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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]

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

Background: Interventions to prevent cognitive decline and dementia in high‐risk populations such as those with remitted Major Depressive Disorder (rMDD) or Mild Cognitive Impairment (MCI) are urgently needed. Method: PACt‐MD was a double‐blind randomized trial conducted between 2015 and 2022 comparing cognitive remediation (CR) plus transcranial Direct Current Stimulation (tDCS) vs. sham‐CR+sham‐tDCS delivered 5 days/week for 8 weeks followed by 5‐day semi‐annual boosters and at‐home daily CR, in participants with rMDD or MCI. Participants were assessed at baseline, week‐8, and yearly. The hypotheses were that compared to sham+sham, CR+tDCS would: slow cognitive decline (H1); reduce progression to MCI or dementia (H2); and acutely improve cognition (H3). The primary outcome composite score was calculated when at least half of the tests for at least four of six cognitive domains were completed. Due to COVID‐19, some participants did not complete enough tests and a second composite score using all available data was generated. Result: 375 participants were randomized (Active: N = 188, Mean Age = 72.1 ± 6.3; Sham: N = 187, Mean Age = 72.3 ± 6.4) and received at least one intervention session. Over up to six years, there was no time‐by‐treatment interaction using the primary composite score but there was using the all‐data score. Change in composite score differed between the two intervention groups for the primary and all‐data scores for all years except for year‐6 primary score. The year‐5 adjusted z‐score difference was ‐0.15 (95%CI [‐0.29, ‐0.005]) for the primary and ‐0.21 (95%CI [‐0.34, ‐0.067]) for all‐data score (Fig.1). Comparing active vs. sham at 8‐week (H3), the adjusted z‐score difference was ‐0.06 (95%CI: [‐0.12, 0.005]; p = 0.072); and for progression (H2), HR was 0.66 (95%CI [0.40, 1.08] p = 0.101) in a stratified Cox model. In a preplanned secondary analysis of domain scores, there was a time‐by‐treatment interaction for verbal memory with a year‐5 adjusted z‐score difference of ‐0.30 (95%CI [‐0.53, ‐0.074]) (Fig.2) but not the other domains. In another preplanned secondary analysis, the model with a randomization diagnosis‐by‐time‐by‐treatment was different from the model without this three‐way interaction (p = 0.012; Fig.3). Conclusion: CR+tDCS may be effective in slowing cognitive decline (particularly verbal memory) in older patients with rMDD or MCI. [ABSTRACT FROM AUTHOR]

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

Background: Emotion dysregulation was studied as a potential risk marker for Alzheimer's disease (AD) by assessing emotional memory in high AD‐risk groups characterized by the presence of mild cognitive impairment (MCI) or remitted major depressive disorder (rMDD) and by evaluating the relationship between emotional memory and in vivo cerebral amyloid‐β deposition. Method: 435 participants enrolled in the PACt‐MD clinical trial of cognitive remediation plus transcranial direct current stimulation were evaluated at baseline. The sample included 127 older adults with amnestic mild cognitive impairment (aMCI), 51 non‐amnestic MCI (naMCI), 60 rMDD without MCI, 81 rMDD+aMCI, 42 rMDD+naMCI, and 74 cognitively unimpaired older adults (CU). Diagnoses were established during a consensus conference based on psychiatric, medical, and neuropsychological assessment. Emotional memory was assessed by evaluating immediate and short‐term delayed recall of 15 personality adjectives (5 each of positive, negative and neutral words) from the Emotional Verbal Learning Test (Mah et al., 2017, American Journal of Geriatric Psychiatry, 25:1160). A subset (N = 167) completed a Positron Emission Tomography (PET) scan with carbon‐11 Pittsburgh Compound B ([11C] PIB). Valence and diagnostic group effects on recall were assessed using mixed ANOVA. Regression modelling assessed the association between emotional memory bias and amyloid‐β burden. Result: Relative to CU, both aMCI and rMDD+aMCI groups showed enhanced memory for negative words at immediate recall, which persisted after short delay in the aMCI group only (F(1, 339) = 2.66, p =.048; Figure 1). Enhanced memory for negative words at short delay was predictive of in vivo cerebral amyloid‐β deposition (standardized beta =.117, t = 1.84, p =.067), over and above the contributions of age, sex, Apolipoprotein E genotype, depression diagnosis and symptoms, and long delayed verbal recall (F(4,154) = 25.8, p<.001, R2 =.41; Figure 2). Conclusion: The association between enhanced memory for negative personality adjectives and aMCI replicates earlier work in single‐domain aMCI (Mah et al., 2017) and suggests that aMCI is characterized by a negativity bias in memory. These findings, taken together with the relationship between a negativity bias in memory and amyloid‐β burden, suggest that emotion dysregulation, in the form of enhanced memory for negative information, is a potential marker of AD risk. [ABSTRACT FROM AUTHOR]

Background: Hypertension and diabetes have each been associated with an increased risk of progression to Alzheimer's disease (AD) dementia. Here, we investigated their combined impact on progression from cognitively normal to clinically‐diagnosed AD. Method: Cognitively normal individuals from the National Alzheimer's Coordinating Center were identified as having neither hypertension nor diabetes (HTN‐/DM‐), hypertension without diabetes (HTN+/DM‐), or hypertension with diabetes (HTN+/DM+). The presence of HTN and DM were based on their diagnosis from recent medical history or medication use. This study investigated whether HTN+/DM‐ or HTN+/DM+ were predictors of progression to clinically‐diagnosed AD compared to HTN‐/DM‐. In a subgroup analysis with post‐mortem data, we investigated whether HTN+/DM‐, and HTN+/DM+ were predictors of progression to clinically diagnosed AD due to underlying AD‐ and/or vascular neuropathology. Result: This study included N = 11074 cognitively normal individuals (mean age: 71.7 (9.0), MMSE: 28.9 (1.4), male: N = 3818 (34%)). Approximately 7% (N = 830) progressed to clinically‐diagnosed AD, and the average duration of follow‐up was 5.2 (3.6) years. Forty‐two percent (N = 4608) were HTN‐/DM‐, 45% (N = 5034) were HTN+/DM‐, and 13% (N = 1432) were HTN+/DM+. Both HTN+/DM‐ (hazard ratio (HR): 1.24 (1.17‐1.32), p<.001), and HTN+/DM+ (HR: 1.31 (1.19‐1.44), p<.001) were significant predictors of progression to clinically‐diagnosed AD. Subgroup analyses with post‐mortem data (N = 919) demonstrated that compared to HTN‐/DM‐, those with HTN+/DM‐ had a higher risk of progressing to clinically‐diagnosed AD with underlying cerebrovascular disease (CVD) neuropathology (HR: 1.54 (1.17‐2.03), p =.002), whereas those with HTN+/DB+ had a higher risk of progression to clinically‐diagnosed AD with underlying AD (HR: 2.10 (1.16‐3.79), p =.01) and cerebral amyloid angiopathy (CAA) neuropathology (HR: 1.52 (1.09‐2.12), p =.01). Conclusion: These findings demonstrate that underlying CVD neuropathology contributes to the risk of clinically‐diagnosed AD in individuals with HTN+/DM‐, while both AD and CAA neuropathology contributes to the risk of clinically‐diagnosed AD in individuals with HTN+/DM+. This suggests that individuals with HTN+/DM‐ and HTN+/DM+ vary phenotypically and may warrant the need for different treatment strategies to reduce the future risk of AD. [ABSTRACT FROM AUTHOR]

