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Introduction: Few studies have examined memory decline among patients with type 2 diabetes using different oral hypoglycemic drugs., Methods: Participants with normal cognition (NC) or Alzheimer's disease (AD) dementia using a hypoglycemic medication (2005 to 2019) were identified from the National Alzheimer's Coordinating Center database. Delayed memory was assessed using the Wechsler Memory Scale Revised-Logical Memory test. Associations between oral drug classes and memory over time were examined using mixed-effects models with inverse probability treatment weights., Results: In NC (n = 1192), metformin use was associated with better memory performance over time, whereas in AD (n = 807), dipeptidyl peptidase-4 (DPP4) inhibitor use was associated with a slower rate of memory decline. Interaction effects suggested greater benefit associated with DPP4 inhibitor use among APOE ε4 carriers., Discussion: Associations between different oral hypoglycemic drugs and memory change were not consistent between cognitively normal elderly and those with AD dementia. APOE ε4 genotype modified some relationships., (© 2020 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

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; F 1, 35 = 6.41, P = .016), and the proinflammatory cytokine, tumor necrosis factor-α (TNF-α; F 1, 29 = 3.97, 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, F 2, 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.

Background: Patients with coronary artery disease have an increased risk for developing vascular cognitive impairment. Endothelial function is often diminished and has been associated with lower cognitive performance in these patients. The link between endothelial function and cognition in coronary artery disease is not fully understood. Angiogenesis may play a role in mediating the association between endothelial function and cognition since angiogenic processes rely heavily on the endothelium., Objective: The aim of this study was to determine if markers of angiogenesis mediate the relationship between endothelial function and cognition in coronary artery disease patients., Methods: In 50 participants with coronary artery disease, endothelial function was assessed using peripheral arterial tonometry. Vascular endothelial growth factor (pro-angiogenic) and endostatin (anti-angiogenic) were measured in peripheral serum samples. Cognition was assessed using the Montreal Cognitive Assessment. A mediation analysis, using a bias corrected inferential bootstrapping method with 10,000 permutations, was used to determine if vascular endothelial growth factor or endostatin mediated an association between peripheral arterial tonometry measures and cognitive performance on the Montreal Cognitive Assessment., Results: Endostatin, but not vascular endothelial growth factor, mediated a relationship between endothelial function and cognitive performance when controlling for total years of education, body mass index, coronary artery bypass graft, stent, diabetes, and diuretic use. This analysis was also significant when delayed recall was substituted for the overall score on the Montreal Cognitive Assessment., Conclusion: These results suggest that endostatin mediates an association between endothelial function and cognitive performance in coronary artery disease.

Background: New onset of mood and behavioral changes in middle-aged patients are frequently the first manifestations of an unrecognized neurocognitive disorder. Impairment of social cognition, the cognitive ability to process social information coming from others, such as emotions, to attribute mental states to others, and to respond appropriately to them, is often at the origin of behavioral manifestations in neurodegenerative disorders., Methods: This paper reviews the current literature on social cognition impairment in neurocognitive disorders, particularly in prodromal stages of behavioral-variant frontotemporal dementia (bvFTD), Alzheimer's disease (AD), idiopathic Parkinson's disease (IPD), and Lewy body dementia (LBD). The concepts of social cognition will be reviewed, including its impairment and neural basis, its clinical assessment, and the different therapeutic interventions available clinically., Results: Socially inappropriate behaviors, such as loss of empathy, inappropriateness of affect, and disinhibition are frequently reported in prodromal bvFTD and in prodromal AD. Lack of self-control, reduced perception of social cues, such as recognition of facial emotions and sarcastic speech, and impaired Theory of Mind all contribute to the neuropsychiatric symptoms and are secondary to neurodegeneration in specific brain regions. In contrasts to bvFTD and AD, deficits in social cognition in IPD occur later in the course of the disease and are often multifactorial in origin., Conclusions: Through various manifestations, social inappropriateness is frequently the first clinical sign of a neurodegenerative process, especially in AD and bvFTD, years before noticeable impairment on classical neuropsychological assessment and brain atrophy on imaging.

Objectives: To quantitatively summarize changes in cognitive performance in individuals with severe aortic stenosis undergoing transcatheter aortic valve implantation (TAVI)., Design: Metaanalysis., Participants: Individuals undergoing TAVI (N = 1,065 (48.5% male) from 18 studies, average age ≥80)., Measurements: The MEDLINE, EMBASE, and Cochrane Central databases were searched for original peer-reviewed reports assessing cognitive performance using standardized cognitive tests before and after TAVI. Data were extracted for cognitive scores before TAVI; perioperatively (within 7 days after TAVI); 1, 3, and 6 months after TAVI, and 12 to 34 months after TAVI (over the long term). Standardized mean differences (SMDs) were generated using random-effects models for changes in cognition at each time point. Metaregression analyses were conducted to assess the association between population and procedural characteristics and cognitive outcomes. Risk of bias was assessed., Results: There were no significant changes from baseline in perioperative cognitive performance (SMD = 0.05, 95% confidence interval (CI) = -0.08-0.18; z = 0.75, P = .46), although overall cognitive performance had improved significantly 1 month after TAVI (SMD = -0.33, 95% CI = -0.50 to -0.16; z = 3.83, P < .001). There were no differences in cognitive performance 3 and 6 months after TAVI or over the long term. Cognitive outcomes were not associated with any covariates in regression analyses., Conclusion: Cognitive performance is preserved after TAVI, suggesting TAVI is not detrimental to cognition., (© 2017, Copyright the Authors Journal compilation © 2017, The American Geriatrics Society.)

