Dementia Rating Scale Sum Of Boxes Research Articles

Subjective Cognitive Decline in Community-Dwelling Older Adults With Objectively Normal Cognition: Mediation by Depression and Instrumental Activities of Daily Living.

Subjective cognitive decline (SCD) refers to self-reported memory loss despite normal cognitive function and is considered a preclinical stage of Alzheimer's disease. This study aimed to examine the mediating effects of depression and Instrumental Activities of Daily Living (IADL) on the association between the scoring of Clinical Dementia Rating Scale-Sum of Boxes (CDR-SB) and Subjective Cognitive Decline Questionnaire (SCD-Q). A sample of 139 community-dwelling older adults aged 65-79 with normal cognitive function completed the SCD-Q, a comprehensive neuropsychological battery, and functional/psychiatric scales. We conducted 1) a correlation analysis between SCD-Q scores and other variables and 2) a path analysis to examine the mediating effects of depression and IADL on the relationship between CDR-SB and SCD-Q. CDR-SB was found to be indirectly associated with SCD-Q, with depressive symptoms mediating this relationship. However, no direct association was observed between SCD-Q and CDR-SB. Additionally, IADL was not associated with SCD-Q and did not mediate the relationship between CDR-SB and SCD-Q. The model fit was acceptable (minimum discrepancy function by degrees of freedom divided [CMIN/DF]=1.585, root mean square error of approximation [RMSEA]=0.065, comparative fit index [CFI]=0.955, Tucker-Lewis index [TLI]=0.939). Our results suggest that SCD-Q is influenced by depressive symptoms, but not by IADL. The role of depressive symptoms as a mediator between CDR-SB and SCD-Q indicates that psychological factors may contribute to the perception of SCD. Therefore, interventions targeting depression may mitigate the concerns associated with SCD and reduce feelings of worse performance compared to others of the same age group.

Mitochondrial alterations in fibroblasts from sporadic Alzheimer's disease (AD) patients correlate with AD-related clinical hallmarks

Mitochondrial dysfunctions are key features of Alzheimer’s disease (AD). The occurrence of these disturbances in the peripheral cells of AD patients and their potential correlation with disease progression are underinvestigated. We studied mitochondrial structure, function and mitophagy in fibroblasts from healthy volunteers and AD patients at the prodromal (AD-MCI) or demented (AD-D) stages. We carried out correlation studies with clinical cognitive scores, namely, (i) Mini-Mental State Examination (MMSE) and (ii) Dementia Rating-Scale Sum of Boxes (CDR-SOB), and with (iii) amyloid beta (Aβ) plaque burden (PiB-PET imaging) and (iv) the accumulation of peripheral amyloid precursor protein C-terminal fragments (APP-CTFs). We revealed alterations in mitochondrial structure as well as specific mitochondrial dysfunction signatures in AD-MCI and AD-D fibroblasts and revealed that defective mitophagy and autophagy are linked to impaired lysosomal activity in AD-D fibroblasts. We reported significant correlations of a subset of these dysfunctions with cognitive decline, AD-related clinical hallmarks and peripheral APP-CTFs accumulation. This study emphasizes the potential use of peripheral cells for investigating AD pathophysiology.

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.

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.

Development and validation of the Ascertain Dementia 8 (AD8) Thai version.

