Baseline Mini-Mental State Examination Score Research Articles

Finding Treatment Effects in Alzheimer Trials in the Face of Disease Progression Heterogeneity.

ObjectiveTo investigate the influence of heterogeneity in disease progression for detecting treatment effects in Alzheimer disease (AD) trials, using a simulation study.MethodsIndividuals with an abnormal amyloid PET scan, diagnosis of mild cognitive impairment or dementia, baseline Mini-Mental State Examination (MMSE) score ≥24, global Clinical Dementia Rating (CDR) score of 0.5, and ≥1 follow-up cognitive assessment were selected from the Alzheimer's Disease Neuroimaging Initiative database (n = 302, age 73 ± 6.7; 44% female; 16.1 ± 2.7 years of education; 69% APOE ε4 carrier). We simulated a clinical trial by randomly assigning individuals to a “placebo” and “treatment” group and subsequently computed group differences on the CDR–sum of boxes (CDR-SB), Alzheimer’s Disease Assessment Scale–cognitive subscale–13 and MMSE after 18 months follow-up. We repeated this simulation 10,000 times to determine the 95% range of effect sizes. We further studied the influence of known AD risk factors (age, sex, education, APOE ε4 status, CSF total tau levels) on the variability in effect sizes.ResultsIndividual trajectories on all cognitive outcomes were highly variable, and the 95% ranges of possible effect sizes at 18 months were broad (e.g., ranging from 0.35 improvement to 0.35 decline on the CDR-SB). Results of recent anti-amyloid trials mostly fell within these 95% ranges of effect sizes. APOE ε4 carriers and individuals with abnormal baseline tau levels showed faster decline at group level, but also greater within-group variability, as illustrated by broader 95% effect size ranges (e.g., ±0.70 points for the CDR-SB).ConclusionsIndividuals with early AD show heterogeneity in disease progression, which increases when stratifying on risk factors associated with progression. We provide guidance for a priori effect sizes on cognitive outcomes for detecting true change, which is crucial for future AD trials.

Age-at-Onset and APOE-Related Heterogeneity in Pathologically Confirmed Sporadic Alzheimer Disease.

To characterize age-related clinical heterogeneity in Alzheimer disease (AD) and determine whether it is modified by APOE genotype or concomitant non-AD pathology, we analyzed data from 1,750 patients with sporadic, pathologically confirmed severe AD. In this retrospective cohort study, regression and mixed effects models assessed effects of estimated age at onset, APOE genotype, and their interaction on standardized clinical, cognitive, and pathologic outcome measures from the National Alzheimer's Coordinating Center database. A bimodal distribution of age at onset frequency in APOE ε4- cases showed best separation at age 63. Using this age cutoff, cases were grouped as ε4- early-onset AD (EOAD) (n = 169), ε4+ EOAD (n = 273), ε4- late-onset AD (LOAD) (n = 511), and ε4+ LOAD (n = 797). Patients with EOAD were more likely than patients with LOAD to present with noncognitive behavioral or motor symptoms or nonmemory cognitive complaints, and had more executive dysfunction, but less language impairment on objective cognitive testing. Age at onset and ε4- genotype were independently associated with lower baseline Mini-Mental State Examination scores and greater functional impairment and patients with EOAD had faster cognitive and functional decline than patients with LOAD regardless of APOE genotype. Patients with EOAD were more likely than patients with LOAD to receive a non-AD clinical diagnosis even though they were more likely to have pure AD without concomitant vascular or other non-AD neurodegenerative pathology. Early-onset sporadic AD is associated with a greater likelihood of an atypical, non-memory-dominant clinical presentation, especially in the absence of the APOE ε4 allele, which may lead to misattribution to non-AD underlying pathology.

Blood pressure variability is related to faster cognitive decline in ischemic stroke patients: PICASSO subanalysis

Blood pressure variability (BPV) is associated with higher cardiovascular morbidity risks; however, its association with cognitive decline remains unclear. We investigated whether higher BPV is associated with faster declines in cognitive function in ischemic stroke (IS) patients. Cognitive function was evaluated between April 2010 and August 2015 using the Mini-mental State Examination (MMSE) and Montreal Cognitive Assessment in 1,240 Korean PICASSO participants. Patients for whom baseline and follow-up cognitive test results and at least five valid BP readings were available were included. A restricted maximum likelihood–based Mixed Model for Repeated Measures was used to compare changes in cognitive function over time. Among a total of 746 participants (64.6 ± 10.8 years; 35.9% female). Baseline mean-MMSE score was 24.9 ± 4.7. The median number of BP readings was 11. During a mean follow-up of 2.6 years, mean baseline and last follow-up MMSE scores were 25.4 ± 4.8 vs. 27.8 ± 4.4 (the lowest BPV group) and 23.9 ± 5.2 vs. 23.2 ± 5.9 (the highest BPV group). After adjusting for multiple variables, higher BPV was independently associated with faster cognitive decline over time. However, no significant intergroup difference in cognitive changes associated with mean systolic BP was observed. Further research is needed to elucidate how BPV might affect cognitive function.

