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Background: The co-occurrence of apathy and executive dysfunction, a correlate of vascular cognitive impairment (VCI), is highly prevalent, yet facilitating factors are largely unknown. Objective: This study investigates the relationship between lipid peroxidation, apathy, and executive dysfunction in patients at risk for VCI. Methods: In participants with coronary artery disease, who are at a high risk of VCI, apathy (Apathy Evaluation Scale), and executive function (composite z-score based on age and education population norms from trails making test B, animal naming, and phonemic fluency tests) were assessed. Serum concentrations of an early (lipid hydroperoxide (LPH)) and late (8-isoprostane (8-ISO)) lipid peroxidation marker, were measured and the 8-ISO/LPH ratio was calculated. Results: Participants (n = 206, age±SD = 63.0±7.5, 80% men, total years of education = 15.9±3.4, AES score = 28.3±8.8, executive function = 0±1) demonstrated significantly different 8-ISO/LPH ratios between groups (F(3, 202) = 10.915, p

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.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.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).These findings support the biological underpinnings of MBI, emphasizing the importance of later life behavioral changes in dementia detection and prognostication.

Background Transcranial direct current stimulation (tDCS) is a non-invasive type of brain stimulation that uses electrical currents to modulate neuronal activity. A small number of studies have investigated the effects of tDCS on cognition in patients with Mild Cognitive Impairment (MCI) and Alzheimer’s disease (AD), and have demonstrated variable effects. Emerging evidence suggests that tDCS is most effective when applied to active brain circuits. Aerobic exercise is known to increase cortical excitability and improve brain network connectivity. Exercise may therefore be an effective, yet previously unexplored primer for tDCS to improve cognition in MCI and mild AD. Methods Participants with MCI or AD will be randomized to receive 10 sessions over 2 weeks of either exercise primed tDCS, exercise primed sham tDCS, or tDCS alone in a blinded, parallel-design trial. Those randomized to an exercise intervention will receive individualized 30-min aerobic exercise prescriptions to achieve a moderate-intensity dosage, equivalent to the ventilatory anaerobic threshold determined by cardiopulmonary assessment, to sufficiently increase cortical excitability. The tDCS protocol consists of 20 min sessions at 2 mA, 5 times per week for 2 weeks applied through 35 cm2 bitemporal electrodes. Our primary aim is to assess the efficacy of exercise primed tDCS for improving global cognition using the Montreal Cognitive Assessment (MoCA). Our secondary aims are to evaluate the efficacy of exercise primed tDCS for improving specific cognitive domains using various cognitive tests (n-back, Word Recall and Word Recognition Tasks from the Alzheimer’s Disease Assessment Scale-Cognitive subscale) and neuropsychiatric symptoms (Neuropsychiatric Inventory). We will also explore whether exercise primed tDCS is associated with an increase in markers of neurogenesis, oxidative stress and angiogenesis, and if changes in these markers are correlated with cognitive improvement. Discussion We describe a novel clinical trial to investigate the effects of exercise priming before tDCS in patients with MCI or mild AD. This proof-of-concept study may identify a previously unexplored, non-invasive, non-pharmacological combination intervention that improves cognitive symptoms in patients. Findings from this study may also identify potential mechanistic actions of tDCS in MCI and mild AD. Trial registration Clinicaltrials.gov, NCT03670615. Registered on September 13, 2018.

