Oxidative stress is implicated in the etiology of mild cognitive impairment. We hypothesized that oral supplementation with N-acetylcysteine, a precursor to the antioxidant glutathione, would improve cognitive outcomes among individuals with mild cognitive impairment. n this 24-week randomized, double-blind, placebo-controlled trial, participants enrolled in an exercise-based cardiac rehabilitation program with possible vascular mild cognitive impairment were randomized to receive either oral N-acetylcysteine (2400 mg/day) or placebo. Cognition was assessed using a neuropsychological battery, with a standardized executive function composite score as the primary outcome. Secondary outcomes included verbal memory, working memory, non-verbal memory, attention and global cognition. Data were analyzed using linear mixed-effects models, adjusting for relevant covariates. A total of 59 participants [mean (SD) age = 67.6 (7.7), male (

OBJECTIVES:To compare mental illness prevalence, and agreement between mental illness measures, in home care (HC) and long-term care (LTC) using administrative definitions and Resident Assessment Instrument (RAI)-diagnoses. METHODS:Applying a common protocol to linked administrative-RAI datasets in Alberta, Manitoba, and Ontario, Canada, we selected adults receiving HC or LTC between 2012 and 2023. Cross-sectionally, we compared administrative definitions with RAI-diagnoses (depression, anxiety, bipolar disorder and schizophrenia) using kappa, sensitivity, specificity, positive and negative predictive value. We examined discordance-associated factors using multivariable logistic regression. RESULTS:Depression was the most prevalent mental illness (administrative data, HC: 29%-34% of 493,895 people; LTC: 21%-51% of 357,117 people). Prevalence estimates were consistently lower using RAI-diagnoses than administrative definitions. Agreement between data sources was moderate for depression (k = 0.33-0.57) and anxiety disorders (k = 0.35-0.63). Younger age, dementia, and more physician visits were associated with higher likelihood of discordance between data sources; male sex had a lower likelihood. CONCLUSION:While mental illness prevalence is high in HC and LTC populations, RAI-based estimates are lower than administrative data estimates. Discordance between data sources differs by individual characteristics. Concurrent comparison of RAI-diagnoses and administrative data to a gold standard clinical interview would clarify the optimal surveillance strategy.

Introduction In PACt-MD, cognitive remediation with transcranial direct current stimulation (CR+tDCS) slowed cognitive decline in older adults with mild cognitive impairment or remitted major depressive disorder. The effect is thought to be due to CR+tDCS promoting brain plasticity. Amyloid-beta accumulation (Aβ) is associated with disrupted brain plasticity. In PACt-MD, treatment effect had a significant interaction with APOEε4 status. Thus, we examined whether Aβ moderated treatment response in the 172 participants who underwent a baseline PET amyloid scan using the [11C]PiB tracer. We hypothesized that higher Aβ will be associated with a lower treatment effect. Methods PACt-MD participants received CR+tDCS or sham-CR+sham-tDCS (“sham”) 5 days/week for 8 weeks (acute phase) and then for 1 week every 6 months, for up to 6 years (follow-up phase). Baseline Aβ were calculated from brain-wide SUVR. Global cognition (primary outcome) was assessed at baseline, at the end of the acute phase, and then yearly. Models predicting global cognition with and without interaction terms between continuous measure of Aβ and treatment were compared using the likelihood ratio test (LRT). Results Aβ moderated CR+tDCS effect (LRT p < 0.001). Post-hoc analyses showed that this moderation is likely driven by the fact that, following the acute phase, CR+tDCS and sham resulted in similar cognitive improvement at lower Aβ while CR+tDCS resulted in more improvement than sham at higher Aβ. In contrast, during follow-up, while there was a trend towards CR+tDCS slowing cognitive decline at lower Aβ, it was not statistically significant. At high Aβ, cognition declined at similar rates in both groups. Conclusions Amyloid moderated treatment effect of CR+tDCS, but contrary to our hypothesis, higher Aβ were not associated with a poorer effect, particularly following the acute phase. However, this analysis is limited by its relatively small sample, and the results need to be confirmed in a larger study.

