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• What is the primary question addressed by this study? What are the cognitive profiles of older adults with remitted major depressive disorder (rMDD) with or without mild cognitive impairment (MCI)? How do these profiles differ in terms of clinical, demographic, and brain structure features? • What is the main finding of this study? Using latent profile analysis, we identified three cognitive profiles, with differences in cognition, physical health, education, and brain structure. • What is the meaning of the finding? Older patients with rMDD can be grouped cross-sectionally based on distinct data-driven cognitive profiles that differ from the absence or presence of a diagnosis of MCI. To identify data-driven cognitive profiles in older adults with remitted major depressive disorder (rMDD) with or without mild cognitive impairment (MCI) and examine how the profiles differ regarding demographic, clinical, and neuroimaging measures. Secondary cross-sectional analysis using latent profile analysis. Multisite clinical trial in Toronto, Canada. One hundred seventy-eight participants who met DSM-5 criteria for rMDD without MCI (rMDD-MCI; n = 60) or with MCI (rMDD + MCI; n = 118). Demographic, clinical, neuroimaging measures, and domain scores from a neuropsychological battery assessing verbal memory, visuospatial memory, processing speed, working memory, language, and executive function. We identified three latent profiles: Profile 1 (poor cognition ; n = 75, 42.1%), Profile 2 (intermediate cognition ; n = 75, 42.1%), and Profile 3 (normal cognition ; n = 28, 15.7%). Compared to participants with Profile 3, those with Profile 1 or 2 were older, had lower education, experienced a greater burden of medical comorbidities, and were more likely to have MCI. The profiles did not differ on the severity of residual symptoms, age of onset of rMDD, number of depressive episodes, psychotropic medication, cerebrovascular risk, ApoE4 carrier status, or family history of depression, dementia, or Alzheimer's disease. The profiles differed in cortical thickness of 15 regions, with the most prominent effects for left precentral and pars opercularis, and right inferior parietal and supramarginal. Older patients with rMDD can be grouped cross-sectionally based on data-driven cognitive profiles that differ from the absence or presence of a diagnosis of MCI. Future research should determine the differential risk for dementia of these data-driven subgroups. [ABSTRACT FROM AUTHOR]

• What is the primary question addressed by this study? Do clinical characteristics of participants in the ADMET 2 trial predict better response to methylphenidate for the treatment of apathy in Alzheimer's disease? • What is the main finding of this study? Participants without anxiety or agitation, who were younger, taking a cholinesterase inhibitor, with 73–80 mm Hg diastolic blood pressure, having low functional capacity, were found to respond better to methylphenidate. Combining these characteristics in a multivariate model provided individualized prediction of treatment response. • What is the meaning of the finding? These clinical characteristics may affect the efficacy of methylphenidate in treating apathy, and may help clinicians identify patients most likely to respond to treatment. The Apathy in Dementia Methylphenidate Trial 2 (ADMET 2) found that methylphenidate was effective in treating apathy with a small-to-medium effect size but showed heterogeneity in response. We assessed clinical predictors of response to help determine individual likelihood of treatment benefit from methylphenidate. Univariate and multivariate analyses of 22 clinical predictors of response chosen a priori. Data from the ADMET 2 randomized, placebo controlled multi-center clinical trial. Alzheimer's disease patients with clinically significant apathy. Apathy assessed with the Neuropsychiatric Inventory apathy domain (NPI-A). In total, 177 participants (67% male, mean [SD] age 76.4 [7.9], mini-mental state examination 19.3 [4.8]) had 6-months follow up data. Six potential predictors met criteria for inclusion in multivariate modeling. Methylphenidate was more efficacious in participants without NPI anxiety (change in NPI-A -2.21, standard error [SE]:0.60) or agitation (-2.63, SE:0.68), prescribed cholinesterase inhibitors (ChEI) (-2.44, SE:0.62), between 52 and 72 years of age (-2.93, SE:1.05), had 73–80 mm Hg diastolic blood pressure (-2.43, SE: 1.03), and more functional impairment (-2.56, SE:1.16) as measured by the Alzheimer's Disease Cooperative Study Activities of Daily Living scale. Individuals who were not anxious or agitated, younger, prescribed a ChEI, with optimal (73–80 mm Hg) diastolic blood pressure, or having more impaired function were more likely to benefit from methylphenidate compared to placebo. Clinicians may preferentially consider methylphenidate for apathetic AD participants already prescribed a ChEI and without baseline anxiety or agitation. [ABSTRACT FROM AUTHOR]

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

Background: Diagnostic criteria for apathy have been published but have yet to be evaluated in the context of clinical trials. The Apathy in Dementia Methylphenidate Trial 2 (ADMET 2) operationalized the diagnostic criteria for apathy (DCA) into a clinician-rated questionnaire informed by interviews with the patient and caregiver.Objective: The goal of the present study was to compare the classification of apathy using the DCA with that using the Neuropsychiatric Inventory-apathy (NPI-apathy) subscale in ADMET 2. Comparisons between NPI-Apathy and Dementia Apathy Interview Rating (DAIR) scale, and DCA and DAIR were also explored.Methods: ADMET 2 is a randomized, double-blind, placebo-controlled phase III trial examining the effects of 20 mg/day methylphenidate on symptoms of apathy over 6 months in patients with mild to moderate Alzheimer's disease (AD). Participants scoring at least 4 on the NPI-Apathy were recruited. This analysis focuses on cross-sectional correlations between baseline apathy scale scores using cross-tabulation.Results: Of 180 participants, the median age was 76.5 years and they were predominantly white (92.8%) and male (66.1%). The mean (±standard deviation) scores were 7.7 ± 2.4 on the NPI-apathy, and 1.9 ± 0.5 on the DAIR. Of those with NPI-defined apathy, 169 (93.9%, 95% confidence interval [CI] 89.3%-96.9%) met DCA diagnostic criteria. The DCA and DAIR overlapped on apathy diagnosis for 169 participants (93.9%, 95% CI 89.3%-96.9%).Conclusion: The measurements used for the assessment of apathy in patients with AD had a high degree of overlap with the DCA. The NPI-apathy cut-off used to determine apathy in ADMET 2 selects those likely to meet DCA criteria. [ABSTRACT FROM AUTHOR]

