BACKGROUND:Adherence to treatment guidelines for agitation in dementia is suboptimal and inconsistent. We designed and evaluated an Integrated Care Pathway (ICP) for the management of agitation in dementia. METHODS:This was a double-blind randomized controlled trial at 12 inpatient units and long-term-care homes (LTCHs) across Canada. Participants were randomized 1:1 to the ICP or treatment-as-usual (TAU). Primary outcomes were Cohen Mansfield Agitation Inventory (CMAI) and psychotropic polypharmacy at 12 weeks. RESULTS:We randomized 185 participants (93 inpatients, 92 in LTCHs). For CMAI, there were no significant time-by-treatment-group interactions among inpatients (F4, 299.3 = 1.7, p = 0.14) or LTCH residents (F4, 296.0 = 0.87, p = 0.48). For polypharmacy, there were significant time-by-treatmentgroup interactions among both inpatients ( χ 7 2 = 15.3, p = 0.032) and LTCH residents ( χ 7 2 = 30.0, p < 0.001), with lower rates of polypharmacy in the ICP group at certain time points, but not at week 12. CONCLUSIONS:Standardizing care for agitation in dementia may result in lesser polypharmacy without affecting efficacy. Future studies should assess the ICP in the broader community and outpatients.

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.

BACKGROUND AND HYPOTHESIS:Impaired insight into illness affects up to 95% of individuals with schizophrenia, depending on the stage of illness, and is a predictor of antipsychotic nonadherence and poor clinical outcomes. Despite its importance, no effective treatment exists. Interhemispheric imbalance in frontoparietal regions may serve as a biomarker of impaired insight into illness and target for transcranial direct current stimulation (tDCS). Meta-analyses suggest that sham-controlled multisession tDCS applied to frontotemporoparietal areas improves insight in schizophrenia. However, no randomized controlled tDCS trial has targeted the posterior parietal areas to improve insight into illness. We hypothesized that multisession biparietal tDCS would lead to both immediate (ie, following 2-weeks of tDCS) and sustained (ie, up to 4-weeks) improvement in insight in schizophrenia. STUDY DESIGN:Thirty-four participants with schizophrenia/schizoaffective disorder and impaired insight into illness were randomized to receive either active (n = 18) or sham (n = 16) biparietal tDCS (anodal/cathodal:P4/P3), administered twice daily over 10 days. Insight was assessed using the VAGUS Insight into Psychosis scale at baseline pre-treatment, post-treatment, and weekly for 4 weeks. Linear mixed-effects models compared estimated marginal mean VAGUS scores between conditions, with and without adjusting for Intelligence Quotient (IQ), illness severity, and clozapine use. STUDY RESULTS:Active tDCS significantly improved average VAGUS scores immediately following and up to 4 weeks post-treatment. CONCLUSIONS:Biparietal tDCS appears to be a promising intervention for improving insight in schizophrenia. Future research should explore its adjunctive use with medication to enhance treatment adherence.

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.

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.

IntroductionObesity is a complex condition that negatively impacts health, quality of life, and life expectancy. Nonadherence to existing clinical interventions remains a significant barrier for patients with obesity, with 80% of overweight individuals struggling to maintain long-term weight loss. Impaired illness awareness is a factor that may contribute to treatment nonadherence. Previous functional imaging studies in other conditions have suggested that impaired illness awareness may be related to altered activity or dysconnectivity in frontoparietal regions, including the posterior parietal area (PPA) and dorsolateral prefrontal cortex (dlPFC). As such, this exploratory study aimed to investigate the brain regions associated with impaired illness awareness in individuals with obesity.MethodsA total of 26 participants (Age = 50.4 (14.5), 75% female) with a mean BMI of 37.4 (SD = 5.1) were included. Participants completed an individually tailored subjective obesity awareness task during fMRI. The task paradigm consisted of a bank of brief stimuli, including ‘yes/agree’ or ‘no/disagree’ questions/statements derived from the core domains of illness awareness and control stimuli. Obesity awareness was assessed based on response accuracy to the paradigm’s obesity-related stimuli. Participants were also grouped into impaired (≤80% response accuracy, n = 14) versus intact obesity awareness (>80%, n = 12). Regression and non-parametric between-group analyses were conducted to assess brain activation, as measured by fMRI blood oxygen level dependent (BOLD) response during the obesity awareness task. Regions of interest for impaired obesity awareness were the PPA, dlPFC, and insula, controlling for age and gender.ResultsImpaired subjective obesity awareness was related to increased BOLD responses in the left PPA, but not the dlPFC and insula during an obesity awareness fMRI task. Similarly, participants with impaired obesity awareness showed increased BOLD response to the obesity awareness task in PPA compared to those with intact obesity awareness.DiscussionImpaired obesity awareness may be related to increased brain activation in the PPA, though future replication is needed. Identifying neuroimaging biomarkers of impaired obesity awareness can help provide brain targets for intervention, with a goal of facilitating treatment adherence.