White matter hyperintensities (WMHs) in persons with vascular mild cognitive impairment (vMCI), particularly frontal WMHs, have been associated with decreased executive function (EF). While N-acetylcysteine (NAC) and exercise therapy may improve EF in patients with vMCI, identifying predictors of response could help personalize treatment. We hypothesized that lower baseline frontal WMH volume in vMCI patients treated with NAC and exercise will correlate with increasing improvement in EF over 6 months of treatment. Participants received 24 weeks of NAC or placebo in combination with exercise therapy ( n  = 60) as part of the Efficacy and Safety of N-acetylcysteine in patients with mild vascular cognitive impairment (MOVE-IT) clinical trial. Composite z scores for EF were calculated using Trail Making Part Test B, F-A-S Test, and Animal Naming Test administered at baseline, week 12, and week 24. Frontal WMH volumes were captured from baseline MRI scans. Linear mixed models were used that accounted for sex differences, age, years of education, and baseline executive function. Both treatment groups had a significant improvement in EF at midpoint (β = 0.194, SE = 0.059, p  =  0.002) and endpoint (β = 0.342, SE = 0.058, p  < 0.001). Lower baseline frontal WMH and treatment group was not associated with greater improvement in EF at midpoint (β = -0.260, SE = 0.144, p  =  0.075) or at endpoint (β = -0.162, SE = 0.144, p  =  0.266). Lower baseline frontal WMH volume was significantly associated with greater improvement in performance on the Trail Making Test Part B at midpoint (β = -0.597, SE = 0.197, p  =  0.003) but not at endpoint (β = -0.328, SE = 0.197, p  =  0.099) among participants randomized to the NAC and exercise group, but not the placebo and exercise group. This study found a predictive value of frontal WMH burden for novel interventions aiming to improve cognitive outcomes in patients with vMCI. WMH burden could help guide the development of targeted, effective therapies that address the complexities of cognitive impairment in aging populations.

Alzheimer's dementia (AD) is a neurodegenerative condition characterized by progressive cognitive decline. Synaptopathy—defined as loss and dysfunction of existing synapses—is a hallmark pathological feature of AD and can directly contribute to underlying cognitive deficits. In this study, we meta-analyzed several cerebrospinal fluid (CSF) and blood exosomal biomarkers associated with synaptopathy in AD and healthy controls (HCs). Original peer-reviewed articles that reported synaptic biomarker concentrations in CSF or blood exosomes were reviewed. Specifically, synaptosome associated protein-25 (SNAP-25), growth associated protein-43 (GAP-43), neuronal pentraxin receptor (NPTXR), neuronal pentraxin-1 (NPTX-1), neuronal pentraxin-2 (NPTX-2), complexin-2, syntaxin-1B, syntaxin-7, and vesicle-associated membrane protein-2 (VAMP-2) in AD and HCs were included for meta-analysis. A random-effects model was used to determine standardized mean differences (SMDs) and 95% confidence intervals (CIs). Heterogeneity was quantified using I 2 . The meta-analysis included 43 study cohorts. In CSF, concentrations of SNAP-25 (N AD /N HC  = 394/539, SMD [95% CI] = 1.08 [0.73, 1.42], p  < 0.001; I 2  = 81.43%), GAP-43 (N AD /N HC  = 851/557, SMD [95% C] = 1.02 [0.69, 1.34], p  < 0.001; I 2  = 83.97%), and VAMP-2 (N AD /N HC  = 398/490, SMD [95% CI] = 0.32 [0.05, 0.60], p  = 0.02; I 2  = 64.91%) were elevated, and NPTXR (N AD /N HC  = 575/470, SMD [95% CI] = -0.68 [-0.96, -0.40], p  < 0.001; I 2  = 75.59%), NPTX-1 (N AD /N HC  = 344/333, SMD [95% CI] = -0.48 [-0.64, -0.31], p  < 0.001; I 2  = 9.05%), and NPTX-2 (N AD /N HC  = 462/496, SMD [95% CI] = -0.78 [-1.02, -0.54], p  < 0.001; I 2  = 66.43%) were decreased in AD compared to HCs. In blood exosomes, SNAP-25 (N AD /N HC  = 161/159, SMD [95% CI] = -1.05 [-1.28, -0.82], p  < 0.001; I 2  = 0%) and GAP-43 (N AD /N HC  = 110/110, SMD [95% CI] = -1.66 [-2.43, -0.88], p  < 0.001; I 2  = 77%) concentrations were decreased in AD. This study found that several synaptic biomarkers were significantly altered in AD in CSF and blood exosomes. There was significant heterogeneity for most comparisons (with the exception of CSF NPTX-1 and blood exosome SNAP-25) that remains to be explored. Nonetheless, further review of the identified biomarkers may provide fundamental insight into AD pathophysiology and disease trajectory.

