[Identifying the neurostimulation target for treatment of cognitive impairment in aging and early cerebral small vessel disease]. / Vybor misheni neiromodulyatsii dlya korrektsii kognitivnykh rasstroistv pri starenii i rannei tserebral'noi mikroangiopatii.

OBJECTIVE: To develop individualized approaches to the use of neuromodulation as a non-pharmacological treatment of cognitive impairment (CI) based on the assessment of compensatory brain reserves in functional MRI (fMRI). MATERIAL AND METHODS: Twenty-one adults over 45 years of age, representing a continuum from healthy norm to mild cognitive impairment due to aging and early cerebral small vessel disease, were studied. All participants underwent fMRI while performing two executive tasks - a modified Stroop task and selective counting. To assess the ability to compensate for CI in real life, functional activation and connectivity were analyzed using the BRIEF-MoCA score as a covariate, which is the difference in ratings between the Behavior Rating Inventory of Executive Function (BRIEF) and the Montreal Cognitive Assessment Scale (MoCA). RESULTS: Both fMRI tasks were associated with activation of areas of the frontoparietal control network, as well as supplementary motor area (SMA) and the pre-SMA, the lateral premotor cortex, and the cerebellum. An increase in pre- SMA connectivity was observed during the tasks. The BRIEF-MoCA score correlated firstly with connectivity of the left dorsolateral prefrontal cortex (DLPFC) and secondly with involvement of the occipital cortex during the counting task. CONCLUSIONS: The developed technique allows identification of the functionally relevant target within the left DLPFC in patients with CI in aging and early cerebral microangiopathy.

[Cerebral Small Vessel Disease: Advances in Understanding its Pathophysiology]. / Zerebrale Mikroangiopathie: Fortschritte im Verständnis der Pathophysiologie.

Sporadic cerebral small vessel disease determines age- and vascular-risk-factor-related processes of the small brain vasculature. The underlying pathology develops in a stage-dependent manner - probably over decades - often already starting in midlife. Endothelial and pericyte activation precedes blood-brain barrier leaks, extracellular matrix remodeling and neuroinflammation, which ultimately result in bleeds, synaptic and neural dysfunction. Hemodynamic compromise of the small vessel walls promotes perivascular drainage failure and accumulation of neurotoxic waste products in the brain. Clinical diagnosis is mainly based on magnetic resonance imaging according to the Standards for Reporting Vascular Changes on Neuroimaging 2. Cerebral amyloid angiopathy is particularly stratified according to the Boston v2.0 criteria. Small vessel disease of the brain could be clinically silent, or manifested through a heterogeneous spectrum of diseases, where cognitive decline and stroke-related symptoms are the most common ones. Prevention and therapy are centered around vascular risk factor control, physically and cognitively enriched life style and, presumably, maintenance of a good sleep quality, which promotes sufficient perivascular drainage. Prevention of ischemic stroke through anticoagulation that carries at the same time an increased risk for large brain hemorrhages - particularly in the presence of disseminated cortical superficial siderosis - remains one of the main challenges. The cerebral small vessel disease field is rapidly evolving, focusing on the establishment of early disease stage imaging and biofluid biomarkers of neurovascular unit remodeling and the compromise of perivascular drainage. New prevention and therapy strategies will correspondingly center around the dedicated targeting of, e. g., cellular small vessel wall and perivascular tissue structures. Growing knowledge about brain microvasculature bridging neuroimmunological, neurovascular and neurodegenerative fields might lead to a rethink about apparently separate disease entities and the development of overarching concepts for a common line of prevention and treatment for several diseases.

New horizons in cognitive and functional impairment as a consequence of cerebral small vessel disease.

Cerebral small vessel disease (cSVD) is a frequent finding in imaging of the brain in older adults, especially in the concomitance of cardiovascular disease risk factors. Despite the well-established link between cSVD and (vascular) cognitive impairment (VCI), it remains uncertain how and when these vascular alterations lead to cognitive decline. The extent of acknowledged markers of cSVD is at best modestly associated with the severity of clinical symptoms, but technological advances increasingly allow to identify and quantify the extent and perhaps also the functional impact of cSVD more accurately. This will facilitate a more accurate diagnosis of VCI, against the backdrop of concomitant other neurodegenerative pathology, and help to identify persons with the greatest risk of cognitive and functional deterioration. In this study, we discuss how better assessment of cSVD using refined neuropsychological and comprehensive geriatric assessment as well as modern image analysis techniques may improve diagnosis and possibly the prognosis of VCI. Finally, we discuss new avenues in the treatment of cSVD and outline how these contemporary insights into cSVD can contribute to optimise screening and treatment strategies in older adults with cognitive impairment and multimorbidity.