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

Objectives Intensive control of hypertension has been reported to decrease risk of cognitive decline. However, the effect of this in older adults with hypertension and comorbid depression is not well understood. We aim to identify whether intensive control of systolic blood pressure (BP) is associated with reduced risk of Alzheimer's dementia (AD) in a clinical population. Methods Using data from the National Alzheimer's Coordinating Center, we conducted survival analyses in older adults with normal cognition at baseline and treated hypertension. We also examined those with comorbid depression, to determine if intensive control of systolic BP (≤120 mmHg) was associated with reduced risk of AD. Results In all older adults with treated hypertension (n = 4505), 298 (6.6%) developed AD during a median follow-up duration of 4.2 years. In the comorbid depression subgroup (n = 1327), 152 (11.5%) developed AD. Intensive control of systolic BP was not significantly associated with reduced risk of AD in the overall sample (HR 1.13, 95%, 0.79-1.64). However, in the comorbid depression subgroup, intensive control of systolic BP (≤120 mmHg) was associated with increased risk of AD (HR 1.49, 95%, 1.03-2.15) compared to standard control (121-139 mmHg). Conclusions In a clinical population of older adults with hypertension and comorbid depression, we found that an intensive systolic BP target of ≤120 mmHg was associated with increased risk of AD. While these findings are preliminary, they suggest that a more cautious approach to hypertension treatment may be warranted in this vulnerable subgroup.

Previous studies regarding the relationship between depression and Alzheimer's neuropathology in older adults without dementia have reported conflicting findings. This study examined whether depression is associated with Alzheimer's neuropathology and whether sex moderates these relationships.This is a cross-sectional study of older adults without dementia (normal cognition or mild cognitive impairment, age 50+; CDR ≤ 0.5) who had autopsy within 1 year of their last clinic visit in the National Alzheimer's Coordinating Center database (2005-2020). Logistic regression models were fitted to determine if a recent or remote history of depression was associated with amyloid spread beyond the neocortex measured by modified Thal phase score, density of amyloid plaques measured by CERAD score or tau neuropathology measured by modified Braak score. A moderator analysis was performed to determine if any of these associations were moderated by sex.This study included 407 participants (96 Thal, 405 Braak, and 406 CERAD). Those who had recently active depression (within previous 2 years) but not remote depression only were more likely to have higher Thal phase score compared to those without a history of depression (OR = 3.74; 95% CI, 1.15-12.17; p = 0.028). Sex did not moderate this association. No significant associations between recent depression and Braak or CERAD scores were observed.Our findings indicate that the association between late life depression and Alzheimer's neuropathology is associated with spread of amyloid pathology beyond the neocortex to include allocortical and subcortical regions critical for regulation of mood and motivated behavior.

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.

Background Agitation is a prevalent and difficult-to-treat symptom of Alzheimer's disease (AD). The endocannabinoid system (ECS) has been a target of interest for the treatment of agitation. However, ECS signaling may interact with AD-related changes in brain cholesterol metabolism. Elevated brain cholesterol, reflected by reduced serum 24-S-hydroxycholesterol (24S-OHC), is associated with reduced membrane fluidity, preventing ligand binding to cannabinoid receptor 1. Objective To assess whether 24S-OHC was associated with agitation severity and response to nabilone. Methods 24S-OHC was collected from AD patients enrolled in a clinical trial on nabilone at the start and end of each phase. This allowed for the cross-sectional and longitudinal investigation between 24S-OHC and agitation (Cohen Mansfield Agitation Inventory, CMAI). Post-hoc analyses included adjustments for baseline standardized Mini-Mental Status Exam (sMMSE), and analyses with CMAI subtotals consistent with the International Psychogeriatric Association (IPA) definition for agitation (physical aggression and nonaggression, and verbal aggression). Results 24S-OHC was not associated with CMAI scores cross-sectionally or longitudinally, before and after adjusting for baseline sMMSE. However, 24S-OHC was associated with greater CMAI IPA scores at baseline (F(1,36) = 4.95, p = 0.03). In the placebo phase only, lower 24S-OHC at baseline was associated with increases in CMAI IPA scores (b = -35.2, 95% CI -65.6 to -5.0, p = 0.02), and decreases in 24S-OHC were associated with increases in CMAI IPA scores (b = -20.94, 95% CI -57.9 to -4.01, p = 0.03). Conclusion 24S-OHC was associated with agitation severity cross-sectionally, and longitudinally in patients with AD. However, 24S-OHC did not predict treatment response, and does not change over time with nabilone.

