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• What is the primary question addressed by this study? What are the cognitive profiles of older adults with remitted major depressive disorder (rMDD) with or without mild cognitive impairment (MCI)? How do these profiles differ in terms of clinical, demographic, and brain structure features? • What is the main finding of this study? Using latent profile analysis, we identified three cognitive profiles, with differences in cognition, physical health, education, and brain structure. • What is the meaning of the finding? Older patients with rMDD can be grouped cross-sectionally based on distinct data-driven cognitive profiles that differ from the absence or presence of a diagnosis of MCI. 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. Secondary cross-sectional analysis using latent profile analysis. Multisite clinical trial in Toronto, Canada. 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). Demographic, clinical, neuroimaging measures, and domain scores from a neuropsychological battery assessing verbal memory, visuospatial memory, processing speed, working memory, language, and executive function. 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. 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. [ABSTRACT FROM AUTHOR]

• What is the primary question addressed by this study? Do clinical characteristics of participants in the ADMET 2 trial predict better response to methylphenidate for the treatment of apathy in Alzheimer's disease? • What is the main finding of this study? Participants without anxiety or agitation, who were younger, taking a cholinesterase inhibitor, with 73–80 mm Hg diastolic blood pressure, having low functional capacity, were found to respond better to methylphenidate. Combining these characteristics in a multivariate model provided individualized prediction of treatment response. • What is the meaning of the finding? These clinical characteristics may affect the efficacy of methylphenidate in treating apathy, and may help clinicians identify patients most likely to respond to treatment. 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. Univariate and multivariate analyses of 22 clinical predictors of response chosen a priori. Data from the ADMET 2 randomized, placebo controlled multi-center clinical trial. Alzheimer's disease patients with clinically significant apathy. Apathy assessed with the Neuropsychiatric Inventory apathy domain (NPI-A). 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. 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. [ABSTRACT FROM AUTHOR]

• What is the primary question addressed by this study? To determine whether lipopolysaccharide and inflammatory biomarkers are key drivers of cerebral amyloid-beta (Abeta) deposition in older adults with mild cognitive impairment (MCI) and remitted major depressive disorder (rMDD). • What is the main finding of this study? While many participants demonstrated high Abeta deposition we did not find significant associations between lipopolysaccharide, peripheral inflammatory biomarkers, remitted major depressive disorder, and cerebral deposition of Abeta. • What is the meaning of the finding? While this study did not demonstrate a significant cross sectional association it is possible that inflammatory activation may be associated with Abeta deposition earlier in the disease process and may be more relevant among those with chronic inflammatory activation and more persistent depression. Future longitudinal studies would help clarify whether these potentially modifiable risk factors play a role in the evolution of Alzheimer's neuropathology. Inflammatory activation and increased immune response to lipopolysaccharide occur in both depression and cognitive decline and may link these two conditions. We investigated whether lipopolysaccharide (LPS), LPS binding protein (LBP) and peripheral biomarkers of immune response were associated with increased cerebral deposition of amyloid-beta (Abeta) in older adults with mild cognitive impairment (MCI) and remitted major depressive disorder (rMDD). Cross-sectional analysis. Five academic health centers in Toronto. Older adults with MCI with/without rMDD. We investigated the associations among serum LPS, LBP, biomarkers of inflammatory activation – Interleukin-6 (IL-6), C-reactive protein (CRP), monocyte chemoattractant protein-1 (MCP-1), and cerebral Abeta deposition quantified by positron emission tomography. Among 133 study participants (82 with MCI and 51 with MCI+rMDD) there was no association between LPS (beta – 0.17, p = 0.8) or LBP (beta - 0.11, p = 0.12) and global deposition of Abeta following adjustment for age, gender, and APOE genotype in multivariable regression analyses. LBP was positively correlated with CRP (r = 0.5, p <0.001) and IL-6 (r = 0.2, p = 0.02) but no inflammatory biomarker was associated with Abeta deposition; rMDD was not associated with deposition of Abeta (beta -0.09, p = 0.22). In this cross-sectional analysis, we did not find an association among LPS/LBP, immune biomarkers or rMDD and global deposition of Abeta. Future analyses should assess the longitudinal relationships between peripheral and central biomarkers of immune activation, depression and cerebral Abeta deposition. [ABSTRACT FROM AUTHOR]

Objective: This study compared diagnostic rates and clinical predictors of discrepancies between diagnoses conferred via: 1) a comprehensive neuropsychological evaluation and National Institute on Aging-Alzheimer's Association (NIA-AA) criteria versus 2) a cognitive screener and Diagnostic Statistical Manual of Mental Disorders (DSM-5) criteria.Design: Cross-sectional examination of baseline data from the Prevention of Alzheimer's dementia (AD) using Cognitive remediation and transcranial direct current stimulation in Mild Cognitive Impairment (MCI) and Depression (PACt-MD; ClinicalTrials.gov Identifier: NCT02386670) trial.Setting: Five geriatric psychiatry and memory clinics located at academic hospitals affiliated with the Department of Psychiatry, University of Toronto.Participants: Older adults (N = 431) with a history of major depressive disorder (MDD) in remission, MCI, or both.Measurements: Main outcome was a comparison of NIA-AA diagnostic rates of MCI or dementia versus DSM-5 rates of mild or major neurocognitive disorder. Secondary analyses examined demographic, race, gender, premorbid intellectual ability, psychosocial, health-related, and genetic predictors of discrepancy between DSM-5 and NIA-AA diagnoses.Results: There were 103 (23.8%) discrepant cases, with most (91; 88.3%) of these discrepant cases reflecting more impairment with the detailed neuropsychological testing and NIA-AA criteria. Discrepancies were more likely in individuals with a history of MDD or who had at least one ApoE4 allele.Conclusion: The NIA-AA criteria, in conjunction with comprehensive neuropsychological testing, identified a greater prevalence of cognitive impairment than DSM-5 criteria, in conjunction with the Montreal Cognitive Assessment. Detailed neuropsychological evaluations are recommended for older adults who have a history of MDD or a genetic vulnerability to dementia. [ABSTRACT FROM AUTHOR]

Objectives: Anticholinergic burden has been associated with deleterious effects on cognition particularly in those with an underlying brain disorder. We developed a new assay based on cultured cells to measure serum anticholinergic activity (cSAA). We report on its relationships with established anticholinergic burden rating scales and cognitive assessments in older patients with mild cognitive impairment (MCI) or major depressive disorder (MDD) in remission or both.Design: The study was cross sectional in nature.Setting: This was a five-centre study conducted in Toronto, Canada.Participants: Serum samples were collected and cSAA levels were measured in 311 participants aged 60 years or older (154 with MCI, 57 with MDD, and 100 with MCI + MDD).Measurements: The cSAA assay uses radio-ligand binding to cultured cells stably expressing the muscarinic M1 receptors, with an added procedure to remove potential confounds associated with serum proteins. Lists of medications were used to calculate Anticholinergic Burden and Anticholinergic Drug Scale total scores. Participants also completed a comprehensive cognitive battery.Results: Higher cSAA levels were associated with higher anticholinergic burden and anticholinergic drug scale scores, and also with lower performance on executive function tests, after adjusting for age, gender, education, and diagnosis.Conclusions: These results support the use of the cSAA assay as a laboratory measure of anticholinergic burden. [ABSTRACT FROM AUTHOR]