Objectives Obstructive Sleep Apnea (OSA) often remains undiagnosed in Late Life Depression (LLD) and complicates treatment. We investigated the feasibility of Home Sleep Apnea Testing (HSAT) to improve detection. Methods One hundred older adults (age 50+) attending a hospital clinic with LLD and no dementia were screened. Results Of 100 screened, 58 (with known OSA, recent negative sleep test or inability to comply with testing) were excluded. Among 42 older adults offered HSAT, 26 consented and 20 successfully completed testing. Fourteen (70%) of those tested had OSA (4 (20%) with moderate-severe OSA). STOP-BANG questionnaire score ≥ 3 detected 75% with moderate to severe OSA. Most (73.7%) rated their experience of HSAT as neutral to excellent, while a minority described difficulty using the device. Conclusions HSAT may be a feasible and acceptable way to improve detection of OSA among patients with LLD who are reluctant or unable to access in-laboratory testing.

OBJECTIVE:To identify which patients with remitted major depressive disorder (rMDD) or mild cognitive impairment (MCI) benefit from cognitive remediation (CR) plus transcranial direct current stimulation (tDCS). DESIGN:We conducted a moderator analysis to examine the effects of baseline brain magnetic resonance imaging (MRI) measures on the impact of CR + tDCS on cognitive decline in Prevention of Alzheimer's dementia with CR plus tDCS in MCI and Depression (PACt-MD), a double-masked randomized two-arm controlled trial with assessments at baseline, two months, and yearly for three to seven years. SETTING:Five academic hospitals in Toronto, Canada. PARTICIPANTS:A total of 246 participants with rMDD, MCI, or both, with an analyzable baseline MRI. INTERVENTION:CR + tDCS or sham CR + sham tDCS. MEASUREMENTS:Overall cortical thickness, overall fractional anisotropy, and cortical thickness in an a-priori composite region of interest (ROI); changes in global cognition, executive function, or verbal memory. RESULTS:Overall cortical thickness moderated decline in global cognition (Χ² = 10.43, df = 3, p = 0.015); ROI cortical thickness moderated treatment-related changes in global cognition (Χ² = 29.05, df = 3, p <0.001), executive function (Χ² = 11.57, df = 3, p = 0.009), and verbal memory (Χ² = 16.08, df = 3, p = 0.001). CONCLUSION:Future work needs to confirm that cortical thickness can be used to select adults at risk for dementia who are the most likely to benefit from CR + tDCS. CLINCIALTRIALS. GOV IDENTIFIER:NCT02386670.

