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. 2021 Feb 14;7(1):e12106.
doi: 10.1002/trc2.12106. eCollection 2021.

Rasagiline effects on glucose metabolism, cognition, and tau in Alzheimer's dementia

Dawn C Matthews  1 , Aaron Ritter  2 , Ronald G Thomas  3 , Randolph D Andrews  1 , Ana S Lukic  1 , Carolyn Revta  4 , Jefferson W Kinney  5 , Babak Tousi  6 , James B Leverenz  7 , Howard Fillit  8 , Kate Zhong  9 , Howard H Feldman  10 , Jeffrey Cummings  2   11
Affiliations

Rasagiline effects on glucose metabolism, cognition, and tau in Alzheimer's dementia

Dawn C Matthews et al. Alzheimers Dement (N Y). .

Abstract

Background: A Phase II proof of concept (POC) randomized clinical trial was conducted to evaluate the effects of rasagiline, a monoamine oxidase B (MAO-B) inhibitor approved for Parkinson disease, in mild to moderate Alzheimer's disease (AD). The primary objective was to determine if 1 mg of rasagiline daily for 24 weeks is associated with improved regional brain metabolism (fluorodeoxyglucose-positron emission tomography [FDG-PET]) compared to placebo. Secondary objectives included measurement of effects on tau PET and evaluation of directional consistency of clinical end points.

Methods: This was a double-blind, parallel group, placebo-controlled, community-based, three-site trial of 50 participants randomized 1:1 to receive oral rasagiline or placebo (NCT02359552). FDG-PET was analyzed for the presence of an AD-like pattern as an inclusion criterion and as a longitudinal outcome using prespecified regions of interest and voxel-based analyses. Tau PET was evaluated at baseline and longitudinally. Clinical outcomes were analyzed using an intention-to-treat (ITT) model.

Results: Fifty patients were randomized and 43 completed treatment. The study met its primary end point, demonstrating favorable change in FDG-PET differences in rasagiline versus placebo in middle frontal (P < 0.025), anterior cingulate (P < 0.041), and striatal (P < 0.023) regions. Clinical measures showed benefit in quality of life (P < 0.04). Digit Span, verbal fluency, and Neuropsychiatric Inventory (NPI) showed non-significant directional favoring of rasagiline; no effects were observed in Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-cog) or activities of daily living. Rasagiline was generally well tolerated with low rates of adverse events and notably fewer neuropsychiatric symptoms in the active treatment group.

Discussion: These outcomes illustrate the potential benefits of rasagiline on clinical and neuroimaging measures in patients with mild to moderate AD. Rasagiline appears to affect neuronal activity in frontostriatal pathways, with associated clinical benefit potential warranting a more fully powered trial. This study illustrated the potential benefit of therapeutic repurposing and an experimental medicine proof-of-concept design with biomarkers to characterize patient and detect treatment response.

Keywords: Alzheimer's disease; FDG‐PET; MAO‐B; QoL‐AD; dopamine; flortaucipir; glucose metabolism; rasagiline; tau PET.

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Conflict of interest statement

Dawn C. Matthews, Randolph D. Andrews, and Ana S. Lukic are employees of ADM Diagnostics, Inc., which provides clinical trial imaging services and image analysis products. Carolyn Revta has received grants from Toyama Pharmaceuticals, Biohaven Pharmaceuticals, and Vivoryon (Probiodrug) during the conduct of the study. Babak Tousi has received a grant from the Alzheimer's Drug Discovery Foundation during the study. James B. Leverenz has received research support from the Alzheimer's Association, Avid Radiopharmaceuticals, Department of Defense, GE Healthcare, Lewy Body Dementia Association, Michael J Fox Foundation, National Institutes of Health, and Sanofi/Genzyme. Howard Fillit is founding Executive Director and Chief Science Officer of the Alzheimer's Drug Discovery Foundation, which funded the rasagiline clinical trial, and has provided consulting to the following pharmaceutical companies: Axovant, vTv, Lundbeck, Otsuka, Lilly, Biogen (RTI), Roche, Genentech, Merck, Samus, Pfizer, and Alector. Howard H. Feldman reports a service agreement through UCSD with the Cleveland Clinic for data management and biostatistics during the conduct of this study; grants from Toyama Pharmaceuticals, Biohaven Pharmaceuticals, and Vivoryon (Probiodrug); service agreements through UCSD for consulting with Eisai Pharmaceuticals, Merck Pharmaceuticals, Tau RX, Samus Therapeutics, Arkuda Therapeutics, Samumed, and Axon Neurosciences Roche/Genentech Pharmaceuticals for DMC and DSMB activities; Tau Consortium for Scientific Advisory Board; and Novo Nordisk for Advisory Board. Jeffrey Cummings reports grants from National Institute of General Medical Sciences (NIGMS) COBRE grant #P20GM109025, during the conduct of the study; personal fees from Acadia, Actinogen, AgenBio, Alkahest, Alzheon, Avanir, Axsome, Biogen, Cassava, Cerecin, Cerevel, Cognoptix, Cortexyme, EIP, Eisai, Foresight, Green Valley, Grifols, Idorsia, Karuna, Nutricia, Orion, Otsuka, Probiodrug, QR Pharma, ReMYND, Resverlogix, Roche, Samumed, Samus Therapeutics, Third Rock, Signant Health, Sunovion, Suven, and United Neuroscience pharmaceutical and assessment companies; other from Alzheimer Drug Discovery Foundation; other from ADAMAS, BioAsis, MedAvante, QR Pharma, and United Neuroscience; personal fees from Neuropsychiatric Inventory (NPI), outside the submitted work; and is Chief Scientific Advisor for CNS Innovations. Aaron Ritter, Jefferson Kinney, Ronald G. Thomas, and Kate Zhong have nothing to disclose.

Figures

FIGURE 1
FIGURE 1
Baseline FDG and Tau burden. a‐c, Tau burden for three participants age 61, 72, and 79 years shown with baseline clinical and FDG scores. d, Pattern of hypometabolism and preservation relative to whole brain that is quantified by the AD Progression score. e, Relationship between participant age and total tau SUVR. f, Relationship between tau burden in a composite of temporal and parietal regions involved in the pattern of (d) versus FDG‐AD Progression score
FIGURE 2
FIGURE 2
a, Twenty‐four‐week change in FDG SUVR in placebo‐ versus rasagiline‐treated patients. b, Longitudinal voxel‐based classifier results showing regions where rasagiline‐treated participants declined less in glucose metabolism than placebo‐treated participants
FIGURE 3
FIGURE 3
a, Longitudinal change in clinical end points by study arm. b, Individual participant longitudinal QoL‐AD scores in the Younger subgroup. c, Change in QoL by study arm, younger, and older subgroups (PL = placebo, RAS = rasagiline treated). d, Change in QoL‐AD from baseline in placebo and rasagiline group after matching for baseline clinical characteristics; decreases reflect worsening and increases represent improvement
FIGURE 4
FIGURE 4
a, Example of increases in tau burden in a high tau imaging participant over 24 weeks. b, Twenty‐four‐week changes in flortaucipir SUVRs for middle frontal, posterior cingulate‐precuneus, and an adaptive region determined by baseline and week 24 suprathreshold voxels, by study arm
See this image and copyright information in PMC

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