The public health burden of Alzheimer's disease (AD) is related not only to cognitive symptoms, but also to neuropsychiatric symptoms, including apathy. Apathy is defined as a quantitative reduction of goal-directed activity in comparison to a previous level of functioning and affects 30%-70% of persons with AD. Previous attempts to treat apathy in AD-both nonpharmacologically and pharmacologically-have been wanting. Catecholaminergic treatment with methylphenidate has shown encouraging results in initial trials of apathy in AD. Understanding the neuronal circuits underlying motivated behavior and their reliance on catecholamine actions helps provide a rationale for methylphenidate actions in the treatment of apathy in patients with AD. Anatomical, physiological, and behavioral studies have identified parallel, cortical-basal ganglia circuits that govern action, cognition, and emotion and play key roles in motivated behavior. Understanding the distinct contributions to motivated behavior of subregions of the prefrontal cortex-dorsolateral, orbital-ventromedial, and dorsomedial-helps to explain why degeneration of these areas in AD results in apathetic behaviors. We propose that the degeneration of the prefrontal cortex in AD produces symptoms of apathy. We further propose that methylphenidate treatment may ameliorate those symptoms by boosting norepinephrine and dopamine actions in prefrontal-striatal-thalamocortical circuits. [ABSTRACT FROM AUTHOR]

Objective: To investigate the efficacy and safety of nabilone for agitation in patients with moderate-to-severe Alzheimer's disease (AD).Design: This 14-week randomized double-blind crossover trial compared nabilone to placebo (6 weeks each) with a 1-week washout between phases.Setting: Patients were recruited from a long-term care facility and geriatric psychiatry clinics.Participants: Patients had AD (standardized Mini-Mental State Examination [sMMSE ≤24]) and agitation (Neuropsychiatric Inventory-Nursing Home version [NPI-NH]-agitation/aggression subscore ≥3).Intervention: Nabilone (target 1-2 mg) versus placebo.Measurements: The primary outcome was agitation (Cohen Mansfield Agitation Inventory [CMAI]). Secondary outcomes included NPI-NH total, NPI-NH caregiver distress, cognition (sMMSE and Severe Impairment Battery [SIB] or Alzheimer's Disease Assessment Scale of Cognition), global impression (Clinician's Global Impression of Change [CGIC]), and adverse events.Results: Thirty-nine patients (mean ± SD age = 87 ± 10, sMMSE = 6.5 ± 6.8, CMAI = 67.9 ± 17.6, NPI-NH total = 34.3 ± 15.8, 77% male, nabilone dose = 1.6 ± 0.5 mg) were randomized. There were no crossover or treatment-order effects. Using a linear mixed model, treatment differences (95% CI) in CMAI (b = -4.0 [-6.5 to -1.5], t(30.2) = -3.3, p = 0.003), NPI-NH total (b = -4.6 [-7.5 to -1.6], t(32.9) = -3.1, p = 0.004), NPI-NH caregiver distress (b = -1.7 [-3.4 to -0.07, t(33.7) = -2.1, p = 0.041), and sMMSE (b = 1.1 [0.1-2.0], t(22.6) = 2.4, p = 0.026) all favored nabilone. However, in those who completed the SIB (n = 25) treatment differences favored placebo (b = -4.6 [-7.3 to -1.8], t(20.7) = -4.8, p = 0.003). CGIC improvement during nabilone (47%) and placebo (23%) was not significantly different (McNemar's test, exact p = 0.09). There was more sedation during nabilone (45%) compared to placebo (16%) phases (McNemar's test, exact p = 0.02), but treatment-limiting sedation was not significantly different (McNemar's test, exact p = 0.22).Conclusions: Nabilone may be an effective treatment for agitation. However, sedation and cognition should be closely monitored. [ABSTRACT FROM AUTHOR]

Objective: Apathy and depression have each been associated with an increased risk of conversion from mild cognitive impairment (MCI) to Alzheimer disease (AD).These symptoms often co-occur and the contribution of each to risk of AD is not clear.Methods: National Alzheimer's Coordinating Center participants diagnosed with MCI at baseline and followed until development of AD or loss to follow-up (n = 4,932) were included. The risks of developing AD in MCI patients with neuropsychiatric symptoms (NPS) (apathy only, depression only, or both) were compared to that in those without NPS in a multivariate Cox regression survival analysis adjusting for baseline cognitive impairment, years of smoking, antidepressant use, and AD medication use.Results: Thirty-seven percent (N = 1713) of MCI patients developed AD (median follow-up 23 months). MCI patients with both apathy and depression had the greatest risk (hazard ratio [HR] = 1.37; 95% confidence interval [CI]: 1.17-1.61; p < 0.0001; Wald χ2 = 14.70; df = 1). Those with apathy only also had a greater risk (HR = 1.24; 95% CI: 1.05-1.47; p = 0.01; Wald χ2 = 6.22; df = 1), but not those with depression only (HR = 1.08; 95% CI: 0.95-1.22; p=0.25; Wald χ2 = 1.30; df = 1). Post-hoc analyses suggested depression may exacerbate cognitive decline in MCI patients with apathy (odds ratio = 0.70; 95% CI 0.52-0.95; p = 0.02; Wald χ2 = 5.28; df = 1), compared to those without apathy.Conclusion: MCI patients with apathy alone or both apathy and depression are at a greater risk of developing AD compared to those with no NPS. Interventions targeting apathy and depression may reduce risk of AD. [ABSTRACT FROM AUTHOR]