Background: Neuropsychiatric symptoms (NPS) are features of Alzheimer's Disease (AD) and a main cause of institutionalization. NPS in AD include agitation, depression, anxiety, elation, apathy, disinhibition, irritability, delusions, hallucinations and aberrant motor behavior. The onset of NPS worsens functional deficits by accelerating patients' cognitive decline and in 80% of cases increases caregiver burden and distress. NPS are difficult to treat and currently used medications have black‐box warnings, and weak evidence of efficacy in dementia patients. Here, we present preliminary data for improvement in NPI scores and NPI Caregiver Distress (NPI‐D) scores using IGC‐AD1, a combination of tetrahydrocannabinol (THC) and melatonin (IGC‐AD1). Method: Twelve patients with mild (15.38%) to moderate (84.6%) AD (NIA‐criteria, 10‐active, 2‐placebo, 81.5±5.5yrs, 69.2% women) participated in a three Cohort Phase‐1, MAD, safety and tolerability trial (IND146069, NCT04749563). In Cohort‐1, IGC‐AD1 was administered QD at 1ml for 14‐days (EOT). In Cohorts‐2 and 3, one ml BID and TID were administered respectively with a minimum of 4‐days washout between Cohorts. For all three Cohorts the NPI / NPI‐D were administered at baseline and EOT of each Cohort. Daily, solicited and non‐solicited adverse events (AEs) were monitored along with vital signs. A Wilcoxon matched‐pairs signed‐rank test (R‐Studio, dplyr) was used to independently compare differences between mean NPI and NPI‐D scores at baseline and EOT. Result: In Cohort‐1 mean NPI at baseline and EOT was 31.5 and 14.8 respectively (mean difference = ‐16.7, v = 55, p = 0.003). In Cohort‐2 mean NPI at baseline and EOT was 22.2 and 12.4 respectively (mean difference = ‐9.8, v = 48, p = 0.021). In Cohort‐3 mean NPI at baseline and EOT was 16 and 7.9 respectively (mean difference = ‐8.1, v = 35, p = 0.010). We report similar improvements in NPI‐D. (Cohort‐1: mean difference = ‐7, v = 15, p = 0.031; Cohort‐2: mean difference = ‐6.3, v = 43, p = 0.009; Cohort‐3: mean difference = ‐3.4, v = 30, p = 0.053). No changes in concomitant medication were observed. No serious AEs, no deaths, and no dropouts due to AEs were reported. Conclusion: GC‐AD1 was safe and well tolerated and is potentially efficacious in reducing NPS and associated caregiver distress, clinically and statistically, in AD as measured by the NPI, warranting a larger placebo‐controlled study. [ABSTRACT FROM AUTHOR]

Background: In 2020, the Lancet Commission identified 12 modifiable risk factors that may increase dementia risk at the population level. At the individual level, these risk factors may co‐occur; therefore, this study aimed to identify profiles of dementia risk factors in later midlife, and to explore differences in biological markers associated with those profiles. Methods: Participants aged 60‐64 without dementia at baseline and who identified as Caucasian were identified from the UK Biobank. Data for each risk factor (education, hearing loss, traumatic brain injury, hypertension, alcohol consumption, obesity, smoking, depression, social isolation, physical inactivity, air pollution, and diabetes) were collected using a standardized clinical assessment or through linkage of inpatient records. Latent class analysis was performed to identify latent classes of individuals; missing data were handled using full information maximum likelihood. A multigroup analysis was used to consider differences by self‐reported sex. Associations between the classes and a panel of 29 blood biomarkers across six broad categories (hormonal, inflammatory, kidney, liver, lipids, and metabolic) were explored using the Bolck, Croon, and Hagenaars (BCH) method, considering sex and controlling for age; pairwise comparisons between classes were made using z‐tests. Results: Among n = 117,275 participants (males: n = 53,426, females: n = 63,849), a 4‐class solution was identified based on model fit statistics. Invariance testing revealed significantly different class solutions between sexes (Δχ2 = 11,615, Δdf = 52, p < 0.001). In general, the following four groups were identified in both males and females: low risk, psychosocial risk, cardiometabolic risk, and risk related to substance use (Figure 1). These classes differed in their blood biomarkers in both males and females, with the greatest differences observed in females. Specifically, the largest differences were observed between the cardiometabolic risk class vs. other classes, and in biomarkers for inflammation and metabolism (e.g. c‐reactive protein, triglyceride:HDL cholesterol ratio). Conclusion: In both males and females in later midlife, four classes defined by modifiable dementia risk factors were identified. These profiles were associated with unique biomarker signatures. might further examine the effects of these risk factor profiles on dementia‐related pathophysiological changes. [ABSTRACT FROM AUTHOR]

Background: Apathy is one of the most frequent and long‐lasting neuropsychiatric symptoms (NPS) in Alzheimer's disease (AD). Up to 78% of AD patients exhibit apathy, which is related to caregiver distress, decreased quality of life, and increased morbidity. While many medications and behavioral interventions are used to treat apathy, the effects are often limited and lack in‐depth research to support these approaches. We present preliminary data for improvement in NPI‐apathy (NPI‐ap) scores and NPI Caregiver Distress (NPI‐D) scores using IGC‐AD1, a tetrahydrocannabinol (THC) and melatonin combination. Method: Twelve patients with mild (15.38%) to moderate (84.6%) AD (NIA‐criteria, 10‐active, 2‐placebo, 81.5±5.5yrs, 69.2% women) participated in a three Cohort, Phase‐1, MAD, safety and tolerability trial (IND146069, NCT04749563). In Cohort‐1, IGC‐AD1 was administered QD at 1ml for 14‐days (EOT). In Cohorts‐2 and 3, one ml BID and TID were administered respectively, with a minimum of 4‐days washout between Cohorts. Solicited and non‐solicited adverse events (AEs) were monitored daily. In each Cohort, seven participants (5‐active, 2‐placebo) had apathy at baseline, as rated by the NPI‐ap. They were administered the NPI‐ap at EOT and the Wilcoxon matched pairs signed‐rank test (R‐Studio, dplyr) was used to compare the difference in NPI‐ap scores between baseline and EOT. A similar analysis was carried out for NPI‐D. Result: In Cohort‐1 mean NPI‐ap at baseline and EOT was 5.4 and 3 respectively (mean difference = ‐2.4, v = 6, p = 0.091). In Cohort‐2 mean NPI‐ap at baseline and EOT was 5.2 and 2.4 respectively (mean difference = ‐2.8, v = 6, p = 0.087). In Cohort‐3 mean NPI‐ap at baseline and EOT was 5.2 and 2.6 respectively (mean difference = ‐2.6, v = 6, p = 0.087). Results for NPI‐D: (Cohort‐1:mean difference = ‐0.6, 37.5%, v = 6, p = 0.075; Cohort‐2:mean difference = ‐1.8, 69.2%, v = 15, p = 0.028; Cohort‐3:mean difference = ‐0.2, 12.5%, v = 2, p = 0.5). No serious AEs, no deaths, and no dropouts due to AEs were reported. No major changes in concomitant medications were observed. Conclusion: As IGC‐AD1 contains THC, the results are intriguing because cannabis use has been associated with apathy but also increased empathy and sociality. In Cohort‐1, Cohort‐2, and Cohort‐3 NPI‐ap was reduced 44.44%, 53.85%, and 50% respectively. These results, while not statistically significant (p>0.05), appear clinically significant (reduction≥30%). A larger placebo‐controlled study is warranted. [ABSTRACT FROM AUTHOR]