Objective: Our understanding of why older adults with depression are at increased risk of Alzheimer's disease (AD) remains incomplete. Most adults living with AD are women, and women have a near twofold lifetime risk of depression. We examined the risk of depression upon incident AD, and how sex influences this risk.Methods: Using the National Alzheimer's Coordinating Center database, older adults (age 50+) with normal cognition, who visited memory clinics across the United States between September 2005 and December 2019, were followed until first diagnosis of AD or loss to follow up. Multivariable survival analyses were performed to determine if recent and/or remote depression were independent risk factors for AD, if this depression-related risk exists for each sex or was moderated by sex.Results: Six hundred and fifty-two of 10,739 enrolled participants developed AD over a median follow-up of 55.3 months. Recent depression (active within the last 2 years) was independently associated with increased risk of AD (hazard ratio [HR] = 2.0; 95%CI, 1.5-2.6) while a remote history of depression was not (HR = 1.0; 95%CI, 0.7-1.5). After stratification by sex, recent depression was an independent predictor in females (HR = 2.3; 95%CI, 1.7-3.1) but not in males (HR = 1.4; 95%CI, 0.8-2.6). No interaction between recent depression and sex was observed.Conclusion: Only a recent history of depression was associated with higher risk of AD. This association was significant among women only, but was not moderated by sex. Future analyses should determine if these findings extend to other populations and may be explained by variable distribution of neurobiological or other modifiable risk factors between the sexes. [ABSTRACT FROM AUTHOR]

Background: Diagnostic criteria for apathy have been published but have yet to be evaluated in the context of clinical trials. The Apathy in Dementia Methylphenidate Trial 2 (ADMET 2) operationalized the diagnostic criteria for apathy (DCA) into a clinician-rated questionnaire informed by interviews with the patient and caregiver.Objective: The goal of the present study was to compare the classification of apathy using the DCA with that using the Neuropsychiatric Inventory-apathy (NPI-apathy) subscale in ADMET 2. Comparisons between NPI-Apathy and Dementia Apathy Interview Rating (DAIR) scale, and DCA and DAIR were also explored.Methods: ADMET 2 is a randomized, double-blind, placebo-controlled phase III trial examining the effects of 20 mg/day methylphenidate on symptoms of apathy over 6 months in patients with mild to moderate Alzheimer's disease (AD). Participants scoring at least 4 on the NPI-Apathy were recruited. This analysis focuses on cross-sectional correlations between baseline apathy scale scores using cross-tabulation.Results: Of 180 participants, the median age was 76.5 years and they were predominantly white (92.8%) and male (66.1%). The mean (±standard deviation) scores were 7.7 ± 2.4 on the NPI-apathy, and 1.9 ± 0.5 on the DAIR. Of those with NPI-defined apathy, 169 (93.9%, 95% confidence interval [CI] 89.3%-96.9%) met DCA diagnostic criteria. The DCA and DAIR overlapped on apathy diagnosis for 169 participants (93.9%, 95% CI 89.3%-96.9%).Conclusion: The measurements used for the assessment of apathy in patients with AD had a high degree of overlap with the DCA. The NPI-apathy cut-off used to determine apathy in ADMET 2 selects those likely to meet DCA criteria. [ABSTRACT FROM AUTHOR]

The public health burden of Alzheimer's disease (AD) is related not only to cognitive symptoms, but also to neuropsychiatric symptoms, including apathy. Apathy is defined as a quantitative reduction of goal-directed activity in comparison to a previous level of functioning and affects 30%-70% of persons with AD. Previous attempts to treat apathy in AD-both nonpharmacologically and pharmacologically-have been wanting. Catecholaminergic treatment with methylphenidate has shown encouraging results in initial trials of apathy in AD. Understanding the neuronal circuits underlying motivated behavior and their reliance on catecholamine actions helps provide a rationale for methylphenidate actions in the treatment of apathy in patients with AD. Anatomical, physiological, and behavioral studies have identified parallel, cortical-basal ganglia circuits that govern action, cognition, and emotion and play key roles in motivated behavior. Understanding the distinct contributions to motivated behavior of subregions of the prefrontal cortex-dorsolateral, orbital-ventromedial, and dorsomedial-helps to explain why degeneration of these areas in AD results in apathetic behaviors. We propose that the degeneration of the prefrontal cortex in AD produces symptoms of apathy. We further propose that methylphenidate treatment may ameliorate those symptoms by boosting norepinephrine and dopamine actions in prefrontal-striatal-thalamocortical circuits. [ABSTRACT FROM AUTHOR]

The APOE gene is implicated in the development of Alzheimer's disease (AD), with the ε4 allele being the strongest known genetic risk factor for sporadic AD. In individuals with Alzheimer's disease, female APOE e4 homozygotes have recently been shown to be at increased risk of neuropsychiatric symptom (NPS) burden. This sex-specific association has also been found in groups at increased risk of developing AD, specifically those with mild cognitive impairment (MCI) and/or a history of major depressive disorder (MDD). While the mechanisms underlying this association are not yet known, one potential contributing factor is regional cortical thinning, which has been found to occur in early AD. The purpose of this study was to examine whether there is a female-specific association between cortical thickness and APOE ε4 status. Data was obtained from PACt-MD (Prevention of Alzheimer's dementia with cognitive remediation plus transcranial direct current stimulation in mild cognitive impairment and depression"), a clinical trial that included older adults with MCI and MDD. Patients for whom the following data was available were included in the analysis: age, sex, highest level of education, MMSE score, MoCA score, APOE genotyping, Neuropsychiatric Inventory Questionnaire (NPI-Q) score, and measurements of cortical thickness from brain MRI. For APOE status, patients were categorized as either E4-positive (hetero- or homozygous) or E4-negative. Statistical analyses were conducted using RStudio. Multiple regression models were used to examine 1) the E4-by-sex interaction effect on cortical thickness, and 2) the association between cortical thickness and NPI-Q total scores. There were 61 individuals (34 females) in the E4-positive group, and 158 individuals (97 females) in the E4-negative group. There was a statistically significant E4-by-sex interaction on thickness of the left (p=0.02) and right (p=0.01) inferior parietal cortices, and the right pericalcarine cortex (p=0.003). Specifically, there was a reduction in cortical thickness for males who were E4-positive compared to E4-negative. Meanwhile, there was either no change (inferior parietal cortices) or an increase (right pericalcarine cortex) in cortical thickness for females who were E4-positive compared to E4-negative. The mean NPI-Q total score was 2.37. No significant association was found between the cortical thickness in these, or any other, brain regions and NPI-Q total scores. The presence of the APOE ε4 allele has a sex-specific effect on cortical thickness in the bilateral inferior parietal cortices and right pericalcarine cortex. However, this sex-based difference was not in the direction we hypothesized based on previous studies. [ABSTRACT FROM AUTHOR]

