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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 Physical exercise has positive impacts on health and can improve angiogenesis, which is impaired during aging, but the underlying mechanisms of benefit are unclear. This meta-analysis and systematic review investigated the effects of exercise on several peripheral angiogenesis markers in older adults to better understand the relationship between exercise and angiogenesis. Methods MEDLINE, Embase, and Cochrane CENTRAL were searched for original, peer-reviewed reports of peripheral concentrations of angiogenesis markers before and after exercise interventions in older adults (> 50 years). The risk of bias was assessed with standardized criteria. Standardized mean differences (SMD) with 95% confidence intervals (CIs) were calculated from random-effects models. Publication bias was assessed with Egger’s test, funnel plots, and trim-and-fill. A priori subgroup analyses and meta-regressions were performed to investigate heterogeneity where possible. Results Of the 44 articles included in the review, 38 were included in meta-analyses for five proteins. Vascular endothelial growth factor (VEGF) was found to be higher after exercise (SMD[95%CI] = 0.18[0.03, 0.34], p = 0.02), and e-selectin (CD62E) was found to be lower after exercise (SMD[95%CI]= -0.72[-1.42, -0.03], p = 0.04). Endostatin (SMD[95%CI] = 0.28[-0.56, 1.11], p = 0.5), fibroblast growth factor 2 (SMD[95%CI] = 0.03[-0.18, 0.23], p = 0.8), and matrix metallopeptidase-9 (SMD[95%CI] = -0.26[-0.97, 0.45], p = 0.5) levels did not change after exercise. Conclusions Of the five angiogenesis blood markers evaluated in this meta-analysis, only VEGF and CD62E changed with exercise. Although more studies are needed, changes in angiogenesis markers may explain the beneficial effects of exercise on angiogenesis and health in older adults.

Recent work suggests that APOEɛ4/4 females with Alzheimer's disease (AD) are more susceptible to developing neuropsychiatric symptoms (NPS).To examine the interaction of sex and APOEɛ4 status on NPS burden using two independent cohorts: 1) patients at risk for AD with mild cognitive impairment and/or major depressive disorder (n = 252) and 2) patients with probable AD (n = 7,261).Regression models examined the interactive effects of sex and APOEɛ4 on the number of NPS experienced and NPS Severity. APOEɛ3/4 and APOEɛ4/4 were pooled in the at-risk cohort due to the sample size.In the at-risk cohort, there was a significant sex*APOEɛ4 interaction (p = 0.007) such that the association of APOEɛ4 with NPS was greater in females than in males (incident rate ratio (IRR) = 2.0). APOEɛ4/4 females had the most NPS (mean = 1.9) and the highest severity scores (mean = 3.5) of any subgroup. In the clinical cohort, APOEɛ4/4 females had significantly more NPS (IRR = 1.1, p = 0.001, mean = 3.1) and higher severity scores (b = 0.31, p = 0.015, mean = 3.7) than APOEɛ3/3 females (meanNPS = 2.9, meanSeverity = 3.3). No association was found in males.Our study suggests that sex modifies the association of APOEɛ4 on NPS burden. APOEɛ4/4 females may be particularly susceptible to increased NPS burden among individuals with AD and among individuals at risk for AD. Further investigation into the mechanisms behind these associations are needed.

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.

With an increasing global ageing population, the psychiatry of old age has become increasingly important. This revised second edition remains a succinct manual on the practice of psychiatry of old age, providing an up-to-date summary of existing knowledge, best practice and future challenges for the specialty, from a global perspective. Written by four leading clinicians, teachers and researchers, the book offers a much-needed international focus and is designed for use in a wide variety of countries and settings. Chapters are presented in a clear and practical way, enhanced by current and comprehensive further reading sections as well as tables and diagrams for quick assimilation and reference. The new edition is updated to incorporate new developments in assessment, investigation, classification, treatment and care since the publication of the first edition, including the ICD-11 and DSM-5. Essential reading for practising psychiatrists and geriatricians, as well as trainees, nurses and medical students.

