Session Chairs: Joanna Wardlaw, United Kingdom and Marco Düring, Germany

Report by Marialuisa Zedde, Italy

This session covers recent topics in SVD, because it is a major cause of loss of independency in the elderly. Indeed SVD has a high presence, causes both ischemic and hemorrhagic stroke, acute and chronic manifestations and it is a key contributor to cognitive impairment. It includes multiple diseases both sporadic and monogenic ones.

Treatment Approaches to Cerebral SVD

The session starts with the talk presented by Prof. Joanna Wardlaw about treatment approaches to cerebral SVD. SVD accounts for 25% of strokes and has a number of typical and well-known neuroradiological features (overt stroke and covert signes: recent lacunar lesions DWI +, leucoaraiosis, EPVSs, microbleeds and cortical superficial siderosis (these last ones related mainly to amyloid- related diseases) also linked to other general manifestations such as cognitive impairment and depression.The tissue inflammatory moment is also a fundamental element in the development and progression of SVD. At the moment, the treatment of SVD is to deal with the risk factors and many of them are not modificable. The most common cause of vascular dementia and many mixed dementias is SVD and the commonest clinical manifestation of cerebrovascular disease is probably dementia and not stroke. Classical vascular risk factors receive the most attention but, if combined, they explain only 2% of variance in SVD, of which hypertension, then smoking, are the most important. Socieconomic stress and cognitive ability/education in the early life are determinants of SVD and lack of exercise and diet too. Managing these emergent risk factors is very important. Data about the control of the most prevalent risk factor (arterial hypertension) come from SPS3 trial and no statistical difference was obtained comparing high intensive v. standard pressure target on recurrence of lacunar stroke. Moreover, no effect on cognition was demonstrated. The meta analysis of trial results shows an overall reduction of stroke but not specifically in the subgroup of lacunar stroke. Trials on the effect of high intensity antihypertensive therapy in the hypertensive patient have however shown that there is a reduction in MCI but not in the primary outcome dementia and in some a reduction in the progression of the volume of WMHs is evident. In SPS3 tria ASA + clopidogrel v. clopidogrel in patients with lacunar stroke increased death and hemorrhage without preventing recurrent stroke. Lacunar stroke and atherothrombotic stroke are different. Data relating to statin therapy are overall on a smaller number of patients, but a meta-analysis highlights the possibility that statin therapy slows post-stroke cognitive decline.

Other potential therapeutic targets are; blood-brain barrier impairment, vascular smooth muscle contractility impairment and inflammation. The proposals for the use of cilostazol, a phosphodiesterase III inhibitor with a vasodilator effect and inhibition of the growth of smooth muscle cells of the vessel wall as well as an increase in myelin repair and antiplatelet, go in this sense. However, there are many ongoing trials on various therapeutic strategies to prevent the evolution of SVD. The new ESO Guidelines on SVD management are in preparation for 2021.