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

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.

BACKGROUND AND OBJECTIVES:Plasma biomarkers of Alzheimer disease (AD), neuroinflammation, and neurodegeneration are increasingly being used in clinical trials for diagnosis and monitoring of dementia. However, their association with longitudinal structural brain MRI changes, an important outcome measure across neurodegenerative and cerebrovascular diseases, is less known. We investigated how baseline plasma biomarkers reflect MRI markers of progression over time in patients with neurodegenerative and cerebrovascular diseases. METHODS:This longitudinal cohort study included patients from the Ontario Neurodegenerative Disease Research Initiative diagnosed with AD or mild cognitive impairment (AD/MCI), Parkinson disease (PD), frontotemporal dementia spectrum disorders (FTD), or cerebrovascular disease (CVD), followed annually for 2 years. Recruitment took place at specialized university-based dementia, movement disorders, and/or stroke clinics in the province of ON, Canada. MRI outcomes included markers of cerebral atrophy (ventricular CSF and regional gray matter volumes) and of small vessel disease pathology (white matter hyperintensity [WMH], perivascular spaces, and lacunar volumes). Hemorrhagic markers at baseline were also included. Plasma levels of glial fibrillary acidic protein (GFAP), neurofilament light chain (NfL), phosphorylated tau181 and tau217 (p-tau181, p-tau217), and β-amyloid (Aβ42/40) were quantified from blood samples collected at baseline using Simoa and used as predictors in linear mixed models adjusted for time (months), age, sex, apolipoprotein E (APOE)-ε4 carrier status, kidney function, vascular risk factors, microtubule-associated protein tau (MAPT) diplotypes, waist-hip circumference ratio, and disease duration. RESULTS:We analyzed 1,240 MRIs from 473 patients (age: 69.2 ± 7.4 [range: 49-87]; 32.8% women). Elevated baseline levels of GFAP, NfL, p-tau181, and p-tau217, and to a lesser extent decreased levels of Aβ42/40, were significantly associated with more cerebral atrophy and WMH burden at baseline (|B| = 0.02 to 1.69, p = 0.044 to <0.001) and with progression over time (|B| = 0.001 to 0.028, p = 0.049 to <0.001) in the pooled disease-agnostic group. Within disease-specific cohorts, GFAP and NfL were associated with cerebral atrophy and/or small vessel disease copathology in AD/MCI, PD, FTD, or CVD. P-tau181 and p-tau217 were associated with cerebral atrophy and/or small vessel disease copathology in AD/MCI, CVD, PD-MCI, or PD-dementia. DISCUSSION:Selected plasma biomarkers seem useful as prognosis and monitoring tools of longitudinal imaging changes within real-world populations of neurodegenerative and/or cerebrovascular diseases, and provide insight into overlap across diseases in shared pathologic burden.

