Mechanisms of sporadic cerebral small vessel disease:insights from neuroimaging

The term “cerebral small vessel disease” (SVD) describes a range of neuroimaging, pathological and associated clinical features. The latter range from none, to discrete focal neurological symptoms (stroke), to insidious global neurological dysfunction and dementia. The public health burden is considerable. The pathogenesis is largely unknown. Although associated with vascular risk factors, and generally considered to result from an intrinsic cerebral arteriolar occlusive disease, the pathological processes leading to the arteriolar disease, how these result in brain disease, how SVD lesions contribute to neurological or cognitive symptoms and the relationship to risk factors, have been the subject of much speculation. Pathology often reflects end-stage disease making determination of the earliest stages difficult. Neuroimaging provides considerable insights: the small vessels are not easily seen themselves, but the effects of their malfunction on the brain can be tracked on detailed brain imaging. We review the growing evidence for the most likely mechanisms

Magnetic resonance imaging characteristics of CADASIL

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a hereditary small-vessel disease caused by mutations in the NOTCH3 gene on chromosome 19. Magnetic resonance (MR) imaging plays an important role in the diagnostic work-up of CADASIL patients. In this thesis we describe the presence of microbleeds and a new, highly characteristic radiological finding in CADASIL patients, the so called subcortical lacunar lesions (SLL). We describe the natural history of the various brain lesions that can be observed in CADASIL patients, the microbleeds, SLL, lacunar infarcts, and white matter hyperintensities (WMHs). Also included are the results of a study on the differences of the lesions seen in CADASIL as compared to the lesions that occur in multiple sclerosis, a disease with radiological and clinical similarities to CADASIL. We found that MR lesions develop in a predictable way during the course of the disease and that SLL and WMHs in the anterior temporal lobe are helpful radiological hallmarks for the of detection CADASIL. The WMHs in the anterior lobe especially in combination with one of the other CADASIL MR hallmarks should distinguish CADASIL patients from patients with multiple sclerosis.UBL - phd migration 201

Rationale and design of a longitudinal study of cerebral small vessel diseases, clinical and imaging outcomes in patients presenting with mild ischaemic stroke: Mild Stroke Study 3

Background: Cerebral small vessel disease is a major cause of dementia and stroke, visible on brain magnetic resonance imaging. Recent data suggest that small vessel disease lesions may be dynamic, damage extends into normal-appearing brain and microvascular dysfunctions include abnormal blood–brain barrier leakage, vasoreactivity and pulsatility, but much remains unknown regarding underlying pathophysiology, symptoms, clinical features and risk factors of small vessel disease. Patients and Methods: The Mild Stroke Study 3 is a prospective observational cohort study to identify risk factors for and clinical implications of small vessel disease progression and regression among up to 300 adults with non-disabling stroke. We perform detailed serial clinical, cognitive, lifestyle, physiological, retinal and brain magnetic resonance imaging assessments over one year; we assess cerebrovascular reactivity, blood flow, pulsatility and blood–brain barrier leakage on magnetic resonance imaging at baseline; we follow up to four years by post and phone. The study is registered ISRCTN 12113543. Summary: Factors which influence direction and rate of change of small vessel disease lesions are poorly understood. We investigate the role of small vessel dysfunction using advanced serial neuroimaging in a deeply phenotyped cohort to increase understanding of the natural history of small vessel disease, identify those at highest risk of early disease progression or regression and uncover novel targets for small vessel disease prevention and therapy

Small Vessel Disease in the Heart and Brain: Current Knowledge, Unmet Therapeutic Need and Future Directions

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Neuroimaging standards for research into small vessel disease and its contribution to ageing and neurodegeneration: A united approach

Item does not contain fulltextCerebral small vessel disease (SVD) is a common accompaniment of ageing. Features seen on neuroimaging include recent small subcortical infarcts, lacunes, white matter hyperintensities, perivascular spaces, microbleeds, and brain atrophy. SVD can present as a stroke or cognitive decline, or can have few or no symptoms. SVD frequently coexists with neurodegenerative disease, and can exacerbate cognitive deficits, physical disabilities, and other symptoms of neurodegeneration. Terminology and definitions for imaging the features of SVD vary widely, which is also true for protocols for image acquisition and image analysis. This lack of consistency hampers progress in identifying the contribution of SVD to the pathophysiology and clinical features of common neurodegenerative diseases. We are an international working group from the Centres of Excellence in Neurodegeneration. We completed a structured process to develop definitions and imaging standards for markers and consequences of SVD. We aimed to achieve the following: first, to provide a common advisory about terms and definitions for features visible on MRI; second, to suggest minimum standards for image acquisition and analysis; third, to agree on standards for scientific reporting of changes related to SVD on neuroimaging; and fourth, to review emerging imaging methods for detection and quantification of preclinical manifestations of SVD. Our findings and recommendations apply to research studies, and can be used in the clinical setting to standardise image interpretation, acquisition, and reporting. This Position Paper summarises the main outcomes of this international effort to provide the STandards for ReportIng Vascular changes on nEuroimaging (STRIVE)