Vascular mild cognitive impairment (vaMCI) is a prodromal stage of dementia defined by cognitive deficits due to cerebrovascular disease. Increased white matter hyperintensity (WMH) volume has been associated with reduced executive function (EF). We explored whether lower baseline frontal and global WMH volume predicted an improvement in EF in vaMCI participants treated with N-acetylcysteine (NAC) and exercise as compared to placebo and exercise. Fifty-eight individuals with vaMCI received exercise therapy and were randomized to NAC or placebo. EF was assessed using the Trail Making Test Part B (TMT-B), Digit Symbol-Coding Test (DSCT), and a test of phonemic fluency, at baseline, 3 months, and 6 months. WMH volumes were measured from baseline magnetic resonance imaging scans. Linear mixed models were used. All participants improved on TMT-B (β = -0.185, SE = 0.046, p < 0.001) and phonemic fluency (β = 4.440, SE = 0.911, p < 0.001) over 6 months. A significant three-way interaction between baseline frontal WMH volume, treatment group, and timepoint predicted TMT-B performance at 3 months (β = 0.160, SE = 0.076, p = 0.039), but not at 6 months. No significant interactions were found for DSCT or phonemic fluency. Global WMH did not predict treatment response. Participants demonstrated improvement in EF regardless of treatment group and WMH volume. Lower frontal WMH volume predicted a greater improvement in TMT-B performance at 3 months in those treated with NAC versus placebo. These findings underscore the importance of considering participant heterogeneity in trials for vaMCI.

BACKGROUND:In Apathy in Dementia Methylphenidate Trial 2 (ADMET2), apathy in Alzheimer's disease improved with methylphenidate (MPH) in a randomized, placebo-controlled trial, though response varied. Here we evaluated serum biomarkers for their association with apathy and with treatment response. METHODS:All ADMET2 participants with available blood samples were included. Markers of inflammation [interleukin (IL)-6, IL-10, Tumor Necrosis Factor (TNF)], oxidative stress [lipid hydroperoxide (LPH), 4-hydroxynonenal (4-HNE), 8-isoprostane (8-ISO)] and neuronal injury [neurofilament light (NfL), S100B] were assessed and values log-transformed. Neuropsychiatric Inventory-apathy (NPI-A) measured apathy. Least Absolute Shrinkage and Selection Operator (LASSO) regression was performed for feature selection of baseline markers predicting NPI-A at Month-6 (M6). Univariate analyses examined individual biomarker effects and multivariable models evaluated their combined effects. Treatment interactions, baseline and change in biomarker levels in treatment responders (≥4 change in NPI-A) and remitters (M6 NPI-A=0) were explored. RESULTS:In the ADMET2 biomarker subset (n = 44, MPH:21, age:75 years, MMSE:20.2), higher baseline TNF was associated with higher M6 NPI-A [B(SE)= 6.86 (1.71), p = .0003], and multivariable models found lower baseline TNF [B(SE)= 8.28(1.61), p < .001] and higher baseline S100B [B(SE)= -6.41(1.95), p = .002] were associated with lower M6 NPI-A. Exploratory analyses suggested that higher baseline NfL significantly interacted with treatment to predict lower M6 NPI-A [B(SE)= -8.36(4.21), p = .05], only when adjusting for cognition. MPH remitters had lower baseline TNF [B(SE)= -0.27(0.10), p = .02], higher baseline NfL [B(SE)= 0.33(0.14), p = .03], and a greater decrease in IL-6 [B(SE)= -0.44 (0.17), p = .02]. CONCLUSIONS:Inflammatory and neuronal injury biomarkers may have prognostic value and may potentially inform treatment response and remission outcomes in apathy. Apathy in Dementia Methylphenidate Trial 2 (ADMET2), NCT02346201, https://clinicaltrials.gov/study/NCT02346201.

INTRODUCTION:Alzheimer's disease (AD) is characterized by synaptopathy, a neuropathological feature that can contribute to underlying cognitive decline. Here, we evaluate potential cerebrospinal fluid (CSF) and blood-based synaptic biomarkers in AD dementia and its earliest clinical stage, mild cognitive impairment (MCI). METHODS:Articles that measured a subset of CSF and/or blood-based synaptic biomarkers in AD dementia, MCI, and/or healthy controls were included. A random-effects model was used to determine standardized mean differences and 95% confidence intervals. RESULTS:In total, 65 study cohorts were included for meta-analysis and 12 for qualitative review. Several CSF (synaptosomal-associated protein 25 [SNAP-25], growth-associated protein 43 [GAP-43], neuronal pentraxin receptor, neuronal pentraxin-1, neuronal pentraxin-2, synaptotagmin-1, syntaxin-1B, and vesicle-associated membrane protein 2) and blood-based (SNAP-25, GAP-43, and synaptotagmin-1) synaptic biomarkers were altered in AD dementia and/or MCI. DISCUSSION:Further evaluation of these identified biomarkers may enrich our understanding of AD pathophysiology and disease trajectory, as well as inform future treatment interventions.

