating behavior, euphoria, hallucinations, irritability, and sleep disturbances. Meta-regression analyses revealed no consistent association between the effect sizes across studies and method of NPS assessment and demographic and clinical characteristics., Discussion: Female sex was associated with a higher prevalence and greater severity of several specific NPS, while male sex was associated with more severe apathy. While more research is needed into factors underlying these sex differences, our findings may guide tailored treatment approaches of NPS in AD dementia., (© 2022. The Author(s).)

Introduction: Studies suggest associations between proton pump inhibitors (PPIs) and dementia risk; however, many neither considered histamine-2 receptor antagonists (H2RAs) nor baseline cognitive status., Methods: Participants (National Alzheimer's Coordinating Center Database; 2005-2021) using a PPI or H2RA were compared. Covariate-adjusted Cox regression was used to estimate hazard ratios (HR) for progression from normal cognition to mild cognitive impairment (MCI), and from MCI to dementia over 5 years. In a propensity-score-matched subsample of mild-moderate Alzheimer's disease (AD), mixed-effects negative binomial regression was used to estimate decline in delayed recall memory., Results: Compared to PPI, H2RA use was associated with earlier progression from MCI to dementia (HR = 1.40 [1.09-1.81]; n  = 1701), and with faster memory decline in AD over time (rate ratio = 0.76 [0.64-0.92]; n  = 628), but not with progression from normal cognition to MCI (HR = 0.94 [0.71-1.24]; n  = 2784)., Discussion: Compared to PPIs, H2RAs were associated with cognitive decline, specifically among people with pre-existing cognitive impairment., Competing Interests: The authors declare no conflicts of interest., (© 2022 The Authors. Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring published by Wiley Periodicals, LLC on behalf of Alzheimer's Association.)

Background: Increasing evidence implicates oxidative stress (OS) in Alzheimer disease (AD) and mild cognitive impairment (MCI). Depletion of the brain antioxidant glutathione (GSH) may be important in OS-mediated neurodegeneration, though studies of post-mortem brain GSH changes in AD have been inconclusive. Recent in vivo measurements of the brain and blood GSH may shed light on GSH changes earlier in the disease., Aim: To quantitatively review in vivo GSH in AD and MCI compared to healthy controls (HC) using meta-analyses., Method: Studies with in vivo brain or blood GSH levels in MCI or AD with a HC group were identified using MEDLINE, PsychInfo, and Embase (1947-June 2020). Standardized mean differences (SMD) and 95% confidence intervals (CI) were calculated for outcomes using random effects models. Outcome measures included brain GSH (Meshcher-Garwood Point Resolved Spectroscopy (MEGA-PRESS) versus non-MEGA-PRESS) and blood GSH (intracellular versus extracellular) in AD and MCI. The Q statistic and Egger's test were used to assess heterogeneity and risk of publication bias, respectively., Results: For brain GSH, 4 AD (AD=135, HC=223) and 4 MCI (MCI=213, HC=211) studies were included. For blood GSH, 26 AD (AD=1203, HC=1135) and 7 MCI (MCI=434, HC=408) studies were included. Brain GSH overall did not differ in AD or MCI compared to HC; however, the subgroup of studies using MEGA-PRESS reported lower brain GSH in AD (SMD [95%CI] -1.45 [-1.83, -1.06], p<0.001) and MCI (-1.15 [-1.71, -0.59], z=4.0, p<0.001). AD had lower intracellular and extracellular blood GSH overall (-0.87 [-1. 30, -0.44], z=3.96, p<0.001). In a subgroup analysis, intracellular GSH was lower in MCI (-0.66 [-1.11, -0.21], p=0.025). Heterogeneity was observed throughout (I 2 >85%) and not fully accounted by subgroup analysis. Egger's test indicated risk of publication bias., Conclusion: Blood intracellular GSH decrease is seen in MCI, while both intra- and extracellular decreases were seen in AD. Brain GSH is decreased in AD and MCI in subgroup analysis. Potential bias and heterogeneity suggest the need for measurement standardization and additional studies to explore sources of heterogeneity., (© 2022. The Author(s).)

