Structural and functional connectivity in cerebral small vessel disease: Mechanistic insights from inherited and sporadic cases

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Cerebral small vessel disease (SVD) is a major cause for the loss of independence in the elderly. The main clinical manifestations impacting on activities of daily living are vascular cognitive impairment, disability & gait impairment as well as psychiatric disorders. The mechanisms underlying these symptoms are largely unknown, which might explain the lack of efficient therapies.Disconnection of brain regions has emerged as a disease hallmark. In recent years several candidate mechanisms have been postulated for how SVD might impact on brain connectivity. These mechanisms include microstructural damage, tissue edema, iron deposition and (cortical) microinfarcts. Disentangling the contribution of these mechanisms is essential for the identification of the prime therapeutic target.Recent advances in magnetic resonance image (MRI) acquisition, post-processing and analysis techniques enable to study brain connectivity in vivo. Connectivity assessment can rely on structural or functional measures. Metrics derived from graph theory (e.g. network efficiency) allow quantifying global and regional brain connectivity.We set out to evaluate structural and functional connectivity in SVD. The main objectives are i) to identify and assess the contribution of different mechanisms towards altered brain connectivity, ii) to assess the impact of altered connectivity on clinical symptoms, and iii) to study complex interactions and mediation among connectivity, cognitive impairment, gait impairment and psychiatric symptoms.The project uses a unique approach comprising two large, prospective samples: Patients with an inherited model disease (Munich sample) and subjects from a population-based study (Graz sample). The project will greatly benefit from the data transfer as well as the specific expertise of the two participating groups. Methods will be jointly developed and discussions will be continued over the project duration in the form of regular teleconferences and face-to-face meetings.This project will provide new mechanistic insight into clinically relevant processes of SVD, which will lead to the development of new research and ultimately treatment strategies.