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Recent work suggests that APOEɛ4/4 females with Alzheimer's disease (AD) are more susceptible to developing neuropsychiatric symptoms (NPS).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).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.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.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.

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.

Antipsychotic medications are routinely prescribed for neuropsychiatric symptoms (NPS) associated with dementia, despite conflicting evidence regarding their safety and comparative effectiveness for this population. The purpose of this review is to examine the efficacy and comparative effectiveness of first and second-generation antipsychotics (SGAs) for the treatment of agitation, psychosis, and overall NPS in patients with Alzheimer’s disease and related dementias. There is a paucity of high quality, randomized controlled clinical trials examining the efficacy of antipsychotic medications on NPS under randomized, placebo-controlled, and double-blind conditions. Based on our review, risperidone has the best evidence for the management of agitation and psychosis, with aripiprazole exhibiting better evidence compared to SGAs as a class for overall NPS, with both drugs exhibiting only a small effect. Current research demonstrates that antipsychotic medications are not particularly effective for the management of NPS of dementia and carry a substantial side effect burden. Although further research is needed to fully determine the safety, tolerability, and efficacy of these treatments, there is a need to develop safe and effective pharmacological and nonpharmacologic interventions for this population.

Introduction Apolipoprotein (APOE) e4 is one of the strongest genetic biomarkers for Alzheimer's disease (AD) however, the relationship between APOE and Neuropsychiatric Symptoms (NPS) remains unclear. Our recent analyses suggested that female sex modulated the association of APOE e4 on specific NPS domains such as psychosis 1 and nighttime behaviours 2 in an autosomal recessive manner. The goal of this new analysis was to investigate the associations between APOE and sex on overall NPS burden in a cohort of participants with a condition putting them at risk for AD: Mild cognitive impairment (MCI) and/or a history of Major Depressive Disorder (MDD). Methods Baseline Neuropsychiatric Inventory Questionnaire (NPI-Q), APOE and demographic data were obtained in 181 participants from an ongoing clinical trial, “Preventing Alzheimer's dementia with cognitive remediation plus transcranial direct current stimulation in mild cognitive impairment and depression (PACt-MD)”. NPS burden was measured with the NPI-Q Total score and NPI-Severity Total. One extreme outlier was omitted from analysis (>7 inter quartile ranges (IQR) from the median NPI-Severity and >2 IQR from the next nearest data point). We tested whether APOE status, sex, or an interaction of the two were associated with our two outcomes using Ordinal Least Square (OLS) regression. Subsequent models were fit adjusting for the effects of age, education and diagnosis group (i.e., MCI or MDD (with/without MCI)). APOE e3/e3, the most common isoform, was used as the baseline category in regression analysis. All findings reported are compared to this baseliine category. Results When analysing the effects of APOE and sex alone, we only found a significant inverse association between NPI-Q Total and APOE e3/e4 carriers compared to APOE e3/e3 carriers (n = 38, b = -1.04, t(170) = -2.28, p = 0.024). When analysing our interaction terms APOE e4/e4 females (n = 6) were significantly associated with higher NPI-Q total scores (b = 1.95, t(171) = 2.14, p = 0.034). We also found that APOE e2/e3 females (n = 10) were associated with higher NPI-Q total scores (b = 1.55, t(171) = 2.04, p = 0.044). Results were consistent after adjusting for covariates. Sex or APOE status alone were not associated with NPI-Q Total severity scores. When analysing the interaction terms, APOE e2/e3 females showed higher NPI-Q Total severity scores than APOE e3/e3 carriers (b = 3.57, t(171) = 2.45, p = 0.015). After adjusting for covariates, being APOE e2/e3 females (b = 3.3, t(162) = 1.49, p = 0.027) or APOE e4/e4 females (b = 3.8, t(162) = 1.78 p = 0.033) was associated with greater NPI-Severity. Conclusions In older adults at risk for progression to AD, sex may play a modulatory role in the association between APOE and NPS burden. Consistent with recent findings 1 , 2 , females who are homozygous for APOE e4 may be susceptible to the highest NPS burden. Further investigation of the interactive effects of sex and APOE e4 on NPS burden with larger samples are needed. Funding This Project has been made possible by Brain Canada through the Canada Brain Research Fund, with the financial support of Health Canada and the Chagnon Family.

