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Exploratory analyses suggest less cognitive decline with nilvadipine treatment in very mild Alzheimer’s disease subjects

View ORCID ProfileL Abdullah, F Crawford, H Langlois, M Tsolaki, A Börjesson-Hanson, M Olde Rikkert, F Pasquier, A Wallin, S Kennelly, S Hendrix, K Blennow, B Lawlor, M Mullan
doi: https://doi.org/10.1101/345652
L Abdullah
1Roskamp Institute, 2040 Whitfield Avenue, Sarasota, FL, 34243 USA
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  • ORCID record for L Abdullah
F Crawford
1Roskamp Institute, 2040 Whitfield Avenue, Sarasota, FL, 34243 USA
2Archer Pharmaceuticals, 2040 Whitfield Avenue, Sarasota, FL, 34228 USA
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H Langlois
1Roskamp Institute, 2040 Whitfield Avenue, Sarasota, FL, 34243 USA
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M Tsolaki
3Department of Neurology, Aristotle University of Thessaloniki, Thessaloniki 541 24, Greece
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A Börjesson-Hanson
4Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, 405 30 Gothenburg, Sweden
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M Olde Rikkert
5Department of Geriatric Medicine, Radboudumc Alzheimer Center, Donders Institute of Medical Neurosciences, Radboudumc, Geert Grooteplein Zuid 10, 6525 GA Nijmegen, The Netherlands
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F Pasquier
6CHU Lille, Univ. Lille, DISTALZ Laboratory of Excellence, 42 Rue Paul Duez, 59000 Lille, France
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A Wallin
7Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, the Sahlgrenska Academy at University of Gothenburg, 405 30 Gothenburg, Sweden
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S Kennelly
8Trinity College Dublin, College Green, Dublin 2, Ireland
9Department of Age Related Healthcare, Tallaght Hospital, Tallaght, Co. Dublin, Ireland
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S Hendrix
10Pentara Corporation, 2261 E 3300 S, Millcreek, UT 84109, USA
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K Blennow
7Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, the Sahlgrenska Academy at University of Gothenburg, 405 30 Gothenburg, Sweden
11Clincial Neurochemistry Laboratory, Sahlgrenska University Hospital/Mölndal, Blå stråket 5, 413 45 Göteborg, Sweden
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B Lawlor
8Trinity College Dublin, College Green, Dublin 2, Ireland
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M Mullan
1Roskamp Institute, 2040 Whitfield Avenue, Sarasota, FL, 34243 USA
2Archer Pharmaceuticals, 2040 Whitfield Avenue, Sarasota, FL, 34228 USA
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  • Abstract
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Abstract

Background We explored whether the effects of nilvadipine on cognition were influenced by baseline Alzheimer’s disease (AD) severity.

Methods Exploratory analyses were performed on the modified intention-to-treat (mITT) dataset (n = 497) of a phase III randomized placebo-controlled trial to examine the response to nilvadipine in very mild, mild and moderate AD subjects. 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), an outcome measure recently developed to detect treatment responses in subjects with prodromal AD. Cerebrospinal fluid (CSF) biomarkers Aβ38, Aβ40, Aβ42, total tau and P181 tau were measured in a subset of samples (n = 55). Regression analyses were adjusted for potential confounders and effect modifiers in order to examine the interactive effects of nilvadipine and AD severity on cognitive outcomes over 78-weeks.

Results Compared to their respective placebo-controls, nilvadipine-treated, very mild AD subjects showed less decline, whereas moderate AD subjects showed greater decline on the ADAS-Cog 12. Also in very mild AD, a beneficial effect (as measured by ADCOMS), was detected in the nilvadipine treated group. Therapeutic effects of nilvadipine were also observed for a composite memory trait in very mild AD subjects and a composite language trait in mild AD subjects. CSF Aβ42/Aβ40 ratios were increased in mild AD and decreased in moderate AD patients treated with nilvadipine, compared to their respective controls.

Conclusion These data suggest that very mild AD subjects benefited from nilvadipine and that future clinical trials of nilvadipine in this population are required to confirm these findings.

Trial Registration NCT02017340 Registered 20 December 2013, https://clinicaltrials.gov/ct2/show/NCT02017340

EUDRACT Reference Number 2012-002764-27 Registered 04 February 2013, https://www.clinicaltrialsregister.eu/ctr-search/search?query=2012-002764-27

Footnotes

  • labdullah{at}roskampinstitute.org

  • fcrawford{at}archerpharmaceuticals.com

  • hlanglois{at}roskampinstitute.org

  • tsolakim1{at}gmail.com

  • anne.borjesson-hanson{at}sll.se

  • marcel.OldeRikkert{at}radboudumc.nl

  • florence.PASQUIER{at}CHRU-LILLE.FR

  • anders.wallin{at}neuro.gu.se

  • sean.kennelly{at}amnch.ie

  • shendrix{at}pentaracorp.com

  • kaj.blennow{at}neuro.gu.se

  • blawlor{at}stjames.ie

  • mmullan{at}archerpharmaceuticals.com

  • Abbreviations

    AD
    Alzheimer’s Disease
    mITT
    modified Intent-to-Treat
    ADAS-Cog12
    Alzheimer’s Disease Assessment Scale Cognitive 12
    CDR-sb
    Clinical Dementia Rating Scale sum of boxes
    ADCOMS
    AD composite score
    CSF
    Cerebral Spinal Fluid
    DHP
    Dihydropyridine
    CCB
    Calcium channel blocker
    MCI
    Mild Cognitive Impairment
    BBB
    blood brain barrier
    Syk
    spleen tyrosine kinase
    IRB
    Institutional Review Board
    NINCDS-ADRDA
    National Institute of Neurological and Communicative Disorders and Stroke/Alzheimer’s Disease and Related Disorders Association Inc.
    MMSE
    Mini-Mental State Examination
    PLS
    Partial Least Square
    MSD
    Meso Scale Discovery
    PCA
    Principal Component Analysis
    KMO
    Kaiser-Meyer-Olkin
    MTL
    medial temporal lobe
  • Copyright 
    The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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    Exploratory analyses suggest less cognitive decline with nilvadipine treatment in very mild Alzheimer’s disease subjects
    L Abdullah, F Crawford, H Langlois, M Tsolaki, A Börjesson-Hanson, M Olde Rikkert, F Pasquier, A Wallin, S Kennelly, S Hendrix, K Blennow, B Lawlor, M Mullan
    bioRxiv 345652; doi: https://doi.org/10.1101/345652
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    Exploratory analyses suggest less cognitive decline with nilvadipine treatment in very mild Alzheimer’s disease subjects
    L Abdullah, F Crawford, H Langlois, M Tsolaki, A Börjesson-Hanson, M Olde Rikkert, F Pasquier, A Wallin, S Kennelly, S Hendrix, K Blennow, B Lawlor, M Mullan
    bioRxiv 345652; doi: https://doi.org/10.1101/345652

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