The primary aim of this thesis is to investigate vascular and structural neuroimaging findings in migraine to ultimately identify possible causes for the well-known increased risk of structural... Show moreThe primary aim of this thesis is to investigate vascular and structural neuroimaging findings in migraine to ultimately identify possible causes for the well-known increased risk of structural brain lesions. To this purpose, we used advanced MRI techniques in migraine patients, retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations (RVCL-S) patients and controls to evaluate vascular function. Moreover, we evaluated structural brain changes in repetitive hemiplegic migraine attacks. Secondary aim of this thesis is to describe the neuroimaging findings in a large Dutch cohort of RVCL-S patients of different ages. Show less
The overarching theme throughout this thesis is the exploration of new and the improvement of existing methods of measuring neurovascular pathology using MRI techniques and postprocessing. As... Show moreThe overarching theme throughout this thesis is the exploration of new and the improvement of existing methods of measuring neurovascular pathology using MRI techniques and postprocessing. As cerebrovascular afflictions are not located at a single location, these methods are applied throughout the cerebrovascular tree. This thesis starts with the large (macro) arteries (chapter 2), to the function of (micro) arteries (chapters 3 and 4), to remnants of hemorrhages in brain tissue (chapter 5), to finally the venous compartment (chapter 6), and takes into account both structure and function of selected parts of the cerebrovascular tree. Show less
Oussoren, F.K.; Schermer, T.R.; Leeuwen, R.B. van; Bruintjes, T.D. 2023
Vascular involvement in the pathophysiology of idiopathic sudden sensorineural hearing loss (iSSNHL) has been previously proposed. The objective of this study was to perform a systematic review of... Show moreVascular involvement in the pathophysiology of idiopathic sudden sensorineural hearing loss (iSSNHL) has been previously proposed. The objective of this study was to perform a systematic review of the current literature and conduct meta-analyses to evaluate associations between cardiovascular risk factors, cerebral small vessel disease, and subsequent stroke after presentation with iSSNHL. Three systematic literature reviews and meta-analyses were conducted using PubMed, Embase, and CINAHL. All studies investigating associations between iSSNHL and the cardiovascular risk factors: body mass index (BMI), diabetes mellitus, hyperlipidemia, hypertension, medical history of myocardial infarction (MI), smoking, the degree of white matter hyperintensities, and incidence of stroke were included. Adhering to the PRISMA guidelines, two independent reviewers reviewed the articles and assessed risk of bias. The cardiovascular risk factors of abnormal BMI, diabetes, hypertension, total cholesterol, low-density lipoprotein cholesterol, and a medical history of MI were significantly associated with iSSNHL. The adjusted hazard ratio of a higher degree of white matter hyperintensities was 0.70 (95% CI 0.44, 1.12). Patients with iSSNHL showed a higher risk of stroke compared to controls, with hazard ratios ranging from 1.22 up to 4.08. Several cardiovascular risk factors are more frequently present in patients with iSSNHL than in the general population. The degree of white matter hyperintensities does not appear to be increased in patients with iSSNHL, while the risk of stroke following ISSNHL is increased. Prospective studies with larger study populations are needed to confirm the associations between generalized cardiovascular disease and iSSNHL and to assess whether these patients benefit from cardiovascular risk management to prevent future cardiovascular and cerebrovascular disease. Show less
Background: Deep medullary vein (DMV) changes occur in cerebral small vessel diseases (SVD) and in Alzheimer's disease. Cerebral amyloid angiopathy (CAA) is a common SVD that has a high co... Show moreBackground: Deep medullary vein (DMV) changes occur in cerebral small vessel diseases (SVD) and in Alzheimer's disease. Cerebral amyloid angiopathy (CAA) is a common SVD that has a high co-morbidity with Alzheimer's disease. So far, DMVs have not been evaluated in CAA. Objective: To evaluate DMVs in Dutch-type hereditary CAA (D-CAA) mutation carriers and controls, in relation to MRI markers associated with D-CAA. Methods: Quantitative DMV parameters length, tortuosity, inhomogeneity, and density were quantified on 7 Tesla 3D susceptibility weighted MRI in pre-symptomatic D-CAA mutation carriers (n = 8), symptomatic D-CAA mutation carriers (n = 8), and controls (n = 25). HemorrhagicMRImarkers (cerebral microbleeds, intracerebral hemorrhages, cortical superficial siderosis, convexity subarachnoid hemorrhage), non-hemorrhagic MRI markers (white matter hyperintensities, enlarged perivascular spaces, lacunar infarcts, cortical microinfarcts), cortical grey matter perfusion, and diffusion tensor imaging parameters were assessed in D-CAA mutation carriers. Univariate general linear analysis was used to determine associations between DMV parameters and MRI markers. Results: QuantitativeDMVparameters length, tortuosity, inhomogeneity, and density did not differ between pre-symptomatic D-CAA mutation carriers, symptomatic D-CAA mutation carriers, and controls. No associations were found between DMV parameters and MRI markers associated with D-CAA.Conclusion: This study indicates that vascular amyloid-beta deposition does not affectDMVparameters. In patients with CAA, DMVs do not seem to play a role in the pathogenesis of MRI markers associated with CAA. Show less
Keller, J.A.; Kant, I.M.J.; Slooter, A.J.C.; Montfort, S.J.T. van; Buchem, M.A. van; Osch, M.J.P. van; ... ; Bresser, J. de 2022
The underlying mechanisms of the association between cardiovascular risk factors and a higher white matter hyperintensity (WMH) burden are unknown. We investigated the association between... Show moreThe underlying mechanisms of the association between cardiovascular risk factors and a higher white matter hyperintensity (WMH) burden are unknown. We investigated the association between cardiovascular risk factors and advanced WMH markers in 155 non-demented older adults (mean age: 71 +/- 5 years). The association between cardiovascular risk factors and quantitative MRI-based WMH shape and volume markers were examined using linear regression analysis. Presence of hypertension was associated with a more irregular shape of periventricular/confluent WMH (convexity (B (95 % CI)): -0.12 (-0.22--0.03); concavity index: 0.06 (0.02-0.11)), but not with total WMH volume (0.22 (-0.15-0.59)). Presence of diabetes was associated with deep WMH volume (0.89 (0.15-1.63)). Body mass index or hyperlipidemia showed no association with WMH markers. In conclusion, different cardiovascular risk factors seem to be related to a distinct pattern of WMH shape markers in non-demented older adults. These findings may suggest that different underlying cardiovascular pathological mechanisms lead to different WMH MRI phenotypes, which may be valuable for early detection of individuals at risk for stroke and dementia. Show less
Perivascular spaces (PVS) are compartments surrounding cerebral blood vessels that become visible on MRI when enlarged. Enlarged PVS (EPVS) are commonly seen in patients with cerebral small vessel... Show morePerivascular spaces (PVS) are compartments surrounding cerebral blood vessels that become visible on MRI when enlarged. Enlarged PVS (EPVS) are commonly seen in patients with cerebral small vessel disease (CSVD) and have been suggested to reflect dysfunctional perivascular clearance of soluble waste products from the brain. In this study, we investigated histopathological correlates of EPVS and how they relate to vascular amyloid-beta (A beta) in cerebral amyloid angiopathy (CAA), a form of CSVD that commonly co-exists with Alzheimer's disease (AD) pathology. We used ex vivo MRI, semi-automatic segmentation and validated deep-learning-based models to quantify EPVS and associated histopathological abnormalities. Severity of MRI-visible PVS during life was significantly associated with severity of MRI-visible PVS on ex vivo MRI in formalin fixed intact hemispheres and corresponded with PVS enlargement on histopathology in the same areas. EPVS were located mainly around the white matter portion of perforating cortical arterioles and their burden was associated with CAA severity in the overlying cortex. Furthermore, we observed markedly reduced smooth muscle cells and increased vascular A beta accumulation, extending into the WM, in individually affected vessels with an EPVS. Overall, these findings are consistent with the notion that EPVS reflect impaired outward flow along arterioles and have implications for our understanding of perivascular clearance mechanisms, which play an important role in the pathophysiology of CAA and AD. Show less
