Abstract
We examined the effects of a dihydropyridine calcium channel blocker nilvadipine with anti-inflammatory properties on cognition and cerebrospinal fluid (CSF) biomarkers by baseline Alzheimer's disease (AD) severity. Exploratory analyses were performed on the dataset (n = 497) of a phase III randomized placebo-controlled trial to examine the response to nilvadipine in AD subjects stratified by baseline AD severity into very mild (MMSE ≥ 25), mild (MMSE 20-24) and moderate AD (MMSE < 20). The outcome measures included total and subscale scores of the Alzheimer's Disease Assessment Scale Cognitive 12 (ADAS-Cog 12), the Clinical Dementia Rating Scale sum of boxes (CDR-sb) and the AD composite score (ADCOMS). Cerebrospinal fluid biomarkers Aβ38, Aβ40, Aβ42, neurofilament light chain (NFL), neurogranin, YKL-40, total tau and P181 tau (ptau) were measured in a subset of samples (n = 55). Regression analyses were adjusted for confounders to specifically examine the influence of nilvadipine and baseline AD severity on cognitive outcomes over 78-weeks. Compared to their respective placebo-controls, nilvadipine-treated, very mild AD subjects showed less decline, whereas moderate AD subjects showed a greater cognitive decline on the ADAS-Cog 12 test and the ADCOMS. A lower decline was observed after nilvadipine treatment for a composite memory trait in very mild AD subjects and a composite language trait in mild AD subjects. Cerebrospinal fluid Aβ42/Aβ40 ratios were increased in mild AD and decreased in moderate AD patients treated with nilvadipine, compared to their respective controls. Among moderate AD subjects, levels of ptau, total tau, neurogranin and YKL-40 increased in subjects treated with nilvadipine compared to placebo. These studies suggest that baseline AD severity influenced the treatment outcome in the NILVAD trial and that future clinical trials of nilvadipine should be restricted to mild and very mild AD patients.Trial Registration: NCT02017340 Registered 20 December 2013, https://clinicaltrials.gov/ct2/show/NCT02017340EUDRACT Reference Number 2012-002764-27 Registered 04 February 2013, https://www.clinicaltrialsregister.eu/ctr-search/search?query=2012-002764-27
Highlights
Alzheimer’s disease (AD) is the most common neurodegenerative disease, affecting nearly 5.3 million US citizens
These analyses explored the potential impact of nilvadipine treatment on cognitive sub-scales of the ADAS-Cog 12 and Clinical Dementia Rating Scale Sum of Boxes (CDR-sb) tests
ADAS-Cog 12 sub-scales were further grouped into specific traits for memory, language and praxis based on the topography of tissue loss in AD depending on the stage of the disease, as previously suggested by 19
Summary
Alzheimer’s disease (AD) is the most common neurodegenerative disease, affecting nearly 5.3 million US citizens. Recent clinical trials have shown that moderate AD patients, with established brain amyloid and tau pathologies, do not benefit cognitively from current therapeutic approaches, some trials have shown potential benefits in mild and early stage AD patients [7,8,9,10,11]. Preplanned subgroup analyses indicated that, compared to placebo-treated controls, nilvadipine-treated mild AD subjects (baseline MMSE ≥ 20) showed cognitive benefits whereas moderate AD subjects (baseline MMSE < 20) showed worsening of cognition [18]. These findings support further exploration of the treatment effects of nilvadipine in AD patients based on the disease severity at baseline
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