Background: Blood pressure (BP) variability (BPV) is a risk factor for Alzheimer's disease (AD). Medications, such as atypical antipsychotics used to treat neuropsychiatric symptoms (NPS) common in AD, contribute to altering BP. Here we present preliminary data on the use of IGC‐AD1, a combination intervention of tetrahydrocannabinol (THC) and melatonin, on BP and BPV. Method: Participants with hypertension (n = 12) and mild (15.38%) to moderate (84.6%) AD (NIA‐criteria, 10‐active, 2‐placebo, 81.5±5.5yrs, 69.2% women) were enrolled in a three‐Cohort Phase‐1, MAD, safety and tolerability trial (IND146069, NCT04749563). In Cohort‐1, Cohort‐2 and Cohort‐3, one ml QD, BID, and TID of IGC‐AD1 were administered respectively for 14‐days with a minimum of 4‐days washout between Cohorts. For all Cohorts, BP was recorded daily. Coefficients of variation (CV), ∆DBP and ∆SBP (diastolic and systolic blood pressure) were calculated to assess SBP‐variability for each Cohort. A chi‐square was performed to verify whether the difference between controlled and uncontrolled SBP (>140mmHg in more than 20% of values per participant) was related to IGC‐AD1. SBP‐CV difference among Cohorts was determined with a one‐way ANOVA. The difference between active and placebo for each Cohort was assessed with independent t‐tests (dplr R‐Studio). BP‐associated adverse events (AEs) were evaluated daily. Result: Variability measures fell within the normal range (∆DVP = 45.0±13.5 mmHg, ∆SBP = 66.44±22.9 mmHg, CV = 7.6±5.3 mmHg) for all three Cohorts. Cohort‐1 (mmHg): ∆SBP = 42.3±15.56, ∆DVP = 25.6±8.86, CV = 10.14±3.84; Cohort‐2 (mmHg): ∆SBP = 41.9±11.73, ∆DVP = 23±9.7, CV = 8.95±1.96; Cohort‐3 (mmHg): ∆SBP = 39.6±11.76, ∆DVP = 23.6±7.82, CV = 8.84±7.83. IGC‐AD1 had no statistically significant effect between controlled and uncontrolled SBP (X2(2) = 1.15, p = 0.562). There was no SBP‐CV mean‐difference among Cohorts (F (2,27) = 0.589, p = 0.562). No differences were detected between placebo and active (Cohort‐1: t(1.64) = 0.315, p = 0.788, Cohort‐2: t(1.31) = ‐0.225, p = 0.85, Cohort‐3: t(3.53) = 1.63, p = 0.188). While BP related AEs were reported, none were deemed, by the PI, to be associated with IGC‐AD1. Conclusion: Preliminary data indicate that IGC‐AD1, a cannabis‐based formulation, in trials to treat NPS did not statistically affect BP or BPV in a MAD study indicating that it may not contribute as a risk factor for AD; warranting a larger placebo‐controlled trial. [ABSTRACT FROM AUTHOR]

Background: Agitation, common in AD, often associated with higher caregiver burden, increases in intensity and duration as the disease progresses. Although about 76% of AD patients suffer from agitation, only 6.9% of ongoing trials for AD target symptoms such as agitation. Here, we present preliminary data for improvement in NPI‐agitation (NPI‐ag) scores and associated caregiver distress (NPI caregiver distress, NPI‐D) scores using IGC‐AD1, a combination of tetrahydrocannabinol (THC) and melatonin (IGC‐AD1). Method: Twelve patients with mild (15.38%) to moderate (84.6%) AD (NIA‐criteria, 10‐active, 2‐placebo, 81.5±5.5yrs, 69.2% women) participated in a three Cohort Phase‐1, MAD, safety and tolerability trial (IND146069, NCT04749563). In Cohort‐1, IGC‐AD1 was administered QD at 1ml for 14‐days (EOT). In Cohorts 2 and 3, one ml BID and TID were administered respectively, with a minimum of 4‐days washout between Cohorts. In Cohort‐1 (QD), 9 participants (7‐active, 2‐placebo) with NPI‐ag and NPI‐D assessment at baseline were analyzed. In Cohort‐2 (BID), and Cohort‐3 (TID) six patients and five patients respectively had NPI‐ag and NPI‐D scores at baseline. Daily, solicited and non‐solicited adverse events (AEs) were monitored along with vital signs. A Wilcoxon matched pairs signed‐rank test (R‐Studio, dplyr) was used to compare separately the difference between the mean NPI‐ag and mean NPI‐D scores at baseline and EOT. Result: In Cohort‐1 mean NPI‐ag at baseline and EOT was 4.71 and 3 respectively (mean difference = ‐1.75, 36.3%, V = 10, p = 0.047). In Cohort‐2 mean NPI‐ag at baseline and EOT was 4.33 and 1.5 respectively (mean difference = ‐2.83, 65.3%, V = 10, p = 0.049). In Cohort‐3 mean NPI‐ag at baseline and EOT was 4.2 and 1.4 respectively (mean difference = ‐2.8, 66.6%, V = 10, p = 0.04). We report similar improvements in NPI‐D. (Cohort‐1: mean difference = ‐1.57, 50%, v = 15, p = 0.028; Cohort‐2: mean difference = ‐2, 66.6%, v = 10, p = 0.049; Cohort‐3: mean difference = ‐1.45, 8.3%, v = 10, p = 0.049). No serious AEs, no deaths, and no dropouts due to AEs were reported. No major changes in concomitant medications were observed. Conclusion: IGC‐AD1 was safe and well tolerated and is potentially efficacious in reducing agitation and associated caregiver distress in AD as measured by the NPI, warranting a larger placebo‐controlled study. [ABSTRACT FROM AUTHOR]

Background: Suicide ideation in young adults increases with regular use of marijuana. Separately, prevalence of suicide and dementia also increases with age, and Alzheimer's disease (AD) is associated with a moderate risk of suicide. The Columbia‐Suicide Severity Scale (C‐SSRS) has been used since the FDA guidance in 2012, however, it has not been validated. Studies show its effectiveness in mild to moderate dementia, but not in severe dementia. Here, we present preliminary data on the application of C‐SSRS in a Phase 1 trial on AD patients using IGC‐AD1, a combination of tetrahydrocannabinol (THC) and melatonin (IGC‐AD1). Method: Twelve patients with mild (15.38%) to moderate (84.6%) AD (NIA‐criteria, 10‐active, 2‐placebo, 81.5 ± 5.5yrs, 69.2% women) participated in a three Cohort Phase‐1, MAD, safety, and tolerability trial (IND146069, NCT04749563). In Cohort‐1, IGC‐AD1 was administered QD at 1ml for 14‐days (EOT). In Cohorts 2 and 3, one ml BID and TID were administered respectively with a minimum of 4‐days washout between Cohorts. Daily, solicited, and non‐solicited adverse events (AEs) were monitored along with vital signs. For all three Cohorts the C‐SSRS was administered at baseline and again on days 5,10, EOT and EOT+2 by a neuropsychologist. In addition, suicidal ideation was included as a solicited adverse event (AE) that was reported daily. Result: In 420 man‐days (10 patients on active * 14 days * 3‐Cohorts) of dosing there was one day on which a participant on active medication self‐reported suicidal ideation as part of the solicited AEs. It self‐resolved the next day. All 150 administrations of C‐SSRS to the participants on active medication, across all three Cohorts, showed no suicide ideation or behavior. Likewise, across 30 administrations in the placebo group there were no suicide ideations or behaviors. No serious AEs, no deaths, and no dropouts due to AEs were reported. No major changes in concomitant medications were reported. Conclusion: THC and melatonin in IGC‐AD1 did not increase the risk of developing suicidal ideation or behavior as assessed by the C‐SSRS in the mild to moderate AD trial population. The preliminary results also show that IGC‐AD1 was well tolerated and safe. [ABSTRACT FROM AUTHOR]