The Ascertain Dementia 8 (AD8) is a brief informant-based questionnaire which reliably distinguishes patients with neurocognitive disorder (NCD) and normal cognition. Our objective was to translate the AD8 into Thai and test its validity as a potentially useful measure to detect patients with the mild stage of major NCD due to Alzheimer disease (major NCD-AD). Evaluations of 144 informant-patient dyads were made. Participants were patients who attended the memory clinic at Ramathibodi Hospital and non-patient volunteers. The AD8-Thai version was administered separately from doctor's interviews and neuropsychological assessments. Diagnostic workups included a complete medical history, physical and neurological examinations, neuropsychological testing, the Clinical Dementia Rating Scale-Sum of Boxes (CDR-SOB), Montreal Cognitive Assessment (MoCA), blood tests and brain imaging, preferably with magnetic resonance imaging. All researchers were blinded to the AD8 results. An AD8 score ≥3 had a sensitivity of 95.5%, a specificity of 89.5%, a positive predictive value of 84%, and a negative predictive value of 97.1% for screening major NCD-AD and those with normal cognition. A subgroup analysis with participants aged ≥65 years and with ≥12 years of education revealed comparable ability to the whole group. AD8 scores had a moderate negative relationship with MoCA scores (r= -0.470) and a strong positive relationship with CDR-SOB scores (r= 0.547). The performance of AD8 scores in differentiating mild NCD from normal cognition was not as good as for major NCD-AD. AD8-Thai version is an acceptable screening tool for major NCD-AD. For patients aged 65 years or older, with at least 12 years of education, and with cognitive complaints in memory clinic, an AD8-Thai score of 3 or more would be sufficient to work on major NCD diagnosis. The performance of the AD8-Thai in mild NCD needs further investigation.

Application of Meta-analysis to Evaluate Relationships Among ARIA-E Rate, Amyloid Reduction Rate, and Clinical Cognitive Response in Amyloid Therapeutic Clinical Trials for Early Alzheimer's Disease.

Removal of the extracellular Aβ plaques in the brain is one of the mechanisms to treat Alzheimer's disease (AD). Separate clinical trials for several therapeutic compounds that target amyloid plaque reduction have shown noteworthy correlations among plaque removal, the Amyloid-Related Imaging Abnormalities (ARIA) rate, and clinical efficacy of the treatment. The relationships among therapeutic dose levels, the rate of amyloid removal, and the clinical efficacy deserve further investigation across therapeutic agents, particularly for clinical trials to provide insights for strategies to develop amyloid therapies in Alzheimer's disease. Published data summaries from clinical trials with amyloid therapies of aducanumab, donanemab, lecanemab, and gantenerumab are evaluated with meta-analyses. Linear mixed models for repeated measurements for visits and random study effects are applied to analyze amyloid centiloid value reduction from baseline and clinical cognition change from baseline for treatment groups according to doses and compounds for the clinical trials. Logistic regression analysis is applied to evaluate the relationship between the amyloid removal rate and the ARIA-Edema (ARIA-E) rate across different dose groups and clinical trials. The extent of amyloid removal varies among therapeutic agents and their dose levels. Across treatment groups and clinical trials, amyloid centiloid value reductions at Weeks 26 and 52 are strongly correlated with both ARIA-E rate over 78weeks and the clinical efficacy response in the Clinical Dementia-Rating Scale Sum of Boxes (CDR-SB) score change from baseline at Week 78; and the Spearman rank correlations for amyloid reduction at Week 52 are stronger as - 0.79 with the ARIA-E rate over 78weeks and 0.73 with the Week 78 CDR-SB score change from baseline. Aβ plaques removal in the brain due to amyloid therapy is strongly correlated with a better clinical response in patients with early Alzheimer's disease and a higher ARIA-E rate for the treatment groups and clinical trials in this meta-analysis. These relationships suggest that the balance between the clinical efficacy response and safety in ARIA-E rate is relevant for the choice of doses for amyloid therapies in confirmatory clinical trials.

Linking the Clinical Dementia Rating Scale-Sum of Boxes, the Clinician's Interview-Based Impression Plus Caregiver Input, and the Clinical Global Impression Scale: Evidence based on Individual Participant Data from Five Randomized Clinical Trials of Donepezil.

