Disease Tracking Markers for Alzheimer's Disease at the Prodromal (MCI) Stage

Issue title: Imaging the Alzheimer Brain

Guest editors: J. Wesson Ashford, Allyson Rosen, Maheen Adamson, Peter Bayley, Osama Sabri, Ansgar Furst, Sandra E. Black and Michael Weiner

Article type: Research Article

Authors: Drago, Valeria^a | Babiloni, Claudio^b | Bartrés-Faz, David^c | Caroli, Anna^{a; e} | Bosch, Beatriz^c | Hensch, Tilman^d | Didic, Mira^f | Klafki, Hans-Wolfgang^g | Pievani, Michela^a | Jovicich, Jorge^h | Venturi, Luca^a | Spitzer, Philipp^g | Vecchio, Fabrizioⁱ | Schoenknecht, Peter^d | Wiltfang, Jans^g | Redolfi, Alberto^a | Forloni, Gianluigi^j | Blin, Olivier^k | Irving, Elaine^l | Davis, Ceri^l | Hårdemark, Hans-goran^m | Frisoni, Giovanni B.^{a; *}

Affiliations: [a] LENITEM Laboratory of Epidemiology, Neuroimaging and Telemedicine, IRCCS “San Giovanni di Dio – Fatebenefratelli”, Brescia, Italy | [b] Department of Biomedical Sciences, University of Foggia, Foggia, Italy | [c] Institut d'Investigació Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Departament de Psiquiatria i Psicobiologia Clínica, Facutat de Medicina, Universitat de Barcelona, and Alzheimer's disease and other cognitive disorders unit, Neurology Service, Hospital Clínic de Barcelona, Barcelona, Spain | [d] Department of Psychiatry, University of Leipzig, Leipzig, Germany | [e] Medical Imaging Unit, Biomedical Engineering Department, Mario Negri, Institute for Pharmacological Research, Bergamo | [f] Service de Neurologie et de Neuropsychologie, Pôle de neurosciences cliniques, Assistance Publique des Hôpitaux de Marseille, Hôpitaux de la Timone, CMRR PACA Ouest & INSERM U751, Faculté de Médecine, Université de la Méditerranée, Marseille, France | [g] Department of Psychiatry and Psychotherapy, University of Duisburg-Essen, LVR-Klinikum, Essen, Germany | [h] Functional NeuroImaging Laboratory, Center for Mind Brain Sciences, University of Trento | [i] A.Fa.R., Dip. Neurosci. Osp. FBF, Isola Tiberina, Rome, Italy | [j] Istituto di Ricerche Farmacologiche “Mario Negri” | [k] Clinical Investigation Centre (CIC-UPCET) and Department of Clinical Pharmacology, UMR-CNRS, 6193 Institute of Cognitive Neurosciences, CHU, Timone, Marseille, France | [l] Neurosciences CEDD, GlaxoSmithKline, Harlow, Essex, UK | [m] AstraZencea R&D Clinical Neuroscience Therapy Area SE-151 85 Södertälje, Sweden

Correspondence: [*] Correspondence to: Giovani B. Frisoni, Via Pilastroni 1, 25125, Brescia, Italy. Tel.: +39 030 35011; Fax: +39 030 348255; E-mail: gfrisoni@fatebenefratelli.it.

Abstract: Older persons with Mild Cognitive Impairment (MCI) feature neurobiological Alzheimer's Disease (AD) in 50% to 70% of the cases and develop dementia within the next 5 to 7 years. Current evidence suggests that biochemical, neuroimaging, electrophysiological, and neuropsychological markers can track the disease over time since the MCI stage (also called prodromal AD). The amount of evidence supporting their validity is of variable strength. We have reviewed the current literature and categorized evidence of validity into three classes: Class A, availability of multiple serial studies; Class B a single serial study or multiple cross sectional studies of patients with increasing disease severity from MCI to probable AD; and class C, multiple cross sectional studies of patients in the dementia stage, not including the MCI stage. Several Class A studies suggest that episodic memory and semantic fluency are the most reliable neuropsychological markers of progression. Hippocampal atrophy, ventricular volume and whole brain atrophy are structural MRI markers with class A evidence. Resting-state fMRI and connectivity, and diffusion MR markers in the medial temporal white matter (parahippocampus and posterior cingulum) and hippocampus are promising but require further validation. Change in amyloid load in MCI patients warrant further investigations, e.g. over longer period of time, to assess its value as marker of disease progression. Several spectral markers of resting state EEG rhythms that might reflect neurodegenerative processes in the prodromal stage of AD (EEG power density, functional coupling, spectral coherence, and synchronization) suffer from lack of appropriately designed studies. Although serial studies on late event-related potentials (ERPs) in healthy elders or MCI patients are inconclusive, others tracking disease progression and effects of cholinesterase inhibiting drugs in AD, and cross-sectional including MCI or predicting development of AD offer preliminary evidence of validity as a marker of disease progression from the MCI stage. CSF Markers, such as Aβ1-42, t-tau and p-tau are valuable markers which support the clinical diagnosis of Alzheimer's disease. However, these markers are not sensitive to disease progression and cannot be used to monitor the severity of Alzheimer's disease. For Isoprostane F2 some evidence exists that its increase correlates with the progression and the severity of AD.

Keywords: Alzheimer's disease, Mild cognitive impairment, neuropsychology, neuroimaging, diffusion tensor imaging, functional MRI, spectroscopy, positron emission tomography, EEG, cerebrospinal fluid

DOI: 10.3233/JAD-2011-0043

Journal: Journal of Alzheimer's Disease, vol. 26, no. s3, pp. 159-199, 2011