Clinical Dementia Rating Scale Sum Of Boxes Research Articles

Comparative Efficacy and Safety of Monoclonal Antibodies for Cognitive Decline in Patients with Alzheimer's Disease: A Systematic Review and Network Meta-Analysis.

Recent clinical trials of anti-Aβ monoclonal antibodies (mAbs) in the treatment of early Alzheimer's disease (AD) have produced encouraging cognitive and clinical results. The purpose of this network meta-analysis (NMA) was to compare and rank mAb drugs according to their efficacy and safety. PubMed, Embase, Web of Science, and the Cochrane Library were searched for randomized controlled trials testing various mAbs for the treatment of cognitive decline in patients with AD, up to March 31, 2023. R software (version 4.2.3) along with JAGS and STATA software (version 15.0) were used for statistical analysis. Odds ratio (OR) for binary variables, mean difference (MD) for continuous variables, and their 95% confidence intervals (CI) were utilized to estimate treatment effects and rank probabilities for each mAb in terms of safety and efficacy outcomes. We calculated the surface under the cumulative ranking area (SUCRA) to evaluate each mAb, with higher SUCRA values indicating better efficacy or lower likelihood of adverse events. Thirty-three randomized controlled trials with a total of 21,087 patients were included in the current NMA, involving eight different mAbs. SUCRA values showed that aducanumab (87.01% and 99.37%, respectively) was the most likely to achieve the best therapeutic effect based on the changes of Mini-Mental State Examination (MMSE) and Clinical Dementia Rating scale Sum of Boxes (CDR-SB) scores. Donanemab (88.50% and 99.00%, respectively) performed better than other therapies for Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog) and Positron Emission Tomography-Standardized Uptake Value ratio (PET-SUVr). Lecanemab (87.24%) may be the most promising way to slow down the decrease of Alzheimer's Disease Cooperative Study-Activities of Daily Living (ADCS-ADL) score. In the analysis of the incidence of adverse events (subjects with any treatment-emergent adverse event), gantenerumab (89.12%) had the least potential for adverse events, while lecanemab (0.79%) may cause more adverse events. Solanezumab (95.75% and 80.38%, respectively) had the lowest incidence of amyloid-related imaging abnormalities characterized by edema and effusion (ARIA-E) and by cerebral microhemorrhages (ARIA-H) of the included immunotherapies. While SUCRA values provided a comprehensive measure of treatment efficacy, the inherent statistical uncertainty required careful analysis in clinical application. Despite immunotherapies significantly increasing the risks of adverse events and ARIA, the data suggest that mAbs can effectively improve the cognitive function of patients with mild and moderate AD. According to the NMA, aducanumab was the most likely to achieve significant improvements in different cognitive and clinical assessments (statistically improved MMSE and CDR-SB), followed by donanemab (statistically improved ADAS-Cog, and PET-SUVr) and lecanemab (statistically improved ADCS-ADL).

Progression analysis versus traditional methods to quantify slowing of disease progression in Alzheimer’s disease

BackgroundThe clinical meaningfulness of the effects of recently approved disease-modifying treatments (DMT) in Alzheimer’s disease is under debate. Available evidence is limited to short-term effects on clinical rating scales which may be difficult to interpret and have limited intrinsic meaning to patients. The main value of DMTs accrues over the long term as they are expected to cause a delay or slowing of disease progression. While awaiting such evidence, the translation of short-term effects to time delays or slowing of progression could offer a powerful and readily interpretable representation of clinical outcomes.MethodsWe simulated disease progression trajectories representing two arms, active and placebo, of a hypothetical clinical trial of a DMT. The placebo arm was simulated based on estimated mean trajectories of clinical dementia rating scale–sum of boxes (CDR-SB) recordings from amyloid-positive subjects with mild cognitive impairment (MCI) from Alzheimer’s Disease Neuroimaging Initiative (ADNI). The active arm was simulated to show an average slowing of disease progression versus placebo of 20% at each visit. The treatment effects in the simulated trials were estimated with a progression model for repeated measures (PMRM) and a mixed model for repeated measures (MMRM) for comparison. For PMRM, the treatment effect is expressed in units of time (e.g., days) and for MMRM in units of the outcome (e.g., CDR-SB points). PMRM results were implemented in a health economics Markov model extrapolating disease progression and death over 15 years.ResultsThe PMRM model estimated a 19% delay in disease progression at 18 months and 20% (~ 7 months delay) at 36 months, while the MMRM model estimated a 25% reduction in CDR-SB (~ 0.5 points) at 36 months. The PMRM model had slightly greater power compared to MMRM. The health economic model based on the estimated time delay suggested an increase in life expectancy (10 months) without extending time in severe stages of disease.ConclusionPMRM methods can be used to estimate treatment effects in terms of slowing of progression which translates to time metrics that can be readily interpreted and appreciated as meaningful outcomes for patients, care partners, and health care practitioners.

Effect of Dietary Habits on Alzheimer's Disease Progression.