Background: The Apathy in Dementia Methylphenidate Trial 2 (ADMET 2) found that methylphenidate (MPH) was modestly efficacious is treating apathy in Alzheimer's disease (AD) with 66% response (> = 4 point decrease on Neuropsychiatric Inventory – apathy (NPI‐A). Here, we evaluated if blood‐based biomarkers potentially associated with treatment‐limiting neuronal damage predicted the probability of treatment response. Method: ADMET 2 participants with baseline and endpoint (6 month) NPI‐A and baseline concentrations of (i) neuronal damage: neurofilament light (NFL) and S‐100B, (ii) inflammation: interleukin (IL)‐6, IL‐10, Tumor Necrosis Factor‐alpha (TNFα), and (iii) oxidative stress: lipid hydroperoxide (LPH), 4‐hydroxynonenal (4‐HNE), 8‐isoprostane (8‐ISO) were included. Biomarkers were normalized by log transformation and pareto scaling. Univariate models examined whether each biomarker interacted with the treatment condition to predict a change of at least 2 points on the NPI‐A. Next, biomarkers with significant associations were included in a multivariate logistical regression model that was used to predict treatment response to MPH and placebo. The index score (difference between response probabilities for MPH and placebo) of each participant indicated their favourability for MPH treatment. Participants were grouped into quartiles by their index score with confidence intervals estimated using non‐parametric bootstrapping. Result: Forty‐nine participants (placebo = 26, MPH = 23, age = 75.4 years (standard deviation [SD] = 7.6), 57% males, Mini Mental State Examination = 19.7 [SD = 4.6]) were included. MPH was more efficacious than placebo in those with higher baseline NFL (‐5.8, t = ‐3.1, p = 0.003), and less efficacious in those with higher LPH (2.0, t = 1.48, p = 0.15). Apathy worsened in participants with high TNFα (2.71, t = 1.94, p = 0.06) in both MPH and placebo groups. Participants in the top quartile of the biomarker index score (66.7% on MPH) were more likely to respond to MPH than placebo (index score = 0.58, 95%CI: 0.48, 0.69). Conclusion: Individuals with greater neuronal injury were more likely to respond to MPH, suggesting that MPH supplementation provides more benefit when neuronal injury is more severe. Combining blood biomarkers yielded a prediction score where participants with high NFL and low LPH levels were more likely to respond to MPH. This approach utilizes biomarkers to address heterogeneity in treatment response to MPH. [ABSTRACT FROM AUTHOR]

Background: Recent trials of anti‐amyloid therapies have shown it is possible to change the course of early symptomatic Alzheimer's disease (AD). However, the limited durations of these trials with the associated limited decline in the patient populations have left questions about the clinical meaningfulness of the observed treatment differences. Through progression analysis, one can quantify trial results in terms of time delay of progression. Compared to treatment differences on clinical scales, time delays are arguably more interpretable to patients and their families. However, it is yet to be established what constitutes a meaningful time delay in AD progression. Method: Assess how different hypothetical delays in disease progression in early symptomatic AD translate into treatment differences on the Clinical Dementia Rating Sum of Boxes (CDR‐SB) based on published results placebo‐arm trajectories in recent anti‐amyloid trials. Estimates are compared to published estimates of minimal clinically important differences (MCIDs) in AD and meaningful delays in progression in other diseases. Result: Based on placebo arms from six recent trials of anti‐amyloid antibodies, a 6‐month delay over 18 months (33% slowing) corresponded to treatment differences on CDR‐SB between ‐0.5 and ‐0.8, a 12‐month delay (67% slowing) corresponded to treatment differences between ‐1.0 and ‐1.7, and completely stopping progression (18‐month delay) corresponded to treatment differences between ‐1.6 and ‐2.3 (Figure 1, Table 1). Observed treatment effects in the EMERGE, CLARITY‐AD and TRAILBLAZER‐ALZ trials are consistent with approximately 4‐6 months delay of progression (22‐30% slowing, Figure 1). Established MCIDs in CDR‐SB in early AD range between 1.0 and 1.6, suggesting that a 12‐month delay or 67% slowing of disease progression in an 18‐month trial would be considered borderline in terms of clinical meaningfulness. Conclusion: Quantifying treatment effects in progressive diseases such as AD in terms of time delays or slowing of progression may offer a more meaningful interpretation of the treatment effects. Based on the trajectories of placebo group in recent trials, we found that treatment effects matching conventionally used MCIDs in AD would correspond to a very substantial slowing of disease (>67%), suggesting that current MCIDs for CDR‐SB are likely inflated. [ABSTRACT FROM AUTHOR]

Background: Agitation is a prevalent and disabling neuropsychiatric symptom of dementia that comprises a constellation of behaviours involving excessive motor activity, physical aggression, and verbal aggression. Pro re nata (PRN) injections of antipsychotics and benzodiazepines can be administered for severe acute agitation, but best practices surrounding their use remain poorly characterized. The aim of this study was to compare the frequency of use of injectable PRN haloperidol, olanzapine, and lorazepam for acute agitation in Canadian long‐term care (LTC) residents with dementia before and during the COVID‐19 pandemic. Methods: A retrospective chart review was conducted for patients from two Canadian LTC facilities who had orders for PRN haloperidol, olanzapine, or lorazepam between January 1, 2018–May 1, 2019 (i.e. pre‐COVID‐19) and January 1, 2020–May 1, 2021 (i.e. COVID‐19). We reviewed electronic medical records to document PRN administrations of these psychotropic medications and collect data on age, sex, dementia diagnosis, days of observation, care type, medical history, and concomitant medications. Descriptive statistics and multivariate logistic and Poisson regression models were used to analyze the data. Results: Of the 250 residents with dementia included, 45 of 103 (44%) people in the pre‐COVID‐19 period and 85 of 147 (58%) people in the COVID‐19 period with standing orders for injectable PRN haloperidol, olanzapine, or lorazepam received ≥1 injections of their prescribed medication. Haloperidol was the most frequently used agent (74% pre‐COVID‐19 and 81% during COVID‐19) and excessive motor activity (85% and 80%) was the most common indication for use in both time periods. Residents in the COVID‐19 period were two times more likely to receive PRN injections compared with those in the pre‐COVID‐19 period (OR = 1.96; 95% CI = 1.15‐3.34; p = 0.01). Count of injections per patient was not significantly different between the two time periods (IRR = 1.35; 95% CI = 0.78‐2.33; p = 0.3). Conclusion: Our results contribute to the mounting evidence that agitation worsened in LTC residents with dementia during the pandemic and add to the limited existing literature on actual use of PRN psychotropic medications for acute agitation. The increased need for PRN rescue medications may be an indirect consequence of COVID‐19 restrictions, particularly the restrictions on socialization. [ABSTRACT FROM AUTHOR]