Background: In a recent report, 76 weeks' treatment with a gamma-secretase inhibitor (semagacestat) was associated with poorer cognitive outcomes in Alzheimer's disease (AD)., Objective: We sought to examine the effect of semagacestat treatment on neuropsychiatric symptoms (NPS)., Methods: 1,537 participants with mild to moderate AD were randomized to 76 weeks' treatment with placebo versus two doses of semagacestat. NPS were assessed with the Neuropsychiatric Inventory (NPI-Total and subdomains). Cognition was assessed with the Alzheimer's Disease Assessment Scale-Cognitive (first 11 items, ADAS11). Mixed-Model Repeated Measures was used to compare the effects of treatment assignment on change in NPI-total and subdomains over time. Survival analysis was used to assess the treatment effect on time to first worsening of NPS (NPI-Total ≥10 or NPI subdomain ≥4) for subjects with no or minor NPS at baseline., Results: Participants on high dose semagecestat (140 mg) had greater increase in NPI-Total and greater risk of incident first worsening in NPI-Total and in subdomains of aberrant motor behavior, appetite, depression/dysphoria, and sleep. ADAS11 increased more in participants whose NPI-Total increased., Conclusion: In participants with mild to moderate AD, high dose semagacestat treatment was associated with greater severity and faster worsening of NPS in a pattern resembling an agitated depression. Increased NPS was associated with cognitive decline regardless of treatment assignment. These findings suggest that greater NPS may be the result of gamma-secretase treatment and emphasize the importance of monitoring NPS as potential adverse events in trials of novel treatments for AD.

Objective: Coronary artery disease (CAD) is associated with an increased risk of cognitive decline. Although cerebral white matter (WM) damage predicts cognitive function in CAD, conventional neuroimaging measures only partially explain the effect of CAD on cognition. The purpose of this study was to determine if WM microstructural integrity and CAD using diffusion tensor imaging (DTI) correlates with cognitive function in older adults with CAD., Methods: Forty-nine CAD patients (66 ± 7 years old, 86% male) underwent neurocognitive assessments using the cognitive battery recommended by the National Institute of Neurological Disorders and Stroke-Canadian Stroke Network for the study of vascular cognitive impairment. Composite scores for each cognitive domain were calculated. Microstructural integrity in normal-appearing WM was quantified as fractional anisotropy (FA) using DTI in nine bilateral and two interhemispheric WM tracts from the Johns Hopkins University WM Tractography Atlas. Linear regression models examined associations between FA and cognitive performance, controlling for age, sex, and education, with correction for multiple comparisons using a false discovery rate of 5%., Results: Executive function was most significantly associated with FA in the left parahippocampal cingulum (β = 0.471, t = 3.381, df = 44, p = 0.002) and left inferior fronto-occipital fasciculus (β = 0.430, t = 2.984, df = 44, p = 0.005). FA was not associated with memory in any of the WM tracts examined., Conclusion: These results suggest that WM microstructural integrity may be an important neural correlate of executive function even in cognitively intact CAD patients. This study suggests WM damage may be relevant to subtle cognitive decline in a population that may have early neural risk for dementia., (Copyright © 2015 American Association for Geriatric Psychiatry. Published by Elsevier Inc. All rights reserved.)

Background: Cognitive function is a significant determinant of overall quality of life in patients with coronary artery disease. Medications prescribed to control vascular risk factors often have anticholinergic effects, which can cause central side effects and affect cognitive function., Objective: This cross-sectional study aimed to identify cognitive deficits associated with the use of anticholinergic medications in patients with coronary artery disease., Methods: Demographics, medications, and vascular risk factors were assessed for each patient by interview and chart review. Anticholinergic burden was estimated using the anticholinergic cognitive burden scale. Cognition was assessed objectively using a battery of neuropsychologic tests, including the California Verbal Learning Test second edition, Revised Brief Visuospatial Memory Test, Stroop test, Trail-Making Test Parts A and B, Digit-Symbol Coding, FAS test, and animal naming., Results: Patients with coronary artery disease (mean ± standard deviation age 64.2 ± 9.1, 15.3% female) presented with 2.6 ± 1.4 vascular risk factors and were using 5.1 ± 1.8 medications. Scores on the anticholinergic cognitive burden scale were associated with poorer performance on the Trail-Making Test Part A (β = 0.280, p = 0.002), Trail-Making Test Part B (β = 0.256, p = 0.004), and animal naming (β = -0.212; p = 0.015) tasks in models controlling for age, gender, years of education, number of vascular risk factors and total medications. Beta-blockers frequently prescribed in this population (i.e., metoprolol and atenolol) accounted for a large proportion of the total anticholinergic cognitive burden score, and their use was independently associated with poorer cognitive performance in a post hoc model including the anticholinergic estimate., Conclusions: Anticholinergic exposure was associated with poorer performance on tests of attention, speed, and executive function in patients with coronary artery disease., (Copyright © 2014 The Academy of Psychosomatic Medicine. Published by Elsevier Inc. All rights reserved.)