People with type 2 diabetes mellitus (T2DM) are at increased risk of mild cognitive impairment and dementia. Systemic inflammation has been proposed as a common risk factor. This study aimed to summarize the clinical data pertaining to peripheral blood inflammatory markers. We identified original peer-reviewed articles reporting blood inflammatory marker concentrations in groups of people with a T2DM diagnosis who have cognitive impairment (CI; including mild cognitive impairment, Alzheimer's disease, vascular cognitive impairment) vs. normal cognition (NC). Between-group standardized mean differences (SMD) were summarized in random effects meta-analyses. From 2108 records, data were combined quantitatively from 40 studies. Concentrations of interleukin-6 (IL-6; N CI /N NC  = 934/3154, SMD 0.74 95% confidence interval [0.07, 1.42], Z 5  = 2.15, p = 0.03; I 2  = 98.08%), C-reactive protein (CRP; N CI /N NC  = 1610/4363, SMD 0.80 [0.50, 1.11], Z 14  = 5.25, p < 0.01; I 2  = 94.59%), soluble vascular cell adhesion molecule-1 (sVCAM-1; N CI /N NC  = 104/1063, SMD 1.64 95% confidence interval [0.21, 3.07], Z 2  = 2.25, p = 0.02; I 2  = 95.19%), and advanced glycation end products (AGEs; N CI /N NC  = 227/317, SMD 0.84 95% confidence interval [0.41, 1.27], Z 2  = 3.82, p < 0.01; I 2  = 81.07%) were higher among CI groups compared to NC. Brain derived neurotropic factor (BDNF) concentrations were significantly lower in CI compared to NC (N CI /N NC  = 848/2063, SMD -0.67 95% confidence interval [-0.99, -0.35], Z 3  = -4.09, p < 0.01; I 2  = 89.20%). Cognitive impairment among people with T2DM was associated with systemic inflammation and lower BDNF concentrations. These inflammatory characteristics support an increased inflammatory-vascular interaction associated with cognitive impairment in T2DM. PROSPERO (CRD42020188625)., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: Medical cannabis use is growing among older adults. In this retrospective study, we aimed to assess the characteristics of older medical cannabis users including the indications, type and amount of cannabis used, perceived changes in symptoms after cannabis use, change in dose of concurrent medications, and adverse effects., Methods: Data were collected between October 2014 and October 2020 from patients who were consulting the Canada-wide network of clinics of a medical cannabis provider and who were willing to answer questionnaires based on their medical status. The current study included older adults (≥ 65 years) who completed questionnaires at intake and first follow-up visits. Data were summarized with descriptive statistics, which were compared between men and women with t tests or chi-squared tests. Tests of proportions assessed categorical responses for perceived effects after cannabis use. Logistic regression was used to assess trends in cannabis usage., Results: Data included that from 9766 older adult users at intake (mean ± SD age = 73.2 ± 6.8 years, females = 60.0%), among whom 4673 (females = 61.4%) returned for follow-up after 90.6 ± 58 days. The most common primary indication for which medical cannabis was sought was pain (67.7%), which was more common in women, whereas oncological and neurological conditions were more common in men. At follow-up, cannabis oil was used by 81.0% of older adults, among whom compositions containing only or mostly cannabidiol (CBD) had been used by 83.6%. Adverse effects reported by older adults at the follow-up visit included dry mouth (12.8%), drowsiness (8.6%), and dizziness (4.0%). The majority of older adults reported improvements in pain (72.7%, z = 1482.6, p < 0.0001, compared to worsening or no change), sleep (64.5%, z = 549.4, p < 0.0001), and mood (52.8%, z = 16.4, p < 0.0001), with 35.6% reporting use of a reduced dose of opioids and 19.9% a reduced dose of benzodiazepines., Interpretation: Among older adults, medical cannabis is used more often by women, with CBD-containing cannabis oils being the most commonly used. Users reported improved pain, sleep, and mood symptoms at follow-up after cannabis use. This study describes the patterns of use of medical cannabis by older adults and highlights the need for research to determine appropriate indications, precise doses of active ingredients, and short- and long-term outcomes among older adults., (© 2021. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Apathy is a highly prevalent symptom of dementia. Despite its association with faster cognitive and functional decline, decreased quality of life and increased mortality, no therapies are currently approved to treat apathy. The objective of this review was to summarize the drugs that have been studied for apathy treatment in patients with dementia (specifically Alzheimer's disease [AD], Huntington's disease [HD] and Parkinson's disease [PD] dementia; dementia with Lewy bodies [DLB]; vascular dementia [VaD]; and frontotemporal dementia [FTD]) based on their putative mechanisms of action. A search for relevant studies was performed using ClinicalTrials.gov and PubMed. Eligible studies were randomized controlled trials that were available in English and included at least one drug intervention and an apathy measure scale. A total of 52 studies that included patients with AD (n = 33 studies), PD (n = 5), HD (n = 1), DLB (n = 1), FTD (n = 3), VaD (n = 1), VaD and AD (n = 4), VaD and mixed dementia (n = 1), and AD, VaD and mixed dementia (n = 3) were eligible for inclusion. These studies showed that methylphenidate, olanzapine, cholinesterase inhibitors, choline alphoscerate, citalopram, memantine, and mibampator are the only beneficial drugs in AD-related apathy. For PD-related apathy, only methylphenidate, rotigotine and rivastigmine showed benefits. Regarding FTD- and DLB-related apathy, initial studies with agomelatine and rivastigmine showed benefits, respectively. As for HD- and only-VaD-related apathy, no drugs demonstrated benefits. With regards to mixed populations, memantine, galantamine and gingko biloba showed effects on apathy in the AD plus VaD populations and nimodipine in the VaD plus mixed dementia populations. Of the drugs with positive results, some are already prescribed to patients with dementia to target other symptoms, some have characteristics-such as medical contraindications (e.g., cardiovascular) and adverse effects (e.g., gastrointestinal disturbances)-that limit their clinical use and some require further study. Future studies should investigate apathy as a primary outcome, making use of appropriate sample sizes and study durations to ensure durability of results. There should also be a consensus on using scales with high test/retest and interrater reliabilities to limit the inconsistencies between clinical trials. In conclusion, there are currently no US FDA-approved drugs that target apathy in dementia, so there is an ongoing need for the development of such drugs., (© 2022. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)