In patients with Alzheimer's disease, global assessment scales, such as the Clinical Dementia Rating-Sum of Boxes (CDR-SB), the Clinician's Interview-Based Impression Plus Caregiver Input (CIBI plus), and the Clinical Global Impression (CGI) are commonly used. To clinically understand and interpret the associations between these scales, we examined the linkages for the total and change scores of CDR-SB, CIBI plus, and CGI. Individual participant data (N = 2,198) from five pivotal randomized placebo-controlled trials of donepezil were included. Data were collected at baseline and scheduled visits for up to 6 months. Spearman's correlation coefficients ρ were examined between corresponding total and change scores of simultaneous CDR-SB, CIBI plus, and CGI ratings. To link between the simultaneous ratings, equipercentile linking was used. We found strong evidence that the Spearman's correlation coefficients between the CDR-SB and CGI, and CDR-SB and CIBI plus total scores were at least adequately correlated (ρ= 0.50 to 0.71, with p < 0.01). The correlation coefficients between the change scores of CDR-SB and CGI were deemed adequate for weeks 6 to 24 (ρ= 0.44 to 0.65); the remaining correlations were smaller in magnitude (ρ= 0.09 to 0.35). Overall, the linkages were in-line with expectations, e.g., CDR-SB range score of 3-4 (= very mild dementia) was linked to a CGI score of 3 (= mildly ill), and an increase of CDR-SB of 1 was linked to a change of 5 (= minimal worsening) in both CGI and CIBI plus. The study findings can be useful for clinicians wishing to compare scores of different scales across patients. They can also help researchers understand results of studies using different scales and can facilitate meta-analyses, to increase statistical power.

Simultaneous modeling of Alzheimer's disease progression via multiple cognitive scales.

Analyzing the progression of Alzheimer's disease (AD) is challenging due to lacking sensitivity in currently available measures. AD stages are typically defined based on cognitive cut-offs, but this results in heterogeneous patient groups. More accurate modeling of the continuous progression of the disease would enable more accurate patient prognosis. To address these issues, we propose a new multivariate continuous-time disease progression (MCDP) model. The model is formulated as a nonlinear mixed-effects model that aligns patients based on their predicted disease progression along a continuous latent disease timeline. The model is evaluated using long-term follow-up data from 2152 participants in the Alzheimer's Disease Neuroimaging Initiative. The MCDP model was used to simultaneously model three cognitive scales; the Alzheimer's Disease Assessment Scale-cognitive subscale, the Mini-Mental State Examination, and the Clinical Dementia Rating scale-sum of boxes. Compared with univariate modeling and previously proposed multivariate disease progression models, the MCDP model showed superior ability to predict future patient trajectories. Finally, based on the multivariate disease timeline estimated using the MCDP model, the sensitivity of the individual items of the cognitive scales along the different stages of disease was analyzed. The analysis showed that delayed memory recall items had the highest sensitivity in the early stages of disease, whereas language and attention items were sensitive later in disease.

TauIQ: A Canonical Image Based Algorithm to Quantify Tau PET Scans.

Recently, AmyloidIQ was introduced as a new canonical image-based algorithm to quantify amyloid PET scans and demonstrated increased power over traditional SUV ratio (SUVR) approaches when assessed in cross-sectional and longitudinal analyses. We build further on this mathematical framework to develop a TauIQ algorithm for the quantitative analysis of the more complex spatial distribution displayed by tau PET radiotracers. Methods: Cross-sectional (n = 615) and longitudinal (n = 149) 18F-flortaucipir data were obtained from the Alzheimer's Disease Neuroimaging Initiative along with necessary adjunct amyloid PET and T1-weighted structural MRI data. A subset of these data were used to derive a chronological tau dataset, using AmyloidIQ analysis of associated amyloid PET data to calculate the subject's temporal position in the canonical AD disease process, from which canonical images for the nonspecific and specific binding components of 18F-flortaucipir in AD were calculated. These 2 canonical images were incorporated into the TauIQ algorithm that enables the quantification of both global and local tau outcome measures using an image-based regression and statistical parametric analysis of the initial residual image. Performance of the TauIQ algorithm was compared with SUVR approaches for cross-sectional analyses, longitudinal analyses, and correlation with clinical measures (Alzheimer Disease Assessment Scale-Cognitive Subscale [ADAS-Cog], Clinical Dementia Rating scale-sum of boxes [CDR-SB], and Mini-Mental State Examination [MMSE]). Results: TauIQ successfully calculated global tau load (TauL) in all 791 scans analyzed (range, -3.5% to 185.2%; mean ± SD, 23% ± 20.5%) with a nonzero additional local tau component being required in 31% of all scans (cognitively normal [CN], 22%; mild cognitive impairment [MCI], 35%; dementia, 72%). TauIQ was compared with the best SUVR approach in the cross-sectional analysis (TauL increase in effect size: CN- vs. CN+, +45%; CN- vs. MCI+, -5.6%; CN- vs. dementia+, +2.3%) (+/- indicates amyloid-positive or -negative) and correlation with clinical scores (TauL increase in r2: CDR-SB+, 7%; MMSE+, 38%; ADAS-Cog+, 0%). TauIQ substantially outperformed SUVR approaches in the longitudinal analysis (TauIQ increase in power: CN+, >3.2-fold; MCI+, >2.2-fold; dementia+, >2.9-fold). Conclusion: TauL as calculated by TauIQ provides a superior approach for the quantification of tau PET data. In particular, it provides a substantial improvement in power for longitudinal analyses and the early detection of tau deposition and thus should have significant value for clinical imaging trials in AD that are investigating the attenuation of tau deposition with novel therapies.