Background: Post-traumatic stress disorder (PTSD) has been reported to increase the risk for dementia in veterans and civilians. Conversely, case reports have described the delayed onset of PTSD in individuals developing dementia, suggesting a complex relationship between these two conditions.Objectives: To critically review studies investigating the association between PTSD and dementia and to assess the evidence for a bidirectional relationship between the two conditions.Methods: A systematic review of Web of Science Core databases was carried out from inception of databases up to November 2018 to identify observational studies pertaining to both PTSD and dementia. Populations enrolled, stressors and neuropathologies, and main outcomes of studies were extracted, in addition to age at trauma and at onset of PTSD and dementia. The different temporal relationships between trauma and onset of the conditions were characterized.Results: Twenty-five articles were included in the review; 14 articles assessed the association of PTSD with subsequent dementia and 11 articles reported the delayed onset of PTSD with the onset of dementia. Most reported traumas occurred in early-life (<40 years) and were related to war combat experiences. PTSD in mid-life (between 40 and 60 years of age) was associated with an increased risk of late-onset dementia. Numerous case series reported the delayed onset of PTSD in Alzheimer's disease and vascular dementia.Conclusion: Current evidence suggests that PTSD and dementia have a bidirectional relationship: PTSD increases the risk for late-onset dementia and dementia increases the risk for delayed-onset PTSD in those who experienced a significant trauma earlier in life. [ABSTRACT FROM AUTHOR]

Objective: To investigate the efficacy and safety of nabilone for agitation in patients with moderate-to-severe Alzheimer's disease (AD).Design: This 14-week randomized double-blind crossover trial compared nabilone to placebo (6 weeks each) with a 1-week washout between phases.Setting: Patients were recruited from a long-term care facility and geriatric psychiatry clinics.Participants: Patients had AD (standardized Mini-Mental State Examination [sMMSE ≤24]) and agitation (Neuropsychiatric Inventory-Nursing Home version [NPI-NH]-agitation/aggression subscore ≥3).Intervention: Nabilone (target 1-2 mg) versus placebo.Measurements: The primary outcome was agitation (Cohen Mansfield Agitation Inventory [CMAI]). Secondary outcomes included NPI-NH total, NPI-NH caregiver distress, cognition (sMMSE and Severe Impairment Battery [SIB] or Alzheimer's Disease Assessment Scale of Cognition), global impression (Clinician's Global Impression of Change [CGIC]), and adverse events.Results: Thirty-nine patients (mean ± SD age = 87 ± 10, sMMSE = 6.5 ± 6.8, CMAI = 67.9 ± 17.6, NPI-NH total = 34.3 ± 15.8, 77% male, nabilone dose = 1.6 ± 0.5 mg) were randomized. There were no crossover or treatment-order effects. Using a linear mixed model, treatment differences (95% CI) in CMAI (b = -4.0 [-6.5 to -1.5], t(30.2) = -3.3, p = 0.003), NPI-NH total (b = -4.6 [-7.5 to -1.6], t(32.9) = -3.1, p = 0.004), NPI-NH caregiver distress (b = -1.7 [-3.4 to -0.07, t(33.7) = -2.1, p = 0.041), and sMMSE (b = 1.1 [0.1-2.0], t(22.6) = 2.4, p = 0.026) all favored nabilone. However, in those who completed the SIB (n = 25) treatment differences favored placebo (b = -4.6 [-7.3 to -1.8], t(20.7) = -4.8, p = 0.003). CGIC improvement during nabilone (47%) and placebo (23%) was not significantly different (McNemar's test, exact p = 0.09). There was more sedation during nabilone (45%) compared to placebo (16%) phases (McNemar's test, exact p = 0.02), but treatment-limiting sedation was not significantly different (McNemar's test, exact p = 0.22).Conclusions: Nabilone may be an effective treatment for agitation. However, sedation and cognition should be closely monitored. [ABSTRACT FROM AUTHOR]

Objective: Apathy and depression have each been associated with an increased risk of conversion from mild cognitive impairment (MCI) to Alzheimer disease (AD).These symptoms often co-occur and the contribution of each to risk of AD is not clear.Methods: National Alzheimer's Coordinating Center participants diagnosed with MCI at baseline and followed until development of AD or loss to follow-up (n = 4,932) were included. The risks of developing AD in MCI patients with neuropsychiatric symptoms (NPS) (apathy only, depression only, or both) were compared to that in those without NPS in a multivariate Cox regression survival analysis adjusting for baseline cognitive impairment, years of smoking, antidepressant use, and AD medication use.Results: Thirty-seven percent (N = 1713) of MCI patients developed AD (median follow-up 23 months). MCI patients with both apathy and depression had the greatest risk (hazard ratio [HR] = 1.37; 95% confidence interval [CI]: 1.17-1.61; p < 0.0001; Wald χ2 = 14.70; df = 1). Those with apathy only also had a greater risk (HR = 1.24; 95% CI: 1.05-1.47; p = 0.01; Wald χ2 = 6.22; df = 1), but not those with depression only (HR = 1.08; 95% CI: 0.95-1.22; p=0.25; Wald χ2 = 1.30; df = 1). Post-hoc analyses suggested depression may exacerbate cognitive decline in MCI patients with apathy (odds ratio = 0.70; 95% CI 0.52-0.95; p = 0.02; Wald χ2 = 5.28; df = 1), compared to those without apathy.Conclusion: MCI patients with apathy alone or both apathy and depression are at a greater risk of developing AD compared to those with no NPS. Interventions targeting apathy and depression may reduce risk of AD. [ABSTRACT FROM AUTHOR]

Late-life depression (LLD) is a risk factor for Alzheimer's dementia (AD). Over one-half of patients with LLD present with cognitive impairment, with one-third meeting the criteria for a diagnosis of mild cognitive impairment (MCI). Previous studies have explored the associations between brain structure and cognition in LLD; however, most published studies are limited by their small sample sizes, univariate statistical models, and heterogenous results. Here, we investigated the multivariate associations between brain structural alterations (in both gray and white matter) and cognition across three groups of older adults at risk for AD: those with remitted major depressive disorder (rMDD), MCI, or concurrent rMDD+MCI; we also included in the analysis a comparison group of healthy non-depressed controls. We assessed whether the brain-cognition associations identified in the whole sample are driven by diagnostic subgroups. We analyzed cross-sectional magnetic resonance imaging (MRI) data and cognitive domains composite scores derived from a comprehensive cognitive assessment in participants of the PACt-MD study (P revention of A lzheimer's dementia with C ognitive remediation plus t ranscranial direct current stimulation in M ild cognitive impairment and D epression). We assessed cortical thickness and subcortical volumes of selected regions of interest from 283 T1-weighted MRI scans, and white matter integrity (fractional anisotropy) of selected white matter tracts from 226 diffusion-weighted MRI scans. We assessed brain-cognition associations using partial least squares regressions in the whole sample and in each diagnostic subgroup for both imaging modalities. In the T1-weighted analysis, PLS regression in the whole sample showed that atrophy in AD-vulnerable regions (i.e., hippocampus, entorhinal, fusiform and the precuneus) and in subregions of the motor and prefrontal cortex was associated with deficits in verbal and visuospatial memory, language, and, to a lesser extent, processing speed (p<0.0001, multivariate r=0.30, 0.34, 0.26 and 0.18, respectively). In the diffusion-weighted analysis, alterations in distributed white matter tract integrity were associated with cognitive deficits across the higher-order domains of executive function, working memory, and processing speed (p=0.008, multivariate r=0.21, 0.26, 0.35 respectively). In the T1-weighted analysis, associations remained significant in the MCI and rMDD+MCI groups (both p=0.002), but not in the rMDD and HC groups (p=0.78, p=0.30, respectively); in the diffusion-weighted analysis, associations remained significant only in the MCI group (p=0.007). Our results confirm previous findings of brain-cognition associations in MCI and extend them to other groups of older adults at risk for AD, including rMDD+MCI. These results can inform efforts to design and target future preventive interventions for AD. 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. It has also been supported in part by the Queen Elizabeth II/Gregory M. Brown Graduate Scholarships in Science and Technology and the Labatt Family Chair in Biology of Depression in Late-Life Adults at the University of Toronto. [ABSTRACT FROM AUTHOR]