Guidelines that physicians use to assess fitness to drive for dementia are limited in their currency, applicability, and rigor of development. Therefore, we performed a systematic review to determine the risk of motor vehicle collisions (MVCs) or driving impairment caused by dementia, in order to update international guidelines on driving with dementia. Seven literature databases (MEDLINE, CINAHL, Embase, etc.) were searched for all research studies published after 2004 containing participants with mild, moderate, or severe dementia. From the retrieved 12,860 search results, we included nine studies in this analysis, involving 378 participants with dementia and 416 healthy controls. Two studies reported on self-/informant-reported MVC risk, one revealing a four-fold increase in MVCs per 1,000 miles driven per week in 3 years prior, and the other showing no statistically significant increase over the same time span. We found medium to large effects of dementia on driving abilities in six of the seven recent studies that examined driving impairment. We also found that persons with dementia were much more likely to fail a road test than healthy controls (RR: 10.77, 95% CI: 3.00-38.62, z = 3.65, p < 0.001), with no significant heterogeneity (χ2 = 1.50, p = 0.68, I2 = 0%) in a pooled analysis of four studies. Although the limited data regarding MVCs are equivocal, even mild stages of dementia place patients at a substantially higher risk of failing a performance-based road test and of demonstrating impaired driving abilities on the road. [ABSTRACT FROM AUTHOR]

Objective: The important role of serotonin-1A (5-hydroxytryptamine-1A [5-HT(1A)]) receptors in cognition, behavior, and drug response is increasingly being recognized. Postmortem studies suggest decreased 5-HT(1A) receptors in patients with Alzheimer disease (AD), but this has not been confirmed in vivo. Our primary objective was to assess the extent of 5-HT(1A) receptor losses in mild to moderate AD. Methods: The authors examined 5-HT(1A) receptors in 10 patients with mild to moderate AD and 10 healthy volunteers with the same sex and similar age using positron emission tomography imaging with the selective 5-HT(1A) receptor radioligand, [(11)C]WAY-100635. Regions of interest (ROIs) were manually drawn on coregistered magnetic resonance images for the frontal, lateral temporal, medial temporal (MTC), parietal, and cerebellar cortices. Using the simplified reference tissue model, 5-HT(1A) binding potentials (BPs) were calculated relative to the cerebellum. Results: After adjusting for partial volume effects, ROI analysis showed a significant group effect (AD versus comparison group) on BP. Analysis of between-subjects factors showed significantly decreased 5-HT(1A) BP in the right MTC, but not in the other ROIs. Conclusion: Given the strategic role of these receptors, loss of right medial temporal 5-HT(1A) receptors might play an important role in AD symptomatology. [ABSTRACT FROM AUTHOR]

The article looks at the relationship between coronary artery disease (CAD) and cognitive decline in older people, discussing the authors' research on microstructural characteristics of white matter (WM) in older CAD patients in relation to their cognitive ability.

Objective: To determine predictors of time to readmission to a general psychiatry inpatient unit. Method: Data from the Minimum Data Set-Mental Health (MDS-MH), a standardized assessment used to collect demographic and clinical information, were retrospectively reviewed from April 2006 through October 2008. A total of 758 patients were eligible for the study. A set of clinically relevant predictors was generated based on a literature review. A Cox regression model was applied to determine which variables were most predictive of shorter time to readmission, and their respective hazard ratios (HR). Results: Covariates that were significantly associated with readmission (HR [95% CI]) included receiving a pass (3.48 [2.33, 5.17], p < 0.0005), 1-2 psychiatric admissions in the past two years (15.63 [7.50, 32.55], p < 0.0005), and more than 3 psychiatric admissions in the past two years (24.15 [11.58, 50.36], p < 0.0005). Post hoc analysis indicated that those issued passes were more commonly male (57.1% vs. 43.9%, p = 0.03), with a longer length of stay (25.4 ± 21.2 days vs. 18.7 ± 21.1 days, p = 0.008), and higher GAF score (62.8 ± 11.1 vs. 57.8 ± 13.9, p = 0.003), but were otherwise similar. Conclusions: The factors that were associated with reduced time to readmission were a history of previous admissions and receipt of a pass prior to discharge. These results suggest that while physicians may be able to identify patients at high risk of early readmission, issuing a pass may not fully mitigate this risk. There is a need for critical research evaluating the potential benefits of passes. [ABSTRACT FROM AUTHOR]

The article presents an overview of the design of the Apathy in Dementia Methylphenidate Trial (ADMET), a randomized clinical trial to assess the effectiveness and safety of the psychiatric drug methylphenidate in treating the neuropsychiatric symptom of apathy in Alzheimer disease patients. Topics include the diagnostic definition of apathy and its differentiation from depression, patient recruitment, and primary and secondary medical outcomes.

Objectives: The purposes of this study were first, to evaluate the effectiveness of citalopram in treating behavioral disturbances in frontotemporal dementia (FTD) subjects and second, to determine whether an association exists between serotonergic function, as determined by a neuroendocrine challenge, and treatment response. Design: Single-dose citalopram (30 mg per os) challenge followed by a 6-week open-label study. Setting: Outpatients referred to memory clinics. Participants: Fifteen patients suffering from FTD with severe behavioral and psychological symptoms of dementia. Intervention: Following citalopram challenge, all patients were treated with citalopram titrated to a target dose of 40 mg once daily. Measurements: Behavioral disturbances, using the Neuropsychiatric Inventory (NPI) (primary outcome) and Frontal Behavioural Inventory (secondary outcome), were assessed. Change in prolactin concentration following citalopram challenge was used as an index of central serotonergic response. Results: Citalopram treatment was effective in treating behavioral symptoms, with significant decreases in NPI total score (F[2, 28] = 6. 644, p = 0.004), disinhibition (F[2, 28] = 4.030, p = 0.029), irritability (F[2, 28] = 7.497, p = 0.003) and depression (F[2, 28] = 3.467, p = 0.045) scores over the 6 weeks. Significant improvement in Frontal Behavioural Inventory scores suggested that citalopram was also effective in the treatment ofbehaviors specific to FTD. A lower change score in concentration of prolactin was significantly positively correlated with greater im- provement in the total NPI score from baseline to endpoint (r = 0.687, p = 0.005). A blunted response to a citalopram challenge, implying a dysfunctional serotonergic system, predicted a more positive treatment outcome. Conclusions: The results suggest that despite the endogenous serotonin deficiency of FTD, citalopram treatment may be effective in targeting the behavioral disturbances characteristic of FTD. [ABSTRACT FROM AUTHOR]

