Baseline Mini-Mental State Examination Research Articles

Cognitive and functional progression along the continuum from mild cognitive impairment (MCI) to Alzheimer’s disease (AD): A latent class analysis using the U.S. National Alzheimer’s Coordinating Center (NACC) data set

AbstractBackgroundThe trajectory of AD progression is heterogeneous between individuals, and the predictors of cognitive and functional decline associated with rapid progression remain poorly understood. Better understanding of the cognitive and functional trajectories and predictors of decline is critical for articulating the natural history of the disease, identifying subgroups of individuals with MCI at higher risk of developing dementia, and contextualizing clinical trial data for AD treatments.MethodSubjects newly diagnosed with MCI in the NACC uniform data set from September 2005 to February 2019 were identified. Cognition and function were measured by the Clinical Dementia Rating‐Sum of Boxes (CDR‐SB). CDR‐SB score trajectories were fitted using a linear multi‐step growth mixture model, which was then used to identify three latent classes of subjects based on the similarity of progression patterns. Multivariate multinomial logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs) for baseline predictors across the latent classes.ResultOf 830 subjects included in the study sample, 42% were male, and the median age was 79.0 years. Median CDR‐SB at the time of MCI diagnosis was 0.5 (interquartile range=0.5–1.0; Table). Average follow‐up after initial MCI diagnosis was 3.6 years (standard deviation=2.5). Subjects were classified in three latent classes with differing CDR‐SB trajectories: fast progressors (21% of sample; average CDR‐SB increase=1.87 points/year), slow progressors (22%; average CDR‐SB increase=0.51 points/year), and non‐progressors (57%; no CDR‐SB increase) (Figure). Independent factors at MCI diagnosis associated with fast progressors vs non‐progressors were: older age (OR 1.04, 95% CI 1.01–1.07), female sex (2.00, 1.23–3.23), one copy of apo ε4 (1.89, 1.18–3.02), higher baseline CDR‐SB score (3.20, 2.25–4.54), and lower baseline Mini Mental State Examination (MMSE) score (0.89, 0.81–0.98).ConclusionIn this NACC‐based study, three latent classes of subjects were identified based on CDR‐SB progression trajectories. Older age, female sex, one copy of apo ε4, and worse baseline cognitive scores (CDR‐SB and MMSE) were associated with faster progression on CDR‐SB.

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.

Early-start vs delayed-start donepezil against cognitive decline in Parkinson disease: a randomized clinical trial

ABSTRACT Background Cholinergic neurotransmission regulates neuroinflammation in Parkinson disease (PD). Research design and methods The authors conducted a delayed-start study of donepezil for cognitive decline in non-demented PD patients. The study consisted of a 96-week randomized placebo-controlled double-blind phase 1, followed by a 24-week donepezil extension phase 2. The primary outcome measure was a change in the Mini-Mental State Examination (MMSE) at week 120. Results A total of 98 patients were randomly allocated to the early-start (donepezil-to-donepezil) and delayed-start (placebo-to-donepezil) groups. Mean (SD) of the baseline MMSE was 27.6 (2.0) and 28.0 (2.1), respectively. MMSE change at week 120 was better in the early-start group than in the delayed-start group, but the difference was not significant. The MMSE declined in apolipoprotein ε4 carriers, but not in non-carriers, and the factor interaction (intervention × ε4 genotype) was highly significant (P < 0.001). Analyzed with the interaction, the difference was significant (group difference 1.95 [0.33 to 3.57], P = 0.018). The MMSE decline slope in phase 1 was significantly better in the early-start group than in the delayed-start group (P = 0.048). Conclusions Cognitive function deteriorated in ε4 carriers, but not in non-carriers, and early-start donepezil may postpone cognitive decline in the former.

Predicting rate of cognitive decline at baseline using a deep neural network with multidata analysis.