Background Previous studies examining the link between neuropsychiatric symptoms (NPS) and biomarkers of Alzheimer's disease (AD) may be confounded by remitted or past history of psychiatric illness, which in itself is associated with AD biomarkers such as reduced medial temporal lobe (MTL) volume. Objective We examined associations between mood and anxiety-related NPS and MTL in older adults with mild cognitive impairment (MCI) free of lifetime history of depression. We hypothesized an inverse relationship between NPS severity and MTL. Methods Forty-two MCI participants without current or past history of depression or other major psychiatric illness were assessed using the Neuropsychiatric Inventory-Questionnaire (NPI-Q). Correlation and regression analyses were performed between selected NPI-Q items and regional MTL volumes from structural magnetic resonance imaging. Results Sleep disturbances were inversely associated with several regional volumes within the MTL. Sleep disturbances remained significantly correlated with left hippocampal and amygdala volume following correction for multiple comparisons. In contrast, depression and anxiety were not correlated with MTL. Conclusions The relationship between reduced MTL and sleep, but not with depressed or anxious states, in MCI free of lifetime history of depression, suggests a potential mechanism for sleep as a risk factor for AD. The current findings highlight the importance of accounting for remitted psychiatric conditions in studies of the link between NPS and AD biomarkers and support the need for further research on sleep as clinical biomarker of AD and target for AD prevention.

Background: Current surgical risk assessment tools fall short of appreciating geriatric risk factors including cognitive deficits, depressive, and frailty symptoms that may worsen outcomes post-transcatheter aortic valve implantation (TAVI). This study hypothesized that a screening tool, SMARTIE, would improve detection of these risks pre-TAVI, and thus be predictive of postoperative delirium (POD) and 30-day mortality post-TAVI. Design: Prospective observational cohort study, using a historical cohort for comparison. Participants: A total of 234 patients (age: 82.2±6.7 years, 59.4% male) were included. Half were screened using SMARTIE. Methods: The SMARTIE cohort was assessed for cognitive deficits and depressive symptoms using the Mini-Cog test and PHQ-2, respectively. Measures of frailty included activities of daily living inventory, the Timed Up and Go test and grip strength. For the pre-SMARTIE cohort, we extracted cognitive deficits, depression and frailty symptoms from clinic charts. The incidence of POD and 30-day mortality were recorded. Bivariate chi-square analysis or t-tests were used to report associations between SMARTIE and pre-SMARTIE groups. Multivariable logistic regression models were employed to identify independent predictors of POD and 30-day mortality. Results: More patients were identified with cognitive deficits (χ2=11.73, p=0.001), depressive symptoms (χ2=8.15, p=0.004), and physical frailty (χ2=5.73, p=0.017) using SMARTIE. Cognitive deficits were an independent predictor of POD (OR: 8.4, p

Objectives:To compare the prevalence of select cardiovascular risk factors (CVRFs) in patients with mild cognitive impairment (MCI) versus lifetime history of major depression disorder (MDD) and a normal comparison group using baseline data from the Prevention of Alzheimer’s Dementia with Cognitive Remediation plus Transcranial Direct Current Stimulation (PACt-MD) study.Design:Baseline data from a multi-centered intervention study of older adults with MCI, history of MDD, or combined MCI and history of MDD (PACt-MD) were analyzed.Setting:Community-based multi-centered study based in Toronto across 5 academic sites.Participants:Older adults with MCI, history of MDD, or combined MCI and history of MDD and healthy controls.Measurements:We examined the baseline distribution of smoking, hypertension and diabetes in three groups of participants aged 60+ years in the PACt-MD cohort study: MCI (n = 278), MDD (n = 95), and healthy older controls (n = 81). Generalized linear models were fitted to study the effect of CVRFs on MCI and MDD as well as neuropsychological composite scores.Results:A higher odds of hypertension among the MCI cohort compared to healthy controls (p < .05) was noted in unadjusted analysis. Statistical significance level was lost on adjusting for age, sex and education (p > .05). A history of hypertension was associated with lower performance in composite executive function (p < .05) and overall composite neuropsychological test score (p < .05) among a pooled cohort with MCI or MDD.Conclusions:This study reinforces the importance of treating modifiable CVRFs, specifically hypertension, as a means of mitigating cognitive decline in patients with at-risk cognitive conditions.

