title: Brain connectivity in neurodegenerative diseases--from phenotype to proteinopathy.
abstract: Functional and structural connectivity measures, as assessed by means of functional and diffusion MRI, are emerging as potential intermediate biomarkers for Alzheimer disease (AD) and other disorders. This Review aims to summarize current evidence that connectivity biomarkers are associated with upstream and downstream disease processes (molecular pathology and clinical symptoms, respectively) in the major neurodegenerative diseases. The vast majority of studies have addressed functional and structural connectivity correlates of clinical phenotypes, confirming the predictable correlation with topography and disease severity in AD and frontotemporal dementia. In neurodegenerative diseases with motor symptoms, structural--but, to date, not functional--connectivity has been consistently found to be associated with clinical phenotype and disease severity. In the latest studies, the focus has moved towards the investigation of connectivity correlates of molecular pathology. Studies in cognitively healthy individuals with brain amyloidosis or genetic risk factors for AD have shown functional connectivity abnormalities in preclinical disease stages that are reminiscent of abnormalities observed in symptomatic AD. This shift in approach is promising, and may aid identification of early disease markers, establish a paradigm for other neurodegenerative disorders, shed light on the molecular neurobiology of connectivity disruption and, ultimately, clarify the pathophysiology of neurodegenerative diseases.
authors.affiliation: Laboratory of Epidemiology, Neuroimaging and Telemedicine (LENITEM), Istituto Centro San Giovanni di Dio, Fatebenefratelli, via Pilastroni 4, 25125 Brescia, Italy.
authors.forename: Michela
authors.initials: M
authors.lastname: Pievani
authors.affiliation: University Department of Psychiatry, Warneford Hospital, Warneford Lane, Oxford OX3 7JX, UK.
authors.forename: Nicola
authors.initials: N
authors.lastname: Filippini
authors.affiliation: Brain Center Rudolf Magnus, University Medical Center, Heidelberglaan 100, 85500 3908 GA Utrecht, Netherlands.
authors.forename: Martijn P
authors.initials: MP
authors.lastname: van den Heuvel
authors.affiliation: Istituto Universitario di Studi Superiori (IUSS), Piazza della Vittoria 15, 27100 Pavia, Italy.
authors.forename: Stefano F
authors.initials: SF
authors.lastname: Cappa
authors.affiliation: Memory Clinic and LANVIE-Laboratory of Neuroimaging of Aging, University Hospitals and University of Geneva, Chemin du Petit Bel-Air 2 (Bâtiment Voirons), CH-1225 Chêne-Bourg, Genève, Switzerland.
authors.forename: Giovanni B
authors.initials: GB
authors.lastname: Frisoni
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism / Q000503:physiopathology*; D001921:Brain / Q000378:metabolism / Q000503:physiopathology*; D038524:Diffusion Magnetic Resonance Imaging; D057180:Frontotemporal Dementia / Q000378:metabolism / Q000503:physiopathology*; D059907:Functional Neuroimaging; D006801:Humans; D008279:Magnetic Resonance Imaging; D009434:Neural Pathways / Q000378:metabolism / Q000503:physiopathology*; D019636:Neurodegenerative Diseases / Q000378:metabolism / Q000503:physiopathology; D010641:Phenotype; D062706:Prodromal Symptoms