Purpose: Our study investigates whether a machine-learning-based system can predict the rate of cognitive decline in mildly cognitively impaired patients by processing only the clinical and imaging data collected at the initial visit. Approach: We built a predictive model based on a supervised hybrid neural network utilizing a three-dimensional convolutional neural network to perform volume analysis of magnetic resonance imaging (MRI) and integration of nonimaging clinical data at the fully connected layer of the architecture. The experiments are conducted on the Alzheimer's Disease Neuroimaging Initiative dataset. Results: Experimental results confirm that there is a correlation between cognitive decline and the data obtained at the first visit. The system achieved an area under the receiver operator curve of 0.70 for cognitive decline class prediction. Conclusion: To our knowledge, this is the first study that predicts "slowly deteriorating/stable" or "rapidly deteriorating" classes by processing routinely collected baseline clinical and demographic data [baseline MRI, baseline mini-mental state examination (MMSE), scalar volumetric data, age, gender, education, ethnicity, and race]. The training data are built based on MMSE-rate values. Unlike the studies in the literature that focus on predicting mild cognitive impairment (MCI)-to-Alzheimer's disease conversion and disease classification, we approach the problem as an early prediction of cognitive decline rate in MCI patients.

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.

The contribution of vascular risk factors in neurodegenerative disorders: from mild cognitive impairment to Alzheimer\u2019s disease

BackgroundOptimization of vascular risk factor control is emerging as an alternative approach to improve cognitive outcomes in Alzheimer’s disease, although its efficacy is still under debate. We aimed to investigate the contribution of vascular risk factors on Alzheimer’s biomarkers and conversion rate to dementia in subjects with mild cognitive impairment (MCI) with low cerebral small vessel disease burden.MethodsTwo hundred ninety-five newly diagnosed MCI subjects were enrolled from March 2005 to May 2017 for a cross-sectional assessment of vascular risk factors and Alzheimer’s plasma and imaging biomarkers, followed by a cognitive outcome assessment 24 months after enrollment. The association between vascular risk factors and Alzheimer’s biomarkers were tested using multivariable linear regression models adjusted with age, gender, education, and APOE ε4 allele. The association between vascular risk factors and conversion to dementia was tested using multivariable logistic regression models adjusted with age, gender, education, and baseline Mini-Mental State Examination (MMSE) score.ResultsAt baseline, higher low-density lipoprotein (LDL) cholesterol level was associated with more advanced plasma biomarkers, including Aβ42/Aβ40 ratio (P = 0.012) and tau level (P = 0.001). A history of hypertension was associated with more advanced white matter hyperintensity (P = 0.011), while statin therapy for dyslipidemia was associated with less advanced white matter hyperintensity (P = 0.002). At 24 months, individual vascular risk factor was not significantly associated with cognitive outcome. By contrast, statin therapy for dyslipidemia was associated with reduced conversion to dementia (adjusted OR = 0.191, 95% CI = 0.062~0.586, P = 0.004).ConclusionsFor MCI subjects, dyslipidemia may contribute to AD-related neurodegeneration while hypertension may contribute to vascular pathology. The association between statin therapy for dyslipidemia and reduced conversion to dementia supports further interventional study to evaluate the potential beneficial effect of statin in MCI subjects.

Hippocampal sclerosis, TDP-43, and the duration of the symptoms of dementia of AD patients.

ObjectivesTo examine the relationship between duration of the cognitive symptoms, from the earliest reported symptom to death, and hippocampal sclerosis (HS) and TAR‐DNA binding protein of 43kDA (TDP‐43) in Alzheimer’s disease (AD) patients.MethodsThe study was conducted in 359 cognitively impaired patients who met the pathological criteria for AD (NIA‐Reagan intermediate or high). The mean age at onset was 69.5 ± 8.8 years (range 37‐95) and the mean duration of the symptoms was 10.5 ± 4.2 years. The association between symptoms duration and HS and TDP‐43 was examined with logistic regression analyses controlling for age at death, atherosclerosis in the Circle of Willis (CW), cerebral infarcts, gender, baseline Mini Mental State Examination scores, APOE‐4 allele, and presence of Lewy bodies (LB).ResultsHS was present in 18% (n = 64) and TDP‐43 in 51.5% (n = 185) of the patients. HS and TDP‐43 were more frequent in patients whose symptoms lasted more than 10 years. LBs were present in 72% of the patients with HS and in 64% of the patients with TDP‐43. Age at onset was not associated with TDP‐43 or HS. HS was associated with duration of symptoms and LB, TDP‐43, and atherosclerosis in the CW. TDP‐43 was associated with duration of symptoms, LB, and HS.InterpretationHS and TDP‐43 are present in early and late onset AD. However, their presence is mainly driven by the duration of symptoms and the presence of LB. This suggests that HS and TDP‐43 are part of the later neuropathological changes in AD.