Effects of linagliptin vs glimepiride on cognitive performance in type 2 diabetes: results of the randomised double-blind, active-controlled CAROLINA-COGNITION study

Aims/hypothesisType 2 diabetes, particularly with concomitant CVD, is associated with an increased risk of cognitive impairment. We assessed the effect on accelerated cognitive decline (ACD) of the DPP-4 inhibitor linagliptin vs the sulfonylurea glimepiride in individuals with type 2 diabetes.MethodsThe CAROLINA-COGNITION study was part of the randomised, double-blind, active-controlled CAROLINA trial that evaluated the cardiovascular safety of linagliptin vs glimepiride in individuals with age ≥40 and ≤85 years and HbA1c 48–69 mmol/mol (6.5–8.5%) receiving standard care, excluding insulin therapy. Participants were randomised 1:1 using an interactive telephone- and web-based system and treatment assignment was determined by a computer-generated random sequence with stratification by center. The primary cognitive outcome was occurrence of ACD at end of follow-up, defined as a regression-based index score ≤16th percentile on either the Mini-Mental State Examination (MMSE) or a composite measure of attention and executive functioning, in participants with a baseline MMSE score ≥24. Prespecified additional analyses included effects on ACD at week 160, in subgroups (sex, age, race, ethnicity, depressive symptoms, cardiovascular risk, duration of type 2 diabetes, albuminuria), and absolute changes in cognitive performance. Participants, caregivers, and people involved in measurements, examinations or adjudication, were all masked to treatment assignment.ResultsOf 6033 participants recruited from hospital and primary care sites, 3163 (38.0% female, mean age/diabetes duration 64/7.6 years, MMSE score 28.5, HbA1c 54 mmol/mol [7.1%]) represent the CAROLINA-COGNITION cohort. Over median 6.1 years, ACD occurred in 27.8% (449/1618, linagliptin) vs 27.6% (426/1545, glimepiride), OR 1.01 (95% CI 0.86, 1.18). Also, no differences in ACD were observed at week 160 (OR 1.07 [0.91, 1.25]), between treatments across subgroups, or for absolute cognitive changes.Conclusions/interpretationIn a large, international outcome trial in people with relatively early type 2 diabetes at elevated cardiovascular risk, no difference in risk for ACD was observed between linagliptin and glimepiride over 6.1 years.FundingThis study was sponsored by Boehringer Ingelheim.Trial registrationClinicalTrials.gov NCT01243424.Graphical abstract

Kidney function and dementia risk in community-dwelling older adults: the Shanghai Aging Study

BackgroundAssociation between kidney dysfunction and dementia has been studied in western cohorts, but with inconsistent conclusions which may be due to the different measurements of kidney function. We aim to verify the hypothesis that lower levels of kidney function would be associated with increased risk of incident dementia in Chinese elderly.MethodsOne thousand four hundred twelve dementia-free participants aged 60 years or older from the Shanghai Aging Study were enrolled and followed up for 5.3 years on average. Glomerular filtration rate (GFR) was calculated by using combined creatinine–cystatin C CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration) equation. Diagnoses of incident dementia and Alzheimer’s disease (AD) were established using DSM-IV and NINCDS-ADRDA criteria based on medical, neurological, and neuropsychological examinations to each participant. Cox proportional regression was used to analyze the association of baseline GFRcrcys levels with incident dementia/AD, adjusting age, gender, education years, APOE-ε4, diabetes, hypertension, baseline Mini-Mental State Examination score, and proteinuria.ResultsA total of 113 (8%) and 84 (7%) participants developed dementia and AD. Comparing to participants with high GFRcrcys (≥ 80 ml/min/1.73 m2), participants with low (< 67 ml/min/1.73 m2) and moderate GFRcrcys (67 ≤ GFR < 80 ml/min/1.73 m2) had increased risk of incident dementia with hazard ratios (HRs) of 1.87 (95% CI 1.02–3.44) and 2.19 (95% CI 1.21–3.95) after adjustment for confounders, respectively. Low (HR = 2.27 [95%CI 1.10–4.68]) and moderate (HR = 2.14 [95% CI 1.04–4.40]) GFRcrcys at baseline was also independently associated with incident AD after adjustments when comparing to high GFRcrcys. The significant association between GFRcrcys and dementia risk was observed in female but not in male participants.ConclusionsGFRcrcys may be considered as a marker of an individual’s vulnerability to the increased risk of cognitive decline.

