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Diffusion imaging markers of cerebral small vessel disease. validation and application
Diffusion imaging markers of cerebral small vessel disease. validation and application
Diffusion magnetic resonance imaging (MRI) is widely used as a research tool to assess (subtle) alterations of the cerebral white matter. Measures derived from diffusion MRI appear to be valuable markers for cerebral small vessel disease (SVD). However, SVD is frequently co-occurring with Alzheimer’s disease (AD), and disturbed white matter integrity and altered diffusion measures are considered key findings in both conditions. Yet, the contribution of SVD and AD to diffusion alterations is unclear, which hampers the interpretation of research studies in patients with mixed disease, e.g. memory clinic patients. Study 1 of this thesis aimed to clarify the effect of SVD and AD on diffusion measures by including multiple (memory clinic) samples covering the entire spectrum of SVD, mixed disease, and AD. We calculated diffusion measures from diffusion tensor imaging (DTI) and free water imaging. Within each sample of the disease spectrum, we applied simple regression analyses and multivariable random forest analyses between AD biomarkers (amyloid-beta, tau), conventional MRI markers of SVD, and global diffusion measures. Furthermore, we investigated regional associations between tau on positron emission tomography (PET) and diffusion measures in voxel-wise analyses. Our main findings are that conventional MRI markers of SVD were strongly associated with diffusion measures and showed a higher contribution than AD biomarkers in multivariable analyses across all memory clinic samples. Regional analyses between tau PET and diffusion measures were not significant. We conclude that SVD rather than AD determines diffusion alterations in memory clinic patients. Our findings validate diffusion measures as markers for SVD. Study 2 applied diffusion MRI markers to study gait impairment in SVD. Gait impairment is a commonly reported clinical deficit in SVD patients, but the underlying mechanisms are still debated. The proposed mechanisms include SVD-related white matter alterations resulting in impaired supraspinal locomotor control, cognitive deficits (e.g. planning and execution of movements), and factors independent of SVD, such as age-related instability (e.g. joint wear, sarcopenia) and comorbidities (e.g. neurodegenerative pathology). A reason for the lack of knowledge on gait impairment in SVD is that studies in elderly, sporadic SVD patients are typically confounded by effects of normal-aging and age-related comorbidities. Therefore, Study 2 of this thesis aimed to study the effect of pure SVD on gait performance in a relatively young sample of genetically defined SVD patients without age-related confounding. We performed comprehensive gait assessment using an electronic walkway to obtain multiple spatio-temporal gait parameters standardized based on data from healthy controls. Importantly, we tested the association between diffusion MRI markers of SVD-related white matter alterations and gait performance, since (strategic) white matter alterations are discussed as a major cause of gait decline in the elderly. Furthermore, we assessed the relation between cognitive deficits and gait performance. Our main finding is that, despite severe white matter alterations in pure SVD patients, gait performance was relatively preserved. Cognitive deficits in our study participants were not related to gait impairment. Thus, our results query isolated white matter alterations, in the absence of comorbidities, as a main factor of gait impairment in SVD and suggest that their combination with age-related comorbidities and/or normal-aging may play a crucial role in gait decline. In conclusion, diffusion measures are valid MRI markers of SVD-related white matter alterations. They have significant value both in future research on altered white matter and potentially also in the diagnostic work-up of memory clinic patients, to differentiate between vascular and neurodegenerative disease. Researchers may select target populations for clinical trials based on diffusion measures, e.g. to identify patients with a low SVD burden as targets for prevention and early intervention in SVD. Clinicians and researchers should always consider SVD as the origin of diffusion alterations in patients with mixed pathology. The field of application of diffusion measures is wide and may provide new insights into effects of subtle white matter alterations on clinical deficits, as shown in Study 2 on gait impairment in pure SVD. Future studies should investigate measures from advanced diffusion models and diffusion-based brain network analysis, to further elucidate the mechanisms of clinical deficits in SVD patients.
