Biomarker Matrix to Track Short Term Disease Progression in Amnestic Mild Cognitive Impairment Patients with Prodromal Alzheimer’s Disease

Article type: Research Article

Authors: Marizzoni, Moira^{a; *} | Ferrari, Clarissa^b | Macis, Ambra^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; l} | Parnetti, Lucilla^m | Payoux, Pierreⁿ | Pizzini, Francesca^o | Rossini, Paolo Maria^p | Salvatore, Marco^q | Schönknecht, Peter^r | Soricelli, Andrea^q | Del Percio, Claudio^q | Hensch, Tilman^r | Hegerl, Ulrich^r | Tsolaki, Magda^s | Visser, Pieter Jelle^t | Wiltfang, Jens^{u; v; w} | Richardson, Jill C.^x | Bordet, Régis^y | Blin, Olivier^z | Frisoni, Giovanni B.^{a; aa} | The PharmaCog Consortium

Affiliations: [a] Laboratory of Neuroimaging and Alzheimer’s Epidemiology, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy | [b] Unit of Statistics, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy | [c] Center for Mind/Brain Sciences, University of Trento, Italy | [d] Department of Neuroscience, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milano, Italy | [e] Department of Physiology and Pharmacology “V. Erspamer”, Sapienza University of Rome, Rome, Italy | [f] Hospital San Raffaele Cassino, Cassino (FR), 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 Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Catalunya, Spain | [k] Department of Neuroscience (DINOGMI), University of Genoa, Genoa, Italy | [l] Clinica Neurologica, IRCCS Ospedale Policlinico San Martino, Genoa, Italy | [m] Clinica Neurologica, Università di Perugia, Ospedale Santa Maria della Misericordia, Perugia, Italy | [n] INSERM; Imagerie cérébrale et handicaps neurologiques UMR 825, Toulouse, France | [o] Department of Diagnostics and Pathology, Neuroradiology, Verona University Hospital, Italy | [p] Department of Gerontology, Area of Neuroscience, Neurosciences & Orthopedics, Catholic University, Policlinic A. Gemelli Foundation Rome, Italy | [q] IRCCS SDN, Napoli | [r] Department of Psychiatry and Psychotherapy, University of Leipzig, Leipzig, Germany | [s] 3rd Neurologic Clinic, Medical School, G. Papanikolaou Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece | [t] Department of Neurology, Alzheimer Centre, VU Medical Centre, Amsterdam, The Netherlands | [u] Department of Psychiatry and Psychotherapy, LVR-Hospital Essen, Faculty of Medicine, University of Duisburg-Essen, Essen, Germany | [v] Department of Psychiatry and Psychotherapy, University Medical Center (UMG), Georg-August-University, Goettingen, Germany | [w] iBiMED, Medical Sciences Department, University of Aveiro, Aveiro, Portugal | [x] Neurosciences Therapeutic Area, GlaxoSmithKline R&D, Gunnels Wood Road, Stevenage, UK | [y] University of Lille, Inserm, CHU Lille, U1171-Degenerative and vascular cognitive disorders, Lille, France | [z] Aix Marseille University, UMR-CNRS 7289, Service de Pharmacologie Clinique, AP-HM, Marseille, France | [aa] 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:Assessment of human brain atrophy in temporal regions using magnetic resonance imaging (MRI), resting state functional MRI connectivity in the left parietal cortex, and limbic electroencephalographic (rsEEG) rhythms as well as plasma amyloid peptide 42 (Aβ42) has shown that each is a promising biomarker of disease progression in amnestic mild cognitive impairment (aMCI) patients with prodromal Alzheimer’s disease (AD). However, the value of their combined use is unknown. Objective:To evaluate the association with cognitive decline and the effect on sample size calculation when using a biomarker composite matrix in prodromal AD clinical trials. Methods:Multicenter longitudinal study with follow-up of 2 years or until development of incident dementia. APOE ɛ4-specific cerebrospinal fluid (CSF) Aβ42/P-tau cut-offs were used to identify aMCI with prodromal AD. Linear mixed models were performed 1) with repeated matrix values and time as factors to explain the longitudinal changes in ADAS-cog13, 2) with CSF Aβ42/P-tau status, time, and CSF Aβ42/P-tau status×time interaction as factors to explain the longitudinal changes in matrix measures, and 3) to compute sample size estimation for a trial implemented with the selected matrices. Results:The best composite matrix included the MRI volumes of hippocampal dentate gyrus and lateral ventricle. This matrix showed the best sensitivity to track disease progression and required a sample size 31% lower than that of the best individual biomarker (i.e., volume of hippocampal dentate gyrus). Conclusion:Optimal matrices improved the statistical power to track disease development and to measure clinical progression in the short-term period. This might contribute to optimize the design of future clinical trials in MCI.

Keywords: Alzheimer’s disease, biomarker matrices, clinical trial, magnetic resonance imaging, mild cognitive impairment

DOI: 10.3233/JAD-181016

Journal: Journal of Alzheimer's Disease, vol. 69, no. 1, pp. 49-58, 2019