The aim of this thesis was to investigate cardiovascular determinants of neurocognitive functioning in old age, in particular cognitive dysfunction, depressive symptoms, and apathy. First, we found... Show moreThe aim of this thesis was to investigate cardiovascular determinants of neurocognitive functioning in old age, in particular cognitive dysfunction, depressive symptoms, and apathy. First, we found that the Geriatric Depression Scale(GDS)-3A, the apathy sub set of the GDS-15, moderately discriminates between presence and absence of apathy, and can be used in large study populations to investigate associations with apathy. Next, we demonstrated that higher levels of high sensitivity cardiac troponin T (hs-cTnT), a clinical cardiac biomarker, are related to accelerated cognitive decline, but not to apathy or depression.In the next chapters, we tested the hypothesis that in those older persons with more vascular brain damage, a lower rather than a higher blood pressure is related to worse neurocognitive function. Indeed, we found that only in those older persons with worse daily functioning and those with more cerebral small vessel disease, lower blood pressure was related to more symptoms of apathy. This pattern was not observed for depression or cognitive function.In conclusion, we found that cardiovascular risk factors are important for neurocognitive functioning in older persons. Moreover, we found that specific cardiovascular determinants, such as blood pressure and hs-cTnT, have different associations with apathy than with depression and cognitive function. Show less
Gravesteijn, G.; Munting, L.P.; Overzier, M.; Mulder, A.A.; Hegeman, I.; Derieppe, M.; ... ; Oberstein, S.A.J.L. 2019
CADASIL is a NOTCH3-associated cerebral small vessel disease. A pathological ultrastructural disease hallmark is the presence of NOTCH3-protein containing deposits called granular osmiophilic... Show moreCADASIL is a NOTCH3-associated cerebral small vessel disease. A pathological ultrastructural disease hallmark is the presence of NOTCH3-protein containing deposits called granular osmiophilic material (GOM), in small arteries. How these GOM deposits develop over time and what their role is in disease progression is largely unknown. Here, we studied the progression of GOM deposits in humanized transgenic NOTCH3(Arg182Cys) mice, compared them to GOM deposits in patient material, and determined whether GOM deposits in mice are associated with a functional CADASIL phenotype. We found that GOM deposits are not static, but rather progress in ageing mice, both in terms of size and aspect. We devised a GOM classification system, reflecting size, morphology and electron density. Six-month-old mice showed mostly early stage GOM, whereas older mice and patient vessels showed predominantly advanced stage GOM, but also early stage GOM. Mutant mice did not develop the most severe GOM stage seen in patient material. This absence of end-stage GOM in mice was associated with an overall lack of histological vascular pathology, which may explain why the mice did not reveal functional deficits in cerebral blood flow, cognition and motor function. Taken together, our data indicate that GOM progress over time, and that new GOM deposits are continuously being formed. The GOM staging system we introduce here allows for uniform GOM deposit classification in future mouse and human studies, which may lead to more insight into a potential association between GOM stage and CADASIL disease severity, and the role of GOM in disease progression. Show less
Thrippleton, M.J.; Backes, W.H.; Sourbron, S.; Ingrisch, M.; Osch, M.J.P. van; Dichgans, M.; ... ; Wardlaw, J.M. 2019
Cerebral small vessel disease (cSVD) comprises pathological processes of the small vessels in the brain that may manifest clinically as stroke, cognitive impairment, dementia, or gait disturbance.... Show moreCerebral small vessel disease (cSVD) comprises pathological processes of the small vessels in the brain that may manifest clinically as stroke, cognitive impairment, dementia, or gait disturbance. It is generally accepted that endothelial dysfunction, including blood-brain barrier (BBB) failure, is pivotal in the pathophysiology. Recent years have seen increasing use of imaging, primarily dynamic contrast-enhanced magnetic resonance imaging, to assess BBB leakage, but there is considerable variability in the approaches and findings reported in the literature. Although dynamic contrast-enhanced magnetic resonance imaging is well established, challenges emerge in cSVD because of the subtle nature of BBB impairment. The purpose of this work, authored by members of the HARNESS Initiative, is to provide an in-depth review and position statement on magnetic resonance imaging measurement of subtle BBB leakage in clinical research studies, with aspects requiring further research identified. We further aim to provide information and consensus recommendations for new investigators wishing to study BBB failure in cSVD and dementia. (C) 2019 The Authors. Published by Elsevier Inc. on behalf of the Alzheimer's Association. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). Show less