Change in cognitive function according to cholinesterase inhibitor use and amyloid PET positivity in patients with mild cognitive impairment

BackgroundCholinesterase inhibitors (ChEIs) are an FDA-approved symptomatic treatment for patients with Alzheimer’s disease (AD). Its efficacy in patients with mild cognitive impairment (MCI), however, is controversial. Nonetheless, ChEIs have often been used in patients with MCI. From the perspective that ChEIs were developed based on the pathomechanism of AD, the effect of ChEIs in MCI patients could be different depending on the amyloid burden. In this retrospective observational study, we aimed to investigate the influence of ChEIs and amyloid burden on cognitive change for 1 year in patients with MCI.MethodsWe included 111 patients with MCI with a Clinical Dementia Rating (CDR) score of 0.5, a 1-year follow-up cognitive assessment, and amyloid positron emission tomography (PET) performed within 6 months before or after the baseline cognitive assessment (73 ChEI users and 38 ChEI non-users) from the Neurocognitive Behavior Center of Seoul National University Bundang Hospital. Additionally, those who had a positive amyloid PET scan more than 6 months before the baseline cognitive assessment and those who had a negative amyloid PET scan more than 6 months after the 1-year follow-up cognitive assessment were also included. Among the total 111 patients, 25 ChEI users and 25 ChEI non-users were matched by baseline Mini-Mental State Examination (MMSE) score, age, educational level, CDR Sum of Boxes, and amyloid PET positivity using propensity score matching. Multiple linear regression analysis was performed to assess the influence of ChEI use and amyloid PET positivity on cognitive change for 1 year. Univariate and multivariate logistic regression analyses were performed to evaluate the association between ChEI use and disease progression to CDR 1 at the 1-year follow-up visit.ResultsChEI use or non-use was not associated with cognitive change for 1 year. Amyloid PET positivity or negativity did not change this non-association. Furthermore, progression to CDR 1 was related to low baseline MMSE score (OR 0.606, CI 0.381–0.873), but not with ChEI use or non-use, and not with amyloid PET result.ConclusionChEI use or non-use was not related to cognitive change at a 1-year follow-up visit in patients with or without amyloid burden. In addition, ChEI use or non-use could not predict disease progression to CDR 1 at 1-year follow-up visit.

Factors associated with slow progression of cognitive impairment following first dementia diagnosis.

To investigate the extent to which slow progression of dementia after diagnosis might be predicted from routine longitudinal healthcare data, in order to clarify characteristics of people who experience this outcome. A retrospective observational study was conducted using data from the South London and Maudsley NHS Foundation Trust Biomedical Research Centre Case Register. This study included all patients receiving a first dementia diagnosis between 2006 and 2017, restricted to those with a baseline Mini-Mental State Examination (MMSE) score within 6 months of initial diagnosis of dementia and at least one MMSE score after 3 years post-diagnosis. Slow progression was defined as a change in MMSE score of -1, 0 or an increase at the follow-up point. This group was compared to the remainder with an MMSE decline of -2 or more. Overall, 682 patients with slow progression were compared to 1045 with faster progression. In the confounder-adjusted multivariate logistic regression model, slow progression was more likely in younger patients (age 65-74 years; odds ratio: 1.18; 95% confidence intervals: 1.04-1.37), males (1.24; 1.01-1.53), those with moderate or severe dementia according to MMSE, patients with mixed-type dementia (2.06; 1.11-3.82) compared to Alzheimer's disease and less likely in those receiving acetylcholinesterase inhibitor (AChEI) treatment (0.57; 0.46-0.71). Slow dementia progression after diagnosis was common in patients with mixed Alzheimer's and vascular dementia, younger age, males and non-receipt of AChEIs, possibly suggesting non-Alzheimer pathologies and clarifying such predictors is important, as there is currently very limited information on which to base prognosis estimates in post-diagnosis counselling.