Adherence to treatment guidelines for agitation in dementia is suboptimal and inconsistent. We designed an Integrated Care Pathway (ICP) that standardized behavioral and pharmacological interventions for agitation in dementia, and evaluated it against treatment-as-usual (TAU). The two primary hypotheses were that, compared to TAU, the ICP would result in (1) lower agitation and (2) lower rates of polypharmacy at study end. The Sta ndardizing Care for N europsychiatric Symptoms and Quality of Life in Dementia (StaN) trial ( ClinicalTrials.gov # NCT03672201) was conducted at five academically affiliated inpatient units (Inpatient) and seven long-term-care homes (LTCHs). Participants with agitation related to Alzheimer’s dementia were randomized 1:1 to receive the ICP or TAU for 12 weeks. Primary outcomes were: (1) Cohen Mansfield Agitation Inventory (CMAI) completed at weeks 3, 8, and 12 (primary), and (2) polypharmacy defined as using more than one psychotropic medication assessed at weeks 1, 3, 4, 6, 8, 10, and 12 (primary) post-randomization. Linear mixed effect models and generalized estimating equations were used to test our hypotheses controlling for age, gender, and stage of dementia. The study was powered for Inpatient and LTCH settings separately. 185 participants were randomized: 93 in Inpatient (46 ICP: 47 TAU; females = 32 (34.4%); mean (standard deviation [SD]) age = 75.0 (8.4) years), and 92 in LTCH (46 ICP: 46 TAU; women = 63 (68.5%); mean (SD) age = 85.9 (7.6) years). There were no significant time*group interactions for the CMAI scores for Inpatient (F 4, 297.9 = 0.8, p = 0.53) or LTCH (F 4, 297.3 = 1.1, p = 0.36) and no significant differences at week-12 (Inpatient: ICP-TAU adjusted difference = 0.025; 95% Confidence Interval (CI): -0.410, 0.460; LTCH: ICP-TAU adjusted difference = -0.214; 95%CI: -0.699, 0.270). However, there were significant time*group interactions for polypharmacy for both Inpatient (χ 2 7 = 18.6, p = 0.01) and LTCH (Χ 2 7 = 22.9, p = 0.002). Differences were not significant at week-12 (Inpatient: ICP-TAU adjusted difference = 0.15; 95%CI: -0.11, 0.40; LTCH: ICP-TAU adjusted difference = 0.33; 95%CI: -0.06, 0.72), the ICP group had lower rates of polypharmacy than TAU group at weeks 3, 4, and 6 on Inpatient, and week 3 in LTCH. Standardizing care for agitation in dementia may result in less polypharmacy without affecting efficacy. Future studies should assess the ICP in broader community and outpatient settings.

BACKGROUND:Cortical excitability has been proposed as a novel neurophysiological marker of neurodegeneration in Alzheimer's dementia (AD). However, the link between cortical excitability and structural changes in AD is not well understood. OBJECTIVE:To assess the relationship between cortical excitability and motor cortex thickness in AD. METHODS:In 62 participants with AD (38 females, mean ± SD age = 74.6 ± 8.0) and 47 healthy control (HC) individuals (26 females, mean ± SD age = 71.0 ± 7.9), transcranial magnetic stimulation resting motor threshold (rMT) was determined, and T1-weighted MRI scans were obtained. Skull-to-cortex distance was obtained manually for each participant using MNI coordinates of the motor cortex (x = -40, y = -20, z = 52). RESULTS:The mean skull-to-cortex distances did not differ significantly between participants with AD (22.9 ± 4.3 mm) and HC (21.7 ± 4.3 mm). Participants with AD had lower motor cortex thickness than healthy individuals (t(92) = -4.4, p = <0.001) and lower rMT (i.e., higher excitability) than HC (t(107) = -2.0, p = 0.045). In the combined sample, rMT was correlated positively with motor cortex thickness (r = 0.2, df = 92, p = 0.036); however, this association did not remain significant after controlling for age, sex and diagnosis. CONCLUSIONS:Patients with AD have decreased cortical thickness in the motor cortex and higher motor cortex excitability. This suggests that cortical excitability may be a marker of neurodegeneration in AD.

Mild Behavioral Impairment (MBI) is a condition characterized by neuropsychiatric symptoms (NPS) in older adults without dementia, serving as a precursor to various forms of dementia. This study explores the association between NPS and functional connectivity (FC) within the default mode network (DMN), executive control network (ECN), and salience network (SN) across three high-risk cohorts: mild cognitive impairment (due to Alzheimer’s) (MCI, n = 79), cerebrovascular disease (CVD, n = 144), and Parkinson’s disease (PD, n = 132). A total of 367 participants were recruited from the Ontario Neurodegenerative Disease Research Initiative (ONDRI). The assessment of NPS utilized the Neuropsychiatric Inventory Questionnaire (NPI-Q), with symptom severity rated on a scale from 1 to 3 (mild, moderate, severe). Resting-state FC was analyzed for the DMN, ECN, and SN, using dual regression analysis to generate subject-specific whole-brain FC maps for each network. The association between FC maps and NPS scores was examined using FSL’s randomise with 5,000 permutations, while controlling for age, sex, and education. Results are presented following cluster False Discovery Rate (FDR) correction. The study revealed significant associations between NPS and FC specific to each cohort. In the MCI group, disturbed appetite and nighttime behaviors were correlated with increased FC of the dorsal DMN (p<0.05, R = 0.47, and p = 0.01, R = 0.47). The CVD group exhibited correlations between higher levels of anxiety and decreased FC of the dorsal DMN (p<0.05, R = -0.4), ventral DMN (p<0.05, R = -0.33), and bilateral ECN (p<0.05, R = -0.35 and R = -0.33). The PD group showed disturbed nighttime behavior associated with increased FC in ventral DMN (p<0.05, R = 0.35) and bilateral ECN (p<0.05, R = 0.43 and R = 0.37). This research underscores disorder-specific correlations between specific NPS domains and FC in MCI, CVD, and PD, emphasizing the unique neural underpinnings of symptomatology in each group. Furthermore, it is essential to note the inherent heterogeneity in all groups. Overall, the pathological substrates of neurodegenerative disorders likely play a pivotal role in shaping the neural correlates of MBI within each disorder. These findings provide valuable insights into targeted interventions and avenues for future research in neurodegenerative disorders.