Research on the relationship between diet and dementia among Koreans are lacking. This study investigated the association between dietary habits and dementia progression over 3 years in patients with Alzheimer's disease dementia (ADD). This study included 705 patients with mild-to-moderate ADD. Dietary habits were assessed using the Mini Dietary Assessment Index, comprising 10 questions. Outcome measures included the Clinical Dementia Rating scale-Sum of Boxes (CDR-SB), Seoul-Instrumental Activities of Daily Living, Caregiver-Administered Neuropsychiatric Inventory (CGA-NPI), and neuropsychological test battery (NTB) z-scores, which were evaluated annually over 3 years. In Q10 (eat all food evenly without being picky), the 3-year mean differences in CDR-SB (increases in scores represent worsening) compared to the "rarely" group were -1.86 [95% confidence interval (CI)=-3.64 - -0.09, p=0.039] for the "usually" group and -2.23 (95% CI=-4.40 - -0.06, p=0.044) for the "always" group. In Q7 (add salt or soy sauce to food when eating), the 3-year mean differences in CDR-SB compared to the "always" group were -2.47 (95% CI=-4.70 - -0.24, p=0.030) for the "usually" group and -3.16 (95% CI=-5.36 - -0.96, p=0.005) for the "rarely" group. The "rarely" and "usually" groups in Q7 showed significantly less decline in NTB z-score and CGA-NPI compared to the "always" group. Eating a balanced diet and reducing salt intake were associated with a slower decline in dementia severity, cognition, and behavioral alterations in patients with ADD.

Effect of altered gene expression in lipid metabolism on cognitive improvement in patients with Alzheimer's dementia following fecal microbiota transplantation: a preliminary study.

The brain-gut axis has emerged as a potential target in neurodegenerative diseases, including dementia, as individuals with dementia exhibit distinct gut microbiota compositions. Fecal microbiota transplantation (FMT), the transfer of fecal solution from a healthy donor to a patient, has shown promise in restoring homeostasis and cognitive enhancement. This study aimed to explore the effects of FMT on specific cognitive performance measures in Alzheimer's dementia (AD) patients and investigate the relationship between cognition and the gut microbiota by evaluating changes in gene expression following FMT. Five AD patients underwent FMT, and their cognitive function [Mini-Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA), and Clinical Dementia Rating Scale Sum of Boxes (CDR-SOB)] was assessed before and after FMT. The patients' fecal samples were analyzed with 16S rRNA to compare the composition of their gut microbiota. We also assessed modifications in the serum mRNA expression of patients' genes related to lipid metabolism using serum RNA sequencing and quantitative real-time polymerase chain reaction. Significant improvements in cognitive function, as measured by the MMSE (pre- and post-FMT was 13.00 and 18.00) and MoCA were seen. The MoCA scores at 3 months post-FMT (21.0) were the highest (12.0). The CDR-SOB scores at pre- and post-FMT were 10.00 and 5.50, respectively. Analysis of the gut microbiome composition revealed changes via 16S rRNA sequencing with an increase in Bacteroidaceae and a decrease in Enterococcaceae. Gene expression analysis identified alterations in lipid metabolism-related genes after FMT. These findings suggest a link between alterations in the gut microbiome, gene expression related to lipid metabolism, and cognitive function. The study highlights the importance of gut microbiota in cognitive function and provides insights into potential biomarkers for cognitive decline progression. FMT could complement existing therapies and show potential as a therapeutic intervention to mitigate cognitive decline in AD.

MACHINE-LEARNING-BASED INTERPRETABLE PREDICTION FOR MILD COGNITIVE IMPAIRMENT: FROM ADNI DATABASE

Abstract Objective An accurate prediction model was still lacking for mild cognitive impairment (MCI). Therefore, this study aimed to predict the 3- and 5-year MCI risk utilizing interpretable machine learning, and to identify possible biomarkers for intervention. Methods A total of 444 participants were obtained from the ADNI database. Sociodemographic, neuropsychological, ApoE gene, and structural MRI imaging information was used as predictors. Data was randomly divided into training (70%) and test sets (30%). Six machine learning methods were constructed to predict the risk of MCI. Model performance was assessed by area under the ROC curve (AUC). SHapley Additive exPlanations (SHAP) was used to select important predictors. We also constructed a simplified MCI prediction model for clinical practice. Results The mean age (standard deviation) of study population was 73.7 (6.1) years old. A total of 40, and 60 participants progressed into MCI within 3, and 5 years, respectively. Logistic regression (AUC: 0.97) and support vector machine (AUC: 0.93) are the optimal model for 3- and 5-year prediction. The simplified models based on top three neuropsychological test scores also showed high prediction accuracy (AUC > 0.90). APOE gene, intracranial volume, and Clinical Dementia Rating Scale Sum of Boxes (CDRSB) score were top three predictors for 3-year prediction, while CDRSB score, modified Preclinical Alzheimer’s Cognitive Composite Test with Follow-up Test scale (mPACCtrailsB) score, and Functional Activity Questionnaire (FAQ) score were top three predictors for 5-year prediction. Conclusion Interpretable machine learning showed promise in early identification of MCI, and would be valuable for targeted prevention.