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

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

The endocannabinoid system has been a target of interest for agitation in Alzheimer disease (AD) because of potential behavioral effects and its potential impact on mechanisms implicated in AD such as oxidative stress (OS) and neuroinflammation. We explored whether serum markers of OS and neuroinflammation were associated with response to the cannabinoid nabilone in agitated patients with AD (N = 38). All participants were enrolled in a 14-week, double-blind, cross-over trial comparing nabilone to placebo (6 weeks each) with a 1-week washout between phases. Samples were collected at the start and end of each phase. The cross-sectional relationship agitation (Cohen Mansfield Agitation Inventory) and OS and inflammatory markers were investigated to select markers of interest. Significant markers were then explored for their relationship with response. The OS marker, 4-hydroxynonenal (4-HNE; F1, 35 = 6.41, P = .016), and the proinflammatory cytokine, tumor necrosis factor-α (TNF-α; F1, 29 = 3.97, P = .06), were associated with agitation severity, and TNF-α remained significantly associated ( F2, 25 = 3.69, P = .04) after adjustment for cognition. In the placebo phase, lower baseline 4-HNE was associated with decreases in agitation severity only (b = 0.01, P = .01), while lower baseline TNF-α was associated with decreases in agitation severity in the nabilone phase only (b = 1.14, P = .045). Changes in 4-HNE were not associated with changes in agitation severity in either phase. In the nabilone phase, lower baseline TNF-α was associated with decreases in agitation severity (b = 1.14, P = .045), and decreases in TNF-α were associated with decreases in agitation severity (b = 1.12, P = .006). These findings suggest that OS and neuroinflammation may be associated with agitation severity, while nabilone may have anti-inflammatory effects.

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

Objective It has been proposed that inflammation may be causally related to depression. If this is the case, it may be possible to distinguish an inflammatory depressive subtype according to illness course, pattern of co-morbidity and symptom profile. Methods Eight hundred and eleven community dwelling older adults with depression (8 item Center for Epidemiologic Studies scale ≥ 4) from the English Longitudinal study of Ageing (ELSA) were followed for a median of 47 months. Participants with depression and inflammation (C Reactive Protein > 3 mg/l) were compared to those with depression alone. Results In a longitudinal analysis, depression with associated inflammation was more likely to persist over time. This association was independent of baseline depression severity and medical co-morbidity (OR 1.47 95% CI 1.03 - 2.10, p = 0.034) but was no longer significant following further adjustment for body mass index (OR 1.37 95% CI 0.94 - 2.01, p = 0.106). Inflammation either partially or completely mediated the association between medical co-morbidity, body mass index and depression at follow-up. Depression with inflammation was associated with more amotivation, less sadness, greater medical co-morbidity and higher body mass index. Conclusions Our findings provide some support for an inflammatory contribution to depression. This subgroup has a worse prognosis and may benefit from interventions targeting co-morbidity, body mass index and associated inflammation. Copyright © 2016 John Wiley & Sons, Ltd.