Evaluation of the Mini-Mental State Examination and the Montreal Cognitive Assessment for Predicting Post-stroke Cognitive Impairment During the Acute Phase in Chinese Minor Stroke Patients

Objective: To assess the value of the Mini-Mental State Examination (MMSE) and the Montreal Cognitive Assessment (MoCA) during acute phase in predicting post-stroke cognitive impairment (PSCI) at 3–6 months.Methods: We prospectively recruited 229 patients who had suffered their first-ever ischemic stroke. PSCI was determined in 104 of these patients by a comprehensive neuropsychological battery performed at 3–6 months. Receiver operating characteristic (ROC) curve analysis was then performed to compare the discriminatory ability of the MMSE and MoCA. Also, we applied a decision tree generated by the classification and regression tree methodology.Results: In total, 66 patients had PSCI when evaluated 3–6 months after the onset of minor stroke. Logistic regression analysis revealed that education, body mass index (BMI), and baseline MoCA scores were independently associated with PSCI. ROC curve analysis showed that the ability to predict PSCI was similar when compared between baseline MoCA scores [area under curve (AUC), 0.821; 95% confidence interval (CI), 0.743–0.898] and baseline MMSE scores (AUC, 0.809; 95% CI, 0.725–0.892, P = 0.75). Both MMSE and MoCA exhibited similar predictive values at their optimal cut-off points (MMSE ≤27; sensitivity, 0.682; specificity, 0.816; MoCA ≤21; sensitivity, 0.636; specificity, 0.895). Classification and regression tree-derived analysis yielded an AUC of 0.823 (sensitivity, 0.803; specificity, 0.842).Conclusion: When applied within 2 weeks of stroke, the MMSE and MoCA are both useful and have similar predictive value for PSCI 3–6 months after the onset of minor stroke.

Trajectories of cognitive function and their determinants in older people: 12 years of follow-up in the Chinese Longitudinal Healthy Longevity Survey.

Cognitive decline in advanced age is closely related to dementia. The trajectory of cognitive function in older Chinese is yet to be fully investigated. We aimed to investigate the trajectories of cognitive function in a nationally representative sample of older people living in China and to explore the potential determinants of these trajectories. This study included 2,038 cognitively healthy persons aged 65-104 years at their first observation in the Chinese Longitudinal Healthy Longevity Survey from 2002 to 2014. Cognitive function was measured using the Chinese version of the Mini-Mental State Examination (MMSE). Group-based trajectory modeling was used to identify potential heterogeneity of longitudinal changes over the 12 years and to investigate associations between baseline predictors of group membership and these trajectories. Three trajectories were identified according to the following types of changes in MMSE scores: slow decline (14.0%), rapid decline (4.5%), and stable function (81.5%). Older age, female gender, having no schooling, a low frequency of leisure activity, and a low baseline MMSE score were associated with the slow decline trajectory. Older age, body mass index (BMI) less than 18.5 kg/m2, and having more than one cardiovascular disease (CVD) were associated with the rapid decline trajectory. Three trajectories of cognitive function were identified in the older Chinese population. The identified determinants of these trajectories could be targeted for developing prevention and intervention strategies for dementia.

Longitudinal Maintenance of Cognitive Health in Centenarians in the 100-plus Study

Some individuals who reach ages beyond 100 years in good cognitive health may be resilient against risk factors associated with cognitive decline. Exploring the processes underlying resilience may contribute to the development of therapeutic strategies that help to maintain cognitive health while aging. To identify individuals who escape cognitive decline until extreme ages and to investigate the prevalence of associated risk factors. The 100-plus Study is a prospective observational cohort study of community-based Dutch centenarians enrolled between 2013 and 2019 who were visited annually until death or until participation was no longer possible. The centenarians self-reported their cognitive health, as confirmed by a proxy. Of the 1023 centenarians approached for study inclusion, 340 fulfilled the study criteria and were included in analyses. Data analysis was performed from April 2019 to December 2019. Cognition was assessed using the Mini-Mental State Examination (MMSE). To identify centenarians who escape cognitive decline, this study investigated the association of baseline cognition with survivorship and cognitive trajectories for at least 2 years of follow-up using linear mixed models, adjusted for sex, age, and education. This study investigated the prevalence of apolipoprotein E (APOE) genotypes and cardiovascular disease as risk factors associated with cognitive decline. At baseline, the median age of 340 centenarians was 100.5 years (range, 100.0-108.2 years); 245 participants (72.1%) were female. The maximum survival estimate plateaued at 82% per year (95% CI, 77% to 87%) across centenarians who scored 26 to 30 points on the baseline MMSE (hazard ratio, 0.56; 95% CI, 0.42 to 0.75; P < .001), suggesting that an MMSE score of 26 or higher is representative of both cognitive and physical health. Among the 79 centenarians who were followed up for 2 years or longer, those with baseline MMSE score less than 26 experienced a decline in MMSE score of 1.68 points per year (95% CI, -2.45 to -0.92 points per year; P = .02), whereas centenarians with MMSE scores of 26 or higher at baseline experienced a decline of 0.71 point per year (95% CI, -1.08 to -0.35 points per year). For 73% of the centenarians with baseline MMSE scores of 26 or higher, no cognitive changes were observed, which often extended to ensuing years or until death. It is estimated that this group is representative of less than 10% of Dutch centenarians. In this group, 18.6% carried at least 1 APOE-ε4 allele, compared with 5.6% of the centenarians with lower and/or declining cognitive performance. Most centenarians who scored 26 or higher on the MMSE at baseline maintained high levels of cognitive performance for at least 2 years, in some cases despite the presence of risk factors associated with cognitive decline. Investigation of this group might reveal the processes underlying resilience against risk factors associated with cognitive decline.