Investigation of tau post‐translational modification based on T217 and T231 in human plasma as new biomarkers

AbstractBackgroundPost‐translational modification (PTM) of human tau protein is of high importance as an indicator for predicting the progress of Alzheimer’s disease (AD). Particularly, phosphorylation and O‐glycosylation on tau have been observed at relatively high levels in Alzheimer’s disease (AD) patients and healthy controls, respectively [1]. Recently, a study reported that an increase in the level of phosphorylation at T217 and T231 was observed in the initial stages of the preclinical Alzheimer’s continuum [2]. Reference: [1] C. Alquezar et al. Frontiers in Neurology, 11 (2021) 595532. [2] Marc Suárez‐Calvet et al. EMBO Molecular Medicine, 12 (2020) e12921.MethodTo investigate the PTM of tau protein in human blood plasma, an electrochemical sensor with 1 µm gap between working and counter electrodes was performed and obtained Taumeter indicating the ratio of phosphorylation and O‐glycosylation on the surface of tau protein, where antibodies for phosphorylated T217 and T231 were used [3]. To explore the clinical association, standardized uptake value ratio (SUVR) of amyloid‐positron emission tomography (PET), mini‐mental state examination (MMSE), and clinical dementia rating scale sum of boxes (CDR‐SB) were also investigated and compared to Taumeters. Reference: [3] Yoon et al. Alzheimer’s & Dementia, 18 (2022) e061465.ResultA total of 43 participants (normal control (NC, n = 15), mild cognitive impairment (MCI, n = 14), and AD (n = 14) were investigated. Taumeters for T217 (p = 0.00423, AUC = 0.82667) and T231 (p = 0.00034, AUC = 0.86222) were obtained and analyzed through one‐way analysis of variance (ANOVA) between NC and AD groups (Figure 2). In regression analysis, Taumeter for T217 (r = 0.23824, p = 0.12394) was more correlated with amyloid‐PET SUVR than Taumeter for T231 (r = 0.28072, p = 0.06824) (Figures 3a‐b). Taumeter for T217 (r = ‐0.51246, p = 0.00044) was also more correlated with MMSE score than Taumeter for T231 (r = ‐0.07186, p = 0.64701) (Figures 3c‐d). Taumeter for T217 (r = 0.57937, p<0.0001) was more correlated with the CDR‐SB score than Taumeter for T231 (r = 0.16254, p = 0.29768) (Figures 3e‐f).ConclusionIn this study, we investigated the correlation between Taumeters for T217 and T231, amyloid‐PET SUVR, MMSE score, and CDR‐SB score. As a result, Taumeter for T217 indicates more strong correlation with analytical results of amyloid‐PET SUVR, MMSE score, and CDR‐SB score than Taumter for T231.

GRADUATE I AND II: Revisiting the key findings from two Phase III studies evaluating the efficacy and safety of subcutaneous gantenerumab in early Alzheimer’s disease (AD)

AbstractBackgroundGantenerumab is a fully human monoclonal antibody administered subcutaneously. It binds to aggregated forms of amyloid‐beta protein. GRADUATE I (NCT03444870) and GRADUATE II (NCT03443973) were two 27‐month, global, Phase III, randomized, placebo‐controlled trials designed to investigate the efficacy and safety of gantenerumab in participants with early AD (mild cognitive impairment due to AD or mild AD dementia).MethodEligible participants with early AD were randomized 1:1 to receive gantenerumab or placebo. A universal titration scheme was used for all participants receiving gantenerumab, irrespective of APOEε4 genotype, in order to reach target dose of 510 mg every 2 weeks. The primary endpoint was change from baseline to Week 116 in Clinical Dementia Rating scale – Sum of Boxes (CDR‐SB). Secondary efficacy endpoints, imaging and fluid biomarkers were also assessed.ResultGRADUATE I and II enrolled 985 and 980 participants, respectively. The studies did not meet their primary endpoints. Change from baseline in CDR‐SB at Week 116 for the gantenerumab and placebo groups respectively was 3.35 and 3.65 in GRADUATE I (difference –0.31; 95% confidence interval [CI] –0.66 to 0.05; p = 0.095; 8% relative reduction [RR]) and 2.82 and 3.01 in GRADUATE II (difference –0.19; 95% CI –0.55 to 0.17; p = 0.2998; 6% RR). Secondary measures including ADAS‐Cog13, ADCS‐ADL, FAQ had non‐significant point estimates in favor of gantenerumab, as did the majority of exploratory measures, including NPI‐Q (Table 1). In the gantenerumab arm, change in amyloid PET from baseline to Week 116 was –57.4 (SE 2.84) centiloids for GRADUATE I and –48.0 (SE 2.85) centiloids for GRADUATE II. ARIA‐E occurred with gantenerumab and were manageable and mostly asymptomatic. Plasma exposure using Q2W dosing was comparable to previous data and similar between the GRADUATE studies (At steady state: mean Cmax and Cmin: GRADUATE I 88.1 µg/mL and 54.1 µg/mL; GRADUATE II 88.5 µg/mL and 56.8 µg/mL).ConclusionThe GRADUATE studies did not meet their primary endpoints, although non‐statistically significant effects favoring gantenerumab were observed across the majority of clinical outcome measures. Clinical benefit may require amyloid plaque removal to a threshold level; however, the parameters remain to be defined.