Psychotropic Medication and Cognitive, Functional, and Neuropsychiatric Outcomes in Alzheimer's Disease (AD).

There are growing concerns about the safety and efficacy of psychotropic medications in Alzheimer's disease (AD). We sought to examine associations between psychotropic medication exposure and longitudinal change in cognitive, functional, and neuropsychiatric outcomes in a large clinical AD cohort. Longitudinal observational study. National Alzheimer's Disease Coordinating Center combining data from 39 Alzheimer's disease centers. 8,034 participants with AD dementia. Mini-Mental State Exam (MMSE), Clinical Dementia Rating Scale-Sum of Boxes (CDR-SB), and Neuropsychiatric Inventory Questionnaire (NPI-Q) Total. Probability of exposure to medication (the propensity score, PS) calculated via logistic regression. Medication classes included all antipsychotics (atypical vs conventional), antidepressants (Selective Serotonin Reuptake Inhibitor [SSRI] vs non-SSRI), and benzodiazepines. Participants treated with a medication class were matched with participants not treated with that class with the closest-matched PS. The effect of medication treatment was assessed using linear mixed-effects models. Participants had a mean (SD) age of 75.5 (9.8) years, and mean (SD) scores of MMSE 21.3 (5.7), CDR-SB 5.5 (3.4), and NPI-Q Total 4.5 (4.4). Mean duration of follow-up was 2.9-3.3 years depending on medication class. Non-SSRI antidepressant use was associated with better CDR-SB (2-year difference in change-DIC: -0.38 [-0.61, -0.15], P = .001). Atypical antipsychotic use was associated with greater decline on MMSE (DIC: -0.91 [-1.54, -0.28] P = .005) and CDR-SB scores (DIC: 0.50 [0.14, 0.86], P = .006). Notably, no drug class was associated with better NPI-Q scores. Use of atypical antipsychotics was associated with poorer cognition and function, and no drug class was associated with improvement in neuropsychiatric symptoms.

Discordant Alzheimer's neurodegenerative biomarkers and their clinical outcomes.

