Alzheimer's Disease Assessment Scale Research Articles

Individualized, cross-validated prediction of future dementia using cognitive assessments in people with mild cognitive symptoms.

We aimed to develop an algorithm to predict the individualized risk of future dementia using brief cognitive tests suitable for primary care. We included 612 participants with subjective cognitive decline (SCD) or mild cognitive impairment (MCI) from the Alzheimer's Disease Neuroimaging Initiative (ADNI) study, assessed for at least 4 years or until progression to dementia. A logistic regression model, using cognitive tests as predictors and dementia progression as an outcome, stratified participants into low, intermediate, or high risk. A second model, including 1-year cognitive test changes, was applied to the intermediate group. The models were replicated in 392 SCD/MCI participants from the BioFINDER-1 study. The best two-step model for predicting dementia incorporated Trail Making Test B (attention/executive function), Animal Fluency (verbal fluency), Mini-Mental State Examination (global cognition), and 10-word list recall (memory). The model's positive predictive value in ADNI was 85.8% and negative predictive value was 92.2% versus 62.5% and 95.6%, respectively, in BioFINDER-1. This two-step model accurately predicts individualized dementia risk. To our knowledge, this is the first algorithm for predicting all-cause dementia using a novel two-step model utilizing brief cognitive tests. Applying a validated model including the Trail Making Test B, Animal Fluency, MMSE, Alzheimer's Disease Assessment Scale delayed, and immediate recall can robustly and accurately categorize individuals into low, intermediate, or high risk of dementia progression and can facilitate clinical decision-making and personalized patient care. We created an app that is available for research and educational purposes at https://brainapps.shinyapps.io/PredictAllCauseDementia to provide an individualized risk score for dementia progression.

Increases in amyloid-β42 slow cognitive and clinical decline in Alzheimer's disease trials.

Positive effects of new anti-amyloid-β (Aβ) monoclonal antibodies in Alzheimer's disease (AD) have been attributed to brain amyloid reduction. However, most anti-Aβ antibodies also increase the CSF levels of the 42-amino acid isoform (Aβ42). We evaluated the associations of changes in CSF Aβ42 and brain Aβ-PET with cognitive and clinical end points in randomized trials of anti-Aβ drugs that lowered (β- and γ-secretase inhibitors) or increased CSF Aβ42 levels (anti-Aβ monoclonal antibodies) to test the hypothesis that post-treatment increases in CSF Aβ42 levels are independently associated with cognitive and clinical outcomes. From long-term (≥12 months) randomized placebo-controlled clinical trials of anti-Aβ drugs published until November 2023, we calculated the post-treatment versus baseline difference in ADAS-Cog (cognitive subscale of the Alzheimer's Disease Assessment Scale) and CDR-SB (Clinical Dementia Rate-Sum of Boxes) and z-standardized changes in CSF Aβ42 and Aβ-PET Centiloids (CL). We estimated the effect size [regression coefficients (RCs) and confidence intervals (CIs)] and the heterogeneity (I2) of the associations between AD biomarkers and cognitive and clinical end points using random-effects meta-regression models. We included 25 966 subjects with AD from 24 trials. In random-effects analysis, increases in CSF Aβ42 were associated with slower decline in ADAS-Cog (RC: -0.55; 95% CI: -0.89, -0.21, P = 0.003, I2 = 61.4%) and CDR-SB (RC: -0.16; 95% CI: -0.26, -0.06, P = 0.002, I2 = 34.5%). Similarly, decreases in Aβ-PET were associated with slower decline in ADAS-Cog (RC: 0.69; 95% CI: 0.48, 0.89, P < 0.001, I2 = 0%) and CDR-SB (RC: 0.26; 95% CI: 0.18, 0.33, P < 0.001, I2 = 0%). Sensitivity analyses yielded similar results. Higher CSF Aβ42 levels after exposure to anti-Aβ drugs are independently associated with slowing cognitive impairment and clinical decline. Increases in Aβ42 may represent a mechanism of potential benefit of anti-Aβ monoclonal antibodies in AD.

Neural basis of false recognition in Alzheimer's disease and dementia with lewy bodies.