Lewy body co‐pathology contributes to frontal lobe atrophy in Alzheimer’s disease and primary age‐related tauopathy

AbstractBackgroundAlzheimer’s disease (AD) is a heterogeneous proteinopathy. Co‐pathology with Lewy bodies (LB) is frequent and known to contribute to a differential pattern of executive cognitive impairment compared to typical AD. While primary age‐related tauopathy (PART) presents with neurofibrillary tangles, mainly restricted to the temporal lobe and in the absence of amyloid‐beta plaques, LB co‐pathology is also present. However, it is still unknown how the combination of these proteinopathies affects patterns of brain atrophy, which might help clarify the clinical importance and pathophysiology of combined pathology within these groups. Here we investigated the influence of LB on patterns of brain atrophy in AD and PART.MethodsWe selected 214 patients with AD neuropathological change (ADNC) with no LB (n = 102), ADNC with LB (ADNC+LB) (n = 77), PART with no LB (n = 22) and PART with LB (PART+LB) (n = 13) with ante‐mortem volumetric MRI from the National Alzheimer’s Coordinating Center, after exclusion of other neurodegenerative pathologies. Dementia severity was compared using Clinical Dementia Rating Scale Sum of Boxes (CDR‐SB). Cortical and subcortical MRI volume residuals were compared between groups after correction for age. Statistical significance was considered at p‐value < 0.05 after false discovery rate correction for multiple comparisons.ResultsWe found that ADNC, ADNC+LB and PART+LB presented similar levels of dementia severity, whereas PART with no LB was the least affected group. MRI revealed higher atrophy of the right frontal operculum and amygdala in ADNC+LB compared to ADNC. ADNC and ADNC+LB showed increased atrophy in regions across all cortical lobes, hippocampus, amygdala and putamen compared to PART, but did not reveal significant differences compared to PART+LB. Interestingly, PART+LB showed higher atrophy of the frontal poles bilaterally, right superior frontal gyrus, left frontal operculum and right putamen compared to PART.ConclusionsAltogether, these results suggest that LB co‐pathology contributes to frontal lobe regional atrophy in ADNC and likely drives it in PART. Particularly in PART+LB, it suggests that cognitive impairment might derive from alpha‐synuclein pathology rather than tauopathy. These findings indicate that LB pathology determines disease severity within the PART‐ and AD‐continuums.

Precuneus magnetic stimulation for Alzheimer’s disease: a novel TMS‐EEG based peronsalized therapeutic strategy

AbstractBackgroundRepetitive transcranial magnetic stimulation (rTMS) may improve cognition in patients with Alzheimer’s disease (AD). rTMS therapy is currently limited by the relative short duration and the uncertainty on the most appropriate brain target area. AD patients primarily show alterations of the default mode network (DMN), a brain functional network for which the precuneus (PC) is a key node.MethodWe hypothesized that a long‐term 6 month course of rTMS applied over the precuneus could modify cognitive functions in patients with mild‐to‐moderate AD, by restoring cortical activity in the target network. To test this hypothesis we performed a randomized, double‐blind, sham‐controlled, phase II, 24‐weeks trial (NCT03778151). The primary outcome measure was change from baseline to week 24 of the Clinical Dementia Rating Scale–Sum of Boxes (CDR‐SOB). Secondary outcomes included score changes in the Alzheimer’s Disease Assessment Scale– Cognitive Subscale (ADAS‐Cog)11, Mini Mental State Examination (MMSE) and Alzheimer’s Disease Cooperative Study–Activities of Daily Living scale (ADCS‐ADL).Personalization of treatment and monitoring of cortical activity changes were refined by combining TMS and electroencephalography (TMS‐EEG).ResultWe found that AD patients treated with PC‐rTMS showed almost no decline in the CDR‐SB score, showing a clear advantage in terms of cognitive functions and functional abilities as compared to the sham group. rTMS induced in parallel remarkable changes in cortical activity, as demonstrated by TMS‐EEG recordings.Conclusion24 weeks of PC‐ rTMS may slow down cognitive and functional decline in AD patients by enhancing brain plasticity. Non‐invasive brain stimulation of the DMN could represent a novel therapeutic approach in AD patients.

Lewy body co‐pathology contributes to frontal lobe atrophy in Alzheimer’s disease and primary age‐related tauopathy

AbstractBackgroundAlzheimer’s disease (AD) is a heterogeneous proteinopathy. Co‐pathology with Lewy bodies (LB) is frequent and known to contribute to a differential pattern of executive cognitive impairment compared to typical AD. While primary age‐related tauopathy (PART) presents with neurofibrillary tangles, mainly restricted to the temporal lobe and in the absence of amyloid‐beta plaques, LB co‐pathology is also present. However, it is still unknown how the combination of these proteinopathies affects patterns of brain atrophy, which might help clarify the clinical importance and pathophysiology of combined pathology within these groups. Here we investigated the influence of LB on patterns of brain atrophy in AD and PART.MethodsWe selected 214 patients with AD neuropathological change (ADNC) with no LB (n = 102), ADNC with LB (ADNC+LB) (n = 77), PART with no LB (n = 22) and PART with LB (PART+LB) (n = 13) with ante‐mortem volumetric MRI from the National Alzheimer’s Coordinating Center, after exclusion of other neurodegenerative pathologies. Dementia severity was compared using Clinical Dementia Rating Scale Sum of Boxes (CDR‐SB). Cortical and subcortical MRI volume residuals were compared between groups after correction for age. Statistical significance was considered at p‐value < 0.05 after false discovery rate correction for multiple comparisons.ResultsWe found that ADNC, ADNC+LB and PART+LB presented similar levels of dementia severity, whereas PART with no LB was the least affected group. MRI revealed higher atrophy of the right frontal operculum and amygdala in ADNC+LB compared to ADNC. ADNC and ADNC+LB showed increased atrophy in regions across all cortical lobes, hippocampus, amygdala and putamen compared to PART, but did not reveal significant differences compared to PART+LB. Interestingly, PART+LB showed higher atrophy of the frontal poles bilaterally, right superior frontal gyrus, left frontal operculum and right putamen compared to PART.ConclusionsAltogether, these results suggest that LB co‐pathology contributes to frontal lobe regional atrophy in ADNC and likely drives it in PART. Particularly in PART+LB, it suggests that cognitive impairment might derive from alpha‐synuclein pathology rather than tauopathy. These findings indicate that LB pathology determines disease severity within the PART‐ and AD‐continuums.