The PACt-MD study demonstrated that combined cognitive remediation (CR) and transcranial direct current stimulation (tDCS) slows global cognitive decline in individuals with mild cognitive impairment (MCI) or remitted major depressive disorder (rMDD) over a median follow-up of four years. Prefrontal theta-gamma coupling (TGC), measured via electroencephalography (EEG), is a marker of prefrontal cortical function and may index cognitive compensation, the mechanism thought to underlie CR+tDCS effects. This secondary analysis investigated whether baseline TGC influenced the efficacy of CR+tDCS, hypothesizing that participants with high baseline TGC-indicating better prefrontal function-would benefit more from CR+tDCS than those with low baseline TGC. TGC was assessed during an N-back task at baseline in 260 participants (mean age=71.9, SD = 6.0) and dichotomized by median split into high vs low groups. Cognition was evaluated two months post-baseline and annually up to six years. Baseline TGC significantly moderated the effects of CR+tDCS on global cognition (χ²=12.46, p = 0.006), verbal memory (χ²=16.93, p = 0.0007), and executive function (χ²=18.57, p = 0.0003). In the high-TGC group, global cognition declined more slowly with active CR+tDCS compared to sham. No such difference was observed in the low-TGC group. Lower baseline TGC may reflect reduced capacity for cognitive compensation, limiting CR+tDCS effectiveness in at-risk older adults. Higher TGC may identify those most likely to benefit from this intervention. ClinicalTrials.gov Identifier: NCT02386670.

BackgroundLimited epidemiologic data exists for mental illnesses among at-risk home care (HC) and residential long-term care (LTC) recipients.ObjectiveTo estimate the annual prevalence (April 1, 2012-March 31, 2023) of various mental illnesses among HC and LTC populations (versus matched comparators) with and without dementia in the Canadian provinces of Ontario, Alberta, and Manitoba.MethodsParallel repeated cross-sectional studies were conducted in each province using linked health administrative data. HC and LTC recipients aged ≥18 years were matched to comparators on demographics, dementia and comorbidity. Prevalence estimates were derived using validated case definitions for any mental illness, mood/anxiety disorders, depression and anxiety (with/without drug claims), schizophrenia, bipolar disorder and suicide attempt. Prevalence ratios (95% CIs) were estimated with modified Poisson regression models.ResultsIncluded were 682,466 HC clients and 233,499 LTC residents. Mental illnesses were common in HC and LTC settings across all three provinces. Prevalence estimates were typically higher among care recipients versus matched comparators and among persons with versus without dementia. Up to 70% of HC clients and 80% of LTC residents with dementia had any mental illness; in both settings, 40% had mood/anxiety disorders, 4% bipolar disorders, and between 2%-6% schizophrenia. Suicide attempts were rare (0.5-0.6%). Prevalence varied by province and was higher for case algorithms including drug claims.ConclusionsThe high prevalence of mental illness and its common co-occurrence with dementia in HC and LTC recipients illustrates the complexity and challenges of care in these populations and raises concerns about potential unmet mental health needs.