In Alzheimer's disease (AD), reports on the association between false recognition and brain structure have been inconsistent. In dementia with Lewy bodies (DLB), no such association has been reported. This study aimed to identify brain regions associated with false recognition in AD and DLB by analyzing regional gray matter volume (rGMV). We included 184 patients with AD and 60 patients with DLB. The number of false recognitions was assessed using the Alzheimer's Disease Assessment Scale' word recognition task. Brain regions associated with the number of false recognitions were examined by voxel-based morphometry analysis. The number of false recognitions significantly negatively correlated with rGMV in the bilateral hippocampus, left parahippocampal gyrus, bilateral amygdala, and bilateral entorhinal cortex in patients with AD (p < 0.05, family-wise error [FEW] corrected) and in the bilateral hippocampus, left parahippocampal gyrus, right inferior frontal gyrus, right middle frontal gyrus, right basal forebrain, right insula, left medial and lateral orbital gyri, and left fusiform in those with DLB (p < 0.05, FWE corrected). Bilateral hippocampus and left parahippocampal gyrus were associated with false recognition in both diseases. However, we found there were regions where the association between false recognition and rGMV differed from disease to disease.

Hippocampal volume maximally modulates the relationship between subsyndromal symptomatic depression and cognitive impairment in non-demented older adults

BackgroundSubsyndromal symptomatic depression (SSD) is associated with an elevated risk of cognitive impairment in non-demented older adults. Given that hippocampal and middle temporal gyrus atrophy have been shown to cause SSD, our study aimed to investigate the effect of hippocampal volume on the association between SSD and cognitive impairment. Methods338 non-demented older adults from the ADNI (Alzheimer's Disease Neuroimaging Initiative) cohort who underwent cognitive assessments, questionnaires on depressive symptoms and MRI brain were studied. SSD group is defined as a score of 1–5 based on Geriatric Depression Scale scores. We conducted causal mediation analyses to investigate the effect of hippocampal volume on cognitive performance cross-sectionally. ResultsThe SSD group displayed lower left and right hippocampal volume (p<0.01) than the non-SSD group. SSD was linked to poorer cognition and smaller hippocampal volume. We found that hippocampal volume partially mediated the effect of SSD on cognitive performance including the global cognition and the cognitive section of Alzheimer's Disease Assessment Scale, with mediation percentages ranging from 6.45 % to 30.46 %. In addition, we found that the thickness of the left middle temporal, right entorhinal and right fusiform gyrus, brain regions linked to AD, mediate the relationship between SSD and cognition with mediation percentages ranging from 8.67 % to 21.44 %. LimitationsOur article didn't differentiate between mild cognitive impairment and normal population. ConclusionThe associations of SSD and cognitive impairment are linked to alterations in Alzheimer's Disease related brain regions.

3T sodium-MRI as predictor of neurocognition in nondemented older adults: a cross sectional study.

Dementia is a burgeoning global problem. Novel magnetic resonance imaging (MRI) metrics beyond volumetry may bring new insight and aid clinical trial evaluation of interventions early in the Alzheimer's disease course to complement existing imaging and clinical metrics. To determine whether: (i) normalized regional sodium-MRI values (Na-SI) are better predictors of neurocognitive status than volumetry (ii) cerebral amyloid PET status improves modelling. Nondemented older adult (>60 years) volunteers of known Alzheimer's Disease Assessment Scale (ADAS-Cog11), Mini-Mental State Examination (MMSE) and Consortium to Establish a Registry for Alzheimer's Disease (CERAD) neurocognitive test scores, ApolipoproteinE (APOE) e4 +/- cerebral amyloid PET status were prospectively recruited for 3T sodium-MRI brain scans. Left and right hippocampal, entorhinal and precuneus volumes and Na-SI (using the proportional intensity scaling normalization method with field inhomogeneity and partial volume corrections) were obtained after segmentation and co-registration of 3D-T1-weighted proton images. Descriptive statistics, correlation and best-subset regression analyses were performed. In our 76 nondemented participants (mean(standard deviation) age 75(5) years; woman 47(62%); cognitively unimpaired 54/76(71%), mildly cognitively impaired 22/76(29%)), left hippocampal Na-SI, not volume, was preferentially in the best models for predicting MMSE (Odds Ratio (OR) = 0.19(Confidence Interval (CI) = 0.07,0.53), P-value = 0.001) and ADAS-Cog11 (Beta(B) = 1.2(CI = 0.28,2.1), P-value = 0.01) scores. In the entorhinal analysis, right entorhinal Na-SI, not volume, was preferentially selected in the best model for predicting ADAS-Cog11 (B = 0.94(CI = 0.11,1.8), P-value = 0.03). While right entorhinal Na-SI and volume were both selected for MMSE modelling (Na-SI OR = 0.23(CI = 0.09,0.6), P-value = 0.003; volume OR = 2.6(CI = 1.0,6.6), P-value = 0.04), independently, Na-SI explained more of the variance (Na-SI R 2 = 10.3; volume R 2 = 7.5). No imaging variable was selected in the best CERAD models. Adding cerebral amyloid status improved model fit (Akaike Information Criterion increased 2.0 for all models, P-value < 0.001-0.045). Regional Na-SI were more predictive of MMSE and ADAS-Cog11 scores in our nondemented older adult cohort than volume, hippocampal more robust than entorhinal region of interest. Positive amyloid status slightly further improved model fit.

