Background and Purpose: In cerebral small vessel disease, cerebral blood flow and autoregulation are impaired and therefore excessive blood pressure reduction could possibly accelerate white matter damage and worsen outcome. The trial determined, in severe symptomatic cerebral small vessel disease, whether intensive blood pressure lowering resulted in progression of white matter damage assessed using diffusion tensor imaging. Methods: Randomized, parallel, multicenter controlled, blinded-outcomes clinical trial. One hundred eleven participants with magnetic resonance imaging confirmed symptomatic lacunar infarct and confluent white matter hyperintensities and were recruited and randomized to standard (systolic=130–140 mmHg) (N=56) or intensive (systolic<125 mmHg) (N=55) blood pressure targets. The primary end point was change in diffusion tensor imaging white matter mean diffusivity peak height between baseline and 24 months. Secondary end points were other magnetic resonance imaging markers and cognition. Results: Patients were mean 68 years and 60% male. Mean (SD) blood pressure reduced by −15.3 (15.4) and −23.1 (22.04) mm Hg in the standard/intensive groups, respectively ( P <0.001). There was no difference between treatment groups for the primary end point: standard, adjusted mean (SE)=12.5×10 −3 (0.2×10 −3 ); intensive, 12.5×10 −3 (0.2×10 −3 ), P =0.92. In the whole population over 24 months follow-up, there was a significant deterioration in white matter microstructure but no detectable decrease in cognition. Conclusions: Intensive blood pressure lowering in severe cerebral small vessel disease was not associated with progression of white matter damage on diffusion tensor imaging or magnetic resonance imaging. In a multicentre study setting over 2 years, multimodal diffusion tensor imaging-magnetic resonance imaging was more sensitive to detecting change than cognitive testing. REGISTRATION: URL: https://www.isrctn.com ; Unique identifier: ISRCTN37694103.
ImportanceCerebral small vessel disease (SVD) causes a quarter of strokes and is the most common pathology underlying vascular cognitive impairment and dementia. An important step to developing new treatments is better trial methodology. Disease mechanisms in SVD differ from other stroke etiologies; therefore, treatments need to be evaluated in cohorts in which SVD has been well characterized. Furthermore, SVD itself can be caused by a number of different pathologies, the most common of which are arteriosclerosis and cerebral amyloid angiopathy. To date, there have been few sufficiently powered high-quality randomized clinical trials in SVD, and inconsistent trial methodology has made interpretation of some findings difficult.ObservationsTo address these issues and develop guidelines for optimizing design of clinical trials in SVD, the Framework for Clinical Trials in Cerebral Small Vessel Disease (FINESSE) was created under the auspices of the International Society of Vascular Behavioral and Cognitive Disorders. Experts in relevant aspects of SVD trial methodology were convened, and a structured Delphi consensus process was used to develop recommendations. Areas in which recommendations were developed included optimal choice of study populations, choice of clinical end points, use of brain imaging as a surrogate outcome measure, use of circulating biomarkers for participant selection and as surrogate markers, novel trial designs, and prioritization of therapeutic agents using genetic data via Mendelian randomization.Conclusions and RelevanceThe FINESSE provides recommendations for trial design in SVD for which there are currently few effective treatments. However, new insights into understanding disease pathogenesis, particularly from recent genetic studies, provide novel pathways that could be therapeutically targeted. In addition, whether other currently available cardiovascular interventions are specifically effective in SVD, as opposed to other subtypes of stroke, remains uncertain. FINESSE provides a framework for design of trials examining such therapeutic approaches.
ObjectivesIt has been suggested that diffusion tensor imaging (DTI) measures sensitive to white matter (WM) damage may predict future dementia risk not only in cerebral small vessel disease (SVD), but also in mild cognitive impairment. To determine whether DTI measures were associated with cognition cross-sectionally and predicted future dementia risk across the full range of SVD severity, we established the International OPtimising mulTImodal MRI markers for use as surrogate markers in trials of Vascular Cognitive Impairment due to cerebrAl small vesseL disease collaboration which included six cohorts.MethodsAmong the six cohorts, prospective data with dementia incidences were available for three cohorts. The associations between six different DTI measures and cognition or dementia conversion were tested. The additional contribution to prediction of other MRI markers of SVD was also determined.ResultsThe DTI measure mean diffusivity (MD) median correlated with cognition in all cohorts, demonstrating the contribution of WM damage to cognition. Adding MD median significantly improved the model fit compared to the clinical risk model alone and further increased in all single-centre SVD cohorts when adding conventional MRI measures. Baseline MD median predicted dementia conversion. In a study with severe SVD (SCANS) change in MD median also predicted dementia conversion. The area under the curve was best when employing a multimodal MRI model using both DTI measures and other MRI measures.ConclusionsOur results support a central role for WM alterations in dementia pathogenesis in all cohorts. DTI measures such as MD median may be a useful clinical risk predictor. The contribution of other MRI markers varied according to disease severity.
ObjectivesSerum neurofilament light chain (NfL) has been proposed as prognostic markers in neurogenerative disease. A cross-sectional study in cerebral small vessel disease (SVD) reported an association with cognition and disability. If NfL is to be used to predict outcome, studies are required to demonstrate baseline NfL predicts future dementia risk. Furthermore, if it is to be used as a surrogate marker in clinical trials, change in NfL over time periods typical of a clinical trial must be linked to clinical progression. In a longitudinal study of patients with lacunar stroke and confluent white matter hyperintensities, we determined whether both baseline, and change, in NfL levels were linked to changes in MRI markers, cognitive decline and dementia risk.MethodsPatients underwent MRI, cognitive testing and blood taking at baseline and annually for 3 years. Clinical and cognitive follow-up continued for 5 years.ResultsNfL data were available for 113 subjects for baseline analysis, and 90 patients for the longitudinal analysis. Baseline NfL predicted cognitive decline (global cognition β=−0.335, SE=0.094, p=0.001) and risk of converting to dementia (HR=1.676 (95% CI 1.183 to 2.373), p=0.004). In contrast to imaging, there was no change in NfL values over the follow-up period.ConclusionsBaseline NfL predicts changes in MRI markers, cognitive decline and dementia rate over a 5 years follow-up period in SVD, suggesting NfL may be a useful prognostic marker. However, change in NfL values was not detected, and therefore NfL may not be a useful surrogate marker in clinical trials in SVD.
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