Preoperative Frailty Predicts Postoperative Neurocognitive Disorders After Total Hip Joint Replacement Surgery.

Frailty is a reduced capacity to recover from a physiologically stressful event. It is well established that preoperative frailty is associated with poor postoperative outcomes, but it is unclear if this includes cognitive decline following anesthesia and surgery. This retrospective observational study was a secondary analysis of data from a previous study (the Anaesthesia, Cognition, Evaluation [ACE] study). We aimed to identify if preoperative frailty or prefrailty is associated with preoperative and postoperative neurocognitive disorders or postoperative cognitive dysfunction. The ACE study enrolled 300 participants aged ≥60 scheduled for elective total hip joint replacement and who underwent a full neuropsychological assessment at baseline and 3 and 12 months postoperatively. We applied patient data to 2 frailty models; both were based on an accumulation of deficits score: the reported Edmonton frail scale (REFS) and the comprehensive geriatric assessment-frailty index (CGA-FI) based on the comprehensive geriatric assessment. We calculated these 2 scores using baseline data collected from the medical history, demographic and clinical data as well as self-reported questionnaires. Some items on the REFS (3 of 18 or 17%) and the CGA-FI (37 of 51 or 27%) did not have an equivalent item in the ACE data. The mean age (standard deviation [SD]) was 70.1 years (6.6) with more women (197 [66%]). Using the REFS model, 40 of 300 (13.3%) patients were classified as vulnerable, mild, or moderately frail. Using the CGA-FI model, 69 of 300 (23%) were classified as intermediate or high frailty. The REFS and the CGA-FI were strongly correlated (r = 0.75; P < .01) with 34 of 300 (11%) meeting criteria for frailty by both the REFS and the CGA-FI.Frailty or prefrailty was associated with cognitive decline at 3 and 12 months using the REFS (odds ratio [OR], 1.51, 95% confidence interval [CI], 1.02-2.23 and OR, 2.00, 95% CI, 1.26-3.17, respectively) after adjusting for baseline mini-mental state examination (MMSE), smoking, hypertension, diabetes, history of acute myocardial infarction (AMI), and estimated intelligence quotient (IQ). Age did not modify this association. After adjusting for multiple comparisons, 3-month cognitive decline was no longer significantly associated with baseline frailty. This retrospective analysis demonstrates an association between baseline frailty and postoperative neurocognitive disorders, particularly using the more extensive REFS scoring method. This supports preoperative screening for frailty to risk-stratify patients, and identify and implement preventive strategies and to improve postoperative outcomes for older individuals.

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.

TRIAL OF DRONABINOL ADJUNCTIVE TREATMENT OF AGITATION IN ALZHEIMER'S DISEASE (AD) (THC-AD)