Association of modified dementia risk score with cerebrospinal fluid biomarkers and cognition in adults without dementia.

This study aimed to investigate the cognitive profile and prospective cognitive changes in non-demented adults with elevated Modified Dementia Risk Scores (MDRS), while also exploring the potential relationship between these associations and cerebrospinal fluid (CSF) biomarkers of Alzheimer's disease (AD) pathology and neuroinflammation. Within the Chinese Alzheimer's Biomarker and LifestylE (CABLE) database, 994 participants without dementia were assessed on MDRS, CSF biomarkers and cognition. We examined the associations of the MDRS with CSF biomarkers and cognitive scores using linear regressions. Causal mediation analyses were conducted to analyze the associations among MDRS, brain pathologies, and cognition. The Alzheimer's Disease Neuroimaging Initiative (ADNI) study was used to validate the mediation effects and to investigate the longitudinal association between MDRS and cognitive decline. The results revealed that higher MDRS were linked to poorer cognitive performance (Model 1: PFDR < 0.001; Model 2: PFDR < 0.001) and increases in CSF levels of phosphorylated tau (P-tau, Model 1: PFDR < 0.001; Model 2: PFDR < 0.001), total tau (T-tau, Model 1: PFDR < 0.001; Model 2: PFDR < 0.001), P-tau/Aβ42 ratio (Model 1: PFDR = 0.023; Model 2: PFDR = 0.028), T-tau/Aβ42 ratio (Model 1: PFDR < 0.001; Model 2: PFDR < 0.001) and soluble triggering receptor expressed on myeloid cells 2 (sTrem2, Model 1: PFDR < 0.001; Model 2: PFDR < 0.001) in the CABLE study. The impact of MDRS on cognition was partially mediated by neuroinflammation and tau pathology. These mediation effects were replicated in the ADNI study. Baseline MDRS were significantly associated with future cognitive decline, as indicated by lower scores on the Mini-Mental State Examination (MMSE, Model 1: PFDR = 0.045; Model 2: PFDR < 0.001), ADNI composite memory score (ADNI-MEM, Model 1: PFDR = 0.005; Model 2: PFDR < 0.001), ADNI composite executive function score (ADNI-EF, Model 1: PFDR = 0.045; Model 2: PFDR < 0.001), and higher score on the Alzheimer's Disease Assessment Scale (ADAS13, Model 1: PFDR = 0.045; Model 2: PFDR < 0.001). The findings of this study revealed significant associations between MDRS and cognitive decline, suggesting a potential role of tau pathology and neuroinflammation in the link between MDRS and poorer cognitive performance in individuals without dementia. Consequently, the MDRS holds promise as a tool for targeted preventive interventions in individuals at high risk of cognitive impairment.

Association of triglyceride glucose-body mass index with Alzheimer’s disease pathology, cognition and brain structure in non-demented people

The relationship between the triglyceride glucose-body mass index (TyG-BMI) index and Alzheimer’s disease (AD) pathology, cognition, and brain structure remains unclear. This study aimed to investigate these associations, focusing on cerebrospinal fluid (CSF) biomarkers, cognitive measures, and brain imaging data. Eight hundred and fifty-five non-demented participants were included. Linear regression was used to explore associations between the TyG-BMI index and AD pathology, cognition, and brain structure. The association between the TyG-BMI index and AD risk was assessed using Kaplan–Meier and Cox proportional hazards models. Longitudinal relationships were assessed using linear mixed-effects models. Mediation analyses were conducted to examine AD pathology’s potential mediating role between the TyG-BMI index and cognition as well as brain structure. In the linear regression analyses, higher TyG-BMI levels were associated with increased Aβ42 and decreased Tau, pTau, Tau/Aβ42, pTau/Aβ42, and pTau/Tau. Positive correlations were observed with mini-mental state examination (MMSE), memory (MEM), executive function (EF), and the volumes of the hippocampus, entorhinal cortex, and middle temporal regions, while negative correlations were found with Alzheimer’s Disease Assessment Scale (ADAS). Longitudinally, the TyG-BMI index was inversely associated with ADAS, and positively with MMSE, MEM, EF, hippocampus, entorhinal, and middle temporal. High TyG-BMI levels were correlated with lower AD risk (HR 0.996 [0.994, 0.999]). Mediation analyses revealed AD pathology mediated the association between TyG-BMI index and cognition as well as brain structure. Additionally, the TyG-BMI index could mediate cognitive changes by influencing brain structure. The TyG-BMI index is associated with AD pathology, cognition, and brain structure.