ObjectiveIn the 2018 ATN framework, Alzheimer's neurodegenerative biomarkers comprised cerebrospinal fluid (CSF) total tau, 18F‐fluorodeoxyglucose‐positron emission tomography, and brain atrophy. We aimed to assess the clinical outcomes of having discordant Alzheimer's neurodegenerative biomarkers.MethodsA total of 721 non‐demented individuals from the Alzheimer's Disease Neuroimaging Initiative database were included and then further categorized into concordant‐negative, discordant, and concordant‐positive groups. Demographic distributions of the groups were compared. Longitudinal changes in clinical outcomes and risk of conversion were assessed using linear mixed‐effects models and multivariate Cox proportional hazard models, respectively.ResultsDiscordant group was intermediate to concordant‐negative and concordant‐positive groups in terms of APOE ε4 positivity, CSF amyloid‐beta, and phosphorylated tau. Compared with concordant‐negative group, discordant group deteriorated faster in cognitive scores (Mini‐Mental State Examination, the Clinical Dementia Rating Scale‐Sum of Boxes, and the Functional Activities Questionnaire) and demonstrated greater rates of atrophy in brain structures (hippocampus, entorhinal cortex, and whole brain), and concordant‐positive group performed worse over time than discordant group. Moreover, the risk of cognitive decline increased from concordant‐negative to discordant to concordant‐positive. The results from longitudinal analyses were validated in A+T+, cognitively normal, and mild cognitive impairment individuals, and were also validated by applying different cutoffs and neurodegenerative biomarkers.InterpretationDiscordant neurodegenerative status denotes a stage of cognitive function which is intermediate between concordant‐negative and concordant‐positive. Identification of discordant cases would provide insights into intervention and new therapy approaches, particularly in A+T+ individuals. Moreover, this work may be a complement to the ATN scheme.

Abnormal Serum Bilirubin/Albumin Concentrations in Dementia Patients With Aβ Deposition and the Benefit of Intravenous Albumin Infusion for Alzheimer's Disease Treatment.

BackgroundOur previous study in animal models revealed that bilirubin could induce Aβ formation and deposition. Bilirubin may be important in neurodegenerative dementia with Aβ deposition. Hence, lowering the concentration of the free bilirubin capable of crossing the blood brain–barrier may benefit the treatment of Alzheimer’s disease (AD).ObjectivesThe objectives of this study were to examine the change in the serum bilirubin and albumin concentrations of dementia patients with Aβ deposition, and to determine the effects of intravenous administration of albumin in the treatment of AD.MethodsBilirubin and albumin concentrations in dementia patients with Aβ deposition were examined. Cell viability and apoptosis were determined in dopaminergic neuron-like cells MN9D treated with bilirubin in the presence of diverse concentrations of serum. Human albumin at a dose of 10 g every 2 weeks for 24 weeks was administered intravenously to AD patients to examine the effect of albumin on AD symptoms.ResultsSignificantly higher indirect bilirubin (IBIL) concentrations, lower albumin concentrations, and higher ratio of IBIL to albumin (IBIL/ALB) were observed in dementia patients with Aβ deposition, including AD, dementia with Lewy bodies, and general paresis of insane. In vitro assays showed that bilirubin-induced injury in cultured dopaminergic neuron-like cells negatively depends on the concentration of serum in the culture medium. General linear model with repeated measures analysis indicated a main effect of group on the change in albumin concentrations and Alzheimer’s Disease Cooperative Study Activities of Daily Living Inventory scale (ADCS-ADL) scores, and the main effect of time and group, and group-by-time interaction on the change of Clinical Dementia Rating Scale–Sum of Boxes (CDR-SB) scores. Analysis of the combined data of the entire 28 weeks of assessment period using the area under curve convincingly showed significantly improvements in the change of albumin concentrations, ADCS-ADL scores, and CDR-SB scores.ConclusionIBIL and the IBIL/ALB ratio are significantly higher in dementia patients with Aβ deposition, and intravenous administration of albumin is beneficial to AD treatment.Trial RegistrationThe intervention study was registered at http://www.chictr.org.cn (ChiCTR-IOR-17011539). Date of registration: June 1, 2017.

Inflammatory pathway analytes predicting rapid cognitive decline in MCI stage of Alzheimer's disease.