Introduction Although cardiovascular risk factors (CVRFs) have been identified as important risk factors for both major depression and cognitive decline in later life, their association with neuropsychiatric symptoms (NPS) has not been fully elucidated. Furthermore, CVRFs, particularly hypertension, hypercholesterolemia, and diabetes, may ultimately lead to physical conditions such as small vessel disease known to disrupt cognition, thereby leading to the onset of NPS. Thus, a better understanding of the association between CVRFs and NPS could improve the development of treatments and preventative measures for NPS. Methods Using baseline data from the Prevention of Alzheimer's Dementia with Cognitive Remediation plus Transcranial Direct Current Stimulation (PACt-MD) study, a multi-site intervention study targeting older patients with depression and cognitive decline, we analysed the distribution of CVRFs (Framingham risk scores; Hachinski ischemic score; presence of hypertension, hypercholesterolemia, hyperlipidemia, diabetes, and smoking) in patients with and without NPS as determined by a score of 1 and above or 0 on the Neuropsychiatric Inventory-Questionnaire (NPI-Q). Participants fell into one of the following three diagnosis groups: Mild Cognitive Impairment (MCI) with a lifetime history of major depression (MDD); MCI without MDD; and MDD without MCI. Comparisons of distributions of CVRFs between NPI positive and negative groups were conducted using the non-parametric Mann-Whitney U test at a significance level of Results In a combined sample of 140 participants, there were no significant differences in any CVRF between positive and negative total NPI groups. However, some NPI subscale scores, notably agitation/aggression, anxiety, disinhibition, irritability, and night-time behaviour were significantly associated with increased CVRFs (p Conclusions None of the CVRFs were associated with overall total NPI-Q scores, however, these preliminary analyses suggest that some specific CVRFs were associated with certain NPI-Q subdomains. This suggests that CVRFs contribute to specific NPS domains rather than overall NPS burden. This research was funded by This project has been made possible by Brain Canada through the Canada Brain Research Fund, with the financial support of Health Canada and the Chagnon Family.

Introduction Cardiovascular risk factors are associated with both cognitive impairment and depression. However, the extent to which these factors are associated with cognitive impairment in patients with mild neurocognitive disorder with and without a history of lifetime depression needs to be clarified. Methods We looked at the distribution of Framingham Risk Scores (FRS) for cardiovascular disease in three groups of participants age 60 years and older in the Prevention of Alzheimer's Dementia with Cognitive Remediation plus Transcranial Direct Current Stimulation (PACt-MD) study: those with mild cognitive impairment (MCI; n = 42), remitted major depressive disorder (MDD, n =29), or MCI plus remitted MDD (n = 21). We also examined the association between cardiovascular risk factors and cognitive scores on the Mini-Mental State Examination (MMSE) or Montreal Cognitive Assessment (MOCA), and the Montgomery–Asberg Depression Rating Scale (MADRS) using the non-parametric Spearman's rank order correlation test. Results There were no differences in the severity of FRS across the three diagnostic groups (p=0.281). Comparison of age, gender, education, and cognitive scores across FRS severity groups showed a significant correlation of increased FRS severity with higher age (p=0.016) and lower MOCA (p=0.023). When we assessed the correlation between specific cardiovascular risk factors (i.e hypertension, hypercholesterolemia, smoking, diabetes, hyperlipidemia) and MMSE, MOCA, and MADRS, the only significant correlation was found to be between a history of hypertension and lower MOCA scores (p=0.001). Conclusions The similar FRS distribution across MDD and MCI provides further support for the association of cardiovascular burden with both MDD and cognitive impairment. Hypertension was the only cardiovascular risk factor that was correlated with cognitive impairment. Future research is needed to clarify the mechanism behind this association. This research was funded by This Project has been made possible by Brain Canada through the Canada Brain Research Fund, with the financial support of Health Canada and the Chagnon Family.

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.

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.

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.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.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).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.