Predicting and Tracking Short Term Disease Progression in Amnestic Mild Cognitive Impairment Patients with Prodromal Alzheimer’s Disease: Structural Brain Biomarkers

Article type: Research Article

Authors: Marizzoni, Moira^{a; *} | Ferrari, Clarissa^b | Jovicich, Jorge^c | Albani, Diego^d | Babiloni, Claudio^{e; f} | Cavaliere, Libera^a | Didic, Mira^{g; h} | Forloni, Gianluigi^d | Galluzzi, Samantha^a | Hoffmann, Karl-Titusⁱ | Molinuevo, José Luis^j | Nobili, Flavio^k | Parnetti, Lucilla^l | Payoux, Pierre^m | Ribaldi, Federica^{a; n} | Rossini, Paolo Maria^o | Schönknecht, Peter^p | Salvatore, Marco^q | Soricelli, Andrea^q | Hensch, Tilman^p | Tsolaki, Magda^r | Visser, Pieter Jelle^s | Wiltfang, Jens^{t; u; v} | Richardson, Jill C.^w | Bordet, Régis^x | Blin, Olivier^y | Frisoni, Giovanni B.^{a; z} | The PharmaCog Consortium

Affiliations: [a] Laboratory of Neuroimaging and Alzheimer’s Epidemiology, IRCCS Istituto Centro San Giovanni diDio Fatebenefratelli, Brescia, Italy | [b] Unit of Statistics, IRCCS Istituto Centro San Giovanni diDio Fatebenefratelli, Brescia, Italy | [c] Center for Mind/Brain Sciences, University of Trento, Italy | [d] Neuroscience Department, IRCCS - Istituto di Ricerche Farmacologiche Mario Negri, Milano, Italy | [e] Department of Physiology and Pharmacology “V. Erspamer”, Sapienza University of Rome, Rome, Italy | [f] IRCCS San Raffaele Pisana of Rome, Rome, Italy | [g] Aix-Marseille Université, Inserm, INS UMR_S 1106, Marseille, France | [h] APHM, Timone, Service de Neurologie et Neuropsychologie, APHM Hôpital Timone Adultes, Marseille, France | [i] Department of Neuroradiology, University of Leipzig, Leipzig, Germany | [j] Alzheimer’s Disease Unit and Other Cognitive Disorders Unit, Hospital Clínic de Barcelona, and Institut d’Investigacions Biomédiques August Pi i Sunyer (IDIBAPS), Barcelona, Catalunya, Spain | [k] Clinical Neurology, Dept. of Neuroscience (DINOGMI), University of Genoa and IRCCS AOU SanMartino-IST, Genoa, Italy | [l] Clinica Neurologica, Università di Perugia, Ospedale Santa Mariadella Misericordia, Perugia, Italy | [m] INSERM; Imagerie cérébrale et handicapsneurologiques UMR 825, Toulouse, France | [n] Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy | [o] Area of Neuroscience, Department of Gerontology, Neurosciences & Orthopedics, Catholic University, Policlinic A. Gemelli Foundation Rome, Italy | [p] Department of Psychiatry and Psychotherapy, University of Leipzig, Leipzig, Germany | [q] SDN Istituto di Ricerca Diagnostica e Nucleare, Napoli, Italy | [^r] 3rd Neurologic Clinic, Medical School, G. Papanikolaou Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece | [^s] Department of Neurology, Alzheimer Centre, VU Medical Centre, Amsterdam, The Netherlands | [^t] LVR-Hospital Essen, Department of Psychiatry and Psychotherapy, Faculty of Medicine, University of Duisburg-Essen, Essen, Germany | [^u] Department of Psychiatry and Psychotherapy, University Medical Center (UMG), Georg-August-University, Goettingen, Germany | [^v] iBiMED, Medical Sciences Department, University of Aveiro, Aveiro, Portugal | [^w] Neurosciences Therapeutic Area, GlaxoSmithKline R&D, Gunnels Wood Road, Stevenage, United Kingdom | [^x] University of Lille, Inserm, CHU Lille, U1171 - Degenerative and vascular cognitive disorders, Lille, France | [^y] Aix Marseille University, UMR-CNRS 7289, Service de Pharmacologie Clinique, AP-HM, Marseille, France | [^z] Memory Clinic and LANVIE - Laboratory of Neuroimaging of Aging, University Hospitals and University of Geneva, Geneva, Switzerland

Correspondence: [*] Correspondence to: Moira Marizzoni, Laboratory of Neuroimaging and Alzheimer’s Epidemiology, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, via Pilastroni 4, 25125 - Brescia, Italy. Tel.: +39 030 3501362; Fax: +39 030 3501592; E-mail: [email protected].

Abstract: Background:Early Alzheimer’s disease (AD) detection using cerebrospinal fluid (CSF) biomarkers has been recommended as enrichment strategy for trials involving mild cognitive impairment (MCI) patients. Objective:To model a prodromal AD trial for identifying MRI structural biomarkers to improve subject selection and to be used as surrogate outcomes of disease progression. Methods:APOE ɛ4 specific CSF Aβ42/P-tau cut-offs were used to identify MCI with prodromal AD (Aβ42/P-tau positive) in the WP5-PharmaCog (E-ADNI) cohort. Linear mixed models were performed 1) with baseline structural biomarker, time, and biomarker×time interaction as factors to predict longitudinal changes in ADAS-cog13, 2) with Aβ42/P-tau status, time, and Aβ42/P-tau status×time interaction as factors to explain the longitudinal changes in MRI measures, and 3) to compute sample size estimation for a trial implemented with the selected biomarkers. Results:Only baseline lateral ventricle volume was able to identify a subgroup of prodromal AD patients who declined faster (interaction, p = 0.003). Lateral ventricle volume and medial temporal lobe measures were the biomarkers most sensitive to disease progression (interaction, p≤0.042). Enrichment through ventricular volume reduced the sample size that a clinical trial would require from 13 to 76%, depending on structural outcome variable. The biomarker needing the lowest sample size was the hippocampal subfield GC-ML-DG (granule cells of molecular layer of the dentate gyrus) (n = 82 per arm to demonstrate a 20% atrophy reduction). Conclusion:MRI structural biomarkers can enrich prodromal AD with fast progressors and significantly decrease group size in clinical trials of disease modifying drugs.

Keywords: Alzheimer’s disease, biomarkers, clinical trial, magnetic resonance imaging, mild cognitive impairment, precision medicine

DOI: 10.3233/JAD-180152

Journal: Journal of Alzheimer's Disease, vol. 69, no. 1, pp. 3-14, 2019