Utilization Patterns of Amantadine in Parkinson's Disease Patients Enrolled in the French COPARK Study.

Immediate-release (IR) amantadine has been marketed for Parkinson's disease (PD) therapy for 50 years, while two novel extended-release formulations have only recently reached the market in the US. The aim of this study was to describe amantadine IR utilization patterns in the French COPARK cohort, at baseline and after 2 years of follow-up. Overall, 683 PD patients from the COPARK survey were evaluated. All patients were assessed in a standardized manner (demographics, treatments, Unified Parkinson's Disease Rating Scale [UPDRS], Hospital Anxiety and Depression Scale, Pittsburg Questionnaire and health-related quality-of-life scales (Short Form-36 [SF-36], 39-item Parkinson's Disease Questionnaire [PDQ-39]). Longitudinal data were only available for 401/683 patients (59%) with a median (P25-75) follow-up period of 23 months (18-31). Patients were assessed in the same way as in the baseline visit. At baseline, amantadine was prescribed to 61/683 (9%) patients (median dose 200 mg/day, range 100-300mg/day). Amantadine was initiated after a median of 7 years from PD diagnosis, and its prescription was correlated with the presence of dyskinesia (logistic regression odds ratio [OR] 3.72, 95% confidence interval [CI] 1.95-7.08) and hallucinations (UPDRS I.2) [OR 1.57, 95% CI 1.08-2.29]. After 2 years, the amantadine prescription increased from 33 (8%) patients at baseline to 54 (14%) patients in the subset of 401 patients analysed twice (p=0.001). Among the 33 patients receiving amantadine at baseline, 9 (27%) stopped amantadine, 5 (15%) increased the dose, 6 (18%) reduced the dose and 13 (40%) stayed at the same doses. Treatment was initiated in 30/54 new patients (55%). Patients who started amantadine or increased its dose (n=35) had more levodopa-induced dyskinesias at baseline (OR 7.02, 95% CI 3.09-15.90) and higher Mini-Mental State Examination score at follow-up (OR 1.37, 95% CI 1.06-1.79). Undergoing deep brain stimulation was related to stopping or downtitrating amantadine (OR 22.02, 95% CI 4.24-114.44; n=15). In this cohort, amantadine was used in 10% of patients. Its use increased during follow-up, despite the fact that one-third of patients who received amantadine at baseline stopped taking it. Amantadine prescription was mainly correlated with the presence of dyskinesia.

Association between cognitive decline and oral health status in the aging population of Nagpur City: A prospective study

Background: Till date, no longitudinal prospective study has investigated the association between the oral health status and cognitive decline in the geriatric population, possibly due to past studies differing in target groups and methodologies. We aimed to investigate the association between tooth loss, as evaluated through clinical oral examinations, and the development of cognitive decline in the older adults while considering baseline cognitive function. Objectives: The purpose of this study is to find the association between oral health status and the subsequent development of cognitive decline in older adults of Nagpur, Maharashtra state while considering baseline cognitive function. Materials and Methods: This 1-year prospective cohort study followed 140 participants without cognitive impairment aged ≥65 years (mean age: 70.9 ± 4.3 years) living in the Nagpur, Maharashtra. Cognitive function was evaluated with the Mini-Mental State Examination (MMSE) in the baseline and follow-up surveys, whereas oral health examination was carried out using Oral Hygiene Index to investigate the association between oral health status and cognitive decline, we applied a multiple logistic regression analysis adjusted for age, gender, hypertension, diabetes, cerebrovascular/cardiovascular disease, hypercholesterolemia, depressive symptoms, body mass index, smoking status, drinking status, duration of education, and baseline MMSE score. Results: In 1 year after the baseline survey, we have obtained an overall incidence of 20.71%. population who developed cognitive decline (i.e., MMSE scores of ≤24). Multivariable logistic regression analysis indicated that participants with compromised oral health were more likely to develop cognitive decline than those with mild-to-moderate oral health were (odds ratio: 3.31; 95% confidence interval: 1.07–10.2). Age: 1.15 (1.04–1.31), male gender: 4.65 (1.27–16.4), and baseline MMSE scores: 0.49 (0.32–0.75) were also significantly associated with cognitive decline. Conclusion: Poor oral health status was independently associated with the development of cognitive decline within 5 years among the geriatric population of Nagpur. This finding corroborates the hypothesis that oral health may be a predictor or risk factor for cognitive decline.

