Session Report: Cerebral Small Vessel Disease

Prof. Alastair Webb, United Kingdom. “Regulation of cerebral blood flow: insights into the development of cerebral small vessel disease”.

Published data have showed the pivotal role of hypertension as a risk factor but also as a cause of white matter changes as a feature of SVD. The talk focused on the causal role of hypertension, particularly variability of blood pressure, for cerebral SVD. While there are data showing hypoperfusion in white matter, data with dynamic imaging and perfusion imaging also showed that some drugs may enhance cerebral perfusion also in SVD by reducing cerebral resistance. Consistent data showed that factors that may change cerebral perfusion, such as heart rate, blood pressure variability, may also have a causative role for subsequent SVD (e.g. white matter changes). Overall, blood perfusion seems to be part of an integrated mechanism for SVD development, and compensatory mechanisms are part of this complex process, but impaired compensation, as observed in SVD, may partly explain the progression of the disease. Moreover, there is preliminary evidence of complex interactions of such factors with local tissue mechanisms.

Prof. Geert Jan Biessels, Netherlands. “Cognitive performance prediction in CSVD based on large multicentre data”.

One of the main clinical dilemmas on this topic is that in many cases the severity of imaging burden does not match with the cognitive deficits. Some insights may come from the topography and distribution of the lesions, i.e. lesion location. The meta-VCI map was a project based on MRI scans from clinical practice with the aim to identify maps of lesions that may cause cognitive impairment (strategic infarcts). Authors did the following observations:

• subcortical infarcts in specific areas are associated with cognitive impairment
• lesion prevalence, particularly in the basal ganglia, have been associated with cognitive impairment

Also, disconnectome analysis provided valuable insights: by analyzing a single lesion, with disconnectome map is possible to better explain the variance observed in clinical practice regarding cognitive impairment. White matter fibers are interrupted in case of a “strategic” lesion location, causing a deficit in specific cognitive domains: some areas are associated with impairment in verbal memory, other in executive functioning and so on. As a spin-off, Prof. Biessels advanced an intriguing issue: what is the normal white matter hyperintentity burden? During the discussion, Prof. Biessels stated that brain maps elaborated from such results are available online for consultation and professional use.

Prof. Alexandros Polymeris, Switzerland. “How to approach Cerebral Small Vessel Disease in patients with atrial fibrillation?”

SVD and atrial fibrillation (AF) are apparently related: this relation has been illustrated in this wide broad talk. In patients with AF there is a relevant proportion of patients with detectable SVD features, suggesting a link between the two clinical entities. This link may be more than a chance, since there are data that consistently demonstrated that AF, particularly permanent AF, is associated with increasing burden of white matter changes. Moreover, circulating biomarkers of neuronal damage, such as neurofilament light, increase with volumes of white matter changes, confirming this hypothesis. Also, such association may partly explain the association between AF and cognitive impairment. Does the link between AF and SVD have clinical consequences? For example, a hemorrhagic feature of SVD such as cerebral microbleed may potentially influence therapeutic decisions in patients with AF. However, observational data and subanalysis of randomized clinical trials reassure clinicians about this issue, since the absolute risk of ischemic stroke is higher that the risk of hemorrhagic stroke, suggesting that anticoagulation should not withheld if indicated. Regarding ICH, there is the need of more data and evidence to investigate whether the type (cerebral amyloid angiopathy vs hypertensive arteriopathy) modify the effect of direct anticoagulation in ICH survivors with AF. Overall the talk provided a wide overview regarding clinical implications of SVD in patients with atrial fibrillation.

Prof. Fran-Erik De Leeuw, Netherlands. “Vascular Cognitive impairment due to small vessel disease”

To determine whether cognitive deficits of a patient are due to SVD according to the VASCOG-WSO definition, the clinical symptoms of cognitive decline should be associated with imaging findings of SVD (e.g. two or more lacunar infarcts, white matter changes). However, the clinical course however is often slow and associated with many different clinical manifestations, but there is a dose-response effect between incident dementia and burden of white matter changes. SVD has “local” and “remote” effects, such as cortical thinning due to disconnections of nervous fibers due for example to lacunar strokes. The concept of brain resilience may partly explain the clinical variability of SVD, given that compensatory mechanisms may overcome both local and remote SVD effects on the brain functioning. A real valuable point highlighted in the presentation was that we cannot treat diseased brain in advanced age because it is too late and SVD features are too extensive, thus the attention of researchers shifted towards younger “healthy” patients with hypertension. The Hyperintense study – early life 18-55 years has an extensive MRI protocol and cognitive tests. One of the preliminary results of the study shows for example that in patients with hypertension there is a slower response to manual speed task compared to controls, suggesting that subtle clinical symptoms are present also in younger ages. The main message to the audience is that the medical community should prevent/treat SVD -mainly treating hypertension in young ages- before the consequences on the brain will be irreversible.

Prof. Joanna Wardlaw, United Kingdom. “What is the role of cilostazol in stroke prevention?”

Prof. Wardlaw delivered a talk about cilostazole as a potential disease-modifying drug for SVD. Cilostazole is a phosphodiesterase III inhibitor, with similar mechanisms to aspirin but without a prolonged effect, so reducing bleeding risk. Moreover, it has vasodilator effect, sustains vasoreactivity, improves blood delivery and reduces pulsatility. There are diverse systematic reviews on cilostazole. Data on cognition are scarce, most data are on secondary prevention of stroke and in Asiatic population, where the drug is available for secondary prevention of stroke. Also, data specifically targeted on lacunar stroke are unclear since is not clear how lacunar stroke was classified in the index studies. The LACI-2 study provided data on such population, with encouraging results also regarding cognitive outcomes. Further trials are currently evaluating dynamic measurements such as middle cerebral artery pulsatility, cerebrovascular reactivity, while there are ongoing studies regarding cognition and stroke recurrence. However, there may be a problem in outcomes since the incidence of primary outcomes within the study duration is low, so studies may be underpowered. Notwithstanding such issues, cilostazol remains a promising approach to reduce SVD burden.