Apathy is a prevalent neuropsychiatric symptom (NPS) in Alzheimer’s disease (AD), linked to functional impairment and reduced quality of life. The Apathy in Dementia Methylphenidate Trial 2 (ADMET-2) found methylphenidate (MPH) had modest efficacy for treating apathy, but treatment responses varied. MPH blocks dopamine and noradrenaline transporters, inhibiting dopamine and noradrenaline reuptake. Lipids are closely tied to monamine transporter function through their structural and signaling roles in neurotransmission, neuroinflammation, and synaptic plasticity. This study aimed to identify lipid species associated with MPH response and explore lipid pathway disruptions in responders versus non-responders. Participants from ADMET-2 with baseline lipidomic data were included. Responders were defined by a ≥4-point improvement on the Neuropsychiatric Inventory Apathy subscale (NPI-A), or moderate-to-marked improvement on the ADCS-Clinicians Global Impression-Change (ADCS-CGIC). Baseline plasma samples underwent lipidomic profiling. Sparse Partial Least Squares Discriminant Analysis (sPLS-DA) in the MPH group was used to identify lipid species distinguishing responders from non-responders. Model performance was evaluated by area under the curve (AUC). Identified lipid species were analyzed in MetaboAnalyst for pathway enrichment. A secondary analysis in the placebo group assessed specificity of findings to MPH. Of the 43 MPH-treated participants, 28 were NPI-apathy responders, and 10 were ADCS-CGIC responders. The PLS-DA model achieved robust discrimination between responders and non-responders (NPI-apathy: AUC = 0.82 +/- 0.05; ADCS-CGIC: AUC=0.84 +/- 0.07). Pathway analysis revealed disruptions in ceramide, phosphosphingolipid, and glycosphingolipid metabolism for NPI-apathy responders, and ceramide and glycosphingolipid metabolism for ADCS-CGIC responders. In 55 placebo-treated participants (30 NPI-apathy responders), an AUC of 0.79 +/- 0.05 was achieved, with pathway analysis indicating disruption in glycosphingolipid metabolism only. This study demonstrates the utility of lipidomic profiling in identifying biomarkers of response to MPH in AD patients with apathy. The identified lipidomic species are broadly related to monoamine transporter function, reflecting their role in neurotransmission and synaptic plasticity. While glycosphingolipid metabolism appears broadly linked to changes in apathy, disruptions in ceramide and phospholipid metabolism may be specific to MPH treatment. Further study of these pathways may offer insights into the molecular mechanisms underlying apathy and treatment response, and could inform future biomarker-guided interventions.

BackgroundCognitive remediation (CR) combined with transcranial direct current stimulation (tDCS) has been shown to slow cognitive decline in older adults with mild cognitive impairment (MCI) or remitted major depressive disorder (rMDD). Dysregulated angiogenesis is implicated in early neurodegeneration and may influence response to these interventions.ObjectiveTo determine whether baseline plasma angiogenesis markers moderate short-term and long-term cognitive response to CR + tDCS in older adults at risk for dementia.MethodsNineteen angiogenesis-related plasma biomarkers were measured at baseline in participants from the PACt-MD randomized controlled trial. Participants received active or sham CR plus active or sham tDCS for 8 weeks, followed by semi-annual booster sessions and online CR between visits. Cognitive assessments occurred at baseline, 8 weeks, and yearly. Elastic net regression identified relevant markers and baseline variables associated with the 8-week cognitive change. For selected markers, treatment*marker interactions were tested using multivariable linear regression adjusted for relevant demographic, clinical, and genetic covariates. Significant interactions were further examined using likelihood ratio tests in linear mixed-effects models across follow-up.ResultsIn 271 participants, angiopoietin-2, endocan, and VCAM-1 were identified as relevant markers. Out of these three markers, only angiopoietin-2 interacted with treatment (β(SE) = 0.17(0.08), p = 0.04, padj = 0.11, f2 = 0.02), with lower levels associated with greater 8-week cognitive improvement in the active treatment group, controlling for covariates. This moderating effect persisted during follow-up (χ2LRT(3) = 24.9, p < 0.001).ConclusionsLower baseline angiopoietin-2 may identify older adults with MCI or rMDD that are more likely to benefit from CR + tDCS.ClinicalTrials.gov; https://clinicaltrials.gov/study/NCT02386670; NCT02386670.