A precision medicine framework using artificial intelligence for the identification and confirmation of genomic biomarkers of response to an Alzheimer's disease therapy: Analysis of the blarcamesine (ANAVEX2-73) Phase 2a clinical study.

IntroductionThe search for drugs to treat Alzheimer's disease (AD) has failed to yield effective therapies. Here we report the first genome‐wide search for biomarkers associated with therapeutic response in AD. Blarcamesine (ANAVEX2‐73), a selective sigma‐1 receptor (SIGMAR1) agonist, was studied in a 57‐week Phase 2a trial (NCT02244541). The study was extended for a further 208 weeks (NCT02756858) after meeting its primary safety endpoint.MethodsSafety, clinical features, pharmacokinetic, and efficacy, measured by changes in the Mini‐Mental State Examination (MMSE) and the Alzheimer's Disease Cooperative Study‐Activities of Daily Living scale (ADCS‐ADL), were recorded. Whole exome and transcriptome sequences were obtained for 21 patients. The relationship between all available patient data and efficacy outcome measures was analyzed with unsupervised formal concept analysis (FCA), integrated in the Knowledge Extraction and Management (KEM) environment.ResultsBiomarkers with a significant impact on clinical outcomes were identified at week 57: mean plasma concentration of blarcamesine (slope MMSE:P < .041), genomic variants SIGMAR1 p.Gln2Pro (ΔMMSE:P < .039; ΔADCS‐ADL:P < .063) and COMT p.Leu146fs (ΔMMSE:P < .039; ΔADCS‐ADL:P < .063), and baseline MMSE score (slope MMSE:P < .015). Their combined impact on drug response was confirmed at week 148 with linear mixed effect models.DiscussionConfirmatory Phase 2b/3 clinical studies of these patient selection markers are ongoing. This FCA/KEM analysis is a template for the identification of patient selection markers in early therapeutic development for neurologic disorders.

Incidence of postoperative cognitive dysfunction after simultaneous carotid surgery and coronary artery bypass grafting in patients with asymptomatic cerebral atherosclerosis

To evaluate the incidence of early postoperative cognitive dysfunction (POCD) after simultaneous carotid surgery and coronary artery bypass grafting (CABG) in patients with asymptomatic cerebral atherosclerosis. Fifty-three patients with polyvascular disease and asymptomatic cerebral atherosclerosis undergoing simultaneous unilateral carotid endarterectomy (CEE) and CABG were recruited in the study. Core cognitive functions were assessed with the Mini Mental State Examination (MMSE) and Frontal Assessment Battery (FAB) at days 2-3 before the indexed surgery and at days 7-10 after it. All the patients were assigned to two groups based on the baseline MMSE score: one group with mild cognitive impairment (MCI) and another one without MCI. Neurodynamic measurements were performed using the Status-PF hardware-software complex (certificate #2001610233 of the Russian Agency for Patents and Trademarks), followed by the calculation of the integral indicator of the main cognitive domains according to the corresponding algorithms. Attention, memory and neurodynamics were evaluated in all participants. POCD was diagnosed with a decrease from the initial indicators of memory, attention and neurodynamics by 20% in 20% of the tests. Patients had complications in the early postoperative period, regardless of the presence of MCI. A decline among the core cognitive functions was observed in both groups of patients at days 7-10 after the surgery. Patients demonstrated an increase in the reaction time while performing neurodynamic test battery compared with the baseline values. Alterations in memory and attention were not significant. Significant changes in the integral indicator of cognitive status were determined in both groups of patients. It increased by 14% in patients without MCI (0.34±0.2 in the preoperative period vs. 0.39±0.3 in the postoperative period, p=0.04), and by 36% in patients with MCI (0.25±0.19 vs. 0.39±0.3, p=0.003). Regardless of the presence or absence of MCI, all patients had low cognitive status or even that below the average in the perioperative period. Despite the increase in the average values of cognitive status indicators in the postoperative period, 56% of patients (n=14) without MCI and 71% of patients with MCI (n=20) had early POCD. Patients with polyvascular disease, regardless of the presence of MCI, had low cognitive status or even that below the average, probably contributing to the elimination of the expected positive effects of CEE. The absence of MCI at baseline does not guarantee the preservation of cognitive status after surgery. Patients with polyvascular disease after myocardial and cerebral revascularization remain at high risk of exacerbating cognitive impairment, and, therefore, require an individual approach and a reasonable choice of the optimal surgical strategy.