TANGO: a placebo-controlled randomized phase 2 study of efficacy and safety of the anti-tau monoclonal antibody gosuranemab in early Alzheimer’s disease

In Alzheimer’s disease, the spread of aberrantly phosphorylated tau is an important criterion in the Braak staging of disease severity and correlates with disease symptomatology. Here, we report the results of TANGO (NCT03352557), a randomized, double-blind, placebo-controlled, parallel-group and multiple-dose long-term trial of gosuranemab—a monoclonal antibody to N-terminal tau—in patients with early Alzheimer’s disease. The primary objective was to assess the safety and tolerability of gosuranemab compared to placebo. The secondary objectives were to assess the efficacy of multiple doses of gosuranemab in slowing cognitive and functional impairment (using the Clinical Dementia Rating Scale Sum of Boxes (CDR-SB) scores at week 78) and evaluate the immunogenicity of gosuranemab (using the incidence of anti-gosuranemab antibody responses). Participants were randomized (n = 654); received (n = 650) low-dose (125 mg once every 4 weeks (q4w), n = 58; 375 mg q12w, n = 58), intermediate-dose (600 mg q4w, n = 106) or high-dose (2,000 mg q4w, n = 214) gosuranemab or placebo (q4w, n = 214) intravenously for 78 weeks; and assigned to cerebrospinal fluid (n = 327) and/or tau positron emission tomography (n = 357) biomarker substudies. Gosuranemab had an acceptable safety profile and was generally well tolerated (incidence of serious adverse events: placebo, 12.1%; low dose, 10.3%; intermediate dose, 12.3%; high dose, 11.7%). The incidence of treatment-emergent gosuranemab antibody responses was low at all time points. No significant effects were identified in cognitive and functional tests as no dose resulted in a favorable change from the baseline CDR-SB score at week 78 compared to placebo control (adjusted mean change: placebo, 1.85; low dose, 2.20; intermediate dose, 2.24; high dose, 1.85). At week 76, all doses caused significant (P < 0.0001) reductions in the cerebrospinal fluid levels of unbound N-terminal tau compared to placebo.

Neuropsychological features evaluation of data related to Alzheimer’s disease progression using feature selection

BACKGROUND: Alzheimer’s Disease (AD) is normally assessed in clinical settings using neuropsychological tests and medical procedures such as neuroimaging techniques: Magnetic Resonance Imaging (MRI) and Positron Emission Tomography (PET) among others. The latter procedures are expensive and unavailable in most nations, so early diagnosis of AD does not occur, which heavily increases the subsequent treatment costs for the patients. AIMS: This research aims to evaluate cognitive features related to dementia progression based on neuropsychological tests’ data that are related to the Alzheimer’s Disease Neuroimaging Initiative (ADNI) We utilise data related to two neuropsychological tests including the Clinical Dementia Rating Scale Sum of Boxes (CDR-SOB), and Mini-Mental State Examination (MMSE), to assess advancement of the AD. METHODS: To achieve the aim, we develop a data process called Neuropsychological Feature Assessment via Feature Selection (NFAFS) to identify impactful features using Information Gain (IG) and Pearson Correlation to assess class-feature and feature-feature correlations Later we will model a minimal subset of neuropsychological features using machine learning techniques to derive classification models. RESULTS AND IMPLICATIONS: Results obtained show key cognitive features of the MMSE are Time Orientation, Recall and Complex Attention, since they correlate with the progression class being ranked high in results of the feature selection techniques. For the CDR-SOB features, and aside from the memory feature it was difficult to identify other specific features that are signs of the dementia progression Clinicians can use specific features in a digital knowledge base to pay more attention to specific cognitive deficits related to Recall, Orientation and Complex Attention during dementia clinical evaluations in order to seek possible signs of the disease progression early.

Estimated effects of amyloid reduction on cognitive change: A Bayesian update across a range of priors.