Loneliness and social isolation increase the risk of physical and mental disorders in older adults, while resilience may mitigate this risk. The evidence that medial temporal lobe (MTL) structures are associated with loneliness, social isolation, and resilience is largely cross-sectional. This study examined whether baseline MTL structures were associated with loneliness, social isolation, or resilience during the COVID-19 pandemic. 114 older adults (59 females; mean age: 73.8 ± 5.6 years) completed magnetic resonance imaging (MRI) before the pandemic (mean interval: 1182.6 ± 559.1 days). They presented with normal cognition (NC; n = 46), mild cognitive impairment (MCI; n = 28), or remitted major depressive disorder (rMDD; n = 40). Amygdala and hippocampal volumes and entorhinal cortex thickness on T1-weighted MRI scans were analyzed using FreeSurfer 7.0. Measures included the UCLA Loneliness Scale (UCLA), the Social Network Index (SNI), the Brief Resilience Scale (BRS), and the Connor-Davidson Resilience Scale (CD-RISC). Linear regressions were adjusted for demographic and clinical covariates. Larger amygdala and hippocampal volumes at baseline were associated with higher resilience (CD-RISC: B = 0.014, p < .001; B = 0.0042, p = .018, respectively). Larger amygdala volumes were associated with lower loneliness (B = -0.013, p = .027), although this finding did not survive correction for multiple comparisons. Sex was associated with loneliness and BRS resilience; females reported greater loneliness and lower resilience than males. Our findings provide hypothesis-generating evidence that amygdala and hippocampal volumes may represent neural correlates of resilience and loneliness in aging that could inform future interventions.

Alpha-band default mode network (DMN) connectivity declines with aging and Alzheimer's disease (AD), yet most electroencephalography (EEG) connectivity studies used pairwise (two-order) measures, such as mutual information rate (MIR). We leveraged O-information rate (OIR) to quantify three-order interactions and to separate redundant from synergistic information processing across frontal, temporal, and parietal DMN regions. We hypothesized that, extending established findings of reduced pairwise connectivity, (i) OIR (and its components) would be reduced in older versus younger adults and in AD versus healthy controls (HC); (ii) combining MIR with OIR would improve classification compared with MIR alone; and (iii) OIR measures would correlate positively with global cognition (as assessed by the Montreal Cognitive Assessment (MoCA)). Resting-state EEG from two samples—healthy adult lifespan aging (95 younger; 93 older) and AD spectrum (44 HC; 84 amnestic mild cognitive impairment [aMCI]; 41 AD)—was source-localized using eLORETA to DMN regions. Alpha band (8–13 Hz) MIR and OIR were computed through multivariate spectral analysis. Group differences were tested using t-tests or analysis of covariance (ANCOVA) with multiple comparison correction. Classification (OIR, MIR, demographic, and combined feature sets) used cross-validated logistic-regression, linear-SVM, and random-forest models, with bootstrap 95

INTRODUCTION:Previously, nabilone showed a medium effect size for treating agitation in moderate-to-severe Alzheimer's disease (AD), but response varied. These post hoc analyses aimed to identify a group of clinical characteristics that predicted treatment response. METHODS:Data from a double-blind, placebo-controlled crossover trial in AD agitation were used. Nineteen clinical characteristics were categorized (presence/absence) and evaluated for relation to agitation response (change on Cohen-Mansfield Agitation Inventory (CMAI)). Characteristics with a ≥ 8 point response difference between categories were included in a multivariable analysis model to calculate individual predicted response. Linear mixed-effects models with Satterthwaite's approximation evaluated the impact of treatment on the relationship between predicted and observed responses. RESULTS:Thirty-nine participants (77 % male, mean [SD] age 87 [10.2], standardized Mini-Mental State Exam (sMMSE) 6.5 [6.8]) were enrolled. Variable selection identified five characteristics related to greater nabilone efficacy: higher pain (Pain Assessment in Advanced Dementia score ≥3) (difference [SE] in CMAI response = -18.8 [3.2]), greater appetite and eating disorders (-16.4 [5.5]), greater apathy (-14.0 [5.5]), less cognitive impairment (sMMSE greater than 10) (-16.5 [4.2]) and no concomitant cholinesterase inhibitors (-13.9 [4.4]). For those with a predicted response in the top tertile based on those five characteristics, 82 % responded, compared with 40 % in the lowest tertile. A treatment-by-tertile interaction (F(2,29) = 8.48, p = 0.001) indicated observed treatment response varied across tertiles. CONCLUSION:A reliable clinical profile of persons with AD related agitation likely to respond to nabilone may be established with additional research.