Neuropsychiatric symptoms (NPS) are common and may appear early in neurodegenerative disorders. NPS may be more prevalent in dementia with underlying vascular disease than in Alzheimer's disease (AD), suggesting that underlying vascular changes, which appear as white matter hyperintensities (WMH) on brain imaging, underlie their development. However, few studies have investigated such associations, especially in the early stages. Here, we investigated whether NPS differed in prevalence between vascular mild cognitive impairment (v-MCI), mild cognitive impairment (MCI), AD, and mixed dementia (MD), and if NPS were associated with the grade and location of WMH. Participants included in the study were recruited to the Comprehensive Assessment of Neurodegeneration and Dementia (COMPASS-ND) study. Participants underwent neuropsychological assessments, brain imaging and clinical evaluation, and were diagnosed with v-MCI as per the American Heart Association and International Society for Vascular Cognitive and Behavioral Disorders criteria, or with MCI or AD as per the National Institute on Aging-Alzheimer's Association (NIA-AA) criteria or with MD if they had symptoms of AD and non-AD symptoms. Participants without subjective or objective impairments were considered cognitively unimpaired (CU). The neuropsychiatric inventory-questionnaire was administered to informants to evaluate symptoms in 12 behavioral domains, which were classified into five clusters according to domains defined as per criteria for mild behavioral impairment. These domains group neurobiologically related symptoms and reduce the number of statistical tests performed. The five clusters are decreased drive and motivation (NPI-Q item apathy), emotional dysregulation (NPI-Q items elation, anxiety & depression), impulse dyscontrol (NPI-Q items agitation, irritability & motor disturbances), social inappropriateness (NPI-Q item disinhibition), and psychosis (NPI-Q items delusions & hallucinations). WMH were graded by trained experts on the ARWMC scale (CT or MRI scans) and Fazekas scale for periventricular and sub-cortical regions (MRI scans). Analyses were conducted in RStudio version 4.2.0. Differences in prevalence of any NPS or NPS clusters in the diagnostic groups were determined by chi-squared tests. Binary and ordinal logistic regressions were used to predict presence of any NPS or NPS clusters, controlling for age, sex, and years of education. All analyses were considered significant at a two-tailed p-value In total, 307 participants were included (Table 1). NPS prevalence was lower in all patient groups compared to CU and was lower in MCI compared to AD but not in v-MCI compared to MD (Table 1). Decreased drive and motivation was less prevalent in MCI compared to both AD and v-MCI whereas emotional dysregulation was less prevalent in MCI than in AD. The prevalence of other clusters did not differ between patient groups. The prevalence of WMH did not differ between any participant groups. Consistent with inclusion criteria, the grades on the ARWMC scale and Fazekas periventricular and subcortical scales were higher in v-MCI and MD than in MCI and AD, respectively. Across the study cohort, the presence of NPS was associated with an increasing grade on the ARWMC scale (Z=2.0, p \x9D<0.05) and Fazekas periventricular scale (Z=2.4, p =0.01) but not with presence of WMH or with grades on Fazekas subcortical scale. Among NPS clusters, decreased drive and motivation was associated with an increasing grade on the ARWMC scale and Fazekas periventricular scale (Z=2.1, p =0.04; Z=2.5, p =0.01, respectively), whereas emotional dysregulation was only associated with increasing grade on Fazekas periventricular scale (Z=2.3, p =0.02). In analysis restricted to CU, MCI, and v-MCI, presence of any NPS and impulse dyscontrol was associated with an increasing grade on Fazekas periventricular scale (Z=2.4, p =0.01, Z=2.0, p <0.0 5) whereas decreased drive and motivation was associated with increasing grade of ARWMC (Z=2.6, p =0.01) and Fazekas periventricular scale (Z=2.8, p =0.005). These results suggest that NPS, especially apathy and emotional dysregulation, are more frequent in MCI than AD but occur at a similar rate in v-MCI and MD, indicating that NPS might develop earlier with vascular disease than with AD. The increase in prevalence of NPS, apathy, and symptoms of impulse dyscontrol with increasing grade on the Fazekas scale for periventricular regions but not subcortical regions support the contribution of periventricular vascular changes to the development of NPS. ST is supported by the Canadian Consortium on Neurodegeneration in Aging, and EB was supported by the University of Toronto's Comprehensive Research Experience for Medical Students program and by the Toronto Dementia Research Alliance. [ABSTRACT FROM AUTHOR]

Oxidative stress (OS) has been implicated in age-related neurodegeneration and may be important in prodromal states such as mild vascular cognitive impairment (mVCI). Higher peripheral OS is reported in mVCI patients; however, the role of central antioxidant defenses in mVCI is unclear. Glutathione (GSH) is a major brain antioxidant, and so brain GSH in possible mVCI vs. controls was assessed. Possible mVCI patients (1 standard deviation (SD) below population norms in verbal memory, executive function (EF), processing speed, or working memory, age 55-85, and currently enrolled in a cardiac rehabilitation program due to having 2 or more vascular risk factors or previous vascular event) and cognitively normal (CN) controls are recruited from a 6-month exercise rehabilitation program. All participants received 1H magnetic resonance spectroscopy (MEscher–GArwood Point Resolved Spectroscopy) to quantify brain GSH at baseline in the anterior cingulate (AC) and occipital cortex (OC). Spectroscopic analysis was completed using the Gannet toolkit (vers. 3.1) in Matlab (vers. 2020b). In 28 participants (mVCI n = 14, CN n = 14), after correcting for cerebrospinal fluid volume, anterior cingulate (AC) GSH (I.U. ± SD) was higher in mVCI (2.67 ± 0.29) compared to CN (2.25 ± 0.67) (F (1,25) = 4.7, P = 0.04) but not in the occipital cortex (OC, F (1, 25) = 1.3, p = 0.27). Higher AC-GSH was correlated with lower Montreal Cognitive Assessment score (rho (24) = -0.46 p = 0.02). In mVCI participants, higher AC-GSH also correlated with lower EF composite score (r (12) = -0.55 p = 0.04). Preliminary data suggest an upregulation in anterior cingulate glutathione in mVCI, which might reflect a compensatory increase in antioxidants as a response to increase peripheral oxidative stress previously reported in these patients. Recruitment is ongoing and additional participants are needed to reinforce findings. Canadian Institute of Health Research (#376204), the Alzheimer's Association Part the Cloud™ (PTC-18-543823), and the Alzheimer Society of Canada Research Program (21-11) [ABSTRACT FROM AUTHOR]

