F3‐02‐01: Cognitive Impairment Precedes and Predicts Functional Impairment in Mild Alzheimer's Disease

Liu‐Seifert, Hong; Han, Baoqin; Henley, David; Siemers, Eric; Cummings, Jeffrey L.; Raskin, Joel; Price, Karen; Sundell, Karen; Selzler, Katherine J.; Aisen, Paul S.; Mohs, Richard C.

doi:10.1016/j.jalz.2014.04.256

Cited by 5 publications

(7 citation statements)

References 34 publications

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“…Our finding that the functional component of the CFC detected clinical progression whereas the cognitive component did not, may seem counterintuitive as the assumed clinical trajectory of AD entails that cognitive impairment induces and thereby precedes functional impairment [48]. However, our findings do not argue against this conceptual understanding of cognitive impairment preceding functional change, but rather imply that existing paper-andpencil cognitive tests may not provide the right tools to capture subtle cognitive decline.…”

Section: Discussioncontrasting

confidence: 73%

The Cognitive-Functional Composite is sensitive to clinical progression in early dementia: longitudinal findings from the Catch-Cog study cohort

Jutten

Harrison

Brunner

et al. 2020

Preprint

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Introduction: In an attempt to capture clinically meaningful cognitive decline in early dementia, we developed the Cognitive-Functional Composite (CFC). We investigated the CFC's sensitivity to decline in comparison to traditional clinical endpoints. Methods: This longitudinal construct validation study included 148 participants with subjective cognitive decline, mild cognitive impairment or mild dementia. The CFC and traditional tests were administered at baseline, 3, 6 and 12 months. Sensitivity to change was investigated using linear mixed models and R2 effect-sizes. Results: CFC scores declined over time (β=-.16,p <.001), with steepest decline observed in mild Alzheimer's dementia (β=-.25,p <.001). The CFC showed medium-to-large effect-sizes at succeeding follow-up points (R2=.08-.42), exhibiting greater change than the Clinical Dementia Rating scale (R2=.02-.12). Moreover, change on the CFC was significantly associated with informant reports of cognitive decline (β=.38,p<.001). Discussion: By showing sensitivity to decline, the CFC could enhance the monitoring of disease progression in dementia research and clinical practice.

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Section: Discussioncontrasting

confidence: 73%

The Cognitive-Functional Composite is sensitive to clinical progression in early dementia: longitudinal findings from the Catch-Cog study cohort

Jutten

Harrison

Brunner

et al. 2020

Preprint

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“…Our finding of a significant between-group difference in functional decline but not cognitive decline over 36 months was unexpected given that studies of disease progression in patients with mild AD have suggested that cognitive decline generally precedes and predicts functional decline (25). Possible reasons for this include that patients in the GERAS and EXPEDITION cohorts in this study had an MMSE score of ~23 at baseline (towards the middle of the mild MMSE score spectrum [21][22][23][24][25][26]) and would probably have progressed to moderate cognitive decline (MMSE score <20) within 3 years; solanezumab, as a disease-modifying drug, was shown to have no effect on cognition in patients with moderate AD dementia in the EXPEDITION studies (8). Also, although patients in the GERAS study received treatment as part of standard care, this treatment may have been more rigorously applied than usual because they were participating in the study.…”

Section: Discussioncontrasting

confidence: 53%

Utilization of Observational Data as a Proxy Cohort for Comparison Purposes With Open-Label Study Results: An Example From Alzheimer’s Disease