Objective While transcranial direct current stimulation (tDCS) can enhance aspects of memory in patients with mild cognitive impairment (MCI) and Alzheimer disease (AD), there has been wide variability in both the placement of tDCS electrodes and treatment response. This study compared the effects of bifrontal (anodal stimulation over the dorsolateral prefrontal cortices), bitemporal (anodal stimulation over the temporal cortices), and sham tDCS on cognitive performance in MCI and AD. Methods Seventeen patients diagnosed with MCI or mild AD received 3 sessions of anodal tDCS (bifrontal, bitemporal, 2 mA for 20 minutes; and sham) in random order. Sessions were separated by 1 week. The Alzheimer's Disease Assessment Scale-Cognitive Word Recognition Task, Alzheimer's Disease Assessment Scale-Cognitive Word Recall Task, 2-back, and Montreal Cognitive Assessment were used to assess cognition. Results There was a significant effect of stimulation condition on 2-back accuracy (F2,28 = 5.28 P = 0.01, ηp = 0.27), with greater improvements following bitemporal tDCS compared with both bifrontal and sham stimulations. There were no significant changes on other outcome measures following any stimulation. Adverse effects from stimulation were mild and temporary. Conclusions These findings demonstrate that improvements in specific memory tasks can be safely achieved after a single session of bitemporal tDCS in MCI and mild AD patients.

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

Background Increasing evidence implicates oxidative stress (OS) in Alzheimer disease (AD) and mild cognitive impairment (MCI). Depletion of the brain antioxidant glutathione (GSH) may be important in OS-mediated neurodegeneration, though studies of post-mortem brain GSH changes in AD have been inconclusive. Recent in vivo measurements of the brain and blood GSH may shed light on GSH changes earlier in the disease. Aim To quantitatively review in vivo GSH in AD and MCI compared to healthy controls (HC) using meta-analyses. Method Studies with in vivo brain or blood GSH levels in MCI or AD with a HC group were identified using MEDLINE, PsychInfo, and Embase (1947–June 2020). Standardized mean differences (SMD) and 95% confidence intervals (CI) were calculated for outcomes using random effects models. Outcome measures included brain GSH (Meshcher-Garwood Point Resolved Spectroscopy (MEGA-PRESS) versus non-MEGA-PRESS) and blood GSH (intracellular versus extracellular) in AD and MCI. The Q statistic and Egger’s test were used to assess heterogeneity and risk of publication bias, respectively. Results For brain GSH, 4 AD (AD=135, HC=223) and 4 MCI (MCI=213, HC=211) studies were included. For blood GSH, 26 AD (AD=1203, HC=1135) and 7 MCI (MCI=434, HC=408) studies were included. Brain GSH overall did not differ in AD or MCI compared to HC; however, the subgroup of studies using MEGA-PRESS reported lower brain GSH in AD (SMD [95%CI] −1.45 [−1.83, −1.06], pz=4.0, pz=3.96, pp=0.025). Heterogeneity was observed throughout (I2 >85%) and not fully accounted by subgroup analysis. Egger’s test indicated risk of publication bias. Conclusion Blood intracellular GSH decrease is seen in MCI, while both intra- and extracellular decreases were seen in AD. Brain GSH is decreased in AD and MCI in subgroup analysis. Potential bias and heterogeneity suggest the need for measurement standardization and additional studies to explore sources of heterogeneity.

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.

Background Non-invasive brain stimulation (NIBS) techniques have shown some promise in improving cognitive and neuropsychiatric symptoms (NPS) in people with Alzheimer’s disease (AD) and its prodromal stage, mild cognitive impairment (MCI). However, data from clinical trials involving NIBS have shown inconsistent results. This meta-analysis investigated the efficacy of NIBS, specifically repetitive transcranial magnetic stimulation (rTMS), and transcranial direct current stimulation (tDCS) compared to sham stimulation on global cognition and NPS in people with AD and MCI. Method Multi-session randomized sham-controlled clinical trials were identified through MEDLINE, PsycINFO, and Embase until June 2021. Standardized mean difference (SMD) and 95% confidence interval (CI) between the active and sham treatments were calculated using random-effects meta-analyses. Included studies reported outcome measures for global cognition and/or NPS. Heterogeneity, from different NIBS techniques, disease populations, or tests used to assess global cognition or NPS, was measured using chi-square and I2, and investigated using subgroup analyses. Possible effects of covariates were also investigated using meta-regressions. Result The pooled meta-analyses included 19 studies measuring global cognition (Nactive=288, Nsham=264), and 9 studies investigating NPS (Nactive=165, Nsham=140). NIBS significantly improved global cognition (SMD=1.14; 95% CI=0.49,1.78; p = 0.001; I2 = 90.2%) and NPS (SMD=0.82; 95% CI=0.13, 1.50; p = 0.019; I2 = 86.1%) relative to sham stimulation in patients with AD and MCI. Subgroup analyses found these effects were restricted to rTMS but not tDCS, and to patients with AD but not MCI. Meta-regression showed that age was significantly associated with global cognition response (Nstudies=16, p = 0.020, I2 = 89.51%, R2 = 28.96%), with larger effects sizes in younger populations. All significant meta-analyses had large effect sizes (SMD ≥0.8), suggesting clinical utility of NIBS in the short term. There remained substantial heterogeneity across all subgroup analyses and meta-regressions (all I2 > 50%). Egger’s tests showed no evidence of publication biases. Conclusion rTMS improved global cognition and NPS in those with AD. Further studies in MCI and using tDCS will help to fully evaluate the specific NIBS techniques and populations most likely to benefit on global cognition and NPS measures. Additional research should investigate the long term clinical utility of NIBS in these populations.