The results of the CLARITY-AD, GRADUATE I and II, and TRAILBLAZER-ALZ 2 trials have rekindled discussion on the impact of amyloid-targeting drugs. We use a Bayesian approach to quantify how rational observers would have updated their prior beliefs based on new trial results. We used publicly available data from the CLARITY-AD, GRADUATE I and II, and TRAILBLAZER-ALZ 2 trials to estimate the effect of reducing amyloid on the clinical dementia rating scale, sum of boxes (CDR-SB) score. A range of prior positions were then updated according to Bayes' theorem using these estimates. After updating with new trial data, a wide range of starting positions resulted in credible intervals that did not include no effect of amyloid reduction on CDR-SB score. For a range of starting beliefs and assuming the veracity of the underlying data, rational observers would conclude there is a small benefit of amyloid reductions on cognition. This benefit must be weighed against opportunity cost and side-effect risk. The results of recent trials of amyloid-targeting drugs have rekindled discussion on the impact of amyloid reductions achieved with amyloid-targeting drugs on cognition. Prior to the announcement of trial results, beliefs about the effects of altering amyloid levels varied. For a range of starting beliefs, one would conclude there is a small benefit of amyloid reductions due to amyloid-targeting drugs on cognition. The perceived value of individual drugs must balance the magnitude of this benefit against opportunity cost and risk of side effects.

Comparison of white matter hyperintensities between early‐onset Alzheimer’s disease participants and their cognitively normal and early‐onset nonAD peers from LEADS

AbstractBackgroundThe Longitudinal Early‐onset Alzheimer Disease study (LEADS) aims to robustly characterize biomarkers of early‐onset AD (EOAD). Here we quantified white matter hyperintensities (WMH) in EOAD and compared the volume of WMH with that of cognitively normal (CN) and amyloid‐negative early‐onset dementia (EOnonAD) groups.MethodsWe compared WMH of 194 amyloid‐positive EOAD, 59 amyloid‐negative EOnonAD, and 88 cognitively normal participants. WMH in left and right frontal, temporal, parietal, and occipital regions was compared between the group, as well as the sum total in each hemisphere. For distributional considerations, the logarithm of the WMHs was used in the analyses. Group comparisons were performed using t‐tests. Analyses of variance were used to compare the groups after correcting for the effects of age, sex, and education. Linear regression analyses were used to investigate the association between cognitive impairment and WMH using age, sex, and education as covariates. Cognitive impairment was measured using the Mini‐Mental State Exam (MMSE) and Clinical Dementia Rating (CDR) scale sum of boxes (CDR‐sb). All p‐values were corrected for multiple comparisons using the false discovery rate method.ResultsEOAD showed greater WMH compared with both CN and EOnonAD groups across all regions. This relationship holds after correcting for the effects of age, sex, and education (see Figure 1 and Table 1, all p‐values &lt; 0.05). No significant differences were observed between WMHs of CN and EOnonAD groups. Higher WMH values were associated with greater cognitive impairment: MMSE (b = ‐1.69, p‐value &lt;0.0001) and CDR‐sb (b = 0.45, p‐value &lt;0.0001).ConclusionsEOAD consistently show higher WMH compared to their CN and EOnonAD peers. The extent of WMH in CN and EOnonAD groups is similar. No differences in regional distribution were observed, with EOAD having higher WMH across all brain regions. Higher WMHs were associated with worse cognitive impairment measured both using MMSE and CDR sum of boxes.

APOE ε4's impact on response to amyloid therapies in early symptomatic Alzheimer's disease: Analyses from multiple clinical trials.

Apolipoprotein E (APOE) ε4 may interact with response to amyloid-targeting therapies. Aggregate data from trials enrolling participants with amyloid-positive, early symptomatic Alzheimer's disease (AD) were analyzed for disease progression. Pooled analysis of potentially efficacious antibodies lecanemab, aducanumab, solanezumab, and donanemab shows slightly better efficacy in APOE ε4 carriers than in non-carriers. Carrier and non-carrier mean (95% confidence interval) differences from placebo using Clinical Dementia Rating Scale-Sum of Boxes (CDR-SB) were -0.30 (-0.478, -0.106) and -0.20 (-0.435, 0.042) and AD Assessment Scale-Cognitive subscale (ADAS-Cog) values were -1.01 (-1.577, -0.456) and -0.80 (-1.627, 0.018), respectively. Decline in the APOE ε4 non-carrier placebo group was equal to or greater than that in carriers across multiple scales. Probability of study success increases as the representation of the carrier population increases. We hypothesize that APOE ε4 carriers have same or better response than non-carriers to amyloid-targeting therapies and similar or less disease progression with placebo in amyloid-positive trials. Amyloid-targeting therapies had slightly greater efficacy in apolipoprotein E (APOE) ε4 carriers. Clinical decline is the same/slightly faster in amyloid-positive APOE ε4 non-carriers. Prevalence of non-carriers in trial populations could impact outcomes.

Effectiveness and safety of monoclonal antibodies against amyloid-beta vis-à-vis placebo in mild or moderate Alzheimer's disease.

