Project: Mechanisms of Small Vessel Related Brain Damage and Cognitive Impairment: Integrating Imaging Findings from Genetic and Sporadic Disease

Cerebral small vessel disease (SVD) is a major cause of stroke and the leading cause of vascular cognitive impairment (VCI). It also contributes to other disabling symptoms such as gait disturbance and late-life depression and its prevalence strongly increases with age. Recent developments in neuroimaging and image post-processing have enabled novel and important insights into disease mechanisms and expanded the spectrum of pathological alterations associated with SVD. Additional insights have come from the study of rare Mendelian variants. Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), a hereditary condition identified by the applicants and others, represents a pure form of SVD, which has successfully been used as a model. This proposal takes a coordinated approach to identify key pathophysiological mechanisms in SVD and related cognitive impairment. We hypothesise that hereditary and sporadic forms of SVD have mechanisms in common and that integrating findings from CADASIL and sporadic SVD provides a powerful approach to identify general disease mechanisms in SVD. We propose to use data from two complementary cohorts of subjects that have been followed by the applying groups by detailed neuroimaging and cognitive testing over up to 6 years. We suggest applying innovative image post-processing and analytical tools 1) to explore the mechanisms of structural brain lesions (small infarcts and early ischemic as well as secondary degenerative changes) associated with SVD including patterns of evolution and 2) to determine how these lesions contribute to cognitive decline. The four applicants provide highly complementary resources and expertise. MD, HC, and RS provide patient samples and have a long track record in neuroimaging. Specific expertise in analyzing complex datasets is provided by the fourth PI (JFM) who will help integrating findings from the two cohorts into joint models using machine learning processes. The four applicants have successfully collaborated and published together in the past thus enhancing the chances for success. We anticipate that the identification of disease mechanisms will focus future research efforts to relevant mechanism and ultimately provide the field with novel predictive instruments, markers and targets for therapeutic trials.

Acronym	MESCOG
Duration	01/03/2012 - 29/02/2016
Network	NEURON
Call	NEURON-2011 Cerebrovascular Diseases

Project partner

Number	Name	Role	Country
1	Klinikum der Universität München, University of Munich	Coordinator	Germany
2	INSERM UMR-740	Partner	France
3	CEA (Commissariat à l'Energie Atomique et aux Energies Alternatives)	Partner	France
4	University of Graz	Partner	Austria