Abstract: Behavioral and psychological symptoms of dementia (BPSD) include agitation, aberrant motor behavior, anxiety, elation, irritability, depression, apathy, disinhibition, delusions, hallucinations, and sleep or appetite impairment. These symptoms have adverse consequences for patients and caregivers, such as greater impairment in activities of daily living, worsening quality of life and earlier institutionalization. While the etiology of BPSD has not been clearly delineated, studies assessing the benefits of acetylcholinesterase inhibitors on BPSD suggest that some of the neuropsychiatric symptoms of dementia such as agitation, apathy and psychosis may represent a specific central cholinergic deficiency syndrome. Biochemical and neuroimaging studies of BPSD in Alzheimer''s patients support these pharmacological data. This review discusses the literature describing the association between cholinergic deficiency and manifestations of BPSD. [Copyright &y& Elsevier]

Objective: To assess the role of the dopaminergic brain reward system (BRS) in apathy associated with Alzheimer disease (AD). Design: BRS function was probed in 20 AD patients using dextroamphetamine (d-amph) challenge. After baseline behavioral testing, patients were given a single 10 mg dose of d-amph. The time course of the subjective response to d-amph was assessed at hourly intervals for 4 hours. Setting: Three outpatient dementia clinics associated with a university-affiliated hospital Participants: Twenty AD patients aged 77 ± 8years with Neuropsychiatric Inventory (NPI) apathy scores of 3.4 ± 3.5 and Mini-Mental State Examination scores of 20.4 ± 5.1. Measurements: Patients were classified as apathetic based on an NPI apathy subscore of ≥4. Apathy severity was assessed using the Apathy Evaluation Scale (AES). The subjective and behavioral responses to d-amph were assessed using computerized versions of the Addiction Research Centre Inventory (ARCI), Profile of Mood States and Connor's Continuous Performance Task. Results: Repeated measures ANOVA revealed a significant interaction between the presence of apathy and the peak subjective response to d-amph on the ARCI, such that while nonapathetic AD patients were responsive to the rewarding effects of d-amph, apathetic patients were not (Fl,17 = 4.93, p = 0.04). Continuous AES scores were predicted by peak ARCI positive effects scores and baseline overall behavioral disturbances (NPI total) in a backward linear regression analysis using the entire study sample (F2,17 = 10.00, p : 0.01, R2 = 0.49). Conclusions: Apathy in AD is associated with a blunted subjective response to d-amph, which may be indicative of dysfunction in the BRS. [ABSTRACT FROM AUTHOR]

Abstract: Using PET neuroimaging, we demonstrated that four frontotemporal lobar dementia (FTLD) patients had significantly decreased serotonin 5-HT1A binding potential (BP) compared with controls in all 10 brain regions examined. These pilot data suggest that profound 5-HT1A BP losses may be present and contribute to symptomatology and treatment response in FTLD. [Copyright &y& Elsevier]

Objective: The neurobiology of aggression in Alzheimer’s Disease (AD) remains unknown. The objective of this study was to determine if altered central noradrenergic (NE) responsiveness is related to aggression in AD. Methods: Fifteen institutionalized, non-depressed elderly (11 males, four females, mean age 81.5±5.5) with probable AD, severe cognitive impairment (MMSE mean 3.3±4.6) and significant behavioral disturbances (Neuropsychiatric Inventory (NPI) score≥8) were studied. Growth Hormone (GH) response to clonidine challenge (5 μg/kg) was used as an index of central α2-adrenergic function. Results: When patients were divided into those with preserved GH response (GH maximum change from baseline>0, n=6) and those with blunted GH response (GH maximum change from baseline≤0, n=9) there were significant differences in levels of aggression as measured by the Cohen-Mansfield Agitation Inventory (CAMI) physical aggression subscale (p=.026). Patients with blunted GH response also had significantly higher levels of aggression against others on the retrospective Overt Aggression Scale (p=0.027). Conclusions: Certain types of physically aggressive behaviors are associated with a blunted GH response to clonidine challenge. This finding is consistent with compensatory down-regulation of post-synaptic α2-adrenergic receptors in response to enhanced NE outflow in aggressive AD patients. [Copyright &y& Elsevier]

Impaired angiogenesis is associated with cognitive decline in older adults. While exercise has been broadly associated with increased angiogenesis, the relevant mechanisms in older adults are not clear. Here, we present a systematic review and meta-analysis on the relationship between exercise and specific blood angiogenesis markers in older adults to better understand the relevant mechanisms. MEDLINE, Embase, and Cochrane CENTRAL were searched for original reports of angiogenesis markers' concentrations in blood before and after exercise in older adults (≥50 years). Heterogeneity was investigated using sub-group analyses and meta-regressions. Of the 44 articles included in the review, 38 were included in the meta‐analyses for five markers: vascular endothelial growth factor (VEGF), e-selectin (CD62E), endostatin, fibroblast growth factor 2, and matrix metallopeptidase-9. VEGF levels were higher (SMD[95%CI]= 0.18[0.03, 0.34], and CD62E levels were lower (SMD[95%CI]= −0.72[−1.42, −0.03], p = 0.04) after exercise. No other markers were altered. Although more studies are needed, changes in angiogenesis markers may help explain the beneficial effects of exercise on angiogenesis in older adults. • Meta-analysis on exercise and angiogenesis blood markers in older adults. • Only some angiogenesis markers showed changes with exercise. • Vascular endothelial growth factor (VEGF) levels were higher after aerobic exercise. • E-selectin (CD62E) levels were lower after exercise. [ABSTRACT FROM AUTHOR]