Objective: Neuropsychiatric symptoms (NPS) may be the first manifestation of an underlying neurocognitive disorder. We undertook a review to provide an update on the epidemiology and etiological mechanisms of NPS that occur in mild cognitive impairment (MCI) and just before the onset of MCI. We discuss common clinical presentations and the implications for diagnosis and care. Method: The authors conducted a selective review of the literature regarding the emergence of NPS in late life, before and after the onset of MCI. We discuss recent publications that explore the epidemiology and etiological mechanisms of NPS in the earliest clinical stages of these disorders. Results: NPS have been reported in 35% to 85% of adults with MCI and also occur in advance of cognitive decline. The occurrence of NPS for the first time in later life should increase suspicion for an underlying neurocognitive disorder. The presenting symptom may provide a clue regarding the etiology of the underlying disorder, and the co-occurrence of NPS may herald a more accelerated cognitive decline. Conclusions: NPS are prevalent in the early clinical stages of neurocognitive disorders and can serve as both useful diagnostic and prognostic indicators. Recognition of NPS as early manifestations of neurocognitive disorders will become increasingly important as we move towards preventative strategies and disease-modifying treatments that may be most effective when deployed in the earliest stages of disease.

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.

Agitation is a prevalent and difficult-to-treat symptom in patients with moderate-to-severe Alzheimer's disease (AD). Though there are nonpharmacological and pharmacological interventions recommended for the treatment of agitation, the efficacy of these are modest and not always consistent. Furthermore, the safety profiles of currently prescribed medications are questionable. Nabilone, a synthetic cannabinoid, has a distinct pharmacological profile that may provide a safer and more effective treatment for agitation, while potentially having benefits for weight and pain. Additionally, emerging evidence suggests nabilone may have neuroprotective effects. We describe a clinical trial investigating the safety and efficacy of nabilone for the treatment of agitation in patients with moderate-to-severe AD. This will be a double-blind, randomized cross-over study comparing 6 weeks of nabilone (0.5–2 mg) and placebo, with a 1-week washout preceding each phase. Study outcomes will be measured at baseline and end of treatment for each treatment phase. The primary outcome measure will be agitation as assessed by the Cohen-Mansfield Agitation Inventory. The secondary outcomes include safety, behaviour (Neuropsychiatric Inventory), cognition (standardized Mini Mental Status Exam and either Severe Impairment Battery or Alzheimer's disease Assessment Scale-Cognitive subscale) and global impression (Clinician's Global Impression of Change). Exploratory outcomes include pain (Pain Assessment in Advanced AD), nutritional status (Mini-Nutritional Assessment-Short Form), caregiver distress (NPI caregiver distress), and blood-based biomarkers. A safe and efficacious pharmacological intervention for agitation, with effects on pain and weight loss in patients with moderate-to-severe AD could increase quality-of-life, reduce caregiver stress and avoid unnecessary institutionalization and related increases in health care costs. Clinical trials number: NCT02351882 Keywords: Agitation, Cannabinoid, Alzheimer's disease, Neuropsychiatric symptoms, Clinical trial

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

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.

Depressive symptoms have been associated with increased risk of cognitive decline in later life. There are no interventions proven to reduce risk of cognitive decline in older adults with depression, and it is unclear how these effects are mediated. We aim to determine what mediates the relationship between depressive symptoms and cognitive decline in later life.Seven thousand six hundred and sixty six community dwelling older adults (age ≥ 50) from the English Longitudinal study of Ageing (ELSA) underwent clinical assessment. Inflammation was assessed with C Reactive Protein and depressive symptoms were assessed with the 8-item version of the Center for Epidemiologic Studies (CESD) scale.Five thousand, five hundred and ninety (73.5%) had a follow-up cognitive assessment after a median of 47 months. Depressive symptoms were independently associated with cognitive decline (B=0.09, p0.001). Low physical activity, inflammation, metabolic syndrome and vascular risk factors were associated with elevated depressive symptoms. Low physical activity (z=2.16, p=0.03) and inflammation (z=2.3, p=0.02) mediated the relationship between depressive symptoms and cognitive decline while hypertension, diabetes and smoking also contributed.This is an observational study with a limited duration of follow up. Not all variables related to cognitive decline were accounted for in this analysis.The relationship between depressive symptoms and cognitive decline in later life appears to be mediated by low physical activity, increased inflammation and vascular risk factors that may be amenable to modification.

