Structural and functional connectivity in cerebral small vessel disease: Mechanistic insights from inherited and sporadic cases
Final Report Abstract
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 small vessel disease CADASIL. Because CADASIL patients can be diagnosed by molecular genetic testing and develop the disease at young age without age-related comorbidities, they offer a unique opportunity for mechanistic studies in pure cerebral small vessel 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. This finding supports novel pathophysiological concepts, such as the potential role of vasogenic edema following blood-brainbarrier disruption. Moreover, in a large collaborative study using 6 complementary patient samples, including genetically-defined diseases, we were able to convincingly show that cerebral small vessel disease much more than Alzheimer’s disease 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 Alzheimer’s 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. We could only detect moderate gait impairment, even when using sensitive, state-of-the-art dual task paradigms. This suggests a key role of age-related comorbidities, which were absent in these patients, for the development of gait deficits in sporadic small vessel disease and thus opens new therapeutic approaches. 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.
Publications
- Free water determines diffusion alterations and clinical status in cerebral small vessel disease. Alzheimers Dement. 2018;14(6):764-774
Duering M, Finsterwalder S, Baykara E, et al.
(See online at https://doi.org/10.1016/j.jalz.2017.12.007) - Grey-matter network disintegration as predictor of cognitive and motor function with aging. Brain Struct Funct. 2018;223(5):2475-2487
Koini M, Duering M, Gesierich BG, et al.
(See online at https://doi.org/10.1007/s00429-018-1642-0) - Minor gait impairment despite white matter damage in pure small vessel disease. Ann Clin Transl Neurol. 2019;6(10):2026-2036
Finsterwalder S, Wuehr M, Gesierich B, et al.
(See online at https://doi.org/10.1002/acn3.50891) - White Matter Hyperintensities in Alzheimer's Disease: A Lesion Probability Mapping Study. J Alzheimers Dis. 2019;68(2):789-796
Damulina A, Pirpamer L, Seiler S, et al.
(See online at https://doi.org/10.3233/JAD-180982) - Alterations and test-retest reliability of functional connectivity network measures in cerebral small vessel disease. Hum Brain Mapp. 2020;41(10):2629-2641
Gesierich B, Tuladhar AM, Ter Telgte A, et al.
(See online at https://doi.org/10.1002/hbm.24967) - Cross-sectional and Longitudinal Assessment of Brain Iron Level in Alzheimer Disease Using 3-T MRI. Radiology. 2020;296(3):619-626
Damulina A, Pirpamer L, Soellradl M, et al.
(See online at https://doi.org/10.1148/radiol.2020192541) - Gray Matter Covariance Networks as Classifiers and Predictors of Cognitive Function in Alzheimer's Disease. Front Psychiatry. 2020;11:360
Wagner F, Duering M, Gesierich BG, et al.
(See online at https://doi.org/10.3389/fpsyt.2020.00360) - Multi-shell diffusion MRI models for white matter characterization in cerebral small vessel disease. Neurology. 2020
Konieczny M, Dewenter A, ter Telgte A, et.al.
(See online at https://doi.org/10.1212/WNL.0000000000011213) - Small vessel disease more than Alzheimer's disease determines diffusion MRI alterations in memory clinic patients. 2020 Aug 18. Alzheimers Dement. 2020 Nov;16(11):1504-1514
Finsterwalder S, Vlegels N, Gesierich B, et al.
(See online at https://doi.org/10.1002/alz.12150)