Currently, no consensus has been reached on the therapeutic implications of monoclonal antibodies against amyloid-beta (Aβ) in Alzheimer's disease (AD). This study aimed to examine the effectiveness and safety of monoclonal antibodies against Aβ as a whole and also to determine the superiority of individual antibodies vis-à-vis placebo in mild or moderate AD. Literature retrieval, article selection, and data abstraction were performed independently and in duplicate. Cognition and function were appraised by the Mini-Mental State Examination (MMSE), Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog), Disability Assessment for Dementia (DAD), and Clinical Dementia Rating Scale-Sum of Boxes (CDR-SB). Effect sizes are expressed as standardized mean difference (SMD) with a 95% confidence interval (CI). Twenty-nine articles involving 108 drug-specific trials and 21,383 participants were eligible for synthesis. Of the four assessment scales, only CDR-SB was significantly reduced after using monoclonal antibodies against Aβ relative to placebo (SMD: -0.12; 95% CI: -0.2 to -0.03; p = 0.008). Egger's tests indicated a low likelihood of publication bias. At individual levels, bapineuzumab was associated with a significant increase in MMSE (SMD: 0.588; 95% CI: 0.226-0.95) and DAD (SMD: 0.919; 95% CI: 0.105-1.943), and a significant decrease in CDR-SB (SMD: -0.15; 95% CI: -0.282-0.018). Bapineuzumab can increase the significant risk of serious adverse events (OR: 1.281; 95% CI: 1.075-1.525). Our findings indicate that monoclonal antibodies against Aβ can effectively improve instrumental activities of daily life in mild or moderate AD. In particular, bapineuzumab can improve cognition and function, as well as activities of daily life, and meanwhile, it triggers serious adverse events.

Establishing Clinically Meaningful Change on Outcome Assessments Frequently Used in Trials of Mild Cognitive Impairment Due to Alzheimer’s Disease

BackgroundConsensus is lacking on what constitutes a meaningful score change for individual patients on clinical outcome assessments (COAs) that are commonly used in clinical trials of Alzheimer’s disease. Such thresholds are one important approach to help contextualize trial results and demonstrate meaningful treatment benefit.ObjectivesTo estimate meaningful within-patient change thresholds for the Clinical Dementia Rating Scale — Sum of Boxes (CDR-SB), Alzheimer’s Disease Assessment Scale — Cognitive Subscale (ADAS-Cog), and the Mini-Mental State Examination (MMSE) among participants with mild cognitive impairment (MCI).DesignRetrospective anchor- and distribution-based analyses of data from the ADC-008 (NCT00000173) study were used to estimate thresholds for meaningful within-patient change on the target measures.SettingAnalyses were conducted using data from ADC-008 a Phase III, multicenter, randomized, double-blind, placebo-controlled, parallel-group study among participants with the amnestic subtype of MCI, which was conducted by the Alzheimer’s Disease Cooperative Study (ADCS) between March 1999 and January 2004 in the United States and Canada.ParticipantsAnalyses were based on 769 eligible participants who completed the baseline assessment from 69 ADCS sites in the United States and Canada.MeasurementsThe target outcome measures for this analysis included the CDR-SB, the ADAS-Cog, and the MMSE. The anchor measures for this analysis included the Global Deterioration Scale and the MCI—Clinical Global Impression of Change.ResultsFocusing on the 12-month time point, within-patient increases of 1–2.5 points in the CDR-SB and increases of 2–5 points on the 11-item ADAS-Cog and 13-item ADAS-Cog, on average, reflect minimal-to-moderate levels of deterioration, respectively.ConclusionsThese thresholds may be useful to aid the interpretation of Alzheimer’s disease clinical trial data by illustrating meaningful within-patient progression over the course of a clinical trial via supplementary progressor analyses, which may in turn be informative for treatment decisions. Estimates generated via these methods are specifically intended to evaluate within-patient change and are not intended to assess the magnitude and meaningfulness of differences between group-level changes over time.

Selecting appropriate meaningful change thresholds for trials of early (prodromal‐to‐mild) AD: A caregiver‐rated, anchor‐based analysis based on the Tauriel Study

AbstractBackgroundClinically meaningful change thresholds for assessments used in Alzheimer’s disease (AD) trials, including the Clinical Dementia Rating Scale – Sum of Boxes (CDR‐SB), may differ by disease stage and are increasingly important to interpret efficacy. However, anchor‐based estimates for the CDR‐SB have largely used clinician‐ rather than caregiver‐rated anchors. We established meaningful change thresholds for the CDR‐SB using a caregiver‐rated anchor of global change in early (prodromal‐to‐mild) AD patients over an 18‐month clinical trial.MethodAnchor‐based analyses of the Tauriel data (NCT03289143) were conducted to establish CDR‐SB thresholds for biomarker confirmed early AD patients. The Caregiver Global Impression of Change – Alzheimer’s Disease (CaGI‐Alz), a 7‐point caregiver‐rated instrument, provided 2 independent anchors of meaningful decline in memory and activities of daily living (ADLs) (Figure 1). The anchor category of interest for establishing minimal meaningful change thresholds was the ‘Somewhat worse’ category. Average score changes were generated for the ‘No change’ category for comparison. Baseline CDR‐SB and Week 25, 49, and 73 CaGI‐Alz and CDR‐SB data were analyzed; correlations of &gt;0.3 were deemed acceptable for anchor‐based analyses.ResultOur results focus on 49‐ and 73‐week time points based on strength of anchor‐measure correlation and group sample size (Table 1). At 49 weeks, prodromal participants in the ‘Somewhat worse’ category had average CDR‐SB changes of 1.54 (ADL anchor) and 1.08 (memory anchor), mild participants had changes of 2.22 (ADL) and 1.80 (memory), and the combined early AD population had changes of 1.97 (ADL) and 1.51 (memory). At 73 weeks, prodromal participants in the ‘Somewhat worse’ category had average CDR‐SB changes of 2.09 (ADL) and 1.52 (memory), mild participants had changes of 2.25 (ADL) and 2.32 (memory), and the combined early AD population had changes of 2.18 (ADL) and 2.01 (memory).ConclusionAlthough thresholds for meaningful change may differ across disease stages, AD is a continuum and the transition between prodromal to mild is often indistinct. In early (prodromal‐to‐mild) AD populations assessed over longer clinical trials, it may be appropriate to identify meaningful progression on the CDR‐SB using thresholds of 2–2.5 at the individual level.

