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Importance: Older adults with major depressive disorder (MDD) or mild cognitive impairment (MCI) are at high risk for cognitive decline., Objective: To assess the efficacy of cognitive remediation (CR) plus transcranial direct current stimulation (tDCS) targeting the prefrontal cortex in slowing cognitive decline, acutely improving cognition, and reducing progression to MCI or dementia in older adults with remitted MDD (rMDD), MCI, or both., Design, Setting, and Participants: This randomized clinical trial was conducted at 5 academic hospitals in Toronto, Ontario, Canada. Participants were older adults who had rMDD (with or without MCI, age ≥65 y) or MCI without rMDD (age ≥60 y). Assessments were made at baseline, month 2, and yearly from baseline for 3 to 7 years., Interventions: CR plus tDCS (hereafter, active) or sham plus sham 5 days a week for 8 weeks followed by twice-a-year 5-day boosters and daily at-home CR or sham CR., Main Outcomes and Measures: The primary outcome was change in global composite cognitive score. Secondary outcomes included changes in 6 cognitive domains, moderating effect of the diagnosis, moderating effect of APOE ε4 status, change in composite score at month 2, and progression to MCI or dementia over time., Results: Of 486 older adults who provided consent, 375 (with rMDD, MCI, or both) received at least 1 intervention session (mean [SD] age, 72.2 [6.4] years; 232 women [62%] and 143 men [38%]). Over a median follow-up of 48.3 months (range, 2.1-85.9), CR and tDCS slowed cognitive decline in older adults with rMDD or MCI (adjusted z score difference [active - sham] at month 60, 0.21; 95% CI, 0.07 to 0.35; likelihood ratio test [LRT] P = .006). In the preplanned primary analysis, CR and tDCS did not improve cognition acutely (adjusted z score difference [active - sham] at month 2, 0.06, 95% CI, -0.006 to 0.12). Similarly, the effect of CR and tDCS on delaying progression from normal cognition to MCI or MCI to dementia was weak and not significant (hazard ratio, 0.66; 95% CI, 0.40 to 1.08; P = .10). Preplanned analyses showed treatment effects for executive function (LRT P = .04) and verbal memory (LRT P = .02) and interactions with diagnosis (P = .01) and APOE ε4 (P < .001) demonstrating a larger effect among those with rMDD and in noncarriers of APOE ε4., Conclusions and Relevance: The study showed that CR and tDCS, both targeting the prefrontal cortex, is efficacious in slowing cognitive decline in older adults at risk of cognitive decline, particularly those with rMDD (with or without MCI) and in those at low genetic risk for Alzheimer disease., Trial Registration: ClinicalTrials.gov Identifier: NCT02386670.

The association between depression and dementia, particularly Alzheimer's disease (AD) and cerebrovascular disease (CVD), remains an active area of research. This study aimed to investigate the relationship between a history of depression and biomarkers of AD and CVD in patients with dementia in a clinical setting. A total of 126 patients from the University Health Network (UHN) Memory Clinic with comprehensive clinical evaluations, including neuropsychological testing and medical examinations, were included. Lumbar puncture was performed to collect cerebrospinal fluid (CSF) for biomarker analysis, and brain magnetic resonance imaging (MRI) scans were obtained to assess white matter hyperintensity (WMH) burden. The presence of depression was determined through medical records. The study findings did not reveal significant differences between participants with and without a history of depression in terms of AD biomarkers, WMH burden, neurofilament light chain levels, cognitive scores, age of symptom onset, disease duration, or vascular risk scores. Logistic regression analysis did not indicate a meaningful predictive value of these variables for depression status. This clinical study contributes to our understanding regarding the association between depression and AD/CVD biomarkers in patients with cognitive impairment. Further research is needed to elucidate the complex relationship between depression and dementia and to explore the potential mechanisms linking depression, AD, and CVD., (© 2023. The Author(s), under exclusive licence to American Aging Association.)

Major depressive disorder (MDD) is a risk factor for Alzheimer's disease (AD). Cerebrovascular disease (CVD) is implicated in MDD and AD. Our study compared participants with AD positive and negative cerebrospinal fluid (CSF) biomarkers on neuropsychological performance, remitted MDD status, and CVD burden. Next, we compared AD-CSF biomarkers and white matter hyperintensities (WMH) burden among three groups: mild cognitive impairment (MCI) (n = 12), MCI with remitted MDD (MDD+MCI) (n = 12), and remitted MDD alone (MDD) (n = 7). Few participants (18%) with MCI+MDD exhibited AD(+) biomarkers. Nearly all participants had moderate-severe WMH. WMH may contribute to cognitive impairment or depression in MCI patients with AD(-) biomarkers.