et al. 2019

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Background: Randomized placebo-controlled trials in the development of disease-modifying treatments for Alzheimer’s disease are typically of short duration (12–18 months), and health economic modeling requires extrapolation of treatment effects beyond the trial period. OBJECTIVES: To investigate whether observational data can be used to extrapolate data from open-label trials, we compared outcomes (cognition, function, behavior) over 36 months for patients with mild Alzheimer’s disease dementia in the GERAS observational study (proxy for placebo control) with those of the mild Alzheimer’s disease population on active treatment (solanezumab) in two 18-month randomized placebo-controlled trials (EXPEDITION and EXPEDITION2) and the additional 18-month open-label extension study (EXPEDITION-EXT). DESIGN & SETTING: Analysis of longitudinal data from patients with mild Alzheimer’s disease dementia in the GERAS observational study (conducted in France, Germany and the United Kingdom) and the EXPEDITION program (conducted in Europe, North America, South America, Asia and Australia). PARTICIPANTS: European and North American community-living patients, aged ≥55 years, with probable Alzheimer’s disease dementia and their caregivers. Mild Alzheimer’s disease dementia was defined as a Mini-Mental State Examination score of 20–26 in EXPEDITION and 21–26 in GERAS. INTERVENTION: Active treatment in both randomized placebo-controlled trials and the open-label extension study was intravenous solanezumab 400 mg every 4 weeks. Patients in GERAS were receiving treatment as part of standard care. MEASUREMENTS: Between-group differences for changes from baseline over 36 months in cognitive function, ability to perform activities of daily living, and behavioral and psychological symptoms of dementia were assessed using models stratified by propensity score. RESULTS: At baseline, patients and caregivers participating in GERAS were significantly older than those in the EXPEDITION studies, and the GERAS patient cohort had fewer years of education and a shorter time since diagnosis of Alzheimer’s disease. The baseline mean Mini-Mental State Examination score of the GERAS cohort was significantly higher (indicating better cognition) than that of patients receiving placebo or active treatment in the pooled EXPEDITION studies Baseline functional ability scores were significantly lower for the GERAS cohort, indicating poorer functioning. Propensity score stratification achieved a good balance in the baseline variables between GERAS and the two EXPEDITION arms. Over 18 months, least squares mean changes from baseline in outcome measures were similar in the GERAS cohort and the pooled placebo groups from the randomized controlled trials. Also, the 18-month results for the comparison between the GERAS cohort and the pooled active treatment groups from the randomized controlled trials were generally similar to those reported for the comparison with the control group in the randomized trial. Comparison of active treatment (EXPEDITION-EXT) and observational study (GERAS, as proxy control) results over 36 months of the open-label trial showed a significantly smaller decline in activities of daily living (instrumental and basic) in the active treatment group, reflecting better functioning, but no between-group differences at 36 months for cognitive function or behavioral and psychological symptoms of dementia. CONCLUSIONS: Comparing results from clinical trials and observational studies (real-world data) may be a useful methodological approach for informing long-term outcomes in Alzheimer’s disease drug development and could be used to inform health economic modeling. Further research using this methodological approach is needed.

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“…Patients with Mini-Mental Status Examination (MMSE) scores of 16-26 were eligible to participate. 15 Mild AD was defined as screening visit MMSE scores of 20-26; moderate AD was defined as screening visit scores of [16][17][18][19]. Patients were allowed to continue treatment with stable doses of standard-of-care AD treatments throughout the studies.…”

Section: Methodsmentioning

confidence: 99%

Disease‐modifying effect of solanezumab evaluated by delayed‐start analysis in a Japanese subpopulation with mild Alzheimer's disease

Nakamura

Fujikoshi

Funai

et al. 2017

Neurology & Clinical Neurosc

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Background: Solanezumab, an anti-amyloid monoclonal antibody that binds soluble forms of amyloid, might have disease-modifying properties that slow the progression of Alzheimer's disease. Delayed-start design was proposed as a method to show a disease-modifying effect. In the global study, delayed-start analysis suggested that treatment advantages obtained during the placebo-controlled period in the mild subgroup of solanezumab-treated patients were preserved at the primary time-point (108 weeks). Aim: We applied the delayed-start analysis to the Japanese subpopulation with mild Alzheimer's disease who participated in the global studies to see whether a disease-modifying effect was also shown in the Japanese subpopulation. Methods: A possible disease-modifying effect of solanezumab was assessed using a new statistical method including non-inferiority testing. Treatment differences were compared during the placebo-controlled period with those after the placebo patients crossed over to solanezumab in the delayed-start period. Results: A total of 126 Japanese patients with mild Alzheimer's disease were included in the present study. Least squares mean difference for the 14-item Alzheimer's Disease Assessment Scale-Cognitive Subscale at the end of the placebocontrolled period between patients with early-and delayed-start of solanezumab was 2.85 (95% confidence interval 0.01-5.69) and 5.86 (95% confidence interval 2.22-9.51) at 108 weeks. Treatment difference during the placebo-controlled period for the 14-item Alzheimer's Disease Assessment Scale-Cognitive Subscale was preserved at 108 weeks in the delayed-start period. Conclusion: Results from the Japanese subpopulation showed overall consistency with those from the global study, and are supportive for the possible disease-modifying effects of solanezumab.

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F3‐02‐01: Cognitive Impairment Precedes and Predicts Functional Impairment in Mild Alzheimer's Disease

Cited by 5 publications

References 34 publications

The Cognitive-Functional Composite is sensitive to clinical progression in early dementia: longitudinal findings from the Catch-Cog study cohort

The Cognitive-Functional Composite is sensitive to clinical progression in early dementia: longitudinal findings from the Catch-Cog study cohort

Utilization of Observational Data as a Proxy Cohort for Comparison Purposes With Open-Label Study Results: An Example From Alzheimer’s Disease

Disease‐modifying effect of solanezumab evaluated by delayed‐start analysis in a Japanese subpopulation with mild Alzheimer's disease

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