Predicting Major Decline in Older Adults: The Role of Time Spent Out of Home

AbstractBackgroundFor older adults in community settings, predicting undesired outcomes (needing higher levels of care or death) is important for advancing preventative care and achieving successful aging. We examined whether a combination of baseline characteristics (demographic, clinical) and a continuous digital measure of general mobility and socialization (time‐out‐of‐home) would be predictive of transitions of care and mortality.MethodLongitudinal data from community‐dwelling older adults in the Collaborative Aging Research using Technology (CART) Study was examined for occurrences of undesired life transitions: moving residences due to needing more assistance, receiving non‐temporary in‐home assistance, and death. In‐home sensor data (passive infrared motion and contact sensors) was used to create an algorithm for time when no one was home (TOH). For homes with a transition recorded, a 90‐day window preceding the transition was used to calculate average TOH per day; for homes that did not have transitions, a 90‐day window was randomly selected. Logistic regression was used to predict whether mean duration of TOH (hours), age, gender, Clinical Dementia Rating Scale Sum of Boxes (CDR‐SOB), and Cumulative Illness Rating Scale (CIRS) could predict undesired transitions in single‐resident and dual‐resident homes of older adults.Result177 participants residing in 123 homes were included in the analysis: 56.1% of the homes were single‐resident homes. Mean age in years was 72 (6.4), 52% of participants were women, mean CDR‐SOB = 0.30 (0.46), and mean CIRS = 22 (3.9). Transition to needing greater assistance or death was significantly associated with less TOH (OR 0.66 [95% CI 0.44‐0.98]) after controlling for known risk factors that included age, CIRS, CDR‐SOB and gender. Older age (OR=1.07 [CI 0.98‐1.16]), higher CDR‐SOB (OR=2.66 [CI 0.80‐8.87]), higher CIRS (OR=1.05 [CI 0.90‐1.21]), and being male (OR=0.55 [CI 0.19‐1.64]) were associated with a major transition or death with wide CI’s among these mediating factors.ConclusionLess duration of TOH (likely reflecting mobility and motivation) is predictive of major decline in older adults after controlling for known demographic and clinical risk factors. Digital behavioral biomarkers assessing older adults’ day‐to‐day behaviors may provide valuable information in addition to clinical assessments.

Predicting Major Decline in Older Adults: The Role of Time Spent Out of Home.

For older adults in community settings, predicting undesired outcomes (needing higher levels of care or death) is important for advancing preventative care and achieving successful aging. We examined whether a combination of baseline characteristics (demographic, clinical) and a continuous digital measure of general mobility and socialization (time-out-of-home) would be predictive of transitions of care and mortality. Longitudinal data from community-dwelling older adults in the Collaborative Aging Research using Technology (CART) Study was examined for occurrences of undesired life transitions: moving residences due to needing more assistance, receiving non-temporary in-home assistance, and death. In-home sensor data (passive infrared motion and contact sensors) was used to create an algorithm for time when no one was home (TOH). For homes with a transition recorded, a 90-day window preceding the transition was used to calculate average TOH per day; for homes that did not have transitions, a 90-day window was randomly selected. Logistic regression was used to predict whether mean duration of TOH (hours), age, gender, Clinical Dementia Rating Scale Sum of Boxes (CDR-SOB), and Cumulative Illness Rating Scale (CIRS) could predict undesired transitions in single-resident and dual-resident homes of older adults. 177 participants residing in 123 homes were included in the analysis: 56.1% of the homes were single-resident homes. Mean age in years was 72 (6.4), 52% of participants were women, mean CDR-SOB = 0.30 (0.46), and mean CIRS = 22 (3.9). Transition to needing greater assistance or death was significantly associated with less TOH (OR 0.66 [95% CI 0.44-0.98]) after controlling for known risk factors that included age, CIRS, CDR-SOB and gender. Older age (OR=1.07 [CI 0.98-1.16]), higher CDR-SOB (OR=2.66 [CI 0.80-8.87]), higher CIRS (OR=1.05 [CI 0.90-1.21]), and being male (OR=0.55 [CI 0.19-1.64]) were associated with a major transition or death with wide CI's among these mediating factors. Less duration of TOH (likely reflecting mobility and motivation) is predictive of major decline in older adults after controlling for known demographic and clinical risk factors. Digital behavioral biomarkers assessing older adults' day-to-day behaviors may provide valuable information in addition to clinical assessments.