APOLLOE4 Phase 3 study of oral ALZ-801/valiltramiprosate in APOE ε4/ε4 homozygotes with early Alzheimer's disease: Trial design and baseline characteristics.

The approved amyloid antibodies for early Alzheimer's disease (AD) carry a boxed warning about the risk of amyloid-related imaging abnormalities (ARIAs) that are highest in apolipoprotein E (APOE) ε4/ε4 homozygotes. ALZ-801/valiltramiprosate, an oral brain-penetrant amyloid beta oligomer inhibitor is being evaluated in APOE ε4/ε4 homozygotes with early AD. This Phase 3 randomized, double-blind, placebo-controlled, 78-week study of ALZ-801 administered as 265mg twice per day tablets, enrolled 50- to 80-year-old homozygotes with Mini-Mental State Examination (MMSE) ≥ 22 and Clinical Dementia Rating-Global Score 0.5 or 1.0. The study is powered to detect a 2.0 to 2.5 drug-placebo difference on the Alzheimer's Disease Assessment Scale 13-item Cognitive subscale primary outcome with 150 subjects/arm. The key secondary outcomes are Clinical Dementia Rating-Sum of Boxes and Instrumental Activities of Daily Living; volumetric magnetic resonance imaging and fluid biomarkers are additional outcomes. The APOLLOE4 Phase 3 trial enrolled 325 subjects with a mean age of 69 years, 51% female, MMSE 25.6, and 65% mild cognitive impairment. Topline results are expected in 2024. APOLLOE4 is the first disease-modification AD trial focused on APOE ε4/ε4 homozygotes. Oral ALZ-801 has the potential to be the first effective and safe anti-amyloid treatment for the high-risk APOE ε4/ε4 population. The APOLLOE4 Phase 3, placebo-controlled, 78-week study is designed to evaluate the efficacy and safety of ALZ-801 265mg twice per day in early Alzheimer's disease (AD) subjects with the apolipoprotein E (APOE) ε4/ε4 genotype.The enrolled early AD population (N=325) has 51% females, a mean age = 69 years, and a mean Mini-Mental State Examination = 25.6, with the majority being mild cognitive impairment subjects, a similar disease stage to the lecanemab Phase 3 AD trial (Clarity AD).The primary outcome is the cognitive Alzheimer's Disease Assessment Scale 13-item Cognitive subscale, with two functional measures as key secondary outcomes (Clinical Dementia Rating-Sum of Boxes, Amsterdam-Instrumental Activities of Daily Living), and with hippocampal volume and fluid biomarkers as additional outcomes.The study is unique in allowing a large number of microhemorrhages or siderosis at baseline magnetic resonance imaging, lesions that indicate concomitant cerebral amyloid angiopathy (CAA).At baseline, 32% of the enrolled population had at least 1 microhemorrhage, 24% had 1 to 4, and 8% had > 4 microhemorrhages; 10% had at least 1 siderosis lesion; with more males than females having microhemorrhages (63% vs. 37%) and siderosis (68% vs. 32%).Study results will become available in the second half of 2024 and, if positive, ALZ-801 may become the first oral drug to demonstrate a favorable benefit/risk profile in APOE ε4/ε4 AD subjects.

Intelligent prediction of Alzheimer’s disease via improved multifeature squeeze-and-excitation-dilated residual network

This study aimed to address the issue of larger prediction errors existing in intelligent predictive tasks related to Alzheimer’s disease (AD). A cohort of 487 enrolled participants was categorized into three groups: normal control (138 individuals), mild cognitive impairment (238 patients), and AD (111 patients) in this study. An improved multifeature squeeze-and-excitation-dilated residual network (MFSE-DRN) was proposed for two important AD predictions: clinical scores and conversion probability. The model was characterized as three modules: squeeze-and-excitation-dilated residual block (SE-DRB), multifusion pooling (MF-Pool), and multimodal feature fusion. To assess its performance, the proposed model was compared with two other novel models: ranking convolutional neural network (RCNN) and 3D vision geometrical group network (3D-VGGNet). Our method showed the best performance in the two AD predicted tasks. For the clinical scores prediction, the root-mean-square errors (RMSEs) and mean absolute errors (MAEs) of mini-mental state examination (MMSE) and AD assessment scale–cognitive 11-item (ADAS-11) were 1.97, 1.46 and 4.20, 3.19 within 6 months; 2.48, 1.69 and 4.81, 3.44 within 12 months; 2.67, 1.86 and 5.81, 3.83 within 24 months; 3.02, 2.03 and 5.09, 3.43 within 36 months, respectively. At the AD conversion probability prediction, the prediction accuracies within 12, 24, and 36 months reached to 88.0, 85.5, and 88.4%, respectively. The AD predication would play a great role in clinical applications.