Objectives Dementia draws on a variety of public and private resources. There is increasing pressure to define the cost components in this area to improve resource allocation and accountability. The aim of this study was to characterize frailty in a group of cognitively impaired community-dwelling elders and evaluate its relationship with cost and resource utilization. Methods We assessed a cross-sectional, convenient sample of 115 cognitively impaired patients of age >55 years who attended the National Memory Clinic in St James' University Hospital, a Trinity College-affiliated hospital in Dublin, Ireland. Participants had a clinical diagnosis of possible Alzheimer's disease or mild cognitive impairment. Frailty was measured using the biological syndrome model. Formal health and social care costs and daily informal caregiving costs were collected and the total costs of care estimated by applying the appropriate unit cost estimate for each resource activity. Stepwise regression models were constructed to establish the factors associated with increased care costs. Results Patient dependence, frailty and number of co-morbid illnesses explained 43.3% of the variance in observed daily informal care costs in dementia and cognitively impaired patients. Dependence was the sole factor retained in an optimal model explaining 19% of the variance in formal health and social care costs. Conclusion Frailty retained a strong association with daily informal care costs even in the context of other known risk factors for increasing care costs. Interventions that reduce frailty as well as patient dependence on others may be associated with cost savings. Copyright © 2015 John Wiley & Sons, Ltd.

OBJECTIVES: The older population are at a high risk for suicide. This study sought to learn more about the characteristics of suicide in the oldest-old and to use a cluster analysis to determine if oldest-old suicide victims assort into clinically meaningful subgroups. METHODS: Data were collected from a coroner's chart review of suicide victims in Toronto from 1998 to 2011. We compared two age groups (65-79 year olds, n = 335, and 80+ year olds, n = 191) and then conducted a hierarchical agglomerative cluster analysis using Ward's method to identify distinct clusters in the 80+ group. RESULTS: The younger and older age groups differed according to marital status, living circumstances and pattern of stressors. The cluster analysis identified three distinct clusters in the 80+ group. Cluster 1 was the largest (n = 124) and included people who were either married or widowed who had significantly more depression and somewhat more medical health stressors. In contrast, cluster 2 (n = 50) comprised people who were almost all single and living alone with significantly less identified depression and slightly fewer medical health stressors. All members of cluster 3 (n = 17) lived in a retirement residence or nursing home, and this group had the highest rates of depression, dementia, other mental illness and past suicide attempts. CONCLUSIONS: This is the first study to use the cluster analysis technique to identify meaningful subgroups among suicide victims in the oldest-old. The results reveal different patterns of suicide in the older population that may be relevant for clinical care. Copyright © 2015 John Wiley & Sons, Ltd. Language: en

To quantitatively summarize changes in cognitive performance in individuals with severe aortic stenosis undergoing transcatheter aortic valve implantation (TAVI).Metaanalysis.Individuals undergoing TAVI (N = 1,065 (48.5% male) from 18 studies, average age ≥80).The MEDLINE, EMBASE, and Cochrane Central databases were searched for original peer-reviewed reports assessing cognitive performance using standardized cognitive tests before and after TAVI. Data were extracted for cognitive scores before TAVI; perioperatively (within 7 days after TAVI); 1, 3, and 6 months after TAVI, and 12 to 34 months after TAVI (over the long term). Standardized mean differences (SMDs) were generated using random-effects models for changes in cognition at each time point. Metaregression analyses were conducted to assess the association between population and procedural characteristics and cognitive outcomes. Risk of bias was assessed.There were no significant changes from baseline in perioperative cognitive performance (SMD = 0.05, 95% confidence interval (CI) = -0.08-0.18; z = 0.75, P = .46), although overall cognitive performance had improved significantly 1 month after TAVI (SMD = -0.33, 95% CI = -0.50 to -0.16; z = 3.83, P.001). There were no differences in cognitive performance 3 and 6 months after TAVI or over the long term. Cognitive outcomes were not associated with any covariates in regression analyses.Cognitive performance is preserved after TAVI, suggesting TAVI is not detrimental to cognition.