Abstract: Background: Higher intake of omega-3 fatty acids (n-3 FAs) is associated with a reduced risk of Alzheimer''s disease (AD) and milder forms of cognitive impairment (e.g. cognitive impairment no dementia [CIND]); however, findings from interventional trials are inconsistent. This meta-analysis examined the neuropsychological benefit of n-3 FAs in randomized double-blind placebo-controlled studies (RCTs) including healthy, CIND, or AD subjects. Methods: Literature was searched using Medline, Embase, PsycInfo, Cochrane Library, Allied and Complementary Medicine Database (AMED), and Cumulative Index to Nursing and Allied Health Literature (CINAHL) up to September 2011. Treatment effects were summarized across cognitive subdomains, and effect sizes were estimated using Hedge''s g and random effects modeling. Results: Ten RCTs were combined quantitatively. There was no effect of n-3 FAs on composite memory (g = 0.04 [95% CI: −0.06–0.14], N = 934/812, p = 0.452). When examined by domain, no overall benefit for immediate recall (0.04 [−0.05–0.13], N = 934/812, p = 0.358) was detected; however, an effect in CIND subjects (0.16 [0.01–0.31], N = 349/327, p = 0.034) was found. A benefit for attention and processing speed was also detected in CIND (0.30 [0.02–0.57], N = 107/86, p = 0.035), but not healthy subjects. Benefits for delayed recall, recognition memory, or working memory and executive function were not observed. Treatment did not benefit AD patients as measured by the Mini-Mental State Examination (MMSE) or Alzheimer''s Disease Assessment Scale–Cognitive Subscale (ADAS–cog). No differences in adverse events (AE), dropout, or dropout due to AE between groups were observed. Conclusions: These results suggest an effect of n-3 FAs within specific cognitive domains in CIND, but not in healthy or AD subjects. [Copyright &y& Elsevier]

Background: Inflammatory activity plays a role in the development and progression of coronary artery disease (CAD), and exercise confers survival benefit. We performed a meta-analysis of changes in inflammatory biomarkers over the course of exercise interventions in patients with CAD. Methods: We searched MEDLINE, Embase, the Cochrane Collaboration, AMED, and CINAHL for studies reporting peripheral inflammatory biomarker concentrations before and after exercise interventions of ≥2 weeks in patients with CAD. Data were summarized using standard mean differences (SMD) and 95% CIs. Results: Twenty-three studies were included. Concentrations of C-reactive protein (CRP; SMD −0.345, 95% CI −0.444 to −0.246, n = 1,466, P < .001), interleukin 6 (SMD −0.546, 95% CI −0.739 to −0.353, n = 280, P < .001), fibrinogen (SMD −0.638, 95% CI −0.953 to −0.323, n = 247, P < .001), and vascular cell adhesion molecule 1 (SMD −0.413, 95% CI −0.778 to −0.048, n = 187, P = .027) were lower postintervention. Higher total cholesterol (B = −0.328, 95% CI −0.612 to −0.043, P = .026) and higher total/high-density lipoprotein cholesterol ratios (B = −0.250, 95% CI −0.425 to −0.076, P = .008) at baseline were associated with greater reductions in CRP. In controlled studies, follow-up concentrations of CRP (SMD −0.500, 95% CI −0.844 to −0.157, nexercise/control = 485/284, P = .004), and fibrinogen (SMD −0.544, 95% CI −1.058 to −0.030, nexercise/control = 148/100, P = .038) were lower in subjects who exercised compared with controls. Conclusion: Exercise training is associated with reduced inflammatory activity in patients with CAD. C-reactive protein and fibrinogen have provided the strongest evidence. Higher baseline CRP and adverse baseline lipid profiles predicted greater reductions in CRP. [Copyright &y& Elsevier]

This study examined serum cytochrome P450-soluble epoxide hydrolase (CYP450-sEH) oxylipins and depressive symptoms together in relation to cognitive performance in individuals with type 2 diabetes mellitus (T2DM). Clinically cognitively normal T2DM individuals were recruited (NCT04455867). Depressive symptom severity was assessed using the Beck Depression Inventory-II (BDI-II; total scores ≤13 indicated minimal depressive symptoms and ≥ 14 indicated significant depressive symptoms). Executive function and verbal memory were assessed. Fasting serum oxylipins were quantified by ultra-high-performance liquid chromatography tandem mass-spectrometry. The study included 85 participants with minimal depressive symptoms and 27 with significant symptoms (mean age: 63.3 ± 9.8 years, 49 % women). In all participants, higher concentrations of linoleic acid derived sEH (12,13-dihydroxyoctadecamonoenoic acid; DiHOME) and CYP450 (12(13)-epoxyoctadecamonoenoic acid; EpOME) metabolites were associated with poorer executive function (F 1,101 = 6.094, p = 0.015 and F 1,101 = 5.598, p = 0.020, respectively). Concentrations of multiple sEH substrates interacted with depressive symptoms to predict 1) poorer executive function, including 9(10)-EpOME (F 1,100 = 12.137, p < 0.001), 5(6)-epoxyeicosatrienoic acid (5(6)-EpETrE; F 1,100 = 6.481, p = 0.012) and 11(12)-EpETrE (F 1,100 = 4.409, p = 0.038), and 2) verbal memory, including 9(10)-EpOME (F 1,100 = 4.286, p = 0.041), 5(6)-EpETrE (F 1,100 = 6.845, p = 0.010), 11(12)-EpETrE (F 1,100 = 3.981, p = 0.049) and 14(15)-EpETrE (F 1,100 = 5.019, p = 0.027). Associations of CYP450-sEH metabolites and depressive symptoms with cognition highlight the biomarker and therapeutic potential of the CYP450-sEH pathway in T2DM. • Pro-resolving fatty acid epoxides are generated by cytochrome p450s. • Epoxide hydrolases (e.g. sEH) produce inert or toxic diols from fatty acid epoxides. • Higher diols in serum were associated with poor cognitive performance in diabetes. • Serum epoxides were associated with poorer cognition only in those with depression. • Depression in diabetes may involve sEH, which produces markers of poor cognition. [ABSTRACT FROM AUTHOR]