OBJECTIVE:The Anticholinergic Drug Scale (ADS) is a commonly used measure of anticholinergic exposure. This study describes an expanded and revised version of the ADS (rADS) and its relationship with cultured cell-based serum anticholinergic activity (cSAA) and cognitive measures. STUDY PARTICIPANTS:Adults aged 60 years and older with mild cognitive impairment (MCI), remitted major depressive disorder (rMDD), or both, participate in the Prevention of Alzheimer's Dementia with Cognitive Remediation plus Transcranial Direct Current Stimulation (PACt-MD) study. STUDY DESIGN:Cross-sectional investigation of data from the PACt-MD study. MEASURES:The rADS includes ratings for 1047 distinct products, about twice as many as the originally published scale; previously published ratings were revised for 40 drugs. Total rADS scores were calculated as sums of ratings of all drugs taken by participants; cSAA was measured in the participants' sera; cognitive performance included measures of executive function, language, processing speed, verbal memory, visuospatial memory, working memory, and an overall composite score. STATISTICAL ANALYSIS:The relationship between rADS total scores and cSAA was examined using a Spearman rank correlation coefficient. Relationships between rADS total scores and cognitive performance measures were explored in multivariable linear regression models. RESULTS:The sample included 310 participants (mean [standard deviation] age: 72 (6) years; 61.6% were women, and 81.6% had MCI [with or without rMDD]). Total rADS scores were positively correlated with cSAA (Spearman's correlation coefficient: 0.178, p = 0.0016). Total rADS scores were not significantly associated with cognitive performance. CONCLUSIONS:The revised scale is recommended as a replacement for the original ADS since it includes ratings for more drugs and was significantly, albeit weakly, associated with cSAA, similar to previous findings using the original ADS.

Agitation is a challenging neuropsychiatric symptom (NPS) of Alzheimer's disease (AD). A crossover trial found that nabilone significantly improved agitation in AD patients over 6 weeks compared to placebo. Here, we aim to identify a combination of biomarkers that could be used to predict treatment response to nabilone for AD-associated agitation. Agitation was assessed using the Cohen-Mansfield Agitation Inventory (CMAI). Serum concentrations of 13 markers were measured. Linear regression was used to estimate change in CMAI due to nabilone for the high and low groups of each biomarker. Biomarkers with a difference ≥8.5 points between groups were included in subsequent multivariate models. Index scores representing the difference between expected CMAI change given nabilone and placebo were calculated and divided into quartiles. Mean difference in CMAI change and 95% confidence intervals were estimated via bootstrapping. Four of the 13 biomarkers which met criteria specified above were included in multivariate modeling ( n  = 67). Nabilone was more efficacious in participants with higher IL-6 (estimated change in CMAI -15.4, standard error (SE) 5.6), higher ISO-8 (-14.4, SE=5.0), higher 24S-OHC (-14.2, SE=4.1), and lower clusterin (-14.6, SE=4.4). Participants in Q1 of index scores demonstrated better response to nabilone with a mean difference in CMAI change of -20.9 (95% CI: -31.8, -9.2), while those in Q2-4 showed no difference between treatments. Participants with higher levels of inflammation, oxidative stress, and cholesterol metabolite were more likely to benefit from nabilone for agitation in AD. A combination of biomarkers could help in distinguishing responders and non-responders to nabilone.