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

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

Objective To explore the incremental effects of patient dependence and function on costs of care for patients with Alzheimer's disease (AD) and amnestic mild cognitive impairment (MCI) in Ireland. Methods Cost analysis based on reported resource use for a cross-section of 100 community-based people with AD and MCI. Formal care included general practice visits, hospitalizations, outpatient clinic consultations, accident and emergency visits, respite care, meals on wheels services and other health and social care professional consultations. Informal care included time input provided by caregivers. Resource unit costs were applied to value formal care and the opportunity cost method was used to value informal care. Patient dependence on others was measured using the Dependence Scale and patient functional capacity using the Disability Assessment for Dementia scale. Multivariate regression analysis was used to model the cost of care. Results Both dependence and function were independently and significantly associated with total formal and informal care cost: a one point increase in dependence was associated with a €796 increase in total cost and a one point improvement in function with a €417 reduction in total cost over 6 months. Patient function was significantly associated with formal care costs, whereas patient function and dependence were both significantly associated with informal care costs. Conclusion The costs of care for patients with AD and MCI in Ireland are substantial. Interventions that reduce patient dependence on others and functional decline may be associated with important economic benefits. Copyright © 2012 John Wiley & Sons, Ltd.

Background: Our aim was to investigate the relationship between frailty and health-related quality of life (HR-QOL) in cognitively impaired elderly individuals. Methods: A cross-sectional observational study of a convenience sample of 115 patients with a diagnosis of Alzheimer’s dementia or mild cognitive impairment. Frailty was measured using the biological syndrome model and HR-QOL was measured using the DEMQOL-Proxy. Regression models were constructed to establish the factors associated with HR-QOL. Results: Frailty and neuropsychiatric symptoms were associated with HR-QOL, with Mini-Mental State Examination (MMSE) scores ≥21 ( P = .037, P ≤ .001, and R2 = .362). Functional limitation was associated with HR-QOL, with MMSE scores ≤20 ( P = .017 and R2 = .377). Conclusion: Frailty and neuropsychiatric symptoms were the determinants of HR-QOL in the earlier stages of cognitive impairment. Functional limitation predicted HR-QOL in the later stages of cognitive impairment. Frailty may represent a novel modifiable target in early dementia to improve HR-QOL for patients.

Background: Life satisfaction is a subjective expression of well-being and successful aging. Subjective well-being is a major determinant of health outcomes in older people. The aim of this study was to determine which factors predicted well-being in older people living in the community as measured by their satisfaction with life.Methods: The relationship between life satisfaction, as measured by the Life Satisfaction Index (LSI-A) and physical, cognitive and demographic variables was examined in 466 older people living in the community using a stepwise regression modelResults: Depression, loneliness, neuroticism, extraversion, recent participation in physical activity, age and self-reported exhaustion, were the independent predictors of life satisfaction in our elderly cohort.Conclusion: Subjective well-being, as measured by the Life Satisfaction Scale, is predicted by depression, loneliness, personality traits, recent participation in physical activity and self-reported exhaustion. The mental and emotional status of older individuals, as well as their engagement in physical activity, are as important as physical functionality when it comes to life satisfaction as a measure of well-being and successful aging. These areas represent key targets for intervention.

Self-efficacy is the belief that one can perform a specific task or behaviour and is a modifiable attribute which has been shown to influence health behaviours. Few studies have examined the relationship between self-efficacy for dementia-related tasks and symptoms of burden and depression in caregivers.Eighty four patient/caregiver dyads with Alzheimer's disease were recruited through a memory clinic. Patient function, cognition and neuropsychiatric symptoms were assessed together with caregiver burden, personality, depressive symptoms, coping strategies and self-efficacy for completing tasks related to dementia care.33% (28) of caregivers reported significant depressive symptoms (CES-D ≥ 10). In multivariate analyses, caregiver burden was predicted by self-efficacy for symptom management, neuroticism, patient function and neuropsychiatric symptoms while caregiver depression was predicted by self-efficacy for symptom management, caregiver educational level, neuroticism, emotion-focused coping, dysfunctional coping and patient function. In patients with moderate to severe impairment (MMSE ≤ 20), self-efficacy for symptom management behaved as a mediator between patient neuropsychiatric symptoms and symptoms of burden and depression in caregivers.Further longitudinal investigation is warranted to determine if self-efficacy might be usefully considered a target in future interventional studies to alleviate symptoms of burden and depression in Alzheimer's caregivers.