Apathy is common in Alzheimer's disease dementia, where it has been associated with faster disease progression and greater cognitive decline. Apathy is associated with cognitive impairment, particularly executive functions such as selective attention. As such, the nosological position of apathy as a separate syndrome from cognition may be debated. Previous randomized placebo-controlled trials showed improvements in both apathy and cognition with methylphenidate (MPH). ADMET 2 is the largest and most recent trial assessing apathy and cognition to date. This analysis assessed whether changes in apathy correlated to changes in global cognition, selective attention and working memory in ADMET 2. ADMET 2 was a multicenter, phase III, placebo-controlled clinical trial of 200 mild to moderate AD patients with clinically significant apathy, where participants were randomized to receive 20 mg methylphenidate or placebo for 6 months. A Pearson correlation analysis was used to compare change in Mini-Mental Status Examination (MMSE) assessing global cognition and change in apathy on the Neuropsychiatric Inventory (NPI) apathy subscale. Change scores were calculated using the average change in scores between baseline and 6 months. Pearson's correlation was also used to compare the change in digit span forward (DF) for selective attention and digit span backward (DB) for working memory with change in apathy scores on NPI in methylphenidate and placebo groups. Of 200 ADMET 2 participants, 165 completed baseline and post-treatment cognitive tests (82 methylphenidate, 83 placeboes; mean age 76 yrs.; 109 (66%) male). Overall, change in NP apathy was correlated with changes in MMSE (r=0.097, p= 0.03), but not DF (r=-0.079, p=0.08) or DB (r=-0.083, p=0.06). In the placebo group, change in NP Apathy score was correlated with change in MMSE (r=0.15, p=0.015) and change in DF (r=-0.15, p=0.017), but not change in DB (r=-0.013, p=0.84). In the methylphenidate group, there were no correlations between change in NP Apathy Score and change in MMSE (r=0.057, p=0.37), or DF (r=-0.0074, p=0.91), but there was a correlation with change in DB (r=-0.14, p=0.026). In ADMET 2, changes in apathy symptoms were not consistently correlated with changes in global cognition, selective attention or working memory as relationships differed in MPH and placebo groups. This could indicate that apathy and cognition respond independently to MPH. These results are consistent with the view that apathy as a syndrome is related to, but distinct from cognition. Funding was provided by the National Institute on Aging (grant R01 AG046543). [ABSTRACT FROM AUTHOR]

Objective: Older adults with depression are at increased risk of Alzheimer dementia, but predictors of increased risk remain incompletely understood. We aim to identify characteristics of older adults with depression most at risk of progressing to Alzheimer dementia. Identification of high-risk subgroups could facilitate future interventional strategies to reduce risk of Alzheimer dementia in older adults with depression.Methods: Using data from the National Alzheimer's Coordinating Center, 1,965 participants with clinically defined depression and mild cognitive impairment at baseline were followed until development of Alzheimer dementia or loss to follow-up.Results: Seven hundred and eighty (39.7%) developed Alzheimer dementia over a median follow-up duration of 27 months. In survival analyses, age (hazard ratio [HR] 1.04, 95% 1.03-1.05), baseline Mini-Mental State Exam (HR 0.85, 95% confidence interval 0.83-0.87), amnestic subtype of mild cognitive impairment (HR 1.66, 95% 1.30-2.12), presence of APOE4 allele (HR 1.99, 1.69-2.36), and presence of active depression within the last two years (HR 1.44, 95% confidence interval 1.16-1.79) were all independently associated with increased risk of Alzheimer dementia. Six hundred and fifty-six (41.7%) participants with mild cognitive impairment and active depression within the last two years developed Alzheimer dementia compared to 120 (31.6%) of those with a more remote history of depression.Conclusion: Older adults with depression and mild cognitive impairment demonstrated a high rate of progression to Alzheimer dementia over a relatively short duration of follow-up. Individuals with a combination of mild cognitive impairment and recently active depression are a particularly high-risk subgroup. [ABSTRACT FROM AUTHOR]

Guidelines that physicians use to assess fitness to drive for dementia are limited in their currency, applicability, and rigor of development. Therefore, we performed a systematic review to determine the risk of motor vehicle collisions (MVCs) or driving impairment caused by dementia, in order to update international guidelines on driving with dementia. Seven literature databases (MEDLINE, CINAHL, Embase, etc.) were searched for all research studies published after 2004 containing participants with mild, moderate, or severe dementia. From the retrieved 12,860 search results, we included nine studies in this analysis, involving 378 participants with dementia and 416 healthy controls. Two studies reported on self-/informant-reported MVC risk, one revealing a four-fold increase in MVCs per 1,000 miles driven per week in 3 years prior, and the other showing no statistically significant increase over the same time span. We found medium to large effects of dementia on driving abilities in six of the seven recent studies that examined driving impairment. We also found that persons with dementia were much more likely to fail a road test than healthy controls (RR: 10.77, 95% CI: 3.00-38.62, z = 3.65, p < 0.001), with no significant heterogeneity (χ2 = 1.50, p = 0.68, I2 = 0%) in a pooled analysis of four studies. Although the limited data regarding MVCs are equivocal, even mild stages of dementia place patients at a substantially higher risk of failing a performance-based road test and of demonstrating impaired driving abilities on the road. [ABSTRACT FROM AUTHOR]

Apathy is one of the most common neuropsychiatric symptoms in Alzheimer's disease, affecting up to 70% of patients. This paper uses data from the ADMET 2 clinical trial to conduct a cost consequence analysis to investigate whether apathy treatment with methylphenidate is economically attractive. 167 patients with clinically significant apathy participating in ADMET 2 were included. Baseline demographics are included in Table 1. The Resource Utilization in Dementia Lite instrument was used to assess resource utilization for the past 30 days over 3 different time points, and the EuroQol-five dimensions-five levels (EQ-5D-5L) was used to assess health utility at the same time. Health utility is a numerical value (ranging from 0.0 to 1.0) that describes the state of health of a patient. A value of 1.0 represents full health and 0.0 represents a health state equal to death. Utility values can also be negative, below 0.0, which represent health states worse than death. Higher utility values represent better health states. The EQ-5D-5L is a general preference-based measure of health utility that allows patients to describe different aspects of their health and assigns a health utility score based on these descriptions. Costs were analyzed using the societal perspective and a repeated measures ANOVA was used to assess change in cost and utility over time between the treatment and placebo groups. A binary logistics regression was used to assess cost predictors. Costs excluding methylphenidate were not significantly different between the methylphenidate and placebo groups (F(2,330)= 0.626, η p 2= 0.004, p= 0.535). Costs including methylphenidate were not significantly different between the two groups (F(2,330)= 0.629, η p 2= 0.004, p= 0.534). Utility improved with methylphenidate treatment as there was a significant interaction effect with the methylphenidate group and time (F(2,330)= 7.525, η p 2= 0.044, p <0.001). Methylphenidate treatment is not associated with significantly higher costs over 6 months but is associated with significantly improved health utility. These results warrant further investigation that can aid in decision making to improve quality of life in patients with Alzheimer's disease while reducing the burden on the healthcare system. ADMET 2 was funded by the National Institute on Aging. [ABSTRACT FROM AUTHOR]