Background: Recent work suggests that APOEɛ4/4 females with Alzheimer's disease (AD) are more susceptible to developing neuropsychiatric symptoms (NPS)., Objective: To examine the interaction of sex and APOEɛ4 status on NPS burden using two independent cohorts: 1) patients at risk for AD with mild cognitive impairment and/or major depressive disorder (n = 252) and 2) patients with probable AD (n = 7,261)., Methods: Regression models examined the interactive effects of sex and APOEɛ4 on the number of NPS experienced and NPS Severity. APOEɛ3/4 and APOEɛ4/4 were pooled in the at-risk cohort due to the sample size., Results: In the at-risk cohort, there was a significant sex*APOEɛ4 interaction (p = 0.007) such that the association of APOEɛ4 with NPS was greater in females than in males (incident rate ratio (IRR) = 2.0). APOEɛ4/4 females had the most NPS (mean = 1.9) and the highest severity scores (mean = 3.5) of any subgroup. In the clinical cohort, APOEɛ4/4 females had significantly more NPS (IRR = 1.1, p = 0.001, mean = 3.1) and higher severity scores (b = 0.31, p = 0.015, mean = 3.7) than APOEɛ3/3 females (meanNPS = 2.9, meanSeverity = 3.3). No association was found in males., Conclusion: Our study suggests that sex modifies the association of APOEɛ4 on NPS burden. APOEɛ4/4 females may be particularly susceptible to increased NPS burden among individuals with AD and among individuals at risk for AD. Further investigation into the mechanisms behind these associations are needed.

Background: By the time Alzheimer's disease and related disorders (ADRD) are diagnosed, efficacy of treatments is limited. Preventive interventions are urgently needed., Objective: To design a randomized controlled trial to assess a novel intervention that aims to prevent ADRD in high-risk groups., Methods: We report on the rationale and describe the design of a multisite randomized controlled trial that aims to prevent ADRD in older persons with: (1) mild cognitive impairment (MCI); (2) remitted major depressive disorder (MDD) without MCI; or (3) remitted MDD with MCI., Results: PACt-MD (Prevention of Alzheimer's dementia with Cognitive remediation plus transcranial direct current stimulation in Mild cognitive impairment and Depression) is a trial that randomized 375 older participants with MCI, MDD, or MCI + MDD to cognitive remediation (CR) plus transcranial direct current stimulation (tDCS) or sham-CR + sham-tDCS for 5 days/week for 8 weeks followed by boosters for 5 days/week once every 6 months until participants progress to MCI or ADRD, or the end of the study. Between boosters, participants are asked to train on CR daily. At baseline, end of 8 weeks, and yearly from baseline, participants undergo clinical, cognitive, and functional assessments. The primary aims are to compare the efficacy of CR + tDCS versus sham + sham in preventing: 1) long-term cognitive decline; and 2) incidence of ADRD or MCI. The secondary aim is to assess for cognitive improvement after the 8-week course. We will also explore the moderating and mediating effects of several biomarkers collected from the participants., Conclusion: PACt-MD is unique in combining brain stimulation and a psychosocial intervention to prevent ADRD. PACt-MD is also a platform for studying multi-domain biomarkers that will advance our understanding of the relationships among MCI, MDD, and ADRD.

Introduction: Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is an inflammatory disorder of the brain that has garnered significant interest within the medical and lay communities. There is a need for formal guidelines to assist physicians in identifying patients who should undergo testing for NMDAR encephalitis, recognizing the high potential for this potentially treatable disease to mimic more common disorders, and consequently remain undiagnosed., Areas Covered: This review highlights the impact of the discovery of NMDAR encephalitis on the fields of neurology and psychiatry, and discusses the steps that are necessary to improve recognition and treatment of NMDAR encephalitis. Expert commentary: While much progress has been made in our understanding of NMDAR encephalitis, much work remains to be done to delineate the underlying disease mechanisms and their relevance to brain function.

Objective: Cognitive deficits are among the strongest predictors of function in individuals with schizophrenia. This relationship continues to be strong as these individuals grow older into their eight decade. Cognitive remediation (CR) improves cognition in individuals with schizophrenia. This study aims at assessing the feasibility and potential effect of CR in patients with schizophrenia 60 years of age or older., Methods: We adapted a CR protocol involving restorative and strategy-based methods over four cohorts of older outpatients with schizophrenia to target cognitive deficits associated with aging and schizophrenia. CR was provided in eight, 2-h weekly didactic sessions and online at-home exercises. Computerized drill and practice exercises were used with bridging to activities of daily life. Computer exercise selection and difficulty level parameters optimized adherence. Progression individually determined difficulty levels. We modified computer laboratory ergonomics to accommodate mobility needs. Participants were assessed at baseline and end-of-study using clinical and cognitive assessments., Results: Twenty-two participants enrolled: 18 (mean [SD] age: 69.8 [5.3]) completed CR. Mean (SD) global cognition T score from the Measurement and Treatment Research to Improve Cognition in Schizophrenia Consensus Cognitive Battery was 27.7 (10) at baseline and 28.8 (9.7) at the completion of the study. These means are over 2 SD below the norms. The change in global cognition was not statistically significant (paired t(17) = -1.18, p = 0.25)., Conclusions: Our pilot study suggests that CR is well tolerated by most older outpatients with schizophrenia. Future studies need to assess whether increasing the frequency or the number of CR sessions leads to significant improvement in cognition., (Copyright © 2015 John Wiley & Sons, Ltd.)