Some studies suggest that angiotensin II type 1 receptor blockers (ARBs) may protect against memory decline more than angiotensin-converting enzyme inhibitors (ACE-Is), but few have examined possible mechanisms. We assessed longitudinal differences between ARB versus ACE-I users in global and sub-regional amyloid-β accumulation by 18F-florbetapir. In cognitively normal older adults (n = 142), propensity-weighted linear mixed-effects models showed that ARB versus ACE-I use was associated with slower amyloid-β accumulation in the cortex, and specifically in the caudal anterior cingulate and precuneus, and in the precentral and postcentral gyri. In amyloid-positive participants with Alzheimer's disease dementia or mild cognitive impairment (n = 169), ARB versus ACE-I use was not associated with different rates of amyloid-β accumulation. Apolipoprotein E ε4 carrier status explained some heterogeneity in the different rates of amyloid-β accumulation between users of ARBs versus ACE-Is in the study. Replicative studies and clinical trials are warranted to confirm potential benefits of ARBs on rates of amyloid-β accumulation in the contexts of Alzheimer's disease prevention and treatment. • In cognitively normal adults, less amyloid-β accumulation in ARB than ACE-I users. • In Alzheimer''s disease, ARBs and ACE-Is not different in effects on amyloid-β. • ApoE genotype may moderate effects of ARBs and ACE-Is on amyloid-β. [ABSTRACT FROM AUTHOR]

Abstract 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. [ABSTRACT FROM AUTHOR]

Objective We aimed to characterize self-poisoning deaths in people with cardiovascular disease (CVD) and compare to other suicide decedent groups. Methods Suicide deaths by self-poisoning in people with CVD (n = 151) were compared to suicide deaths by other methods in people with CVD (n = 260) and suicide deaths by self-poisoning in people without CVD (n = 509). Sub-analysis of the CVD self-poisoning group compared people with depression and without depression. Toxicology reports were compared between intentional self-poisoning groups. Results A higher proportion of suicide deaths were due to self-poisoning in the CVD group compared to the non-CVD group. People with CVD were less likely to have any identified stressor (excluding medical stressor) prior to dying from self-poisoning compared to those without CVD. Female sex, past suicide attempts, living circumstances, and comorbid substance abuse were each significantly associated with self-poisoning as the method of suicide in people with CVD. Opioid, any antidepressants, benzodiazepines, and tricyclic antidepressants (TCAs) were commonly identified as lethal in people with CVD. Compared to people in the CVD self-poisoning without depression group, people in the CVD self-poisoning with depression group were more likely to have lethal levels of TCAs. Conclusions Our findings characterize suicide deaths in people with CVD, and identified notable differences based on method of death and presence of depression. [ABSTRACT FROM AUTHOR]

Subcortical white matter hyperintensities (WMH), presumed to indicate small vessel ischemic vascular disease, are found commonly in elderly individuals with and without Alzheimer's disease (AD). Oxidative stress may instigate or accelerate the development of vascular disease, and oxidative stress markers are elevated in AD. Here, we assess independent relationships between three serum lipid peroxidation markers (lipid hydroperoxides [LPH], 8-isoprostane, and 4-hydroxynonenal) and the presence of extensive subcortical WMH and/or AD. Patients were recruited from memory and stroke prevention clinics into four groups: minimal WMH, extensive WMH, AD with minimal WMH, and AD with extensive WMH. Extensive WMH, but not AD, was associated with higher serum concentrations of 8-isoprostane and LPH. Peripheral LPH concentrations mediated the effect of hypertension on deep, but not periventricular, WMH volumes. 4-hydroxynonenal was associated with hyperlipidemia and cerebral microbleeds, but not with extensive WMH or AD. We conclude that lipid peroxidation mediates hypertensive injury to the deep subcortical white matter and that peripheral blood lipid peroxidation markers indicate subcortical small vessel disease regardless of an AD diagnosis. [ABSTRACT FROM AUTHOR]

Anodal transcranial direct current stimulation (tDCS) can improve cognition in healthy older adults, those with Alzheimer's disease (AD) and mild cognitive impairment (MCI), albeit with considerable variability in response. This systematic review identifies interindividual factors that may influence tDCS outcomes in older individuals with or without cognitive impairment. Peer-reviewed articles were included if they assessed whether cognitive outcomes (memory or global cognition) after tDCS were associated with pre-intervention factors in healthy older adults or individuals with AD/MCI. We identified eight factors that may affect cognitive outcomes after tDCS. Improved tDCS outcomes were predicted by lower baseline cognitive function when tDCS was combined with a co-intervention (but not when used alone). Preserved brain structure and better baseline functional connectivity, genetic polymorphisms, and the use of concomitant medications may predict better tDCS outcomes, but further research is warranted. tDCS outcomes were not consistently associated with age, cognitive reserve, sex, and AD risk factors. Accounting for individual differences in baseline cognition, particularly for combined interventions, may thus maximize the therapeutic potential of tDCS. • Interindividual factors may influence tDCS outcomes (e.g., memory) in older adults. • Baseline cognitive function and brain features can predict tDCS outcomes. • Weak evidence for age, sex and AD risk factors as predictors of tDCS outcomes. • The influence of cognitive reserve on tDCS outcomes requires further investigation. • Further research on the influence of medications and polymorphisms is also warranted. [ABSTRACT FROM AUTHOR]