Diagnostic Value of Amyloid Pet in Cerebral Amyloid Angiopathy

Dr. Tsai from Taiwan presented a talk on amyloid PET imaging in CAA patients. In fact, the clinical-neuroradiological criteria for the diagnosis of CAA have a good sensitivity and specificity for the classical presentation, or ICH, while in cases where the clinical presentation is not haemorrhagic sensitivity and specificity are respectively 43% and 91% and emerges the need for other tools to help refine the diagnosis. In fact, many patients with CAA are asymptomatic, may have a non-haemorrhagic clinical presentation at diagnosis and may have few microbleeds or have mixed SVD, not only lobar expression. Therefore, a technique that allows for in vivo amyloid imaging could have a broad impact. PET with tracers for amyloid is proposed as a useful tool in this sense, also because the tracer used is not selective for vascular or parenchymal deposition, avoiding a brain biopsy study. Like patients with AD, those with CAA have greater amyloid tracer retention than normal controls. However, it must be considered that a non-negligible percentage of normal controls show a share of amyloid tracer retention, probably reflecting a sort of age-related AD pathology, thus reducing the sensitivity of the method in the diagnosis of AAC but not changing its specificity, i.e. a negative scan helps rule out the diagnosis of AAC. Previous studies have shown that amyloid retention is higher in regions prone to future bleeding. Furthermore amyloid retention is higher in CAA-related ICH patients than in deep ICH patients. However, there are many patients with mixed microhemorrhagic lesions, both lobar and deep, particularly in the Asian population, where they account for about 40% of patients whose clinical presentation is an ICH. Identifying patients with mixed SVD who has concomitant AAC becomes essential in predicting the clinical evolution of the patients themselves and usually this subgroup shows MR characteristics consistent with AAC. In a recent meta-analysis on the use of amyloid PET in (probable) CAA patients it showed a sensitivity of 79% and a specificity of 78%. In comparison, only 66% of patients with probable CAA MR patterns from memory clinics had amyloid PET positive with a close association with the more specific neuroradiological markers of CAA. A fundamental point is the visual or quantitative evaluation of the PET scan, the latter being the most frequent, but with the bias of using the cerebellum as a reference of normal tracer retention, given that the cerebellum is frequently involved in AAC (the pons can be an alternative reference region). Amyloid retention could reflect CAA burden in MR. One of the major issues on the diagnostic utility of PET in AAC is the frequent comorbidity with AD, for which topographical comparisons have been developed with evidence of a greater occipital / global ratio in AAC vs AD patients, as also confirmed by a subsequent meta-analysis. However, the co-presence of CAA and AD does not respect these criteria and is a frequent occurrence.

Advanced MR Imaging Markers in Cerebral SVD

Dr. Duering presented a talk on Advanced MR Imaging Markers in Cerebral SVD, starting from the classic MR markers of SVD, whose description is substantially of a qualitative type with greater difficulty in categorizing the evolution of SVD over time and the differences between patients and diseases . There is a need of novel MRI markers and an ideal marker should be easy to implement, have a robust clinical and biological validation and also a technical validation and of course it should capture small vessel pathology. Diffusion tensor imaging respects all these criteria and it is a strictly quantitative technique. The presentation focuses on skeleton-based analysis of diffusion MRI. It is thus possible to study how SVD markers evolve over time, for example WMHs as in the RUN-DMC study. Also in this case both AD and SVD contribute to diffusion MRI changes and it is not known to what extent they can do so respectively and in cases of co-occurrence of the two diseases. A further area of ​​research is the imaging of small vessels and the functional imaging of perforating vessels and not just the imaging of the consequences of their downstream pathology.

Diagnostic and Therapeutic Approaches to Monogenic SVD: Consensus Statement

Then, Dr. Mancuso illustrated the consensus statement about diagnostic and therapeutic approach of monogenic SVD recently published with the European Academy of Neurology. These pathologies are increasingly known and more frequently diagnosed in clinical practice also in relation to the greater availability of gene sequencing techniques such as NGS and to the greater number of diseases known and identified with exome sequencing, but they remain a diagnostic challenge, often without any treatment. specific and there is no consensus in the management paths. Furthermore, the methodology with which it was possible to produce a consensus in the field of rare diseases was rather complicated. Red flags have been identified and proposed to alert the clinician to the possibility of suspecting monogenic SVD, such as family history, age at onset, the presence of typical signs in neuromaging, etc. In general, monogenic SVD patients should be followed in specialized neurological centers and / or by neurologists experienced in this field, there should be an annual risk factor assessment but not necessarily an annual MRI. After reviewing the main diseases, Dr. Mancuso reinforces the concept that the suspicion of a monogenic SVD should be placed, where there are the necessary red flags, even in the presence of classic vascular risk factors.

Cerebral Microinfarcts Revisited: Causes, Imaging Correlates, And Consequences

Finally, Dr. Hilal concludes the session with a talk on cortical microinfarcts. This particular and neglected form of vascular disease contributes to vascular cognitive impairment also without memory impairment. Cortical microinfarcts are quite an invisible lesion, with an autopsy-based prevalence of 62% in vascular cognitive impairment and of 43% in AD. Their in vivo identification has been validated in 3T MRI and has a total burden of 6.3% in population studies and 32% in memory clinics. They are associated not only to SVD but also to clinical and biological markers of heart disease.

In summary, cortical microinfarcts are lesions of presumed ischemic origin, affected people have hundreds or thousands cortical microinfarcts, they are able to disrupt structural brain connections and are associated to dementia independently from AD.