Safety and tolerability of GRF6019 in mild-to-moderate Alzheimer's disease dementia.

IntroductionThis phase 2 trial evaluated the safety, tolerability, and feasibility of repeated infusions of the plasma fraction GRF6019 in mild‐to‐moderate Alzheimer's disease.MethodsIn this randomized, double‐blind, dose‐comparison trial, 47 patients were randomized 1:1 to receive daily infusions of 100 mL (n = 24) or 250 mL (n = 23) of GRF6019 for 5 consecutive days over two dosing periods separated by a treatment‐free interval of 3 months.ResultsThe mean (standard deviation [SD]) age of the enrolled patients was 74.3 (6.9), and 62% were women. Most adverse events (55%) were mild, with no clinically significant differences in safety or tolerability between the two dose levels. The mean (SD) baseline Mini‐Mental State Examination score was 20.6 (3.7) in the 100 mL group and 19.6 (3.7) in the 250 mL group; at 24 weeks, the within‐patient mean change from baseline was –1.0 points (95% confidence interval [CI], –3.1 to 1.1) in the 100 mL group and +1.5 points (95% CI, –0.4 to 3.3) in the 250 mL group. The within‐patient mean change from baseline on the Alzheimer's Disease Assessment Scale‐Cognitive subscale was –0.4 points (95% CI, –2.9 to 2.2) in the 100 mL group, while in the 250 mL group it was –0.9 points (95% CI, –3.0 to 1.2). The within‐patient mean change from baseline on the Alzheimer's Disease Cooperative Study‐Activities of Daily Living was –0.7 points in the 100 mL group (95% CI, –4.3 to 3.0) and –1.3 points (95% CI, –3.4 to 0.7) in the 250 mL group. The mean change from baseline on the Category Fluency Test, Clinical Dementia Rating Scale–Sum of Boxes, Alzheimer's Disease Cooperative Study–Clinical Global Impression of Change, and Neuropsychiatric Inventory Questionnaire was similar for both treatment groups and did not show any worsening.DiscussionGRF6019 was safe and well tolerated, and patients experienced no cognitive decline and minimal functional decline. These results support further development of GRF6019.

Post-stroke cognitive impairment as an independent predictor of ischemic stroke recurrence: PICASSO sub-study.

To devise appropriate preventive strategies after stroke, knowledge of the association between post-stroke cognitive impairment (PSCI) and prognosis of stroke patients is important. We investigated the association between PSCI and the vascular outcomes in patients with ischemic stroke with best medical care considering their risk factors and adherence to medications. Of the 1534 ischemic stroke patients who randomly assigned to aspirin or cilostazol treatment with best medical therapy by the PICASSO (PreventIon of CArdiovascular events in iSchemic Stroke patients with high risk of cerebral hemOrrhage) trial, 1240 with baseline mini-mental state examination (MMSE) scores were analysed retrospectively. The patients were classified into three groups based on MMSE scores. Recurrence of ischemic stroke, stroke of any type and composite of major vascular events were compared among them. Of the 1240 patients, 376 had MMSE scores of 28-30 (highest tertile), 419 had scores of 24-27 (middle tertile) and 445 had scores of 0-23 (lowest tertile). The average time from stroke onset to MMSE examination was 31.8days. By trend analysis, lower tertile of MMSE score was significantly associated with recurrent ischemic stroke (p = 0.0017), stroke of any type (p = 0.0053) and composite vascular outcome (p = 0.0122). After adjustment for covariates, PSCI was independently associated with risk of recurrent ischemic stroke (HR 2.40, 95% confidence interval 1.12-5.14). Cognitive impairment was associated with recurrence of ischemic stroke in high risk patients during adequate medical therapy including antiplatelet therapy. However, the other vascular events were not.

Memory Complaint Is a Surrogate for Memory Decline in the Middle-Aged: A Register-Based Study.