Introduction Alzheimer's disease (AD) is the most prevalent neurodegenerative disease of aging. Neuropsychiatric symptoms (NPS) in AD are a major cause of burden to patients, caregivers, and society and are near-universal at some point in the AD course. One of the most troubling of these symptoms is agitation (Agit-AD), typified by a variety of problem behaviors including combativeness, yelling, pacing, lack of cooperation with care, insomnia, and restlessness. There is a great need for better interventions that target Agit-AD, a major source of patient disability as well as caregiver burden and stress, particularly in the case of moderate to severe agitation. Dronabinol (Marinol®) is synthetic tetrahydrocannabinol (THC, one of the predominant biochemical constituents of cannabis), which produces anxiolytic, antidepressant, and anti-inflammatory effects and is FDA approved for anorexia and nausea. This pilot trial could open the door to re-purposing dronabinol as a novel and safe treatment for Agit-AD with significant public health impact. Methods THC-AD is a three-week placebo-controlled, double-blind, randomized clinical trial of dronabinol (10?mg QD) in 80 inpatients, assisted living facility (ALF), or nursing home residents with severe Agit-AD. Capsules of dronabinol contain 2.5?mg per dose (5?mg daily) during Week 1, then increase to 5?mg per dose (10?mg daily) for Weeks 2 and 3. The half-life of dronabinol is ∼4?hours, so study medication is administered BID at 08:00 and 14:00 to maximize daytime coverage for agitation and to minimize sundowning. Inclusionary criteria include a diagnosis of AD, severe agitation as determined by the Neuropsychiatric Inventory-Clinician Rating Scale (NPI-C), and being 60-95?years old, while exclusionary criteria include serious or unstable medical illness, seizure disorder, delirium, current use of lithium, and inability to swallow a pill. Primary outcomes include a change in the Pittsburgh Agitation Scale and NPI-C Agitation/Aggression subscales. Secondary outcomes include measures of agitation, cognition, sleep, and global functioning as determined by the following assessments: the NPI-C, Cohen Mansfield Agitation Inventory, Clinical Global Impression of Change, Activities of Daily Living, Mini-Mental State Examination (MMSE), Severe Impairment Battery (8 item), and subjective and observer-rated drug effects. Safety outcomes include monitoring for adverse events (AEs), weekly health assessments, EKG changes, incident delirium (Confusion Assessment Method), and changes in laboratory values. DNA specimens are collected to explore the possibility that cannabinoid receptor polymorphisms may affect response to dronabinol. Serum samples are collected to examine the association of peripheral markers of inflammation with agitation and response to dronabinol. Concomitant medications are limited to currently used antipsychotics, antidepressants, and benzodiazepines, as well as anticonvulsant therapy when not used for seizure disorder, with lorazepam 0.75?mg QD total daily allowed as rescue medication, and can be administered orally or intramuscularly. Additionally, PRN trazodone in doses up to 100?mg total daily dose are allowed for agitation and insomnia. Results We began recruitment in March, 2017 and have enrolled 27 out of 80 participants (mean age 76.96?years, 77.8% female, 85.2% Caucasian, mean total education completed 13.84?years, 55.6% family history of memory impairment). Study participants are significantly cognitively impaired (mean baseline MMSE of 6.69), agitated (mean NPI-C Agitation subtotal 15.19, mean NPI-C Aggression subtotal 6.48) and in reasonable overall health (General Medical Health Rating, 51.9% good and 40.7% fair.) The pace of recruitment is behind initial projections due to a number of factors including adaptation of inpatient units to a culture of research, cost of study medication post clinical trial, difficulty swallowing over-encapsulated pills, prior or current treatment with dronabinol and patient acuity leading to protocol deviations. To meet our recruitment target, we are launching our trial at additional locations (including ALF and nursing homes) and we have expanded the inclusion criteria to increase the maximum age at study entry to 95?years. We have not encountered adverse events or regulatory issues that suggest a rationale to change our study protocol. Conclusions AD is a fatal disease which robs an individual of their memory and personality. Agitation is one of the most common behavioral manifestations of AD and is associated with greater caregiver burden and shorter time to institutionalization. Current treatments for Agit-AD have a plethora of safety limitations, and there is a particularly acute need for interventions for severe Agit-AD in advanced dementia. One important question for treatment development is whether Agit-AD represents a specific target for intervention or a nonspecific syndrome shared with many other diseases. This clinical trial may enable us to understand if targeting the cannabinoid system will be an effective approach to treat this public health issue. This research was funded by: National Institute of Aging, R01AG050515

Does Treatment Response With Antidementia Drugs After 6 Months in Alzheimer's Disease Predict Long-term Treatment Outcome?

Alzheimer's disease (AD) is a chronic, progressive disorder that causes declines in cognitive and physical functions. This condition places severe burdens on families and caregivers. Delaying progressive declines in cognitive function and reducing their burden are thus important. Relationships between early treatment response and subsequent outcomes of schizophrenia and major depressive disorder have been reported. We thus aimed to investigate the relationships between treatment response to antidementia drugs in AD after 6 months (M) and subsequent outcomes. Eligible individuals comprised 194 patients diagnosed with presumed AD. Of these, 110 patients who received antidementia drugs for the first time and were assessed using the Mini-Mental State Examination (MMSE) at 6 M, 12 M, and 24 M were categorized as responders (n = 84) or nonresponders (n = 26). Responders were defined as showing a change in MMSE after 6 M the same as or lower than that in the natural course according to previously reported data. No significant differences in baseline characteristics (age, sex, education, or comorbidities) were seen between groups. Mean MMSE score at baseline was significantly lower in responders (18.0) than in nonresponders (20.7; P = 0.008). Mean change from baseline MMSE was significantly smaller in responders than in nonresponders at both 12 M (-0.46 vs -2.5; P = 0.04) and 24 M (-0.78 vs -4.4; P = 0.001). Treatment response with antidementia drugs after 6 M predicted better outcomes at 12 M and 24 M. Treatment response should be assessed every 6 M, and treatment should be reconsidered accordingly.