Mild cognitive impairment (MCI) is highly prevalent in older adults and is a well-established prodromal stage of Alzheimer's disease (AD). MCI may be accompanied by early signs of neuronal injury that can be difficult to detect, at least non-invasively, and which may be indicative of neurodegeneration. Neurofilament light chain (NfL), a protein released in response to axonal injury, has recently emerged as a potential biomarker for neurodegenerative conditions, such as AD. In the present study, we have systematically assessed the available literature to quantitatively evaluate cerebrospinal fluid (CSF) and peripheral concentrations of NfL in individuals with MCI compared to cognitively healthy controls (HCs). Medline, Embase, APA PsychInfo, and Cochrane Central Register of Controlled Trials databases were searched from inception to May 6th, 2022. Original peer-reviewed articles that assessed CSF and/or peripheral (serum or plasma) NfL concentrations in individuals with MCI and HCs were included for meta-analysis. Standardized mean differences (SMDs) and 95% confidence intervals (CIs) were calculated using a random-effects model. Heterogeneity was assessed using the I2 statistic. In total, 56 studies were included in the meta-analysis. Of these studies, 24 (MCI n=2695, HC n=4185) compared CSF NfL levels and 32 (MCI n=4000, HC n=6986) measured peripheral NFL levels. NfL was elevated in MCI compared to HCs in both CSF (SMD [95% CI] = 0.62 [0.48, 0.76], Z 24 = 8.92, p < 0.001; I2 = 80%) and peripheral blood (SMD [95% CI] = 0.44 [0.35, 0.53], Z 31 = 9.52, p < 0.001; I2 = 73%). The findings from this study suggest that elevated NfL levels may facilitate the detection of neuronal injury associated with MCI. Because heterogeneity was identified, it will be comprehensively explored by assessing the relationship between NfL and factors such as amyloid-β status, sex, and age through sub-group analyses and meta-regression. Nonetheless, this marker provides further insight into the neuropathological alterations occurring in the early stages of cognitive decline. We suggest that future studies should focus on assessing the clinical utility of monitoring NfL levels in this prodromal patient population. We gratefully acknowledge funding support from the Alzheimer's Association (Part the Cloud) and the Canadian Institute of Health Research. [ABSTRACT FROM AUTHOR]

Apathy is a neuropsychiatric symptom that is common across neurodegenerative disorders. Structural imaging studies have associated apathy with grey matter (GM) atrophy in areas including the anterior cingulate cortex and ventral striatum. However, few studies have examined whether similar associations between apathy and GM atrophy are present across neurodegenerative disorders. Here, we aim to determine the relationship between GM atrophy and apathy severity in patients with Alzheimer's Disease (AD), Parkinson's Disease (PD), and Mixed Dementia (MD). Participants in the COMPASS-ND study with a diagnosis of AD, PD, MD, or those who were cognitively unimpaired (CU) were included in the current study. The Neuropsychiatric Inventory Questionnaire (NPI-Q) apathy question was used to determine the presence and severity (mild, moderate, or severe) of apathy. Voxel-based morphometry in the FMRIB Software Library program was used to compare GM volume between participants, controlling for age, sex, and global cognition (based on the Montreal Cognitive Assessment). GM volume of participants without apathy was compared to those with apathy and those with more clinically significant moderate or severe apathy. T-values were considered significant at a Threshold Free Cluster Enhancement (TFCE)-corrected p<0.05. In total, 182 participants (92 male, mean age 71.9) were included. Within the diagnostic groups, apathy (n=60) was present in 2/53 CU, 26/53 AD, 23/55 PD and 9/21 MD participants. Participants with moderate or severe apathy had GM atrophy in the left posterior insula (tmax=4.3, cluster size = 74) compared to participants without apathy. Patients with moderate apathy showed GM atrophy in the left posterior insula (tmax=4.6, cluster size = 675), superior parietal lobule (tmax =4.07, cluster size = 544), supramarginal gyrus (tmax=3.2, cluster size = 479), superior temporal gyrus (tmax= 3.22, cluster size = 168), and temporal fusiform cortex (tmax =3.08, cluster size = 32) compared to participants without apathy. No significant differences in GM atrophy were found between patients without apathy and patients with mild apathy. This exploratory analysis indicated that moderate to severe apathy was associated with GM atrophy in the left posterior insula, in addition to temporal and parietal areas across different neurodegenerative conditions. The insula has previously been associated with GM atrophy in apathetic patients across neurodegenerative disorders, in line with our results. These results indicate that common brain changes may underly apathy across neurodegenerative disorders. Future studies could aim to uncover common and unique associations between GM atrophy and apathy among these disorders, and investigate sex differences in those associations. Shankar Tumati was supported by a fellowship from CCNA Team 11 is supported by CCNA Daksh Datta received supported from the University of Toronto's Comprehensive Research Experience for Medical Students program and from the Toronto Dementia Research Alliance [ABSTRACT FROM AUTHOR]

Objective: To test the hypothesis of an increased incidence of antiparkinson drug prescribing or Parkinson disease (PD) diagnostic codes after chronic lithium treatment compared with chronic valproic acid or antidepressant treatment among older adults.Methods: A retrospective cohort study using healthcare administrative databases in Ontario, Canada included 1,749 lithium users, 1,787 valproic acid users, and 285,154 other antidepressant users ≥ 66 years old having used the drug continuously in monotherapy for at least 1 year. Outcome measures were start of (1) a dopaminergic medication (levodopa or a dopamine agonist), (2) any antiparkinson drug (levodopa, dopamine agonists, anticholinergic medication, amantadine, monoamine oxidase B inhibitors), (3) any antiparkinson drug or a diagnostic code for PD, and (4) any antiparkinson drug in the absence of a diagnostic code for PD.Results: For patients with no previous antipsychotic use, lithium monotherapy was associated with an increased incidence of dopaminergic drug use (adjusted HR: 1.87; 95% CI: 1.06-3.30) and an increased incidence of antiparkinson drug use or a PD diagnosis (adjusted HR: 1. 68; 95% CI: 1.13-2.48) compared with antidepressant monotherapy.Conclusion: Chronic lithium use is associated with an increased incidence of dopaminergic drug use compared with antidepressants, identifying a prescribing cascade related to lithium use in the elderly. Whether this reflects inappropriate treatment of action tremor or treatment of drug-induced parkinsonism should be addressed by a close examination of prescribing practices. [ABSTRACT FROM AUTHOR]

Objective: Guidelines worldwide have cautioned against the use of antipsychotics as first-line agents to treat neuropsychiatric symptoms of dementia. We aimed to investigate the changes over time in the dispensing of antipsychotics and other psychotropics among older adults with dementia living in long-term care facilities.Methods: We used drug claims data from Ontario, Canada, to calculate quarterly rates of prescription dispensing of six psychotropic drug classes among all elderly (≥65 years of age) long-term care residents with dementia from January 1, 2004, to March 31, 2013. Psychotropic drugs were classified into the following categories: atypical and conventional antipsychotics, non-sedative and sedative antidepressants, anti-epileptics, and benzodiazepines. We used time-series analysis to assess trends over time.Results: The study sample increased by 21% over the 10-year study period, from 49,251 patients to 59,785 patients. The majority of patients (within the range of 75%-79%) were dispensed at least one psychotropic medication. At the beginning of the study period atypical antipsychotics (38%) were the most frequently dispensed psychotropic, followed by benzodiazepines (28%), non-sedative antidepressants (27%), sedative antidepressants (17%), anti-epileptics (7%), and conventional antipsychotics (3%). Dispensing of anti-epileptics (2% increase) and conventional antipsychotics (1% decrease) displayed modest changes over time, but we observed more pronounced changes in dispensing of benzodiazepines (11% decrease) and atypical antipsychotics (4% decrease). Concurrently, we observed a substantial growth in the dispensing of both sedative (15% increase) and non-sedative (9% increase) antidepressants. The proportion of patients dispensed two or more psychotropic drug classes increased from 42% in 2004 to 50% in 2013.Conclusions: Utilization patterns of psychotropic drugs in institutionalized patients with dementia have changed over the past decade. Although their use declined slightly over the study period, atypical antipsychotics continue to be used at a high rate. A decline in the use of benzodiazepines along with an increased use of sedative and non-sedative antidepressants suggests that the latter class of drugs is being substituted for the former in the management of neuropsychiatric symptoms. Psychotropic polypharmacy continues to be highly prevalent in these patient samples. [ABSTRACT FROM AUTHOR]

The article looks at the relationship between coronary artery disease (CAD) and cognitive decline in older people, discussing the authors' research on microstructural characteristics of white matter (WM) in older CAD patients in relation to their cognitive ability.