ObjectiveTo determine the inflammatory analytes that predict clinical progression and evaluate their performance against biomarkers of neurodegeneration.MethodsA longitudinal study of MCI‐AD patients in a Discovery cohort over 15 months, with replication in the Alzheimer’s Disease Neuroimaging Initiative (ADNI) MCI cohort over 36 months. Fifty‐three inflammatory analytes were measured in the CSF and plasma with a RBM multiplex analyte platform. Inflammatory analytes that predict clinical progression on Clinical Dementia Rating Scale‐Sum of Boxes (CDR‐SB) and Mini Mental State Exam scores were assessed in multivariate regression models. To provide context, key analyte results in ADNI were compared against biomarkers of neurodegeneration, hippocampal volume, and CSF neurofilament light (NfL), in receiver operating characteristic (ROC) analyses evaluating highest quartile of CDR‐SB change over two years (≥3 points).ResultsCerebrospinal fluid inflammatory analytes in relation to cognitive decline were best described by gene ontology terms, natural killer cell chemotaxis, and endothelial cell apoptotic process and in plasma, extracellular matrix organization, blood coagulation, and fibrin clot formation described the analytes. CSF CCL2 was most robust in predicting rate of cognitive change and analytes that correlated to CCL2 suggest IL‐10 pathway dysregulation. The ROC curves for ≥3 points change in CDR‐SB over 2 years when comparing baseline hippocampal volume, CSF NfL, and CCL2 were not significantly different.InterpretationBaseline levels of immune cell chemotactic cytokine CCL2 in the CSF and IL‐10 pathway dysregulation impact longitudinal cognitive and functional decline in MCI‐AD. CCL2’s utility appears comparable to biomarkers of neurodegeneration in predicting rapid decline.

Hippocampal Neuroimaging‐Informed Clinical Trial Enrichment Tool for Amnestic Mild Cognitive Impairment Using Open Data

Our goal was to assess the enrichment utility of hippocampal volume (HV) as an enrichment biomarker in amnestic mild cognitive impairment (aMCI) clinical trials, and, hence, develop an HV neuroimaging-informed clinical trial enrichment tool. Modeling of integrated longitudinal patient-level data came from open-access natural history studies in patients diagnosed with aMCI-the Alzheimer's Disease Neuroimaging Initiative (ADNI)-1 and ADNI-2-and indicated that a decrease of 1cm3 with respect to the analysis dataset median baseline intracranial volume-adjusted HV (ICV-HV; ~5cm3 ) is associated with >50% increase in disease progression rate as measured by the Clinical Dementia Rating Scale-Sum of Boxes. Clinical trial simulations showed that the inclusion of aMCI subjects with baseline ICV-HV below the 84th or 50th percentile allowed an approximate reduction in trial size of at least 26% and 55%, respectively. This clinical trial enrichment tool can help design more efficient and informative clinical trials.

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.

Evaluation of the efficacy, safety and tolerability of orally administered BI 409306, a novel phosphodiesterase type 9 inhibitor, in two randomised controlled phase II studies in patients with prodromal and mild Alzheimer\u2019s disease

BackgroundThere are currently no approved treatments for the prodromal stage of Alzheimer’s disease (AD). Approved symptomatic treatments for mild-to-moderate AD include acetylcholinesterase inhibitors and memantine, but more efficacious treatments are needed. BI 409306 is a potent and selective phosphodiesterase 9 inhibitor assessed for the symptomatic treatment of AD. Efficacy and safety of BI 409306 was analysed in two phase II proof-of-concept clinical trials in cognitive impairment associated with prodromal AD (study 1) and mild AD (study 2).MethodsTwo multicentre, double-blind, parallel-group, randomised controlled phase II studies were conducted (North America/Europe). Following study run-in, eligible subjects were randomised to one of four oral doses of BI 409306 (10–50 mg daily) or placebo (1:1:1:1:2 ratio) for 12 weeks. The primary efficacy endpoint was the change from baseline in Neuropsychological Test Battery (NTB) total z-score after 12 weeks’ treatment. Secondary efficacy assessments included change from baseline in Clinical Dementia Rating scale-Sum of Boxes (CDR-SB), Alzheimer’s Disease Assessment Scale-cognitive subscale (ADAS-Cog11) and Alzheimer’s Disease Cooperative Study-Activities of Daily Living scale (ADCS-ADL; mild cognitive impairment [MCI] version for prodromal patients) after 12 weeks’ treatment. Safety and tolerability assessments included adverse event reporting and vital sign monitoring. Change from baseline in NTB total z-score (primary endpoint) and CDR-SB were analysed using the restricted maximum likelihood-based mixed-effects model with repeated measurement. An analysis of covariance model was used to assess other secondary endpoints.ResultsFour hundred fifty-seven patients were randomised (study 1 for prodromal AD, N = 128; study 2 for mild AD, N = 329); 427 (93.4%) completed.A prespecified pooled analysis of the primary endpoint revealed no significant changes in NTB total composite z-score at week 12 in the BI 409306 treatment groups compared with placebo, with similar findings observed in the individual studies. The analysis of all secondary endpoints, including pooled analysis of CDR-SB and ADAS-Cog11, ADCS-MCI-ADL (study 1), ADCS-ADL (study 2), also gave no indication of a treatment benefit for BI 409306, compared with placebo. BI 409306 was well tolerated.ConclusionsOverall, the data do not demonstrate efficacy of BI 409306 in improving cognition in patients with prodromal and mild AD. BI 409306 is well tolerated.Trial registrationClinicalTrials.gov, NCT02240693 and NCT02337907. Registered 15 September 2014 and 09 January 2015, respectively.