Improving Regression Analysis with Imputation in a Longitudinal Study of Alzheimer's Disease.

Missing data is prevalent in the Alzheimer's Disease Neuroimaging Initiative (ADNI). It is common to deal with missingness by removing subjects with missing entries prior to statistical analysis; however, this can lead to significant efficiency loss and sometimes bias. It has yet to be demonstrated that the imputation approach to handling this issue can be valuable in some longitudinal regression settings. The purpose of this study is to demonstrate the importance of imputation and how imputation is correctly done in ADNI by analyzing longitudinal Alzheimer's Disease Assessment Scale -Cognitive Subscale 13 (ADAS-Cog 13) scores and their association with baseline patient characteristics. We studied 1,063 subjects in ADNI with mild cognitive impairment. Longitudinal ADAS-Cog 13 scores were modeled with a linear mixed-effects model with baseline clinical and demographic characteristics as predictors. The model estimates obtained without imputation were compared with those obtained after imputation with Multiple Imputation by Chained Equations (MICE). We justify application of MICE by investigating the missing data mechanism and model assumptions. We also assess robustness of the results to the choice of imputation method. The fixed-effects estimates of the linear mixed-effects model after imputation with MICE yield valid, tighter confidence intervals, thus improving the efficiency of the analysis when compared to the analysis done without imputation. Our study demonstrates the importance of accounting for missing data in ADNI. When deciding to perform imputation, care should be taken in choosing the approach, as an invalid one can compromise the statistical analyses.

Machine Learning-Based Perivascular Space Volumetry in Alzheimer Disease.

Impaired perivascular clearance has been suggested as a contributing factor to the pathogenesis of Alzheimer disease (AD). However, it remains unresolved when the anatomy of the perivascular space (PVS) is altered during AD progression. Therefore, this study investigates the association between PVS volume and AD progression in cognitively unimpaired (CU) individuals, both with and without subjective cognitive decline (SCD), and in those clinically diagnosed with mild cognitive impairment (MCI) or mild AD. A convolutional neural network was trained using manually corrected, filter-based segmentations (n = 1000) to automatically segment the PVS in the centrum semiovale from interpolated, coronal T2-weighted magnetic resonance imaging scans (n = 894). These scans were sourced from the national German Center for Neurodegenerative Diseases Longitudinal Cognitive Impairment and Dementia Study. Convolutional neural network-based segmentations and those performed by a human rater were compared in terms of segmentation volume, identified PVS clusters, as well as Dice score. The comparison revealed good segmentation quality (Pearson correlation coefficient r = 0.70 with P < 0.0001 for PVS volume, detection rate in cluster analysis = 84.3%, and Dice score = 59.0%). Subsequent multivariate linear regression analysis, adjusted for participants' age, was performed to correlate PVS volume with clinical diagnoses, disease progression, cerebrospinal fluid biomarkers, lifestyle factors, and cognitive function. Cognitive function was assessed using the Mini-Mental State Examination, the Comprehensive Neuropsychological Test Battery, and the Cognitive Subscale of the 13-Item Alzheimer's Disease Assessment Scale. Multivariate analysis, adjusted for age, revealed that participants with AD and MCI, but not those with SCD, had significantly higher PVS volumes compared with CU participants without SCD ( P = 0.001 for each group). Furthermore, CU participants who developed incident MCI within 4.5 years after the baseline assessment showed significantly higher PVS volumes at baseline compared with those who did not progress to MCI ( P = 0.03). Cognitive function was negatively correlated with PVS volume across all participant groups ( P ≤ 0.005 for each). No significant correlation was found between PVS volume and any of the following parameters: cerebrospinal fluid biomarkers, sleep quality, body mass index, nicotine consumption, or alcohol abuse. The very early changes of PVS volume may suggest that alterations in PVS function are involved in the pathophysiology of AD. Overall, the volumetric assessment of centrum semiovale PVS represents a very early imaging biomarker for AD.

The Association of the 24-Hour Activity Cycle Profiles With Cognition in Older Adults With Mild Cognitive Impairment: A Cross-Sectional Study.