Background: Diagnostic criteria for apathy (DCA) in neurocognitive disorders were developed in 2021. As next steps, we assessed whether commonly‐used validated apathy scales map onto the DCA and identified which scales map best. Method: Using a modified Delphi process, mapping of the Neuropsychiatric Inventory‐Clinician (NPI‐C) Apathy domain and the Apathy Evaluation Scale (AES) onto the DCA were assessed by surveying apathy experts. For each item on the scales, experts were asked to evaluate the degree of correspondence to the DCA globally, and the 3 DCA dimensions [diminished initiative, interest, and emotion]. Respondents voted "not at all" (scored as 0), "weakly" (scored as 1), or "strongly" (scored as 2). For each item, if the mean score was <0.5, the item was considered not mapped, for scores >1.5, the item was considered mapped, and items with scores 0.5‐1.5 were discussed further in a virtual consensus meeting. The surveys were then sent to other scientific community members, and the interrater reliability between the two groups was assessed using Cohen's kappa. Result: The surveys were completed by 12 experts. For NPI‐C apathy, 10/11 (90.9%) questions mapped primarily onto one dimension of the DCA: 2 onto "Initiative", 6 onto "Interest", and 2 onto "Emotion". Of NPI‐C Apathy domain items, 9/11 (81.8%) mapped globally onto the DCA. For the AES, 7/18 (38.9%) questions mapped onto different dimensions of the DCA: 4 onto "Initiative", 2 onto "Interest", and 1 onto "Emotion"; 6/18 (33.3%) items mapped globally onto the DCA. The mean mapping scores of NPI‐C were significantly higher than those of the AES (t (27) = 2.25, p = 0.032) indicating better performance of NPI‐C in this exercise. These findings were confirmed in a consensus discussion. There was substantial agreement (kappa = 0.621) between the experts and the community group regarding mapping of NPI‐C but only moderate agreement (kappa = 0.553) regarding mapping of AES on the DCA. Conclusion: More questions from the NPI‐C Apathy domain mapped strongly and uniquely both globally, and onto the 3 dimensions of the DCA, compared with the AES. Future research using the DCA, NPI‐C Apathy domain, and AES in clinical and research settings are needed to confirm these results. [ABSTRACT FROM AUTHOR]

Background: Mild vascular cognitive impairment (mVCI) is characterized by minor deficits in cognition and memory due to underlying vascular pathology. Anodal transcranial direct current stimulation (atDCS), a non‐invasive neuromodulation technique, has been demonstrated to improve cognition. The effects of atDCS have been suggested to be mediated by γ‐aminobutyric acid (GABA)–a major inhibitory neurotransmitter associated with cerebral perfusion and oxygenation, and cognition and memory. However, previous studies have reported mixed results regarding changes in GABA concentrations following atDCS. Physical activity has been reported to increase cortical GABA levels, and in particular, aerobic exercise (AE) is associated with improved cognition in older adults. Preliminary data from an ongoing trial (EXPRESS‐V) was used to evaluate whether GABA concentration in the motor cortex was altered following AE and/or atDCS and whether this was associated with changes in global cognition in mVCI. Method: In this double‐blind, randomized clinical trial, participants received one of four interventions for two weeks: AE and atDCS, AE and sham atDCS, exercise education and atDCS, or exercise education and sham atDCS. mVCI was determined based on a modified Gorelick criteria. At baseline and endpoint, GABA concentration in the motor cortex was measured using magnetic resonance spectroscopy and quantified with the Mescher‐Garwood point resolved spectroscopy pulse sequence, and global cognition was assessed using the Montreal Cognitive Assessment. Wilcoxon signed rank test was used to determine changes in GABA concentrations (ΔGABA). Spearman correlation was used to determine the association between ΔGABA and changes in global cognition (ΔMoCA). Result: Ten participants have enrolled so far, with nine participants having completed the study (22.2% female, age = 66.4(9.8), years of education = 8.8(3.4), 55.6% White, baseline MoCA score = 22.8(3.1)). To date, ΔGABA was insignificant between baseline and endpoint (Z = 23.0, p = 0.953). However, a positive trend between ΔGABA and ΔMoCA was observed (ρ = 0.650, p = 0.058). Conclusion: Preliminary results from nine participants showed a positive trend between ΔGABA and ΔMoCA. Since the trial is ongoing, with the target of recruiting 80 participants by 2024, analyses on unblinded data upon study completion will determine whether AE and atDCS leads to greater ΔGABA, and whether this is accompanied by greater ΔMoCA in mVCI. [ABSTRACT FROM AUTHOR]

Background: Alzheimer's disease dementia (AD) and mild cognitive impairment (MCI) are often associated with abnormalities in full power spectrum of electroencephalogram (EEG), including the ratio of beta/theta. Full spectrum EEG consists of aperiodic and periodic components with the latter being better associated with cognition. We investigated whether the aperiodic and periodic power components of EEGs are disrupted differently in individuals with MCI vs. AD vs. healthy controls (HC), and whether a periodic based beta/theta ratio better differentiates the three groups than a ratio based on the full spectrum. Method: Data were collected in 199 participants ‐ 44 with HC (mean (SD) age: 69.1 (5.3) years), 114 with MCI (72.3 (7.5)), and 41 with AD (75.6 (6.5)). We cleaned the data using a band‐pass filter with cut‐off frequencies 1 and 45 Hz and then independent component analysis. We then used the "fooof" toolbox to decompose the EEGs into their aperiodic and periodic components. We used the area under the receiver operating characteristic curve (AUCROC) of a logistic regression classifier to distinguish HC from MCI and AD participants, and MCI from AD participants, using beta/theta ratios based on the periodic power spectrum vs. full power spectrum. Result: There was an increase in full spectrum powers for delta, theta, and gamma, and a decrease of relative power for beta in AD participants compared to HC and MCI participants. In contrast, there were no differences in aperiodic background EEG components among HC, MCI, and AD participants. Overall, the periodic and full spectrum comparisons among the three groups were comparable except for the periodic based analysis that showed a difference between MCI and HC in the occipital beta/theta ratio (Bonferroni corrected p = 0.036). Classifiers based on beta/theta power ratio in EEG periodic components distinguished AD from HC and MCI with high AUCROC values (0.94 and 0.83, respectively), and outperformed classifiers based on beta/theta power ratio in EEG all oscillations (0.078 and 0.67, respectively). Conclusion: This study supports an advantage of a periodic based analysis over a full EEG spectrum analysis and the use of occipital beta/theta power ratio based on periodic components as a screening tool for AD. [ABSTRACT FROM AUTHOR]