Vasoreactivity in CADASIL: comparison to structural MRI and neuropsychology

Impaired cerebrovascular reactivity precedes histological and clinical evidence of CADASIL in animal models. We aimed to more fully characterise peripheral and cerebral vascular function and reactivity in a cohort of adult CADASIL patients, and explore the associations of these with conventional clinical, imaging and neuropsychological measures. 22 adults with CADASIL gave informed consent to participate in an exploratorystudy of vascular function in CADASIL. Clinical assessment, comprehensive vascular assessment, MRI and neuropsychological testing were conducted. Transcranial Doppler and arterial spin labelling MRI with hypercapnia challenge both measured cerebral vasoreactivity. Number and volume of lacunes, subcortical hyperintensity volume, microbleeds and normalised brain volume were assessed on MRI scans. Analysis was exploratory and examined associations between different markers. The results showed that cerebrovascular reactivity measured by ASL correlated with peripheral vasoreactivity measured by flow mediated dilatation. Subjects with >5 lacunes were older, with evidence of atherosclerosis and had impaired cerebral and peripheral vasoreactivity. Subjects with depressive symptoms, disability or delayed processing speed, also had impaired vasoreactivity, as well as more lacunes and brain atrophy. Impaired vasoreactivity and vascular dysfunction may play a significant role in the pathophysiology of CADASIL and vascular tests may be important to include in both longitudinal and clinical trials

Cerebrovascular dysfunction in cerebral small vessel disease

INTRODUCTION: Cerebral small vessel disease (SVD) is the cause of a quarter of all ischaemic strokes and is postulated to have a role in up to half of all dementias. SVD pathophysiology remains unclear but cerebrovascular dysfunction may be important. If confirmed many licensed medications have mechanisms of action targeting vascular function, potentially enabling new treatments via drug repurposing. Knowledge is limited however, as most studies assessing cerebrovascular dysfunction are small, single centre, single imaging modality studies due to the complexities in measuring cerebrovascular dysfunctions in humans. This thesis describes the development and application of imaging techniques measuring several cerebrovascular dysfunctions to investigate SVD pathophysiology and trial medications that may improve small blood vessel function in SVD. METHODS: Participants with minor ischaemic strokes were recruited to a series of studies utilising advanced MRI techniques to measure cerebrovascular dysfunction. Specifically MRI scans measured the ability of different tissues in the brain to change blood flow in response to breathing carbon dioxide (cerebrovascular reactivity; CVR) and the flow and pulsatility through the cerebral arteries, venous sinuses and CSF spaces. A single centre observational study optimised and established feasibility of the techniques and tested associations of cerebrovascular dysfunctions with clinical and imaging phenotypes. Then a randomised pilot clinical trial tested two medications’ (cilostazol and isosorbide mononitrate) ability to improve CVR and pulsatility over a period of eight weeks. The techniques were then expanded to include imaging of blood brain barrier permeability and utilised in multi-centre studies investigating cerebrovascular dysfunction in both sporadic and monogenetic SVDs. RESULTS: Imaging protocols were feasible, consistently being completed with usable data in over 85% of participants. After correcting for the effects of age, sex and systolic blood pressure, lower CVR was associated with higher white matter hyperintensity volume, Fazekas score and perivascular space counts. Lower CVR was associated with higher pulsatility of blood flow in the superior sagittal sinus and lower CSF flow stroke volume at the foramen magnum. Cilostazol and isosorbide mononitrate increased CVR in white matter. The CVR, intra-cranial flow and pulsatility techniques, alongside blood brain barrier permeability and microstructural integrity imaging were successfully employed in a multi-centre observational study. A clinical trial assessing the effects of drugs targeting blood pressure variability is nearing completion. DISCUSSION: Cerebrovascular dysfunction in SVD has been confirmed and may play a more direct role in disease pathogenesis than previously established risk factors. Advanced imaging measures assessing cerebrovascular dysfunction are feasible in multi-centre studies and trials. Identifying drugs that improve cerebrovascular dysfunction using these techniques may be useful in selecting candidates for definitive clinical trials which require large sample sizes and long follow up periods to show improvement against outcomes of stroke and dementia incidence and cognitive function