The relationship of cognition and the 24-h activity cycle (24-HAC), encompassing physical activity, sedentary behavior, and sleep, in older adults with mild cognitive impairment (MCI) remains uncertain. Distinct combinations of 24-HAC behaviors can characterize unique activity profiles and influence cognition. We aimed to characterize 24-HAC activity profiles in older adults with MCI and assess whether differences in cognition exist across profiles. We conducted a cross-sectional analysis utilizing baseline data from 3 randomized controlled trials involving 253 community-dwelling older adults (55 + years) with MCI (no functional impairment, dementia diagnosis, and Montreal Cognitive Assessment score <26/30). Using MotionWatch8© wrist-worn actigraphy (+5 days), we captured the 24-HAC. Cognition was indexed by the Alzheimer's Disease Assessment Scale Cognitive Plus (ADAS-Cog-Plus). Compositional data and latent profile analyses identified distinct 24-HAC activity profiles. Analysis of covariance examined whether 24-HAC activity profiles differed in cognition. Four distinct activity profiles were identified. Profile 1 ("Average 24-HAC," n = 103) engaged in all 24-HAC behaviors around the sample average. Profile 2 ("Active Chillers," n = 70) depicted lower-than-average engagement in physical activity and higher-than-average sedentary behavior. Profile 3 ("Physical Activity Masters," n = 54) were the most active and the least sedentary. Profile 4 ("Sedentary Savants," n = 26) were the least active and the most sedentary. Sleep was similar across profiles. There were no significant differences in ADAS-Cog-Plus scores between 24-HAC activity profiles (p > .05). Older adults with MCI exhibited four 24-HAC activity profiles conforming to recommended physical activity and sleep guidelines. Nonetheless, cognition was similar across these profiles.

Discriminant Potential of the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) in Greek Older Adults with Subjective Cognitive Decline and Mild Cognitive Impairment.

Alzheimer's Disease Assessment Scale Cognitive Subscale (ADAS-Cog) is a widely used screening tool for detecting older adults with Alzheimer's disease among their cognitively healthy peers. A previous study in Greek population showed that ADAS-Cog-Greek (G) is a valid tool and can identify people with Alzheimer's disease from older adult control group; however, there is no current data about whether ADAS-Cog can differentiate older adults with mild cognitive impairment (MCI) from those who have subjective cognitive decline (SCD). The current study aimed to examine the discriminant potential of ADAS-Cog-G in Greek older adults who meet the criteria for SCD or MCI. Four hundred eighty-two community-dwelling older adults, visitors of the Greek Alzheimer Association and Related Disorders, were enrolled in the current study. One hundred seventy-six of them met the criteria for SCD and three hundred six had MCI. Path analysis applied to the data showed that age, as well as educational level affected ADAS-Cog-G performance. Results showed that the cut-off scores, which better discriminate people with SCD from MCI as well as their sensitivity and specificity values, were extracted in participants with high educational level (13 educational years<) and mainly under the age of 75 years. The current study provided evidence concerning the discriminant potential of ADAS-Cog-G to differentiate older adults with SCD from those with MCI in the Greek population, and therefore contributes to the relevant literature on the field.

Efficacy and safety of gantenerumab in the treatment of Alzheimer's disease: A meta-analysis of randomized controlled trials

IntroductionGantenerumab has garnered considerable attention for its potential to modify the natural course of Alzheimer's disease. However, recent studies have shown mixed results for the use of this medication for the treatment of Alzheimer's Disease. Therefore, this review compared the effects of Gantenerumab with placebo in patients with Alzheimer's disease. MethodsLiterature searches were conducted in PubMed, Embase and Cochrane database from inception to December 2023. Two independent authors (MS and LV) performed the study selection, data extraction and quality assessment. The outcomes of this review were: Clinical Dementia Rating - Sum of Boxes (CDR-SB), the Alzheimer's Disease Assessment Scale (ADAS-Cog), the Mini-Mental State Evaluation (MMSE) and the incidence of Amyloid-Related Imaging Abnormalities with Edema (ARIA-E) or Amyloid-Related Imaging Abnormalities with Hemosiderosis (ARIA-H). Meta-analysis were performed using Review Manager 5.4 (Cochrane Collaboration). ResultsFour studies reporting data for 2,848 patients were included in this review. The lenght of follow-up assessments ranged from 50 to 104 weeks. When compared to placebo, Gantenerumab was significantly associated with a lower ADAS-Cog score (MD -1.05; 95 % CI: -1.85 to -0.25) and lower MMSE score (MD -0.31; 95 % CI: -0.55 to -0.07). There were no differences in the CDR-SB score. Gantenerumab group had a higher incidence of ARIA-E (RR 8.94; 95 % CI: 6.22 to 12.84). ConclusionGantenerumab showed negative effects on cognitive outcomes of people with Alzheimer's Disease. There was a higher incidence of ARIA-E and ARIA-H for gantenerumab. Additional high quality studies are needed to draw more robust conclusions about this treatment.