The dependence scale has been designed to be sensitive to the overall care needs of the patient and is considered distinct from standard measures of functional ability in this regard. Little is known regarding the relationship between patient dependence and caregiver burden. We recruited 100 patients with Alzheimer’s disease or mild cognitive impairment and their caregivers through a memory clinic. Patient function, dependence, hours of care, cognition, neuropsychiatric symptoms, and caregiver burden were assessed. Dependence was significantly correlated with caregiver burden. Functional decline and dependence were most predictive of caregiver burden in patients with mild impairment while behavioral symptoms were most predictive in patients with moderate to severe disease. The dependence scale demonstrated good utility as a predictor of caregiver burden. Interventions to reduce caregiver burden should address patient dependence, functional decline, and behavioral symptoms while successful management of the latter becomes more critical with disease progression.

Background Depression and anxiety have been reported to be independently predictive of conversion to Alzheimer's disease (AD) in patients with mild cognitive impairment (MCI). Anxiety symptoms have been less well studied and findings in this regard have been inconsistent. The objectives of this study are to determine which symptoms among a range of neuropsychiatric symptoms known to commonly occur in patients with MCI are predictive of later conversion to AD. We also wish to determine whether these symptoms track existing measures of declining cognitive and functional status or may be considered distinct and sensitive biomarkers of evolving Alzheimer's pathology. Methods One hundred and sixty-one patients with MCI were identified from consecutive referrals to a memory clinic. Univariate, multivariate and cox regression analyses were conducted. Results Seventy-six per cent of all patients had at least one neuropsychiatric symptom at baseline of which anxiety (52%), affective disturbance (37%) and aggression (32%) were the most common. Increasing symptom frequency was observed with increasing clinical severity. Anticipatory anxiety and activity disturbances were significantly associated with earlier conversion to AD although this association did not remain significant following adjustment for cognitive status at baseline. Conclusion Neuropsychiatric symptoms and anxiety symptoms in particular are common in patients with MCI. In this sample anxiety for upcoming events and purposeless activity frequently co-occurred and were significant clinical predictors of earlier conversion to AD. However, these findings were not independent of cognitive status at baseline and therefore may be markers of severity rather than independent predictors of disease progression. Copyright © 2010 John Wiley & Sons, Ltd.

Background The Cambridge cognitive examination (CAMCOG) is a mini neuropsychological battery which is well established and widely used. The utility of the CAMCOG in detecting prodromal Alzheimer's disease (AD) in patients with mild cognitive impairment (MCI) has not been determined. The objectives of this study are: to establish which subtests of cognitive domains contained within the CAMCOG are predictive of conversion to AD, to compare these with an extended version of the delayed word recall (DWR) test and to establish optimal cut points for all measures used. Methods 182 patients with MCI were identified from consecutive referrals to a memory clinic. Logistic regression, cox regression and receiver operating characteristic curve (ROC) analyses were conducted. Results The DWR displayed the best sensitivity (77%) and specificity (76%). The composite memory score contained within the CAMCOG achieved similar sensitivity (78%) and specificity (74%). The recognition component of the extended DWR demonstrated good specificity (85%) but poor sensitivity (57%). The optimal predictive model combined category fluency with the DWR and achieved predictive accuracy of 83%. Conclusion The DWR, which is a test specifically designed to have high predictive accuracy for AD, performed best. The composite measure of memory contained within the CAMCOG performed similarly well. The DWR has the advantage of being brief, easy to administer and suitable for use in non-specialist settings. The CAMCOG takes longer to administer but provides information regarding additional cognitive domains and is sensitive to change over time. Category fluency may be usefully combined with the DWR to improve predictive accuracy. Copyright © 2010 John Wiley & Sons, Ltd.