Objectives Cholinesterase inhibitors (ChEIs) offer modest benefits in Alzheimer disease (AD), which must be balanced against risks. Relatively few data delineate the benefits and risks of long-term ChEI administration in institutionalized patients with advanced AD. This study investigated the effects of ChEI discontinuation in institutionalized patients with AD. Design Institutionalized patients with moderate to severe AD (standardized Mini- Mental Status Examination ≤15) and treated with a ChEI for ≥2 years were randomized, double-blind, to ChEI continuation or placebo, with a 2-week tapering phase, for 8-weeks. Measurements The primary outcome of this pilot study was change on the Clinician's Global Impression of Change (CGI-C) scale. Secondary outcomes included safety, efficacy, and tolerability. Baseline (BL) predictors of clinical deterioration were also determined. Results Forty patients (mean ± standard deviation age = 89.3 ± 3.5 years, standardized Mini-Mental Status Examination = 8.1 ± 5.2, Neuropsychiatric Inventory–Nursing Home version total score = 21.1 ± 15.9, 80% male) were randomized to ChEI continuation (n = 21) or placebo (n = 19). There was no significant difference in clinical worsening in the ChEI continuation (28.6%) and placebo groups (36.8%) on CGI-C (odds ratio for worsening 1.58, 95% confidence interval .38–6.55, P = .53). The occurrence of adverse events was similar in both groups. There were no significant differences in any of the secondary outcome measures. In the placebo group, BL hallucinations predicted CGI-C worsening [F(1,17) = 6.4, P = .02], and there was a trend for BL delusions to predict CGI-C worsening [F(1,15) = 3.5, P = .08]. Conclusions These results suggest that ChEI discontinuation is safe and well tolerated in the majority of institutionalized patients with moderate to severe AD. When discontinuing ChEI, the presence of hallucinations and delusions may predict clinical deterioration, suggesting the need for increased caution. [ABSTRACT FROM AUTHOR]

Background: Zinc is an essential micronutrient with diverse biological roles in cell growth, apoptosis and metabolism, and in the regulation of endocrine, immune, and neuronal functions implicated in the pathophysiology of depression. This study sought to quantitatively summarize the clinical data comparing peripheral blood zinc concentrations between depressed and nondepressed subjects. Methods: PubMed, Cumulated Index to Nursing and Allied Health Literature, and PsycINFO were searched for original peer-reviewed studies (to June 2012) measuring zinc concentrations in serum or plasma from depressed subjects (identified by either screening or clinical criteria) and nondepressed control subjects. Mean (±SD) zinc concentrations were extracted, combined quantitatively in random-effects meta-analysis, and summarized as a weighted mean difference (WMD). Results: Seventeen studies, measuring peripheral blood zinc concentrations in 1643 depressed and 804 control subjects, were included. Zinc concentrations were approximately −1.85 µmol/L lower in depressed subjects than control subjects (95% confidence interval: [CI]: −2.51 to −1.19 µmol/L, Z 17 = 5.45, p < .00001). Heterogeneity was detected (χ2 17 = 142.81, p < .00001, I2 = 88%) and explored; in studies that quantified depressive symptoms, greater depression severity was associated with greater relative zinc deficiency (B = −1.503, t 9 = −2.82, p = .026). Effect sizes were numerically larger in studies of inpatients (WMD −2.543, 95% CI: −3.522 to −1.564, Z 9 = 5.09, p < .0001) versus community samples (WMD −.943, 95% CI: −1.563 to −.323, Z 7 = 2.98, p = .003) and in studies of higher methodological quality (WMD −2.354, 95% CI: −2.901 to −1.807, Z 7 = 8.43, p < .0001). Conclusions: Depression is associated with a lower concentration of zinc in peripheral blood. The pathophysiological relationships between zinc status and depression, and the potential benefits of zinc supplementation in depressed patients, warrant further investigation. [ABSTRACT FROM AUTHOR]

Highlights: [•] Platelet activating factors (PAFs) are associated with mechanisms of depression. [•] PAFs are associated with neurodegeneration and with vascular pathology. [•] PAFs may mediate mechanisms of persistent depression and neurodegeneration in CAD. [ABSTRACT FROM AUTHOR]

Agitation is a common neuropsychiatric symptom that becomes more prevalent as Alzheimer's disease (AD) increases in severity. The treatment of agitation is an urgent and unmet need due to the poor outcomes associated with it, its disruptive impact on patients and caregivers, and the lack of efficacious and safe treatments. Recent research on agitation in AD with blood-based biomarkers has advanced the search for its biomarkers beyond the brain and provides new insights to understand its mechanisms and improve treatments. Here, we reviewed studies of blood-based biomarkers of agitation in AD, which show that inflammatory biomarkers are increased in patients with agitation, may predict the development of agitation, and are associated with symptom severity. In addition, they may also track symptom severity and response to treatment. Other biomarkers associated with agitation include markers of oxidative stress, brain cholesterol metabolism, motor activity, and clusterin, a chaperone protein. These results are promising and need to be replicated. Preliminary evidence suggests a role for these biomarkers in interventional studies for agitation to predict and monitor treatment response, which may eventually help enrich study samples and deliver therapy likely to benefit individual patients. Advances in blood-based biomarkers of AD including those identified in "–omic" studies and high sensitivity assays provide opportunities to identify new biomarkers of agitation. Future studies of agitation and its treatment should investigate blood-based biomarkers to yield novel insights into the neurobiological mechanisms of agitation, monitoring symptoms and response to treatment, and to identify patients likely to respond to treatments. • Agitation in Alzheimer's disease is associated with blood-based metabolite changes. • Peripheral markers of inflammation are consistently increased in agitation. • Potential for these biomarkers to predict agitation and monitor treatment response. • Markers of oxidative stress, brain cholesterol metabolism, motor activity, and clusterin also altered. • Opportunities to identify novel biomarkers of agitation with high sensitivity assays. [ABSTRACT FROM AUTHOR]