Background: Neuropsychological testing requires considerable time, expense, and expertise to administer. These factors can limit patient access. Computerized cognitive testing has been proposed as an alternative., Objectives: The objective of this paper is to validate a brief, simple-to-use computer-generated cognitive assessment screening battery for multiple sclerosis (MS) patients that has minimal motor involvement., Methods: A sample of 96 MS patients and 98 healthy controls completed a computer-generated battery that included the Stroop, Symbol Digit Modalities Test (C-SDMT), a two- and four-second visual analog of the Paced Auditory Serial Addition Test (PVSAT-2, PVSAT-4), and simple and choice reaction time tests. The Minimal Assessment of Cognitive Function in MS was used to define cognitive impairment in the MS sample., Results: Each newly developed test successfully distinguished between cognitively impaired patients and healthy controls as well as cognitively intact patients. A combination of three computerized tests (C-SDMT, PVSAT-2, PVSAT-4) with a mean administration time of 10 minutes had a sensitivity of 82.5% and specificity of 87.5% in detecting cognitive impairment. Good test-retest reliability was obtained for each measure., Conclusions: Good sensitivity and specificity, brevity, ease of administration, and a limited motor component highlight the feasibility of introducing this computer-generated cognitive screening instrument in a busy MS clinic.

Objectives: To investigate the association between cardiopulmonary fitness and cognitive performance in subjects with coronary artery disease (CAD)., Design: Cross-sectional observational study., Setting: Outpatient cardiac rehabilitation., Participants: Eighty-one subjects with CAD., Measurements: Cardiopulmonary fitness was assessed by measuring peak oxygen uptake (VO(2Peak) ) in a standardized exercise stress test. The fraction of the predicted age and sex norm for VO(2Peak) was computed for each patient. A battery of neuropsychological tests including the Stroop, Trail-Making Test Part B, Digit Symbol Coding, Revised Brief Visuospatial Memory Test, California Verbal Learning Test 2nd Edition, and Mini Mental State Examination (MMSE) was administered, from which composite Z-scores were computed for tasks involving executive function and memory., Results: Executive function, memory, and MMSE scores were correlated with VO(2Peak) , but only performance in the executive domain was independently associated with VO(2Peak) in multiple linear regression. In a multiple linear regression model controlling for potential clinical confounders, VO(2Peak) (β=.666, P<.001) and covariates accounted for 36% of the variance in executive function scores., Conclusion: Poorer VO(2Peak) is associated with poorer cognition, particularly executive function, in subjects with CAD independent of other cardiac risk factors. Cardiopulmonary fitness may be a protective factor for cognition in patients with CAD., (© 2010, Copyright the Authors. Journal compilation © 2010, The American Geriatrics Society.)

• 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]

Background: Apathy and depression are common neuropsychiatric symptoms across neurodegenerative disorders and are associated with impairment in several cognitive domains, yet little is known about the influence of sex on these relationships. Objectives: We examined the relationship between these symptoms with neuropsychological performance across a combined cohort with mild or major neurodegenerative disorders, then evaluated the impact of sex. Design, Setting and Participants: We conducted a cohort analysis of participants in the COMPASS‐ND study with mild cognitive impairment (MCI), vascular MCI, Alzheimer's disease, mixed dementia, Parkinson's disease, frontotemporal dementia, and cognitively unimpaired (CU) controls. Measurements: Participants with neurodegenerative disease and CU controls were stratified by the presence (severity ≥1 on Neuropsychiatric Inventory Questionnaire) of either depressive symptoms alone, apathy symptoms alone, both symptoms, or neither. A neuropsychological battery evaluated executive function, verbal fluency, verbal learning, working memory, and visuospatial reasoning. Analysis of covariance was used to assess group differences with age, sex, and education as covariates. Results: Groups included depressive symptoms only (n = 70), apathy symptoms only (n = 52), both (n = 68), or neither (n = 262). The apathy and depression + apathy groups performed worse than the neither group on tests of working memory (t(312) = −2.4, p = 0.02 and t(328) = −3.8, p = 0.001, respectively) and visuospatial reasoning (t(301) = −2.3, p = 0.02 and t(321) = −2.6, p = 0.01, respectively). The depression, apathy, and depression + apathy groups demonstrated a similar degree of impairment on tests of executive function, processing speed, verbal fluency, and verbal learning when compared to participants without apathy or depression. Sex‐stratified analyses revealed that compared to the male neither group, the male apathy and depression + apathy groups were impaired broadly across all cognitive domains except for working memory. Females with depression alone showed deficits on tests of executive function (t(166) = 2.4, p = 0.01) and verbal learning (t(167) = −4.3, p = 0.001) compared to the female neither group. Conclusions: This study demonstrated that in neurodegenerative diseases, apathy with or without depression in males was associated with broad cognitive impairments. In females, depression was associated with deficits in executive function and verbal learning. These findings highlight the importance of effectively treating apathy and depression across the spectrum of neurodegenerative disorders with the goal of optimizing neuropsychological outcomes. Key points: Apathy and depression are common symptoms that patients with dementia face during the course of illness, and these symptoms are associated with impairments in several cognitive domains.We examined differences in cognitive performance between patients with either apathy alone, depression alone, both, or neither across a combined cohort with mild or major neurodegenerative disorders. Further, we evaluated this relationship within each sex.Among males, apathy with or without depression was associated with broad cognitive deficits. In females, depression was associated with deficits in executive function and verbal learning.These findings highlight the importance of effectively treating apathy and depression across the spectrum of neurodegenerative disorders with the goal of optimizing neuropsychological outcomes. [ABSTRACT FROM AUTHOR]