Clinical variables contributing to the identification of biologically defined subgroups within cognitively unimpaired and mild cognitive impairment individuals.

A lack of consensus exists in linking demographic, behavioral, and cognitive characteristics to biological stages of dementia, defined by the ATN (amyloid, tau, neurodegeneration) classification incorporating amyloid, tau, and neuronal injury biomarkers. Using a random forest classifier we investigated whether 27 demographic, behavioral, and cognitive characteristics allowed distinction between ATN-defined groups with the same cognitive profile. This was done separately for three cognitively unimpaired (CU) (112 A-T-N-; 46 A+T+N+/-; 65 A-T+/-N+/-) and three mild cognitive impairment (MCI) (128 A-T-N-; 223 A+T+N+/-; 94 A-T+/-N+/-) subgroups. Classification-balanced accuracy reached 39% for the CU and 52% for the MCI subgroups. Logical Delayed Recall (explaining 16% of the variance), followed by the Alzheimer's Disease Assessment Scale 13 (14%) and Everyday Cognition Informant (10%), were the most relevant characteristics for classification of the MCI subgroups. Race and ethnicity, marital status, and Everyday Cognition Patient were not relevant (0%). The demographic, behavioral, and cognitive measures used in our model were not informative in differentiating ATN-defined CU profiles. Measures of delayed memory, general cognition, and activities of daily living were the most informative in differentiating ATN-defined MCI profiles; however, these measures alone were not sufficient to reach high classification performance.

Potential impact of unblinding on observed treatment effects in Alzheimer's disease trials.

Adverse effects of monoclonal antibodies against amyloid beta are common, and may affect validity of randomized controlled trials (RCTs) through unblinding of participants. We used observations from published phase 3 RCTs in Alzheimer's disease to calculate the magnitude of unblinding effects on cognition that would be required to explain observed cognitive benefits in RCTs. In trials of lecanemab, aducanumab, and donanemab, incidence of amyloid-related imaging abnormalities with active treatment ranged from 22% to 44%, the vast majority of which presumably led to unblinding. Effects of unblinding on the Clinical Dementia Rating Sum of Boxes required to fully explain observed drug effects ranged from 1.1 point (95% confidence interval: 0.2-2.0) with aducanumab, to 3.3 points (2.1-4.4) with donanemab and 3.7 points (2.0-5.6) with lecanemab. Infusion-related reactions were common, with potential unblinding effects particularly for lecanemab. Similar patterns were observed for the Alzheimer's Disease Assessment Scale Cognitive subscale. Psychological treatment effects due to unblinding may explain a substantial share of observed treatment effects in RCTs.

Predictors of efficacy, tolerability and discontinuation of Transcranial Direct Current Stimulation (tDCS) for Mild Cognitive Impairment (MCI) and Alzheimer’s Disease (AD): a meta-analysis and meta-regression

Numerous patients with mild cognitive impairment (MCI) or Alzheimer’s disease (AD) are refractory to pharmacological treatment, and non-invasive brain neurostimulation has been investigated as another possibility for improving cognition. The performed meta-analysis and meta-regression verified predictors of efficacy, tolerability, and discontinuation of transcranial direct current stimulation (tDCS) for treating MCI or AD. The analyzed studies used the Mini-Mental State Exam, Montreal Cognitive Assessment, or Alzheimer's Disease Assessment Scale - Cognitive Subscale scores as outcome measures. Databases (PubMed, Embase, and Web of Science - primary collection) were searched, resulting in 12 published randomized and controlled trials. The risk of bias assessment was based on Cochrane Review recommendations, considering study characteristics. Other evaluated outcomes were the number of adverse effects (tolerability) and dropouts. Overall and anodal tDCS improved cognition compared to the sham protocol. Group comparisons did not show statistically significant differences for adverse effects and dropouts. Session duration was a response predictor, as stimulations of up to 20 minutes for ten days or more improved the outcome achievement. The AD diagnosis covariate also affected efficacy. The findings should be interpreted carefully in clinical practice because the stimulation effect may vary among subjects.

Shortening the Alzheimer's disease assessment scale cognitive subscale.