Background: White matter hyperintensity (WMH) is a marker of age‐related cerebrovascular damage and is correlated with cognitive impairment; ischemia and inflammatory mechanisms have been proposed to be involved in its pathogenesis. These processes are associated with oxidative stress (OS), which may impair cellular function and affect antioxidant balance; however, the role of central antioxidant responses is still unclear. Method: Patients (age 55‐85) with ≥2 vascular risk factors or a previous vascular event were assessed at baseline for an exercise rehabilitation program. All participants completed the Montreal Cognitive Assessment (MoCA). Baseline WHM severity was determined using the standardized Canadian Dementia Imaging Protocol and semiautomatic protocols. Brain glutathione (GSH) at baseline was obtained in the anterior cingulate (AC) and occipital region (OC) using 1H magnetic resonance spectroscopy (MEscher–GArwood Point Resolved Spectroscopy). Spectroscopic analysis was completed using the Gannet toolkit (vers. 3.1) in Matlab (vers. 2020b). Result: Of 30 participants (mean age: 66.2 ± 7.42 SD; 80% male) currently enrolled, brain volumetric measurements were completed for 25 participants. Lower MoCA score was associated with greater total WMH volume, controlling for age (b[SE] = ‐0.017 [0.005], t(22) = ‐3.24, p = 0.004); this relationship remained significant when controlling for years of education separately (b[SE] = ‐0.016 [0.006], t(22) = ‐2.86, p = 0.01). Correcting for cerebrospinal fluid volume, lower AC‐GSH level was associated with higher deep WMH volume in the medial middle frontal (MMF) region of interest (b[SE] = ‐0.056 [0.023], t(23) = ‐2.38, p = 0.026), but not with MMF paraventricular WMH volume. After controlling for age, the model was no longer significant (F (2, 22) = 2.87, p = 0.078). No significant associations were found between OC‐GSH and occipital lobe WMH. Conclusion: As expected, total white matter hyperintensity volume was associated with poorer global cognition. In the medial middle frontal (MMF) region of interest, higher deep WMH was associated with lower GSH levels, suggesting altered brain antioxidant levels may be associated with the presence or formation of WMH. Recruitment is ongoing, and additional participants are needed to reinforce findings and to control for confounders in the analysis. [ABSTRACT FROM AUTHOR]

Background: Homocysteine (Hcy) is an amino acid generated as a byproduct of methionine metabolism. It is a risk factor for vascular and neurodegenerative diseases. This study investigated relationships between plasma Hcy concentrations and neurodegenerative biomarkers in people clinically diagnosed with Alzheimer's disease (AD) or mild cognitive impairment (MCI) due to AD. Method: Participants were identified from the Ontario Neurodegenerative Disease Research Initiative. Brain parenchymal fraction (BPF) was quantified using T1‐ and T2‐weighted structural magnetic resonance imaging with an in‐house Semi‐Automated Brain Region Extraction and Lesion Explorer package. Plasma amyloid beta (Aβ) 42, Aβ40, phosphorylated tau 181 (p‐tau181), and neurofilament light chain (NfL) were measured with Single molecule array (Simoa) assays. Linear regression analyses were used to test associations between Hcy and neuroimaging or plasma biomarkers, controlling for age, sex, hypertension, hyperlipidemia, diabetes, cholesterol, and vitamin B12. Analyses were stratified by apolipoprotein E (APOE) ε4 carrier status (non‐carriers: n = 64, mean age = 70.9 years, 41% female; carriers: n = 62, mean age = 71.2 years, 50% female). Result: In APOE ε4 non‐carriers, Hcy was associated negatively with BPF (β = ‐0.233, p = 0.047, 95% CI [‐0.460, ‐0.003]), notably in temporal lobe regions in exploratory regional analyses. Hcy was also associated positively with plasma concentrations of NfL (β = 0.403, p = 0.007, 95% CI [0.117, 0.688]) and p‐tau181 (β = 0.357, p = 0.023, 95% CI [0.051, 0.663]) in APOE ε4 non‐carriers. Also, in APOE ε4 non‐carriers, Hcy was associated positively with Aβ40 (β = 0.367, p = 0.015, 95% CI [0.074, 0.660]) and Aβ42 (β = 0.305, p = 0.041, 95% CI [0.012, 0.598]), but not with the Aβ42/40 ratio (β = 0.155, p = 0.339, 95% CI [‐0.166, 0.476]). None of these associations were seen in APOE ε4 carriers. Conclusion: In non‐carriers of the APOE ε4 allele clinically diagnosed with AD or MCI, homocysteine was associated with Amyloid, tau and neurodegeneration. The specificity of these relationships to ε4 non‐carriers identifies a unique risk factor profile for AD that is independent of APOE ε4 status. [ABSTRACT FROM AUTHOR]

Background: Circulating cell‐free mitochondrial DNA (ccf‐mtDNA), a measure of mitochondrial dysfunction, is emerging as a potential biomarker for early Alzheimer's disease (AD). Decreased levels of cerebrospinal fluid ccf‐mtDNA concentrations have been detected in early AD patients. Few studies have investigated peripheral ccf‐mtDNA in early AD or with cognitive measures, much less evaluating the role of physical activity within the relationships. Considering the hallmark of episodic memory impairment in early AD, we examined the association between serum ccf‐mtDNA and memory, while considering potential contributing factors, physical activity level and age. Methods: Participants were diagnosed with mild cognitive impairment (MCI) or mild AD using the Diagnostic and Statistical Manual of Mental Disorders criteria for mild or major neurocognitive disorder. Serum ccf‐mtDNA concentration (copies/uL) was measured using quantitative polymerase chain reaction from circulating cell free DNA purified by spin columns with primer for the MT‐ND4 gene. Memory was assessed using the Word Recall Task from the Alzheimer's Disease Assessment Scale‐Cog (ADAS‐Cog). Physical activity level was assessed by Leisure‐Time Exercise Questionnaire (LTEQ). Linear regression analyses were used to assess the association between ccf‐mtDNA levels and recall memory with a priori covariates, age and LTEQ score. Ccf‐mtDNA levels were log‐transformed prior to analyses due to significant departure from normality in Shapiro‐Wilk tests. Results: Of 29 participants [17 (59%) male, 21 (72%) MCI], the mean (SD) age was 74.2 (8.7), years of education was 16.2 (2.2), Montreal Cognitive Assessment (MoCA) total score was 22.1 (3.3), LTEQ score was 36.2 (17.4), and ccf‐mtDNA levels were 2545.8 (2223.6) copies/uL. Higher ccf‐mtDNA was associated with worse recall [F(3,25) = 5.21, R2 =.39, p =.006]. Controlling for LTEQ and age, one log ccf‐mtDNA unit was associated with 1.87 (SE =.71) fewer words recalled (p =.01, f2 =.21). Conclusion: In this sample, higher serum ccf‐mtDNA concentrations were associated with worse recall, controlling for age and physical activity level. This relationship supports the potential involvement of mitochondrial dysfunction in cognitive functions and neurodegenerative diseases and suggest the need for further research to explore the role of physical activity and age with mitochondrial dysfunction and memory. [ABSTRACT FROM AUTHOR]