Background: Recent therapeutic approaches for Alzheimer's disease (AD) have had limited success. Considering the association of neuroinflammation with AD symptoms as demonstrated in multiple studies, assessment of the clinical efficacy of molecules that reduce systemic or brain inflammation is warranted. Objective: This clinical trial assessed whether boswellic acids can improve cognitive and neuropsychiatric symptoms while reducing inflammation in AD patients. Methods: A double-blind, placebo-controlled, study was conducted on 85 AD patients randomized to boswellic acids (K-Vie™ as the main ingredient in Memowell™) or placebo for 6 months. Clinical Dementia Rating–Sum of Boxes (CDR-SOB) and Mini-Mental State Examination (MMSE) scores were compared to baseline and between groups and constituted the co-primary clinical efficacy endpoints. Secondary outcomes included neuropsychiatric assessment (Neuropsychiatric Inventory-Questionnaire, NPI-Q) and assessment of AD and inflammation biomarkers. Results: Patients on K-Vie™ showed a 3.1- and 1.6-unit improvement in MMSE and CDR-SOB scores, respectively, when compared to patients on placebo. NPI-Q analysis revealed significant improvement in the K-Vie™ but not in the placebo group. Only mild gastrointestinal side effects were reported in a few patients. Patients on K-Vie™ showed improvement in plasma AD biomarkers and reduction of key inflammatory cytokines including IL-6 and TNF. Conclusion: Our results support the positive cognitive effects of boswellic acids by reducing the systemic inflammation. [ABSTRACT FROM AUTHOR]

Background: The Alzheimer's Disease Assessment Scale Cognitive Subscale (ADAS‐Cog) is used to assess decline in memory, language, and praxis in Alzheimer's disease (AD). Methods: A latent state–trait model with autoregressive effects was used to determine how much of the ADAS‐Cog item measurement was reliable, and of that, how much of the information was occasion specific (state) versus consistent (trait or accumulated from one visit to the next). Results: Participants with mild AD (n = 341) were assessed four times over 24 months. Praxis items were generally unreliable as were some memory items. Language items were generally the most reliable, and this increased over time. Only two ADAS‐Cog items showed reliability >0.70 at all four assessments, word recall (memory) and naming (language). Of the reliable information, language items exhibited greater consistency (63.4% to 88.2%) than occasion specificity, and of the consistent information, language items tended to reflect effects of AD progression that accumulated from one visit to the next (35.5% to 45.3%). In contrast, reliable information from praxis items tended to come from trait information. The reliable information in the memory items reflected more consistent than occasion‐specific information, but they varied between items in the relative amounts of trait versus accumulated effects. Conclusions: Although the ADAS‐Cog was designed to track cognitive decline, most items were unreliable, and each item captured different amounts of information related to occasion‐specific, trait, and accumulated effects of AD over time. These latent properties complicate the interpretation of trends seen in ordinary statistical analyses of trials and other clinical studies with repeated ADAS‐Cog item measures. Highlights: Studies have described unfavorable psychometric properties of the Alzheimer's Disease Assessment Scale Cognitive Subscale (ADAS‐Cog), bringing into question its ability to track changes in cognition uniformly over time. There remains a need to estimate how much of the ADAS‐Cog measurement is reliable, of that how much is occasion specific versus consistent, and of the consistent information, how much represents enduring traits versus autoregressive effects (i.e., effects of Alzheimer's disease [AD] progression carried over from one assessment to the next).A latent state–trait model with autoregressive effects in mild AD found most items to be unreliable, and each item to capture different amounts of occasion‐specific, trait, and autoregressive information. Language items, specifically, naming and the memory item word recall, were the most reliable.Psychometric idiosyncrasies of individual items complicate the interpretation of their summed score, biasing ordinary statistical analyses of repeated measures in mild AD. Future studies should consider item trajectories individually. [ABSTRACT FROM AUTHOR]

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 < 0.001) with increasing levels in the following order: no apathy or executive dysfunction, only executive dysfunction (executive function composite score≤-1), only apathy (AES≥28), and both apathy and executive dysfunction. A model adjusting for demographics showed that lipid peroxidation was associated with both apathy (B(SE) = 4.63 (0.954), t = 4.852, p < 0.001) and executive function (B(SE) = -0.19 (0.079), t = -2.377, p = 0.018). However, when controlling for both demographics and vascular risk factors, lipid peroxidation was associated with only apathy (B(SE) = 3.11 (0.987), t = 3.149, p = 0.002).Conclusion: The results highlight a potentially important involvement of lipid peroxidation in the co-occurrence of apathy and executive dysfunction in those at risk for VCI. [ABSTRACT FROM AUTHOR]

Introduction: Studies suggest associations between proton pump inhibitors (PPIs) and dementia risk; however, many neither considered histamine-2 receptor antagonists (H2RAs) nor baseline cognitive status. Methods: Participants (National Alzheimer's Coordinating Center Database; 2005-2021) using a PPI or H2RA were compared. Covariate-adjusted Cox regression was used to estimate hazard ratios (HR) for progression from normal cognition to mild cognitive impairment (MCI), and from MCI to dementia over 5 years. In a propensity-score-matched subsample of mild-moderate Alzheimer's disease (AD), mixed-effects negative binomial regression was used to estimate decline in delayed recall memory. Results: Compared to PPI, H2RAuse was associated with earlier progression fromMCI to dementia (HR = 1.40 [1.09-1.81]; n = 1701), and with faster memory decline in AD over time (rate ratio=0.76 [0.64-0.92]; n=628), but not with progression from normal cognition toMCI (HR = 0.94 [0.71-1.24]; n = 2784). Discussion: Compared to PPIs, H2RAs were associated with cognitive decline, specifically among people with pre-existing cognitive impairment. [ABSTRACT FROM AUTHOR]