The article reports on research which was conducted to develop physician consensus on the reporting of patients with mild cognitive impairment and dementia to transportation authorities in an area with no mandatory reporting laws. Researchers conducted a literature search of predictors of driving safety in patients with dementia. They found that the strongest predictors of a decision to report were caregiver concern about driving ability and abnormal Clock Drawing Test results for the patient.

The article presents a study aimed at estimating the prevalence of and describing the clinical correlates of renal disease in a cohort of lithium-using older adults. Findings discussed include the higher prevalence rates for chronic kidney disease (CKD) shown by older lithium users, the discovery that lithium duration of more than 2 years is linked to a 1.7 times increased risk of CKD, and the commonality of CKD in geriatric lithium users.

There is a dearth of information on older users (65+ years) of medical cannabis, who may face unique challenges due to altered metabolism with aging, concurrent medication use, and risk of adverse effects. This observational study aimed to describe a large cohort of older medical cannabis users in Canada. From Oct 2014 to Oct 2020, a commercial medical cannabis provider based in Canada collected anonymized data for research purposes from patient volunteers. Data included demographic, social, and health details (at intake) and cannabis products, self-perceived changes in symptoms and change in medications (at follow-up, variable duration). Cannabis products were categorized as cannabidiol (CBD) only, tetrahydocannabinol (THC) only or mixed CBD/THC. Of the mixed, formulations could be in 1:1 ratios (CBD+/THC+), predominantly CBD (CBD+/THC-) or predominantly THC (CBD-/THC+). In total, 9766 subjects in the older cohort (65+ years old) completed the entire questionnaire (mean age (SD) = 73.6 (6.8) y, 60% female). They represented 23.1% of the total dataset (N = 42,267, mean (SD) =51.5 (16.8) y). The proportion of adults in the older cohort tended to increase over time (pre-2018: 17.6%; 2018: 26.7%; 2019: 31.2%; 2020: 22.7%, when the overall intake decreased from 8869 to 5644). Among the older cohort, 15.5% were previous cannabis users and 67.7% were referred for chronic pain (mainly arthritis, chronic pain, lower back pain). Concomitant analgesic use was common (over-the-counter analgesics: 44.5%; opioids: 28.3%; NSAIDs: 24.5%). 7.9% of the sample (compared to 19.9% in the whole sample) were referred for psychiatric disorders, though 21.4% indicated antidepressant use and 12.3% indicated benzodiazepine use. Another 7% were referred for neurological disorders. Follow-up data were captured in visits (11,992) from 4698 older patients, averaging 2.5 visits per patient. The type of medical cannabis used changed over time, with increasing use of cannabis oil compared to herbal cannabis. In 2020, of 2478 visits, 78.9% use was cannabis oil and 6.7% was herbal forms (pre-2018: 57.6% vs 36.2%). The composition of cannabis oil demonstrated a preference for cannabinoid oil (CBD+) over tetrahydrocannabinol (THC+) in 6043 visits: 45.2% were using CBD+ preparations, only 3.2% were using THC+ preparations, and for CBD/THC combinations, CBD predominated (CBD+/THC-: 30.5%; CBD+/THC+: 16.8%; CBD-/THC+: 4.3%). Adverse-effects (7062 visits) included dry mouth (15.8%), drowsiness (8.6%), dizziness (4%) and hallucinations (0.6%). Patients reported improved pain, sleep and mood over time, though 15-20% reported no improvement or worsening. Medication use was mostly unchanged, though 40% of opioid users reported requiring reduced dosages. These data were drawn from a large convenience sample. The data suggest an increasing proportion of older users of medical cannabis, though COVID-19 may have affected recent use. Female users comprised a higher proportion, and cannabis oil containing CBD was preferred. Systematic studies of effectiveness and safety in older users of cannabinoids are needed given its increasing use. No funding was received for this work. [ABSTRACT FROM AUTHOR]

The article presents an overview of the design of the Apathy in Dementia Methylphenidate Trial (ADMET), a randomized clinical trial to assess the effectiveness and safety of the psychiatric drug methylphenidate in treating the neuropsychiatric symptom of apathy in Alzheimer disease patients. Topics include the diagnostic definition of apathy and its differentiation from depression, patient recruitment, and primary and secondary medical outcomes.

Amnestic Mild Cognitive Impairment (aMCI) is a prodromal stage to Alzheimer's disease dementia (AD). Improving prefrontal cortical function in individuals with MCI could prevent progression from aMCI to AD. A key mechanism that has been linked to memory formation and thus may underlie this progression is cortical plasticity. Paired Associative Stimulation (PAS) is an intervention that uses transcranial magnetic stimulation (TMS) to enhance cortical plasticity. When delivered to the prefrontal cortex in individuals with AD, it has shown promise to improve prefrontal cortical plasticity and working memory. PAS-MCI is a randomized controlled trial (RCT) that aims to assess: (1) dorsolateral prefrontal cortex (DLPFC) plasticity in individuals with aMCI and compare it to cognitively unimpaired control participants, (2) the efficacy of PAS delivered for 10 days bilaterally to the DLPFC of individuals with aMCI in enhancing their DLPFC plasticity, working memory, and executive function, and (3) whether changes in DLPFC plasticity mediate changes in working memory and executive function. 100 aMCI and 50 cognitively unimpaired (CU) control participants will be assessed clinically and cognitively, and then undergo a baseline PAS combined with electroencephalography (PAS-EEG) to characterize left DLPFC plasticity. The aMCI participants are randomized (1:1) to receive 10 daily sessions of either active or sham PAS delivered to the left and right DLPFC. On Day 0, 7, and 28 following the 10-day PAS course, participants undergo repeat cognitive testing and PAS-EEG to assess changes in working memory, executive function, and left DLPFC plasticity. Recruitment started on October 12, 2020 and as of October 16, 2021, we have already consented 9 aMCI and 7 CU participants. Of the 16 participants, 4 MCI and 4 CU participants were enrolled and 3 MCI and 4 CU completed the study (1 MCI participant is still active). Among the 5 participants who did not enroll, 3 were excluded because of: a contraindication for TMS (n = 1), having dementia and not MCI (n = 1), and having non-amnestic MCI (n = 1); 1 withdrew before enrolment due to fatigue; and 1 is still undergoing eligibility assessments. Among the 3 CU participants who did not enroll, 2 were excluded because of low cognitive scores and 1 is still undergoing eligibility assessments. Despite the COVID-19 pandemic, we were able to initiate recruitment over the past year. If successful, this RCT will establish the short-term efficacy of PAS, a new TMS approach to enhance prefrontal cortical function in individuals with aMCI. A follow-up longer-term trial will be then needed to assess whether PAS could prevent cognitive decline and progression to AD. Canadian Institutes of Health Research (CIHR) Project Grant # 201809 (PI: Rajji) [ABSTRACT FROM AUTHOR]