Background: Inflammatory activation and increased immune response to lipopolysaccharide (LPS, a cell wall component of gut bacteria) is observed in both depression and cognitive decline. Depression is associated with accelerated cognitive decline, and persistent inflammatory activation may link depression and cognitive decline in later life. We determined if LPS is associated with inflammatory activation and cerebral deposition of amyloid‐beta (Abeta) in older adults with Mild Cognitive Impairment (MCI) and/or remitted Major Depressive Disorder (rMDD). Method: Serum samples of LPS, LPS‐binding protein (LBP, which enhances the inflammatory response to LPS), and inflammatory markers (Interleukin 6 [Il‐6], C‐reactive protein [CRP], Monocyte Chemoattractant Protein 1 [MCP‐1]) were measured using ELISA. Abeta deposition was measured using PET neuroimaging using [11C]‐PIB radiotracer. Global amyloid burden was calculated using a composite Standardized Uptake Value Ratio (SUVR) score with the cerebellar cortex as the reference region. Multivariable linear regression analyses, adjusting for significant demographic and genetic variables, were conducted to determine if LPS, LBP, inflammatory biomarkers, MCI and rMDD were independently associated with global cerebral deposition of Abeta. Result: Among 155 study participants (79 with MCI only, 54 with both MCI and rMDD, 22 with rMDD only) we found a median Abeta SUVR of 1.41 (IQR 0.57). There was no significant association between LPS (beta ‐1.28, 95% CI ‐11.69, 9.13, p = 0.8) or LBP (beta ‐0.02, 95% CI ‐0.05, 0.006, p = 0.12) and global deposition of Abeta, following adjustment for age, sex, and APOE genotype. LBP was positively correlated with inflammatory biomarkers: CRP (r = 0.49, p < 0.001) and IL‐6 (r = 0.21, p = 0.01) but no inflammatory biomarker was significantly associated with Abeta deposition. Having a history of rMDD (beta ‐0.09, 95% CI ‐0.26, 0.08, p = 0.28) or MCI alone (beta ‐0.11, 95% CI ‐0.47, 0.049, p = 0.11) was not associated with deposition of Abeta. Conclusion: In this cross‐sectional analysis, we did not find an association between LPS/LBP, immune biomarkers, remitted MDD and global deposition of Abeta. Future analyses should examine the longitudinal relationships between peripheral and central biomarkers of immune activation with cerebral Abeta deposition in patients and controls. [ABSTRACT FROM AUTHOR]

Apathy is one of the most prevalent, stable and persistent neuropsychiatric symptom across the neurocognitive disorders spectrum. Recent advances in understanding of phenomenology, neurobiology and intervention trials highlight apathy as an important target for clinical intervention. We conducted a comprehensive review and critical evaluation of recent advances to determine the evidence-based suggestions for future trial designs. This review focused on 4 key areas: 1) pre-dementia states; 2) assessment; 3) mechanisms/biomarkers and 4) treatment/intervention efficacy. Considerable progress has been made in understanding apathy as a treatment target and appreciating pharmacological and non-pharmacological apathy treatment interventions. Areas requiring greater investigation include: diagnostic procedures, symptom measurement, understanding the biological mechanisms/biomarkers of apathy, and a well-formed approach to the development of treatment strategies. A better understanding of the subdomains and biological mechanisms of apathy will advance apathy as a treatment target for clinical trials. [ABSTRACT FROM AUTHOR]

Background: Although the majority of individuals with Alzheimer's disease (AD) dementia exhibit neuropsychiatric symptoms (NPS), there is substantial heterogeneity in NPS manifestation. Sex is increasingly recognized as an important factor in explaining clinical variability within AD; yet, prior studies on sex differences in NPS have reported mixed findings. Therefore, we aimed to review the existing literature on sex differences in NPS in AD dementia using a meta‐analytic approach. Method: Effect sizes were extracted from 54 studies (N=19,730; N=12,092 females [61.3%], N=7,638 males [38.7%]). Random‐effects models were used to investigate sex differences in both NPS prevalence and severity for all studies combined, NPS total scores, and for specific NPS separately. Furthermore, meta‐regression analyses were conducted to examine the effects of study characteristics and demographic and clinical variables. Result: The majority of the included studies were of fair quality and we found no indications of publication bias. When combining all studies, female sex was associated with overall greater NPS severity (k=17, g=0.07[0.01–0.14], p<0.05), while no sex‐related differences were observed for NPS prevalence (k=41, OR =1.07[0.89–1.28], p=0.46). Meta‐regression analyses showed that younger age (QM=6.44, p<0.05) and longer disease duration (QM=4.27, p<0.05) were associated with more prevalent NPS for females with AD dementia. Regarding specific NPS, female sex was associated with more prevalent psychotic symptoms (k=4, OR=1.62[1.12–2.33], p<0.01), aberrant motor behaviors (AMB; k=5, OR=1.61[1.15–2.25], p<0.01), depressive symptoms (k=18, OR=1.56 [1.22–1.99], p<0.001), and delusions (k=11, OR=1.56 1.27–1.92], p<0.001). In addition, female sex was related to more severe depressive symptoms (k=10, g =0.20[0.08–0.29], p<0.001), disinhibition (k=6, g=0.16[0.03–0.28], p<0.05), and AMB (k=6, g=0.14[0.01–0.27], p<0.05). Conclusion: Female sex was associated with more severe overall and specific NPS in AD dementia and a higher prevalence of specific NPS. These associations are generally not affected by study setting, measurement type, age, education, disease duration, MMSE score, and APOE status. These findings support the existing literature on sex differences in the clinical manifestation of AD, which could reflect sex‐related differences in neurobiological and psychosocial factors. Determining sex differences in NPS may guide personalized assessment and tailored treatment. [ABSTRACT FROM AUTHOR]

Background: While the effects of cannabis use on driving have been established in younger populations, limited studies have investigated this association among older adults, who represent the fastest growing segment of drivers globally. Method: We conducted a systematic review and meta‐analysis to evaluate the effect of THC exposure on (1) risk of motor vehicle collisions (MVC) and (2) risk of culpability (being responsible for the collision), among adults 50 years and older. Three reviewers screened 7,022 studies identified through MEDLINE, EMBASE, CENTRAL, and PsycINFO and published between inception and 2021. Odds Ratios (OR) were calculated with a random‐effects model using the Mantel‐Haenszel method in Review Manager 5.4.1. Heterogeneity was assessed using I2. An adapted version of the National Heart, Lung, and Blood Institute quality assessment tool was used to assess the quality of each study. Result: 7 cross‐sectional studies were included. Three studies were rated 'Good' quality, one rated 'Fair', and three rated 'Poor'. Three of the included studies evaluated culpability (NTHC+ = 239 NTHC‐ = 4609) while four evaluated MVC risk (NTHC+ = 158, NTHC‐ = 6152). We found that the pooled risk of MVC was not significantly different between older drivers exposed to THC and those who were not (OR, 95% CI 1.15 [0.40, 3.31]; I2 = 72%). In the studies assessing driver culpability, THC exposure was not significantly associated with an increased risk of being culpable for MVC among adults over the age of 50 (OR, 95% CI 1.24 [0.95, 1.61]; I2 = 0%). A visual inspection of the funnel plots did not indicate any publication bias. Conclusion: Our review found that THC exposure was not associated with MVC involvement nor with culpability. However, it would be an oversimplification to conclude that cannabis use does not pose a safety risk to older drivers. Rather, our results may reflect several methodological limitations of the studies included in this review. Due to the increasing prevalence of cannabis use worldwide, we are optimistic that future research will be able to address this research question using more objective methodologies. [ABSTRACT FROM AUTHOR]