Longitudinal invariance indicates that a construct is measured over time in the same way, and this fundamental scale property is a sine qua non to track change over time using ordinary mean comparisons. The Alzheimer's Disease Assessment Scale–cognitive (ADAS-Cog) and its subscale scores are often used to monitor the progression of Alzheimer's disease, but longitudinal invariance has not been formally evaluated. A configural invariance model was used to evaluate ADAS-Cog data as a three correlated factors structure for two visits over 6 months, and four visits over 2 years (baseline, 6, 12, and 24 months) among 341 participants with Alzheimer's disease. We also attempted to model ADAS-Cog subscales individually, and furthermore added item-specific latent variables. Neither the three-correlated factors ADAS-Cog model, nor its subscales viewed unidimensionally, achieved longitudinal configural invariance under a traditional modeling approach. No subscale achieved scalar invariance when considered unidimensional across 6 months or 2 years of assessment. In models accounting for item-specific effects, configural and metric invariance were achieved for language and memory subscales. Although some of the ADAS-Cog individual items were reliable, comparisons of summed ADAS-Cog scores and subscale scores over time may not be meaningful due to a lack of longitudinal invariance. [ABSTRACT FROM AUTHOR]

Background: Coronary artery disease (CAD) increases risk for vascular cognitive impairment-no dementia (VCIND), a precursor to dementia, potentially through persistent oxidative stress.Objective: This study assessed peripheral glutathione peroxidase activity (GPX), which is protective against oxidative stress, in VCIND versus cognitively normal CAD controls (CN). GPX activity was also evaluated as a biomarker of cognition, particularly verbal memory.Methods: 120 CAD patients with VCIND (1SD below norms on executive function or verbal memory (VM)) or without (CN) participated in exercise rehabilitation for 24 weeks. Neurocognitive and cardiopulmonary fitness (VO2peak) assessments and plasma were collected at baseline and 24-weeks.Results: GPX was higher in VCIND compared to CN (F1,119 = 3.996, p = 0.048). Higher GPX was associated with poorer baseline VM (β= -0.182, p = 0.048), and longitudinally with VM decline controlling for sex, body mass index, VO2peak, and education (b[SE] = -0.02[0.01], p = 0.004). Only CN participants showed improved VM performance with increased fitness (b[SE] = 1.30[0.15], p < 0.005).Conclusion: GPX was elevated in VCIND consistent with a compensatory response to persistent oxidative stress. Increased GPX predicted poorer cognitive outcomes (verbal memory) in VCIND patients despite improved fitness. [ABSTRACT FROM AUTHOR]

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<0.01) and 30-day mortality (OR: 4.04, p=0.03). Conclusion: This study emphasized the value of screening for geriatric risk factors prior to TAVI by demonstrating that screening increased identification of at-risk patients. It also confirmed findings that cognitive deficits are predictive of POD and mortality following TAVI. [ABSTRACT FROM AUTHOR]

Objective Psychiatric symptoms, including depression and apathy, may significantly impede functional and cognitive capabilities following a cerebrovascular event. This study examined the role of apathy and depression on learning and memory performance in stroke patients. Method Stroke patients (n = 140 [119 ischemic, 21 hemorrhagic], mean age = 60.6 [ SD = 15.1]) completed the Apathy Evaluation Scale (AES), the Center for Epidemiologic Studies Depression Scale (CES-D), and the California Verbal Learning Test-Second Edition (CVLT-II). Results Using a 2 × 2 MANOVA with depression (CESD ≥ 16) and apathy (AES ≥ 34) as the independent variables and cognitive performance (i.e. verbal acquisition, short-term free recall, and long-term free recall) as the dependent variables, we found a main effect for apathy (F [3,134] = 2.98, p =.034), such that apathetic stroke patients (n = 24) performed significantly worse on verbal acquisition (F [1,136] = 6.44; p =.012), short-term free recall (F [1,136] = 7.86; p =.006), and long-term free recall (F [1,136] = 8.37; p =.004) than nonapathetic stroke patients (n = 116). There was no main effect of depression on cognitive performance (F [1,136] = 1.72, p =.155). Conclusions These results suggest that apathy, not depression, is related to verbal memory performance in stroke patients. Future research should explore whether treatment of apathy (e.g. improving motivation) could be a novel target for improving cognition after stroke. Researchers should also examine whether this model can be applied to other aspects of cognition, including executive function and other areas of memory including autobiographical and working memory. [ABSTRACT FROM AUTHOR]

Background: Exercise prevents recurrent cardiovascular events and it may combat cognitive decline in coronary artery disease (CAD); however, evidence in type 2 diabetes (T2DM) has been mixed. T2DM and memory decline have been associated with differences in the plasma sphingolipidome.Objective: Here, we will investigate whether T2DM-related sphingolipids predict less memory improvement over an exercise intervention for CAD.Methods: Among participants with CAD entering a 6-month exercise intervention, we matched 20 with T2DM to 40 without T2DM for age, sex, and body mass index. We assessed 45 sphingolipid species using high-performance liquid chromatography coupled electrospray ionization tandem mass spectrometry with multiple reaction monitoring. We assessed memory using the California Verbal Learning Test, 2nd Ed, and the revised Brief Visuospatial Learning Test.Results: Partial least squares discriminant analysis identified 8 species that distinguished T2DM from non-T2DM groups with 83% (95% confidence interval [70%, 95%]) accuracy in a receiver operator characteristic curve (validated by internal resampling, 1000 permutations, p = 0.01). At baseline, T2DM-associated sphingolipids (ceramide C22 : 0, monohexylceramide C16 : 1, and lactosylceramide C24 : 0) were associated with poorer memory, attention, and psychomotor processing speed performance. Among 50 completers, an indirect effect of T2DM on less improvement in verbal memory was mediated by monohexylceramide C16 : 1 (0.86 fewer words recalled, 95% bootstrap confidence interval [-2.32, -0.24]), and an indirect effect of T2DM on less visuospatial memory improvement was mediated by ceramide C22 : 0 concentrations (0.42 fewer points, 95% bootstrap confidence interval [-1.17, -0.05]).Conclusions: Ceramide species associated with T2DM predicted poorer cognitive responses to exercise in patients with CAD. [ABSTRACT FROM AUTHOR]