Objective Late-life depression has been associated with increased risk of mild cognitive impairment (MCI) and dementia. Predictors of increased risk are incompletely understood. Identification of potentially modifiable risk factors could facilitate prevention of MCI and dementia. This study aimed to determine which clinical characteristics are associated with increased risk of MCI among older adults with depression and normal cognition at baseline. Methods Data from the National Alzheimer's Coordinating Center dataset were used. Study participants who attended a participating Alzheimer's Disease Center from September 2005 through September 2017 with normal cognition and a history of clinically defined depression (broadly based on DSM criteria) were followed until first diagnosis of MCI (or dementia when MCI was not diagnosed). Results A total of 2,655 study participants were followed for a median duration of 41.8 months. Of these, 586 (22.1%) developed either MCI (n = 509, 19.2%) or dementia (n = 77, 2.9%). In survival analyses, cognitive decline was associated with age, sex, education, baseline cognition, and several potentially modifiable risk factors including vascular risk factors, hearing impairment, vitamin B₁₂ deficiency, active depression within the last 2 years, and increased severity of depression. In an adjusted survival analysis, the only variables that remained significantly associated with development of MCI or dementia were female sex (HR = 0.72; 95% CI, 0.59-0.88), higher education (HR = 0.96; 95% CI, 0.93-0.99), and higher baseline cognition (HR = 0.87; 95% CI, 0.82-0.93), which were associated with reduced risk, and older age (HR = 1.07; 95% CI, 1.05-1.08), active depression within the last 2 years (HR = 1.41; 95% CI, 1.15-1.74), and increased severity of depression (HR = 1.05; 95% CI, 1.02-1.09), which were associated with increased risk. Conclusions Development of MCI is associated with several potentially modifiable risk factors in older adults with depression. Future studies should determine whether active management of risk factors could reduce incidence of MCI in this vulnerable population.

Objective: The association between depression and cardiovascular disease has been well documented but the nature of this relationship continues to be defined. Given the accumulation of epidemiological evidence linking these diseases a number of interventional studies have been undertaken to assess the issue of whether antidepressant treatment in depressed patients with cardiovascular disease improves cardiac outcome. The objective of this paper is to review recent randomised controlled trials on this topic and to explore the implications that these may have for future research in this area.Method: This review is derived from a MEDLINE search using the search terms ‘depressive disorder’ and ‘cardiovascular diseases’. Only randomised controlled trials published in English with clearly defined methods and interventions are included here. Reference sections from the articles were used to identify additional relevant studies.Results: A small number of high quality trials were uncovered which indicated mixed results in terms of the treatment of depression in cardiovascular disease. None indicated a statistically significant difference in cardiac outcome.Conclusions: It is not possible at this time to recommend treatment for depression to reduce cardiovascular risk. However depression remains prevalent in patients with cardiovascular disease and is a treatable cause of morbidity in its own right.

Exercise interventions have been shown to successfully improve depression in patients with major depressive disorder (MDD), but like other forms of antidepressant treatment, exercise is not effective in all patients and its mechanisms of action have not been fully elucidated. Brain-derived neurotrophic factor (BDNF), a key mediator of neurogenesis and neuronal survival, has been shown to be decreased in individuals with MDD. One potential mechanism by which exercise alleviates depression is through an increase in BDNF. In order to evaluate this hypothesis, we conducted a meta-analysis of studies that assessed the effects of a chronic (multi-week) exercise intervention on BDNF concentrations in MDD patients. MEDLINE, Embase, PsycINFO, SPORTDiscus, Rehabilitation & Sports Medicine Source, and CINAHL databases were searched for original, peer-reviewed reports of peripheral blood BDNF concentrations before and after a chronic exercise intervention in MDD patients. Standardized mean differences (SMDs) were generated from random effects models. Potential sources of heterogeneity were explored in meta-regression analyses. In six studies that met inclusion criteria, resting blood concentrations of BDNF were not significantly higher after a chronic exercise intervention (SMD = 0.43, 95% CI: −0.06–0.92, p = 0.09) in MDD patients. This meta-analysis did not find evidence that a chronic aerobic exercise intervention increases resting concentrations of BDNF in the blood of MDD patients; however, there is a lack of studies in this area making it difficult to reach a definitive conclusion. Future studies on this topic with larger sample sizes and longer durations are needed to draw more robust conclusions.