Polypharmacy is common in older individuals with Alzheimer's disease and related dementia (ADRD) who present with neuropsychiatric symptoms (NPS). While it is associated with increased fall risk, specific impact of psychotropic and general medication use on fall risk in this population is not clear. We evaluated fall risk associated with psychotropic and general medication use in patients with ADRD and NPS while controlling for other clinical factors. We used the following data from participants with a clinical diagnosis of AD and clinically significant NPS in the Standardizing Care for Neuropsychiatric Symptoms and Quality of Life in Dementia (StaN) study (ClinicalTrials.gov/NCT03672201): number of psychotropic and general medications and scores on the Cohen Mansfield Agitation Inventory (CMAI) scores, Cumulative Illness Rating Scale-Geriatric (CIRSG), Functional Assessment Staging Tool (FAST). and Morse Fall Scale (MFS). Linear regression analyses evaluated the associations between psychotropic or general medication use and fall risk (MFS) while adjusting for age, CIRS-G, CMAI, and FAST scores. 185 participants (female: 96 (52.5%)) were included, with mean (SD) age of 80.5 (9.8) years, mean FAST score of 9.1 (SD: 0.65; median stage: 6e). Psychotropic or general medications and CMAI or CIRS-G scores were not significantly associated with MFS, but FAST stage of dementia was. Fall risk in AD may be influenced more by functional and cognitive impairment than by medication use. These findings should be considered in the context of unique characteristics of this cohort that include a severe stage of dementia and the presence of significant NPS, and may inform fall risk management strategies in this population. References Gallagher, E., Mehmood, M., Lavan, A., Kenny, R. A., & Briggs, R. (2023). Psychotropic medication use and future unexplained and injurious falls and fracture amongst community-dwelling older people: Data from TILDA. European Geriatric Medicine, 14 (4), 455–463. Zarei S, Choudhury S, Burhan AM, Chu L, Colman S, Derkach P, et al. Determinants of polypharmacy in patients with behavioral and psychological symptoms of dementia. Alzheimers Dement. 2021;17(S6).

Background Multiscale dispersion entropy (MDEnt) is a nonlinear EEG measure that quantifies brain complexity across time scales, reflecting both local and global brain dynamics. Previous research indicates lower complexity at short time scales in Alzheimer's disease (AD) compared to mild cognitive impairment (MCI) and healthy controls (HCs), with MCI also showing lower values than HCs. Major depressive disorder (MDD) has also been preliminarily linked to reduced complexity during acute episodes.Objective To assess whether MDEnt at short time scales can distinguish AD from MCI and HCs, and to examine complexity differences across additional groups, remitted MDD (rMDD) and rMDD + MCI, while exploring associations with cognitive performance.Methods The study included 316 older adults: 44 HCs, 46 with rMDD, 114 with MCI, 71 with rMDD + MCI, and 41 with AD. Resting-state, eyes-closed EEGs were analyzed using MDEnt at 24 ms (short) and 60 ms (long) time scales. Cognitive function was measured with the Montreal Cognitive Assessment and a composite cognitive score.Results Short time scale complexity was lowest in AD, followed by MCI, and highest in HCs; rMDD presence had no impact. Only AD showed reduced complexity at long time scales. Complexity at both time scales was significantly correlated with cognitive performance.Conclusions This study highlights the value of MDEnt to assess complexity at short time scale and differentiate individuals with AD, MCI, or HCs. Reduced complexity in these individuals may underlie their cognitive impairment. In contrast, our study suggests that any MDD impact on complexity is likely related to active depressive symptoms.

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