Background: Biomarkers in cognitively vulnerable populations, like those with coronary artery disease (CAD), may inform earlier intervention in vascular neurodegeneration. Circulating ceramide C18:0 (CerC18:0) is associated with changes in verbal memory in early neurodegeneration and CAD progression.Objective: To investigate whether plasma CerC18:0 accumulation is associated with longitudinal declines in verbal memory performance in CAD.Methods: In addition to total CerC18:0, we assessed its relative abundance to its precursors as ratios: CerC18:0 to monohexosylceramide C18:0 (MHxCer18:0), CerC18:0 to sphingomyelin C18:0 (SM18:0), and CerC18:0 to sphingosine-1-phosphate (S1P). Verbal memory was assessed using the California Verbal Learning Test 2nd Ed. Using mixed models in 60 CAD participants, we evaluated associations between baseline CerC18:0 ratios and changes in verbal memory performance, adjusting for age, body mass index, and education. Given that cognitive decline is more rapid following onset of deficits, these associations were compared between those with possible mild vascular neurocognitive disorder (MVND).Results: Increased baseline CerC18:0 concentrations correlated with worse verbal memory performance over time (b[SE] = - 0.91[0.30], p = 0.003). Increased baseline CerC18:0/SM18:0 (b[SE] = - 1.11[`], p = 0.03) were associated with worse verbal memory performance over time. These associations were not mediated by whether or not patients had possible MVND at baseline.Conclusion: These findings support aberrant CerC18:0 metabolism as an early neurobiological change in vascular neurodegeneration. Future studies should measure enzymes responsible for conversion of sphingolipid precursors into CerC18:0 to assess enzymatic activity. [ABSTRACT FROM AUTHOR]

Background The purpose of this pilot study was to explore the potential of eye-tracking technology in monitoring symptoms and predicting outcomes in apathetic Alzheimer's disease (AD) patients treated with methylphenidate (MTP). Methods Neuropsychological tests and eye-tracking measurements were completed at baseline and following at least four weeks of treatment with MTP (5-10 mg BID). Eye-movements were measured while patients viewed novel and social stimuli. Cognition, behavior, and apathy were assessed using the Standardized Mini-Mental State Exam (sMMSE), Neuropsychiatric Inventory, and Apathy Evaluation Scale (AES), respectively. Results Nine patients were included in the analysis (age: median=75, interquartile range=8; sMMSE: median=22, interquartile range=14). Spearman correlations showed that improvement on the AES was associated with increased visual attention towards novel stimuli (ρ7=-0.809, p=.008). Additionally, lower baseline attention towards social images was associated with improvement on the AES (ρ7=0.905, p=.001). Conclusions Eye-tracking techniques can be developed as an objective and nonverbal method of monitoring symptoms and treatment outcomes in AD patients. [ABSTRACT FROM AUTHOR]

Objectives: This study examined the relationship between apathy and cognition in patients with cerebrovascular disease. Apathy may result from damage to frontal subcortical circuits causing dysexecutive syndromes, but apathy is also related to depression. We assessed the ability of apathy to predict phonemic fluency and semantic fluency performance after controlling for depressive symptoms in 282 individuals with stroke and/or transient ischemic attack. Method: Participants (N = 282) completed the Phonemic Fluency Test, Semantic Fluency Test, Center for Epidemiologic Studies Depression Scale, and Apathy Evaluation Scale. A cross-sectional correlational design was utilized. Results: Using hierarchical linear regressions, apathy scores significantly predicted semantic fluency performance (β = -.159, p = .020), but not phonemic fluency performance (β = -.112, p = .129) after scaling scores by age and years of education and controlling for depressive symptoms. Depressive symptoms entered into the first step of both hierarchical linear regressions did not predict semantic fluency (β = -.035, p = .554) or phonemic fluency (β = -.081, p = .173). Apathy and depressive symptoms were moderately correlated, r(280) = .58, p < .001. Conclusions: The results of this study are consistent with research supporting a differentiation between phonemic and semantic fluency tasks, whereby phonemic fluency tasks primarily involve frontal regions, and semantic fluency tasks involve recruitment of more extended networks. The results also highlight a distinction between apathy and depressive symptoms and suggest that apathy may be a more reliable predictor of cognitive deficits than measures of mood in individuals with cerebrovascular disease. Apathy may also be more related to cognition due to overlapping motivational and cognitive frontal subcortical circuitry. Future research should explore whether treatments for apathy could be a novel target for improving cognitive outcomes after stroke. [ABSTRACT FROM AUTHOR]