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

Background: 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. Method: 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 region (OC). Spectroscopic analysis was completed using the Gannet toolkit (vers. 3.1) in Matlab (vers. 2020b), a cut‐off of 20% was used to reject spectra of poor quality. Result: In 30 participants (mVCI n = 16, CN n = 14), anterior cingulate (AC) GSH (I.U. ± SD) was higher in mVCI (1.86 ± 0.45) compared to CN (1.63 ± 0.50) (F(1,18.8) = 4.6, P = 0.04), this difference became trending after correcting for cerebrospinal fluid volume ((F(1,18.2) = 3.9, P = 0.06). No difference was detected for OC‐GSH before or after correcting for cerebrospinal fluid volume. Higher AC‐GSH was correlated with lower Montreal Cognitive Assessment score (rho (26) = ‐0.42, p = 0.02). Conclusion: 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. [ABSTRACT FROM AUTHOR]

Background: Mild cognitive impairment (MCI) is a well‐established prodromal stage of Alzheimer's disease and is often accompanied by early signs of neurodegeneration (e.g., neuronal loss) that may influence subsequent prognosis. To facilitate a better characterization of the underlying neuropathology, a thorough investigation of proteins associated with neurodegenerative processes in MCI is needed. Thus, the present study systematically assessed the available literature to quantitatively evaluate cerebrospinal fluid (CSF) and peripheral blood concentrations of biomarkers related to neurodegeneration in individuals with MCI compared to healthy controls (HCs). Method: Original peer‐reviewed articles that assessed the following CSF and/or peripheral biomarkers: neurofilament light chain (NFL), total‐tau (T‐tau), glial fibrillary acidic protein (GFAP), heart‐type fatty acid binding protein (HFABP), neuron‐specific enolase (NSE), and S100 calcium‐binding protein B (S100B) in both MCI and HCs were included for meta‐analysis. Standardized mean differences (SMDs) and 95% confidence intervals were calculated using a random‐effects model. Heterogeneity was assessed using the I2 statistic. Result: A total of 109 study cohorts were included in the meta‐analysis. In CSF, concentrations of NFL (MCI n = 2771, HC n = 4263, SMD [95% CI] = 0.69 [0.56, 0.83], p < 0.001), GFAP (MCI n = 513, HC n = 1620, SMD [95% CI] = 0.41 [0.08, 0.74], p = 0.02), and HFABP (MCI n = 363, HC n = 245, SMD [95% CI] = 0.57 [0.23, 0.55], p < 0.001) were elevated in MCI. In peripheral blood, concentrations of NFL (MCI n = 6520, HC n = 9439, SMD [95% CI] = 0.41 [0.32, 0.49], p < 0.001), T‐tau (MCI n = 4463, HC n = 5921, SMD [95% CI] = 0.19 [0.09, 0.29], p < 0.001), and GFAP (MCI n = 1758, HC n = 3179, SMD [95% CI] = 0.39 [0.23, 0.55], p < 0.001) were increased in MCI. Significant heterogeneity was identified for all comparisons and was explored through meta regression and subgroup analysis. Conclusion: The present study identified several fluid biomarkers of neurodegeneration in MCI. Importantly, elevated biomarker levels can be detected in both CSF and less‐invasively through peripheral blood. Future studies should focus on assessing the clinical utility of monitoring these biomarkers as they may provide further insight into neuronal and astroglial pathology occurring in the early stages of cognitive decline. [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]

Introduction: Few studies have examined memory decline among patients with type 2 diabetes using different oral hypoglycemic drugs. Methods: Participants with normal cognition (NC) or Alzheimer's disease (AD) dementia using a hypoglycemic medication (2005 to 2019) were identified from the National Alzheimer's Coordinating Center database. Delayed memory was assessed using the Wechsler Memory Scale Revised–Logical Memory test. Associations between oral drug classes and memory over time were examined using mixed‐effects models with inverse probability treatment weights. Results: In NC (n = 1192), metformin use was associated with better memory performance over time, whereas in AD (n = 807), dipeptidyl peptidase‐4 (DPP4) inhibitor use was associated with a slower rate of memory decline. Interaction effects suggested greater benefit associated with DPP4 inhibitor use among APOE ε4 carriers. Discussion: Associations between different oral hypoglycemic drugs and memory change were not consistent between cognitively normal elderly and those with AD dementia. APOE ε4 genotype modified some relationships. [ABSTRACT FROM AUTHOR]

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

Background: Preclinical evidence suggests that sodium‐glucose cotransporter‐2 (SGLT2) inhibitors may mitigate dementia pathology; however, current clinical evidence is limited. The primary aim is to compare dementia risk between SGLT2 inhibitors and dipeptidyl peptidase‐4 (DPP4) inhibitors, two common second‐line glucose‐lowering medications. Methods: This population‐based retrospective cohort study utilized administrative databases housed at ICES (https://www.ices.on.ca/), and residents of Ontario, Canada with diabetes aged ≥66 years were included. Three different but overlapping new‐user cohorts were created. The primary comparison was SGLT2 inhibitors versus DPP4 inhibitors (entry period: January 1, 2016, to March 31, 2020). The secondary comparisons were SGLT2 inhibitors versus sulfonylureas (January 1, 2016, to March 31, 2020) and DPP4 inhibitors versus sulfonylureas (January 1, 2011, to March 31, 2020), because sulfonylureas are older second‐line therapies still used contemporaneously. Individuals were followed for maximum 4.5 years. The primary outcome was time to incident dementia. Exploratory outcomes were time to incident Parkinson's disease diagnosis, stroke, and long‐term care admission, to examine outcomes related to both glucose‐lowering medications and dementia risk. Propensity‐score weighted Fine‐Gray subdistribution hazard models with all‐cause mortality as competing risk were used to obtain adjusted hazard ratios (aHR) and confidence intervals (CI). Results: Among 119,432 individuals, SGLT2 inhibitors compared with DPP4 inhibitors were associated with lower risks of dementia (14.5/1000 person‐years, aHR [95% CI] = 0.59 [0.52‐0.67]), stroke (10.8/1000 person‐years, aHR [95% CI] = 0.87 [0.77‐0.99]), and long‐term care admission (8.6/1000 person‐years, aHR [95% CI] = 0.43 [0.36‐0.52]). SGLT2 inhibitors compared with sulfonylureas were associated with lower risks of dementia (11.0/1000 person‐years, aHR [95% CI] = 0.57 [0.51‐0.63]), Parkinson's disease (1.7/1000 person‐years, aHR [95% CI] = 0.73 [0.56‐0.97]), stroke (9.8/1000 person‐years, aHR [95% CI] = 0.75 [0.63‐0.84]), and long‐term care admission (5.6/1000 person‐years, aHR [95% CI] = 0.51 [0.44‐0.59]) among 89,114 individuals. DPP4 inhibitors compared with sulfonylureas were associated with lower risks of dementia (16.5/1000 person‐years, aHR [95% CI] = 0.78 [0.74‐0.82]), stroke (10.4/1000 person‐years, aHR [95% CI] = 0.85 [0.79‐0.92]), and long‐term care admission (8.7/1000 person‐years, aHR [95% CI] = 0.82 [0.76‐0.89]) among 152,559 individuals. Conclusion: SGLT2 inhibitor use was associated with lower dementia risk, and with preservation of functional independence, compared with DPP4 inhibitor or sulfonylurea use. Randomized controlled trials are needed to replicate the findings. [ABSTRACT FROM AUTHOR]