Risk Factors for the Progression of Mild Cognitive Impairment in Different Types of Neurodegenerative Disorders.

Objective Mild cognitive impairment (MCI) is a transitional state between normal aging and early dementia. It has a heterogeneous etiology and clinical course. This study aimed to examine the factors associated with the progression of MCI in different types of dementia disorders. Method A retrospective, longitudinal, observational study of outpatients with MCI was conducted at a medical center in northern Taiwan. Patient medical records were reviewed, and risk factors were analyzed by multivariate analysis. Results Among 279 patients with MCI, 163 (58.4%), 68 (24.4%), and 48 (17.2%) were diagnosed with Alzheimer's disease, vascular cognitive impairment, and Lewy body diseases, respectively. During the observation period, 37.2% of patients progressed to dementia. Older age and a higher Clinical Dementia Rating Scale-Sum of Boxes were associated with the risk of progression. Hyperlipidemia was associated with a decreased risk. Converters were more likely to receive an antidementia prescription. Conclusion Our study suggests the importance of comprehensive clinical profiling, risk factor assessment, and detailed drug history evaluations in improving our understanding and management of dementia subtypes.

ANTIDEMENTIA MEDICATION USE IS ASSOCIATED WITH DECREASED INFORMAL COSTS IN MILD DEMENTIA

Antidementia medication use (ADMU) is associated with a delay in the progression of dementia symptoms, but their association with informal costs of dementia care has not been well-studied. Using the Cache County Dementia Progression Study, a population-based sample of persons with dementia (PWD), we examined daily caregiving hours for 219 PWD (46.9% female, mean (SD) age = 85.8 (5.0) years), which were estimated from the Caregiver Activity Survey. Informal costs were then calculated using the replacement cost method by multiplying hours of care by Utahan median wages in the visit year. Cost was adjusted for inflation using the Medical Consumer Price Index and expressed in 2015 dollars. ADMU was based on inspection of each participant’s medications and interview. Linear mixed models, with gamma log-link function, tested the association between antidementia medications and informal costs. Covariates included: psychotropic and anticholinergic medication use, participant’s health status, gender, and dementia severity (measured by the Clinical Dementia Rating Scale-Sum of Boxes). ADMU was 30.7% at baseline and median informal costs were $9.95/day. Overall, ADMU was not associated with informal costs (expβ = .79, p = .090) in the entire sample. In analyses restricted to participants with mild dementia severity at baseline, ADMU was associated with 28% lower costs (expβ = .72, p = .039). Among covariates, only dementia severity (time-varying) was significantly associated with informal costs. These results suggest that ADMU is associated with lower informal costs, particularly among PWD using these medications while in mild stages of dementia severity.

Alzheimer’s Candidate Drug Aducanumab Moves to Phase III

Alzheimer’s Candidate Drug Aducanumab Moves to Phase III