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. 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. The pooled meta-analyses included 19 studies measuring global cognition (N active =288, N sham =264), and 9 studies investigating NPS (N active =165, N sham =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 (N studies =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. 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. • Non-invasive brain stimulation (NIBS) is a potential therapy for Alzheimer's disease (AD) and mild cognitive impairment (MCI). • This meta-analysis showed that NIBS significantly improved global cognition and neuropsychiatric symptoms (NPS) in AD and MCI. • Repetitive Transcranial Magnetic Stimulation (rTMS) significantly improved global cognition and NPS in AD. • More research is needed in MCI population and using transcranial direct current stimulation to clarify the efficacy of NIBS. [ABSTRACT FROM AUTHOR]

The prevalence of depression is higher among people with type 2 diabetes (T2DM). Individually, both conditions are associated with systemic inflammation. This study aimed to summarize the clinical data comparing peripheral inflammatory markers in blood between people with T2DM, with and without comorbid depression. From 2187 records, we identified 20 original peer-reviewed articles from which blood inflammatory marker concentrations could be combined and compared between people with T2DM and comorbid depression (D) vs. no depression (ND) as standardized mean differences (SMD) in random effects meta-analysis. Concentrations of C-reactive protein (CRP; N D /N ND = 1742/15244, SMD = 0.31 95% confidence interval [0.16, 0.45], Z 16 = 4.03, p < 0.01; I2 = 84.0%) and interleukin-6 (IL-6; N D /N ND = 677/4349, SMD = 0.17 [0.04, 0.30], Z 4 = 2.58, p = 0.01; I2 = 48.1%), were higher, and concentrations of brain derived neurotrophic factor (BDNF; N D /N ND = 358/1512, SMD = −0.37 95% confidence interval [−0.64,−0.10], Z 2 = −2.68, p = 0.01; I2 = 61.2%) were lower, among those with depression. Depression in T2DM was associated with systemic inflammation and lower peripheral blood BDNF concentrations. Inconsistency between studies suggests the need to explore further population heterogeneity and pathophysiological elements. PROSPERO (CRD42020188509). • Comorbid depression in type 2 diabetes (T2DM) presents a clinical challenge. • In T2DM, depression was associated with higher interleukin-6 and C-reactive protein. • Higher C-reactive protein may reveal links with vascular comorbidity burden. • Lower brain-derived neurotrophic factor was found in depression in T2DM. [ABSTRACT FROM AUTHOR]

Highlights: [•] Plasma zinc concentrations are lower in major depression. [•] Zinc deficiency induces depression-like behaviors in animals. [•] Zinc interacts with multiple endocrine and immune functions. [•] Synaptic zinc modulates neural networks that regulate mood and cognition. [Copyright &y& Elsevier]

Abstract: Stroke is a leading cause of physical disability with neurodegenerative sequelae such as dementia and depression causing significant excess morbidity. Stroke severity can be exacerbated by apoptotic cell death in ischemic tissue, of which inflammatory activity is a key determinant. Studies have identified harmful and beneficial sets of T lymphocytes that infiltrate the brain post-stroke and their activation signals, suggesting that they might be targeted for therapeutic benefit. Animal models and human studies implicate interleukin(IL)-17 and its congeners (e.g. IL-23, IL-21) as mediators of tissue damage in the delayed phase of the inflammatory cascade and the involvement of T lymphocytes in propagating IL-17 release. In this review, we highlight the current understanding of IL-17 secreting cells, including sets of CD4+ αβ and CD4− γδ T lymphocytes, as potentially important mediators of brain pathology post-stroke. Interactions between the IL-17 axis and innate pathways, positive feedback mechanisms that prolong or amplify IL-17, and IL-17 regulatory pathways may offer intervention targets to enhance recovery, prevent long-term decline, and improve quality of life. [Copyright &y& Elsevier]

Background: Major depression occurs in 4.4% to 20% of the general population. Studies suggest that major depression is accompanied by immune dysregulation and activation of the inflammatory response system (IRS). Our objective was to quantitatively summarize the data on concentrations of specific cytokines in patients diagnosed with a major depressive episode and controls. Methods: We performed a meta-analysis of studies measuring cytokine concentration in patients with major depression, with a database search of the English literature (to August 2009) and a manual search of references. Results: Twenty-four studies involving unstimulated measurements of cytokines in patients meeting DSM criteria for major depression were included in the meta-analysis; 13 for tumor necrosis factor (TNF)-α, 9 for interleukin (IL)-1β, 16 for IL-6, 5 for IL-4, 5 for IL-2, 4 for IL-8, 6 for IL-10, and 4 for interferon (IFN)-γ. There were significantly higher concentrations of TNF-α (p < .00001), weighted mean difference (WMD) (95% confidence interval) 3.97 pg/mL (2.24 to 5.71), in depressed subjects compared with control subjects (438 depressed/350 nondepressed). Also, IL-6 concentrations were significantly higher (p < .00001) in depressed subjects compared with control subjects (492 depressed/400 nondepressed) with an overall WMD of 1.78 pg/mL (1.23 to 2.33). There were no significant differences among depressed and nondepressed subjects for the other cytokines studied. Conclusions: This meta-analysis reports significantly higher concentrations of the proinflammatory cytokines TNF-α and IL-6 in depressed subjects compared with control subjects. While both positive and negative results have been reported in individual studies, this meta-analytic result strengthens evidence that depression is accompanied by activation of the IRS. [Copyright &y& Elsevier]