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.

Development of a prognostic model to predict post-operative mobility of patients with fragility hip fractures: a retrospective cohort study

IntroductionOlder adults with fragility hip fractures have high 1-year mortality and significant functional loss. This study aimed to identify the factors that predict the post-operative ambulatory prognosis of patients with fragility hip fracture. MethodsA total of 233 patients who were consecutively admitted with fragility hip fracture to the orthopaedic unit of an acute hospital in Hong Kong between March and July 2016, were included in this retrospective observational cohort study. The outcome variable was the binary classification of whether patients could or could not walk independently without assistance for more than10 m at the time of discharge from hospital to community. The prognostic model was developed by using multivariate logistic regression. ResultsEighty-nine (38.2%) patients could walk independently upon discharge. The statistically significant factors that affected walking independence on discharge were age (Odds Ratio [OR] = 0.93), Charlson Comorbidity Index (OR = 0.67), baseline Mini-Mental Status Examination score (OR = 1.15) and pre-fracture mobility (p = 0.012). Patients who walked unaided before the fracture had a better prognosis than patients requiring a stick walker (OR = 0.57), quadripod walker (OR = 0.28) or frame walker (OR = 0.12). The area under the ROC curve was 0.848. ConclusionsThe model provides healthcare professionals with evidence to personalize the rehabilitation regime according to the patient's age, comorbidity, baseline cognitive function and pre-fracture mobility.

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.

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.

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.

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.

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.

ACTR-07. LONG-TERM OUTCOMES FROM INTERGROUP NCCTG 86-72-51 (ALLIANCE): FINAL REPORT OF A PHASE III PROSPECTIVE RANDOMIZED TRIAL OF HIGH DOSE VERSUS LOW DOSE RADIATION IN ADULT SUPRATENTORIAL LOW-GRADE GLIOMA

Abstract PURPOSE To provide a final update on oncologic and cognitive outcomes of high dose versus low dose radiation for low-grade glioma. METHODS Between 1986 and 1994, 203 patients with supratentorial low grade glioma were randomized to 50.4 Gy in 28 fractions versus 64.8 Gy in 36 fractions after any degree of resection. Histologic subtype was oligodendroglioma (71%) or astrocytoma (29%). Primary outcome was overall survival (OS). Cognitive status was followed using Folstein Mini-Mental State Examination (MMSE). RESULTS For the entire cohort of 203 patients, median OS was 8.4 years (95% CI: 7.2 – 10.8). Median progression-free survival (PFS) was 5.2 years (95% CI: 4.3 – 6.6). Median follow-up is 17.2 years for the 33 patients still alive. High-dose radiation did not improve OS (15-yr OS: 22.4% vs. 24.9%, log rank p=0.978) or PFS (15-yr PFS: 15.2% vs. 9.5%, p=0.7142). OS was significantly better for patients with pre-operative tumor diameter &lt; 5 cm (15-yr OS: 39.4% vs. 15.2%, p&lt; 0.001), baseline MMSE &gt; 27 (15-yr OS: 27.3% vs. 9.8%, p=0.001), and for patients who underwent gross total resection (GTR) (15-yr OS: 39.3% GTR vs. 16.4% subtotal resection vs. 24.5% biopsy only, p=0.0119). PFS was improved for patients with oligodendroglioma versus astrocytoma (15-yr PFS: 13.8% vs. 8.6%, p=0.0221). PFS was also improved for patients with pre-operative tumor diameter &lt; 5 cm, patients who had GTR, and patients with baseline MMSE &gt; 27. For patients who had normal MMSE at baseline, at 7 years only 1 patient (5%) had a clinically significant decrease in MMSE from the previous time point, with the remainder (95%) stable. None had decrease in MMSE at 10, 12, or 15 years. CONCLUSIONS Long-term follow-up indicates no benefit to high-dose over low-dose radiation for low-grade gliomas. Minimal late decline in cognitive function after radiation was seen by MMSE. SUPPORT: U10CA180821,U10CA180882. https://acknowledgments.alliancefound.org