Magnetic resonance imaging, diffusion tensor imaging, Alzheimer's disease, cerebral small vessel disease, biomarker
Finsterwalder, Sofia
2020
English
Universitätsbibliothek der Ludwig-Maximilians-Universität München
Finsterwalder, Sofia (2020): Diffusion imaging markers of cerebral small vessel disease: validation and application. Dissertation, LMU München: Graduate School of Systemic Neurosciences (GSN)
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Abstract

Diffusion magnetic resonance imaging (MRI) is widely used as a research tool to assess (subtle) alterations of the cerebral white matter. Measures derived from diffusion MRI appear to be valuable markers for cerebral small vessel disease (SVD). However, SVD is frequently co-occurring with Alzheimer’s disease (AD), and disturbed white matter integrity and altered diffusion measures are considered key findings in both conditions. Yet, the contribution of SVD and AD to diffusion alterations is unclear, which hampers the interpretation of research studies in patients with mixed disease, e.g. memory clinic patients. Study 1 of this thesis aimed to clarify the effect of SVD and AD on diffusion measures by including multiple (memory clinic) samples covering the entire spectrum of SVD, mixed disease, and AD. We calculated diffusion measures from diffusion tensor imaging (DTI) and free water imaging. Within each sample of the disease spectrum, we applied simple regression analyses and multivariable random forest analyses between AD biomarkers (amyloid-beta, tau), conventional MRI markers of SVD, and global diffusion measures. Furthermore, we investigated regional associations between tau on positron emission tomography (PET) and diffusion measures in voxel-wise analyses. Our main findings are that conventional MRI markers of SVD were strongly associated with diffusion measures and showed a higher contribution than AD biomarkers in multivariable analyses across all memory clinic samples. Regional analyses between tau PET and diffusion measures were not significant. We conclude that SVD rather than AD determines diffusion alterations in memory clinic patients. Our findings validate diffusion measures as markers for SVD. Study 2 applied diffusion MRI markers to study gait impairment in SVD. Gait impairment is a commonly reported clinical deficit in SVD patients, but the underlying mechanisms are still debated. The proposed mechanisms include SVD-related white matter alterations resulting in impaired supraspinal locomotor control, cognitive deficits (e.g. planning and execution of movements), and factors independent of SVD, such as age-related instability (e.g. joint wear, sarcopenia) and comorbidities (e.g. neurodegenerative pathology). A reason for the lack of knowledge on gait impairment in SVD is that studies in elderly, sporadic SVD patients are typically confounded by effects of normal-aging and age-related comorbidities. Therefore, Study 2 of this thesis aimed to study the effect of pure SVD on gait performance in a relatively young sample of genetically defined SVD patients without age-related confounding. We performed comprehensive gait assessment using an electronic walkway to obtain multiple spatio-temporal gait parameters standardized based on data from healthy controls. Importantly, we tested the association between diffusion MRI markers of SVD-related white matter alterations and gait performance, since (strategic) white matter alterations are discussed as a major cause of gait decline in the elderly. Furthermore, we assessed the relation between cognitive deficits and gait performance. Our main finding is that, despite severe white matter alterations in pure SVD patients, gait performance was relatively preserved. Cognitive deficits in our study participants were not related to gait impairment. Thus, our results query isolated white matter alterations, in the absence of comorbidities, as a main factor of gait impairment in SVD and suggest that their combination with age-related comorbidities and/or normal-aging may play a crucial role in gait decline. In conclusion, diffusion measures are valid MRI markers of SVD-related white matter alterations. They have significant value both in future research on altered white matter and potentially also in the diagnostic work-up of memory clinic patients, to differentiate between vascular and neurodegenerative disease. Researchers may select target populations for clinical trials based on diffusion measures, e.g. to identify patients with a low SVD burden as targets for prevention and early intervention in SVD. Clinicians and researchers should always consider SVD as the origin of diffusion alterations in patients with mixed pathology. The field of application of diffusion measures is wide and may provide new insights into effects of subtle white matter alterations on clinical deficits, as shown in Study 2 on gait impairment in pure SVD. Future studies should investigate measures from advanced diffusion models and diffusion-based brain network analysis, to further elucidate the mechanisms of clinical deficits in SVD patients.