A short yet reliable cognitive measure is needed that separates treatment and placebo for treatment trials for Alzheimer's disease. Hence, we aimed to shorten the Alzheimer's Disease Assessment Scale Cognitive Subscale (ADAS-Cog) and test its use as an efficacy measure. Secondary data analysis of participant-level data from five pivotal clinical trials of donepezil compared with placebo for Alzheimer's disease (N=2,198). Across all five trials, cognition was appraised using the original 11-item ADAS-Cog. Statistical analysis consisted of sample characterization, item response theory (IRT) to identify an ADAS-Cog short version, and mixed models for repeated-measures analysis to examine the effect sizes of ADAS-Cog change on the original and short versions in the placebo versus donepezil groups. Based on IRT, a short ADAS-Cog was developed with seven items and two response options. The original and short ADAS-Cog correlated at baseline and at weeks 12 and 24 at 0.7. Effect sizes based on mixed modeling showed that the short and original ADAS-Cog separated placebo and donepezil comparably (ADAS-Cog original ES=0.33, 95% CI=0.29, 0.40, ADAS-Cog short ES=0.25, 95% CI =0.23, 0.34). IRT identified a short ADAS-cog version that separated donepezil and placebo, suggesting its clinical potential for assessment and treatment monitoring.

Clinically Important Benefits and Harms of Monoclonal Antibodies Targeting Amyloid for the Treatment of Alzheimer Disease: A Systematic Review and Meta-Analysis.

We conducted a meta-analysis to evaluate clinically meaningful benefits and harms of monoclonal antibodies targeting amyloid in patients with Alzheimer dementia. We searched PubMed, Cochrane CENTRAL, and 5 trial registries, as well as the reference lists of identified studies. We included randomized controlled trials comparing a monoclonal antibody with placebo at a dose consistent with that used in phase 3 trials or for Food and Drug Administration approval. Studies had to report at least 1 clinically relevant benefit or harm. Data were extracted independently by at least 2 researchers for random effects meta-analysis. Changes in cognitive and functional scales were compared between groups, and each difference was assessed to determine if it met the minimal clinically important difference (MCID). We identified 19 publications with 23,202 total participants that evaluated 8 anti-amyloid antibodies. There were small improvements over placebo in the Alzheimer's Disease Assessment Scale (ADAS)-Cog-11 to -14 score (standardized mean difference = -0.07; 95% CI, -0.10 to -0.04), Mini Mental State Examination score (0.32 points; 95% CI, 0.13 to 0.50), and Clinical Dementia Rating-Sum of Boxes scale score (mean difference =-0.18 points; 95% CI, -0.34 to -0.03), and the combined functional scores (standardized mean difference = 0.09; 95% CI, 0.05 to 0.13). None of the changes, including those for lecanemab, aducanumab, and donanemab, exceeded the MCID. Harms included significantly increased risks of amyloid-related imaging abnormalities (ARIA)-edema (relative risk [RR] = 10.29; number needed to harm [NNH] = 9), ARIA-hemorrhage (RR = 1.74; NNH = 13), and symptomatic ARIA-edema (RR = 24.3; NNH = 86). Although monoclonal antibodies targeting amyloid provide small benefits on cognitive and functional scales in patients with Alzheimer dementia, these improvements are far below the MCID for each outcome and are accompanied by clinically meaningful harms.

Multi-center open comparative randomized study of efficacy and safety of Akatinol Memantine 20 mg (single-doses) vs Akatinol Memantine 10 mg (double-doses) in patients with vascular dementia

Evaluation of the efficacy and safety of the drug Acatinol Memantine, 20 mg (once daily) in comparison with the drug Acatinol Memantine, 10 mg (twice daily) in patients with moderate to moderate severe vascular dementia. The study included 130 patients aged 50-85 years of both sexes with instrumentally and clinically confirmed vascular dementia. The patients were randomized into 2 groups. Group I consisted of 65 patients receiving Akatinol Memantine, 20 mg once daily, group II - 65 patients receiving Akatinol Memantine, 10 mg twice daily for 24 weeks. Clinical, parametric and statistical research methods were used. The Alzheimer's disease assessment scale, the cognitive subscale (ADAS-cog), the short mental Status Assessment Scale (MMSE) and the general clinical impression scale for patients condition and illness severity (CGI-C and CGI-S) and the Hamilton Depression Rating scale (HAM-D) were used. Adverse events were collected and analyzed. At week 24, both groups showed statistically significant positive change in ADAS-cog total score: in group I the total score was 27.2±8.76 points (absolute difference from baseline 3.5 points; p<0.01), and in group II - 26.1±7.86 points (absolute difference from baseline 2.5 points; p<0.01) with no statistically significant differences between groups. Evaluation of secondary efficacy criteria (change in ADAS-cog total score at week 12 and MMSE at weeks 4, 12, and 24) also revealed statistically significant benefit in both groups compared to baseline with no significant differences between groups. Statistically significant improvement was noticed on CGI-S and CGI-C scales in both groups. Akatinol Memantine was safe and well tolerated in both groups. The study showed no lesser efficacy and safety of Akatinol Memantine, 20 mg (once daily) compared to Akatinol Memantine, 10 mg (twice daily) in patients with moderate and moderately severe vascular dementia.