Objective: Coronary artery disease (CAD) is frequently accompanied by white matter hyperintensities and executive dysfunction. Because acetylcholine is important in executive function, these symptoms may be exacerbated by subcortical hyperintensities (SH) located in cholinergic (CH) tracts. This study investigated the effects of SH on cognitive changes in CAD patients undergoing a 48-week cardiac rehabilitation program.Methods: Fifty patients (age 66.5 ± 7.1 years, 84% male) underwent the National Institute of Neurological Disorders and Stroke - Canadian Stroke Network neurocognitive battery at baseline and 48 weeks. Patients underwent a 48-week cardiac program and completed neuroimaging at baseline. Subcortical hyperintensities in CH tracts were measured using Lesion Explorer. Repeated measures general linear models were used to examine interactions between SH and longitudinal cognitive outcomes, controlling for age, education, and max VO2 change as a measure of fitness.Results: In patients with SH in CH tracts, there was a significant interaction with the Trail Making Test (TMT) part A and part B over time. Patients without SH improved on average 16.6 and 15.0% on the TMT-A and TMT-B, respectively. Patients with SH on average showed no improvements in either TMT-A or TMT-B over time. There were no significant differences in other cognitive measures.Conclusion: These results suggest that CAD patients with SH in CH tracts improve less than those without SH in CH tracts, over 48 weeks of cardiac rehabilitation. Thus, SH in CH tracts may contribute to longitudinal cognitive decline following a cardiac event and may represent a vascular risk factor of cognitive decline. © 2017 The Authors. International Journal of Geriatric Psychiatry Published by John Wiley & Sons Ltd. [ABSTRACT FROM AUTHOR]

It has been hypothesized that one mechanism through which physical activity provides benefits to cognition and mood is via increasing brain-derived neurotrophic factor ( BDNF) concentrations. Some studies have reported immediate benefits to mood and various cognitive domains after a single session of exercise. This meta-analysis sought to determine the effect of a single exercise session on concentrations of BDNF in peripheral blood, in order to evaluate the potential role of BDNF in mediating the beneficial effects of exercise on brain health. 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 acute exercise interventions. Risk of bias within studies was assessed using standardized criteria. Standardized mean differences ( SMDs) were generated from random effects models. Risk of publication bias was assessed using a funnel plot and Egger's test. Potential sources of heterogeneity were explored in subgroup analyses. In 55 studies that met inclusion criteria, concentrations of peripheral blood BDNF were higher after exercise (SMD = 0.59, 95% CI: 0.46-0.72, P < 0.001). In meta-regression analysis, greater duration of exercise was associated with greater increases in BDNF. Subgroup analyses revealed an effect in males but not in females, and a greater BDNF increase in plasma than serum. Acute exercise increased BDNF concentrations in the peripheral blood of healthy adults. This effect was influenced by exercise duration and may be different across genders. [ABSTRACT FROM AUTHOR]

Background: Early subtle deficits in verbal memory, which may indicate early neural risk, are common in patients with coronary artery disease (CAD). While exercise can improve cognition, cognitive response to exercise is heterogeneous. Sphingolipids have been associated with the development and progression of CAD, and impairments in sphingolipid metabolism may play roles in neurodegeneration and in the neural adaptation response to exercise.Objective: In this study, change in plasma concentrations of sphingolipids was assessed in relation to change in verbal memory performance and in other cognitive domains among CAD subjects undertaking a 6-month cardiac rehabilitation (CR) program.Methods: Patients with CAD (n = 120, mean age = 64±6 y, 84% male, years of education = 16±3) underwent CR with neuropsychological assessments and blood collected at baseline, 3-, and 6-months. Z-scores based on age, gender, and education were combined for verbal memory, visuospatial memory, processing speed, executive function, and global cognition tasks to calculate cognitive domain Z-scores. Plasma sphingolipid concentrations were measured from fasting blood samples using high performance liquid chromatography coupled electrospray ionization tandem mass spectrometry (LC/MS/MS). Mixed models were used to identify sphingolipids significantly associated with performance in verbal memory and other cognitive domains, adjusting for potential confounders.Results: A decrease in ceramide C18:0 concentration was significantly associated with improvement in verbal memory performance (b[SE] = -0.51 [0.25], p = 0.04), visuospatial memory (b[SE] = -0.44 [0.22], p = 0.05), processing speed (b[SE] = -0.89 [0.32], p = 0.007), and global cognition (b[SE] = -1.47 [0.59], p = 0.01) over 6 months of CR.Conclusions: Plasma ceramide C18:0 concentrations may be a sensitive marker of cognitive response to exercise in patients with CAD. [ABSTRACT FROM AUTHOR]

This study examined associations between lipid peroxidation markers and cognition, and associations between these markers and cognitive response to an exercise intervention program, in adults with coronary artery disease at risk of dementia. Lipid peroxidation products were measured in serum in 118 patients (29 possible vascular mild cognitive impairment and 89 controls). Ratios of early- (lipid hydroperoxides, LPH) to late-stage (8-isoprostane, 8-ISO; 4-hydroxy-2-nonenal, 4-HNE) lipid peroxidation products were calculated. Cognitive performance was assessed before and at completion of a 24-week exercise intervention program. A global effect of group on lipid peroxidation markers was observed, adjusting for sex, years of education, and cardiopulmonary fitness (main effect of group F (3,102) = 2.957, p = 0.036). Lower lipid peroxidation at baseline, as determined by lower 8-ISO concentration, was associated with greater improvement in verbal memory (F (1, 64) = 4.738, p = 0.03) and executive function (F (1, 64) = 5.219, p = 0.026) performance. Similarly, higher ratios of 8-ISO/LPH (F (1, 65) = 6.592, p = 0.013) and (8-ISO+4-HNE) to LPH (F (1, 65) = 3.857, p = 0.054), were associated with less improvement in executive function performance over a 24-week exercise intervention. Lipid peroxidation may be a biomarker of early vascular cognitive impairment, and elevated lipid peroxidation might limit the cognitive benefits of exercise in this high-risk population. [ABSTRACT FROM AUTHOR]