Memory complaint is one of the earliest symptoms of dementia. The causes and prognosis of memory complaint in the middle-aged population remain largely unknown. We reviewed the register-based data of 2129 patients with memory complaints. Among them, 404 participants were between 40 and 65 years old. The participants were separated into three groups: subjective cognitive decline (SCD), neurodegenerative diseases (ND), and non-neurodegenerative diseases (NND). One-year decline was defined as a decrease of ≥1 on the mini-mental state examination (MMSE). At baseline, 131 participants (32%) were diagnosed with SCD, 141 (35%) with ND, and 132 (33%) with NND. The 1-year cognitive decline rate was higher among patients with ND (36.8%) than in the SCD (7.3%, p = 1.3 × 10−8) and NND groups (7.6%, p = 1.1 × 10−7). One-year decline did not differ between the SCD and NND groups. Lower baseline MMSE score predicted increased risk of 1-year cognitive decline (odds ratio (OR) = 1.126, 95% confidence interval (CI) = 1.076–1.178, p = 2.52 × 10−7). Memory complaint in middle age carried a risk of 1-year cognitive decline, and baseline MMSE is an independent predictor of decline. An initial diagnosis of SCD held the same risk effect for decline as NND. These findings highlighted the necessity for neuropsychological tests in those with memory complaints presenting to the clinic.

Increased CSF tau is associated with a higher risk of seizures in patients with Alzheimer's disease

IntroductionNeurofibrillary tangles and tau protein, the neuropathological hallmarks of Alzheimer's disease (AD), have been identified in patients with epilepsy. Tau protein was also associated with the modulation of neuronal excitability in animal models of AD. Materials and methodsWe evaluated in 292 patients with AD the association between the risk of seizure development and AD cerebrospinal fluid (CSF) biomarkers, demographic characteristics, baseline Mini-Mental State Examination (MMSE) score, comorbidities, and apolipoprotein E status. ResultsThe development of seizures was associated with younger age at dementia's onset, lower baseline MMSE, and higher CSF total tau protein levels, but only MMSE (hazard ratio [HR] = 0.935; 95% confidence interval [CI] = [0.903, 0.968]; p < 0.001) and CSF tau (HR = 1.001; 95%CI = [1.001, 1.002]; p = 0.001) were independent predictors on multivariate analysis. DiscussionWhile CSF tau and lower baseline MMSE association with seizure development could in part be explained by a greater degree of cortical damage, the role of tau in the modulation of neuronal excitability may also play a role and should be further investigated.

The effect of cognitive function on mobility improvement among community-living older adults: A 12-week resistance exercise intervention study

ABSTRACT The purpose of the study was to investigate the association between baseline cognitive function and improvement in mobility after 12 weeks of resistance training (3 times/week; 3 sets, 6-8 repetitions at 75-80% of the 1-repetition maximum) among community-dwelling older adults in Iceland (N=205, 73.5±5.7 years, 57.0% female). Body composition, physical activity status, cardiovascular risk factors, 6-minute walk test (6MWT), and Mini-Mental State Examination (MMSE) were measured. The linear regression model was used to examine the association between baseline MMSE and mobility improvement. Mean distance of 6MWT was 462.8±71.6 meter at baseline and mean change after the exercise intervention was 33.7±34.9 meter. The mean MMSE score at baseline was 27.6±1.9. After adjusting for baseline covariates, we found that baseline MMSE score was significantly associated with improvement in mobility among older adults after the exercise intervention. Cognitive function strongly influences the effect of exercise intervention on mobility among older adults.

White Matter Hyperintensities Predict Cognitive Decline: A Community-Based Study.

White matter hyperintensities (WMHs) were commonly seen in brain magnetic resonance imaging (MRI) of the elderly. Many studies found that WMHs were associated with cognitive decline and dementia. However, the association between WMHs in different brain regions and cognitive decline remains debated. We explored the association of the severity of WMHs and cognitive decline in 115 non-demented elderly (≥50 years old) sampled from the Wuliqiao Community located in urban area of Shanghai. MRI scans were done during 2009-2011 at the beginning of the study. Severity of WMHs in different brain regions was scored by Improved Scheltens Scale and Cholinergic Pathways Hyperintensities Scale (CHIPS). Cognitive function was evaluated by Mini-Mental State Examination (MMSE) every 2 to 4 years during 2009-2018. After adjusting for confounding factors including age, gender, education level, smoking status, alcohol consumption, depression, hypertension, diabetes, hyperlipidemia, brain infarcts, brain atrophy, apoE4 status, and baseline MMSE score, periventricular and subcortical WMH lesions as well as WMHs in cholinergic pathways were significantly associated with annual MMSE decline ( p &lt; 0.05), in which the severity of periventricular WMHs predicted a faster MMSE decline (-0.187 points/year, 95% confidence interval: -0.349, -0.026, p = 0.024). The severity of WMHs at baseline was associated with cognitive decline in the non-demented elderly over time. Interventions on WMH lesions may offer some benefits for cognitive deterioration.