Connectivity in cerebral microangiopathy

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. Keywords: - cerebral small vessel disease - pathomechanisms - brain connectivity - magnetic resonance imaging - genetically defined model disease - population-based validation approach

This D-A-CH collaboration project between Graz and Munich investigated the role of brain connectivity in cerebral small vessel disease, a leading cause of stroke and dementia. Patients with cerebral small vessel disease typically present with cognitive slowing and gait disturbances. These symptoms are often attributed to a disconnection of brain regions, occurring as a result of damage to the fiber connections running in the brain white matter. The aim of the project was to investigate structural and functional brain connectivity to better understand pathophysiology and to develop advanced biomarkers for research studies, trials and clinical routine. As a key asset, our analyses included not only patients with sporadic small vessel disease, but also patients with the inherited and sporadic small vessel disease (CADASIL) and Alzheimers disease. The project delivered several important new insights, which challenge existing paradigms and have a substantial impact on future research and clinical routine. Major advances have been made in the area of diffusion MRI, which became the gold standard MRI marker for cerebral small vessel disease during the course of the project. Using free water imaging, we were able to elucidate the origin of diffusion MRI alterations in brain tissue of small vessel disease patients. An elevated content of extracellular free water, and not damage to fiber structure, was the main determinant of diffusion alterations. Moreover,we were able to convincingly show that cerebral small vessel disease much more than Alzheimers pathology determines diffusion MRI alterations in memory clinic patients. This finding clarifies the role of diffusion MRI as marker for small vessel disease in the memory clinic. The assessment of iron accumulation in neocortical regions was a challenging task, as cortical regions are exposed to macroscopic magnetic field distortions causing increased relaxation rates. However, the implementation of advanced processing techniques allowed us to correct for these macroscopic susceptibility effects and to identify neocortical and subcortical regions susceptible for increased iron accumulations in Alzheimers disease. In a longitudinal analysis of 17 months we found that only increased iron levels in the temporal lobe were related to cognitive decline. A surprising finding was the low effect of cerebral small vessel disease on gait function in young patients with genetically-defined disease. Our study on functional brain connectivity revealed that functional connectivity can be used in the young CADASIL patients to explore cognitively relevant functional disconnection of brain regions. However, reliability of functional network measures, as assessed in a unique high frequency serial imaging study, was low in sporadic patients. The finding that age was a predictor for low reliability has important implications beyond small vessel disease for all future functional connectivity studies in elderly study participants