Background: Apathy, one of the most prevalent neuropsychiatric symptoms in Alzheimer's disease (AD), can be difficult to assess as cognition deteriorates. There is a need for more objective assessments that do not rely on patient insight, communicative capacities, or caregiver observation. Objective: We measured visual scanning behavior, using an eye-tracker, to explore attentional bias in the presence of competing stimuli to assess apathy in AD patients. Methods: Mild-to-moderate AD patients (Standardized Mini-Mental Status Examination, sMMSE >10) were assessed for apathy (Neuropsychiatric Inventory [NPI] apathy, Apathy Evaluation Scale [AES]). Participants were presented with 16 slides, each containing 4 images of different emotional themes (2 neutral, 1 social, 1 dysphoric). The duration of time spent, and fixation frequency on images were measured. Results: Of the 36 AD patients (14 females, age = 78.2±7.8, sMMSE = 22.4±3.5) included, 17 had significant apathy (based on NPI apathy ≥4) and 19 did not. These groups had comparable age and sMMSE. Repeated-measures analysis of covariance models, controlling for total NPI, showed group (apathetic versus non-apathetic) by image (social versus dysphoric) interactions for duration (F(1,32) = 4.31, p = 0.046) and fixation frequency (F(1,32) = 11.34, p = 0.002). Apathetic patients demonstrated reduced duration and fixation frequency on social images compared with non-apathetic patients. Additionally, linear regression models suggest that more severe apathy predicted decreasing fixation frequency on social images (R2 = 0.26, Adjusted R2 = 0.19, F(3,32) = 3.65, p = 0.023). Conclusion: These results suggest that diminished attentional bias toward social-themed stimuli is a marker of apathy in AD. Measurements of visual scanning behavior may have the potential to predict and monitor treatment response in apathy. [ABSTRACT FROM AUTHOR]

Every year, approximately 62 000 people with stroke and transient ischemic attack are treated in Canadian hospitals, and the evidence suggests one-third or more will experience vascular-cognitive impairment, and/or intractable fatigue, either alone or in combination. The 2015 update of the Canadian Stroke Best Practice Recommendations: Mood, Cognition and Fatigue Module guideline is a comprehensive summary of current evidence-based recommendations for clinicians in a range of settings, who provide care to patients following stroke. The three consequences of stroke that are the focus of the this guideline (poststroke depression, vascular cognitive impairment, and fatigue) have high incidence rates and significant impact on the lives of people who have had a stroke, impede recovery, and result in worse long-term outcomes. Significant practice variations and gaps in the research evidence have been reported for initial screening and in-depth assessment of stroke patients for these conditions. Also of concern, an increased number of family members and informal caregivers may also experience depressive symptoms in the poststroke recovery phase which further impact patient recovery. These factors emphasize the need for a system of care that ensures screening occurs as a standard and consistent component of clinical practice across settings as stroke patients transition from acute care to active rehabilitation and reintegration into their community. Additionally, building system capacity to ensure access to appropriate specialists for treatment and ongoing management of stroke survivors with these conditions is another great challenge. [ABSTRACT FROM AUTHOR]

The article presents information on the assessment of the validity of a computerized cognitive testing for multiple sclerosis (MS) patients. It states that minimal motor involvement is required for the functioning of the computer-generated cognitive assessment screening battery. In the end of the article the author concludes that computer-generated cognitive screening instrument is ideally efficient for MS clinics.

Abstract: Cognitive dysfunction affects 40–65% of multiple sclerosis (MS) patients. To date, conventional paper and pencil neuropsychological testing has been the method of choice for detecting deficits. However, the expense and lack of access to these tests make it difficult for many patients to obtain an assessment. With the introduction of computerized cognitive testing, certain barriers to assessment can be reduced. This paper critically reviews the currently available computerized batteries, including the Automated Neuropsychology Assessment Matrix (ANAM), the Mindstreams Computerized Cognitive Battery (MCCB), the Amsterdam Neuropsychological Tasks (ANT), the Cognitive Stability Index (CSI), and the Cognitive Drug Research (CDR) battery. Recent developments in this field show promise, although further research is required before this approach can be more widely implemented. [Copyright &y& Elsevier]

Objective: Depression in later life is associated with a two-fold increased risk of dementia. It is not clear to what extent potentially modifiable risk factors account for this association. Method: Older adults (age 50 +) with objective health measures (n = 14,014) from the Canadian Longitudinal Study on Aging were followed for a mean duration of 35 months. Linear regression analyses were used to determine if clinically significant depression (Centre for Epidemiologic Studies Depression scale score (CESD) ≥ 10) was associated with global cognitive decline, assessed with a neuropsychological battery during follow-up, and if modifiable risk factors mediated this association. Results: Depression was associated with an excess of risk factors for cognitive decline including: vascular disease, hypertension, diabetes, apnoea during sleep, higher body mass index, smoking, physical inactivity and lack of social participation. In regression analyses depression remained independently associated with cognitive decline over time (beta −0.060, P = 0.038) as did cerebrovascular disease (beta −0.197, P < 0.001), HbA1C (beta −0.059, P < 0.001), visual impairment (beta −0.070, P = 0.007), hearing impairment (beta −0.098, P < 0.001) and physical inactivity (beta −0.075, P = 0.014). In mediation analyses, we found that cerebrovascular disease (z = −3.525, P < 0.001), HbA1C (z = −4.976, P < 0.001) and physical inactivity (z = −3.998, P < 0.001) partially mediated the association between depression and cognitive decline. Conclusions: In this large sample of Canadian older adults incorporating several objective health measures, older adults with depression were at increased risk of cognitive decline and had an excess of potentially modifiable risk factors. Clinicians should pay particular attention to control of diabetes, physical inactivity and risk factors for cerebrovascular disease in older adults presenting with depression as they can contribute to accelerated cognitive decline and may be addressed during routine clinical care. [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]