Background:There has been an increasing interest in the relationship between severity of disease and costs in the care of people with dementia. Much of the current evidence is based on cross-sectional data, suggesting the need to examine trends over time for this important and growing cohort of the population.Methods:This paper estimates resource use and costs of care based on longitudinal data for 72 people with dementia in Ireland. Data were collected from the Enhancing Care in Alzheimer's Disease (ECAD) study at two time points: baseline and follow-up, two years later. Patients’ dependence on others was measured using the Dependence Scale (DS), while patient function was measured using the Disability Assessment for Dementia (DAD) scale. Univariate and multivariate analysis were used to explore the effects of a range of variables on formal and informal care costs.Results:Total costs of formal and informal care over six months rose from €9,266 (Standard Deviation (SD): 12,947) per patient at baseline to €21,266 (SD: 26,883) at follow-up, two years later. This constituted a statistically significant (p = 0.0014) increase in costs over time, driven primarily by an increase in estimated informal care costs. In the multivariate analysis, a one-point increase in the DS score, that is a one-unit increase in patient's dependence on others, was associated with a 19% increase in total costs (p = 0.0610).Conclusions:Higher levels of dependence in people with Alzheimer's disease are significantly associated with increased costs of informal care as the disease progresses. Formal care services did not respond to increased dependence in people with dementia, leaving it to families to fill the caring gap, mainly through increased supervision with the progress of disease.

Background: The desire to institutionalize is an important predictor of future institutionalization. Few studies have examined potentially modifiable caregiver characteristics which might be the focus of future interventional strategies. Methods: A total of 102 patient/caregiver dyads with Alzheimer’s disease (n = 84) or mild cognitive impairment were recruited through a memory clinic. Cross-sectional analyses of a range of patients, caregivers, and context of care-related characteristics were conducted. Results: Caregiver desire to institutionalize was significantly associated with a number of potentially modifiable variables including caregiver coping style, self-efficacy, depression, burden, and the presence of an unmet service need. In a multivariate analysis, caregiver burden, depression, and nonspousal status were the only significant independent predictors of caregiver desire to institutionalize in a model which correctly classified 80.4% of caregivers. Conclusions: Interventions which seek to reduce caregiver desire to institutionalize should adopt a multifactorial approach to reduce symptoms of burden and depression in caregivers.

In Ireland, the population aged 65 years and over is projected to increase by 20,000 annually with the proportion of the population aged over 65 years doubling over the next 30 years. It is estimated that up to 60% of older people in hospital have or can develop a mental disorder during their admission (Royal College of Psychiatrists, 2005). The needs of older adults are distinct in many ways and a previous systematic review found that old age psychiatry services for hospitalized older adults are effective (Draper and Low, 2005). With regard to models of service provision, there is evidence that a liaison type service is superior to consultation only. The latter service is limited and reactive whereas a dedicated liaison service is proactive and is more likely to succeed in having good mental healthcare adopted as the standard of care within a hospital (Royal College of Psychiatrists, 2005). Consultation–Liaison (CL) services have been associated with decreased psychiatric morbidity, improved function, reduced length of stay, fewer readmissions, and increased cost-effectiveness compared with usual care (Royal College of Psychiatrists, 2005, Parsonage and Fossey, 2011). In Ireland, specialist community services for older adults have developed steadily, while CL services have remained relatively neglected with no specific recommendations regarding CL services for older adults in national guidelines (Department of Health, 2006). This is not necessarily out of step with international trends where in spite of increasing rates of referral to CL services for older adults in the United Kingdom and the United States there is a reported lack of emphasis upon this important area of service provision (Anderson et al., 2011). Consequently, little is known about age-specific CL services for older adults in Ireland, and service development has proceeded in an unstructured way. In particular, it is not known whether such a service is available within each area and if so, what the nature and extent of the services provided are.