Both the DSM-5 and NIA-AA (Albert et al., 2011) stipulate methods for assessing and diagnosing cognitive decline but differ in their approach for estimating cognitive ability. The DSM suggests that evidence of cognitive decline is demonstrated either through culturally normed neuropsychological evaluation or through the use of "bedside" assessments such as the Mini Mental State Examination (MMSE) or Montreal Cognitive Assessment (MoCA). By contrast, the 2011 recommendations from the National Institute of Aging – Alzheimer Association (NIA–AA) emphasize the use of objective testing ideally via a neuropsychological evaluation of cognitive impairment in one or more cognitive domains. The current study compared differences in diagnostic rates between these two standards. Since the NIA-AA standards emphasize a more detailed cognitive assessment, we hypothesized that these criteria would identify a larger proportion of individuals with cognitive impairment than the DSM-5 criteria. We then examined possible clinical predictors of this discrepancy, including demographic, psychosocial, health-related, and genetic factors. Data was drawn from 604 participants who were recruited into the Prevention of Alzheimer's Disease With Cognitive Remediation Plus tDCS in Mild Cognitive Impairment and Depression (PACt-MD; ClinicalTrials.gov Identifier: NCT02386670) trial. This is a randomized, controlled trial to evaluate brain stimulation and computerized brain training interventions for the prevention of cognitive decline in older adults. Participants either had a clinical history of mild cognitive impairment (MCI), major depressive disorder in remission, both, or were recruited as healthy controls without history of cognitive difficulty or mental disorder. All participants underwent a clinical and neuropsychological evaluation. Cognitive diagnoses were determined during biweekly consensus conferences. Both the DSM-5 and NIA-AA criteria were used during each consensus conference. The current analysis is based on the baseline data (i.e., prior to the intervention) of the 455 participants for whom a consensus conference was completed. We first compared diagnostic rates of MCI (NIA-AA) vs. mild neurocognitive disorder (DSM-5), as well as dementia (NIA-AA) vs. major neurocognitive disorder (DSM-5). We then used binary logistic regression models to examine demographic (age, education, race, sex, premorbid intellectual ability), psychosocial (English as a primary language, history of depression), health-related (severity of medical illness burden), and genetic (APOE e4 carrier status) predictors of diagnostic discrepancy between DSM-5 and NIA-AA criteria. Analyses were conducted separately for two groups of participants: (i) the group for which NIA-AA diagnoses reflected greater cognitive impairment than did the DSM-5 diagnoses (e.g., NIA-AA diagnosis of dementia but DSM-5 diagnosis of mild neurocognitive disorder); and (ii) the group for which DSM-5 diagnoses reflected greater cognitive impairment (e.g., DSM-5 diagnosis of major neurocognitive disorder but NIA-AA diagnosis of MCI. At baseline, there were 103 (22.6%) cases of discrepant diagnoses between the two classification systems: 50 cases had a NIA-AA diagnosis of MCI and no DSM-5 cognitive diagnosis (i.e., normal cognitive status); 41 cases had a NIA-AA diagnosis of dementia and a DSM-5 diagnosis of mild neurocognitive disorder; 12 cases had a DSM-5 diagnosis of mild neurocognitive disorder and no NIA-AA diagnosis. Compared to the 352 cases in agreement, the 91 cases with NIAA diagnoses reflecting greater cognitive impairment were more likely to have a history of major depressive disorder in remission (46% vs. 39%; B=-1.058, p=.003), be an APOE4 carrier (50% vs. 27%; B=-1.120, p=.001), and be older (72?vs. 71 years; B=.063, p=.02). APOE4 status, history of depression, and age were independent predictors. Compared to the 352 cases in agreement, the 12 cases with DSM-5 diagnosis reflecting greater cognitive impairment were less likely to have a history of depression (17% vs. 41%; B=2.414, p=.025). While there was overall agreement with cognitive diagnoses when using NIA-AA or DSM-5 criteria, the two systems were discrepant in 22.6% of cases. Discrepancies were more likely to occur in participants with a history of depression, who were APOE4 carriers, or who were older. Overall, NIA-AA criteria yielded diagnoses reflecting greater cognitive impairment, especially in participants with a history of prior depression or those who were APOE4 carriers. These results suggest that more detailed neuropsychological evaluations may be indicated in older adults with a history of depression or who have a genetic vulnerability to dementia. 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. [ABSTRACT FROM AUTHOR]

Current pharmacotherapies for Alzheimer's disease (AD) are only modestly effective. There remains a critical need for treatments focused on early stages of the disease, when quality of life is still potentially excellent. While transcranial direct current stimulation (tDCS) has been shown to improve memory in some people with Mild Cognitive Impairment (MCI) and mild AD with minimal side-effects, recent evidence suggests that tDCS works better when brain circuits are active. As exercise increases brain activity using mechanisms that may support tDCS response, it may be an effective primer given before tDCS. This study assesses whether exercise priming with tDCS can help improve memory in MCI and mild AD, and whether this combination improves memory better than exercise or tDCS alone. In this 5-week, randomized, blinded, sham-controlled clinical trial, eligible patients receive either 1) combined exercise and tDCS, 2) exercise and sham tDCS, or 3) exercise education only and tDCS. Repeated measures analyses of covariance will be conducted to evaluate between-group differences on cognitive outcomes over time. Blinded preliminary findings are presented (N=10, mean age=74±6?years, 50% female, mean years of education=16.2±2.5?years, mean Montreal Cognitive Assessment (MoCA) score= 21.5±2.9). There was a significant effect of treatment over time on Word Recall scores (F(2,7)=5.5, p=0.036). There were no statistically significant differences between groups over times on MoCA (F(2,7)=3.6, p=0.085) or Word Recognition scores (F(2,7)=4.5, p=0.054). Participants randomized to exercise education only with tDCS did not increase their exercise frequency or intensity according to the Leisure Time Exercise Questionnaire. Participants randomized to exercise priming were able to exercise at a moderate-intensity level for the last two weeks of the study when receiving combined tDCS or sham tDCS treatment. Overall adherence to study interventions was 98%. Recruitment is ongoing (N=10/30). Updated results will be presented. This study may identify a new, feasible, non-invasive combination therapy that improves cognitive function in MCI and early stages of AD, therefore having major health implications. This research was funded by: Canadian Institutes of Health Research [ABSTRACT FROM AUTHOR]

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 <0.05. 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<0.05). 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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Apolipoprotein (APOE) ε4 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 ε4 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). 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 ε3/ε3, the most common isoform, was used as the baseline category in regression analysis. All findings reported are compared to this baseliine category. When analysing the effects of APOE and sex alone, we only found a significant inverse association between NPI-Q Total and APOE ε3/ε4 carriers compared to APOE ε3/ε3 carriers (n = 38, b = -1.04, t (170) = -2.28, p = 0.024). When analysing our interaction terms APOE ε4/ε4 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 ε2/ε3 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 ε2/ε3 females showed higher NPI-Q Total severity scores than APOE ε3/ε3 carriers (b = 3.57, t(171) = 2.45, p = 0.015). After adjusting for covariates, being APOE ε2/ε3 females (b = 3.3, t (162) = 1.49, p = 0.027) or APOE ε4/ε4 females (b = 3.8, t (162) = 1.78 p = 0.033) was associated with greater NPI-Severity. 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 ε4 may be susceptible to the highest NPS burden. Further investigation of the interactive effects of sex and APOE ε4 on NPS burden with larger samples are needed. 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. [ABSTRACT FROM AUTHOR]