[Cerebral small vessel disease]. / Microangiopathie cérébrale.

Cerebral microangiopathy is the second leading cause of dementia after Alzheimer's disease and is a co-factor in the majority of dementias. Its clinical manifestations are multiple and include in addition to cognitive and neuropsychiatric manifestations, also problems of gait, urinary continence, and lacunar-ischaemic and haemorrhagic strokes. Patients with similar radiologic images can present very variable clinical pictures, partially resulting from damage to the neurovascular unit, not visible on conventional MRI, and affecting different neural networks. Management and prevention are possible and effective with well-known, readily available and affordable treatments, through aggressive management of cerebrovascular risk factors.

La microangiopathie cérébrale est la deuxième cause de démence après la maladie d'Alzheimer et est un cofacteur dans la majorité des démences. Ses manifestations cliniques sont multiples et incluent, en plus des troubles cognitifs, des troubles de la marche, de la continence urinaire, neuropsychiatriques, et des AVC lacunaires-ischémiques et hémorragiques. Des patients avec des images radiologiques similaires peuvent présenter des tableaux cliniques très variables, en partie découlant d'atteintes de l'unité neurovasculaire, non visibles en IRM conventionnelle, et altérant des réseaux neuronaux différents. Une prise en charge et une prévention sont possibles et efficaces avec des traitements bien connus, disponibles à un prix abordable, par un traitement agressif des facteurs de risque cérébrovasculaire.

Diagnosis and Management of Cerebral Small Vessel Disease.

OBJECTIVE: Cerebral small vessel disease (CSVD) is a common neurologic condition that contributes to considerable mortality and disability because of its impact on ischemic and hemorrhagic stroke risk and dementia. While attributes of the disease have been recognized for over two centuries, gaps in knowledge remain related to its prevention and management. The purpose of this review is to provide an overview of the current state of knowledge for CSVD. LATEST DEVELOPMENTS: CSVD can be recognized by well-defined radiographic criteria, but the pathogenic mechanism behind the disease is unclear. Hypertension control remains the best-known strategy for stroke prevention in patients with CSVD, and recent guidelines provide a long-term blood pressure target of less than 130/80 mm Hg for patients with ischemic and hemorrhagic stroke, including those with stroke related to CSVD. Cerebral amyloid angiopathy is the second leading cause of intracerebral hemorrhage and may be increasingly recognized because of newer, more sensitive imaging modalities. Transient focal neurologic episodes is a relatively new term used to describe "amyloid spells." Guidance on distinguishing these events from seizures and transient ischemic attacks has been published. ESSENTIAL POINTS: CSVD is prevalent and will likely be encountered by all neurologists in clinical practice. It is important for neurologists to be able to recognize CSVD, both radiographically and clinically, and to counsel patients on the prevention of disease progression. Blood pressure control is especially relevant, and strategies are needed to improve blood pressure control for primary and secondary stroke prevention in patients with CSVD.

Total Cerebral Small Vessel Disease Burden Predicts the Outcome of Acute Stroke Patients after Intra-Arterial Thrombectomy.

INTRODUCTION: Various types of cerebral small vessel diseases (cSVD) markers commonly coexist. The neurological function outcome is affected by their combined effect. To investigate the effect of cSVD on intra-arterial thrombectomy (IAT), our study aimed at developing and testing a model with fusing a combination of multiple cSVD markers as total cSVD burden to predict the outcome of acute ischemic stroke (AIS) patients after IAT treatment. METHODS: From October 2018 to March 2021, continuous AIS patients with IAT treatment were enrolled. We calculated the cSVD markers identified by magnetic resonance imaging. The outcomes of all patients were assessed according to the modified Rankin Scale (mRS) score at 90 days after stroke. The relationship between total cSVD burden and outcomes was analyzed by logistics regression analysis. RESULTS: A total of 271 AIS patients were included in this study. The proportions of score 0∼4 in the total cSVD burden group (i.e., score 0, 1, 2, 3, and 4 groups) were 9.6%, 19.9%, 23.6%, 32.8%, and 14.0%, respectively. The higher the cSVD score, the more patients with a poor outcome. Heavier total cSVD burden (1.6 [1.01∼2.27]), diabetes mellitus (1.27 [0.28∼2.23]), and higher national institute of health stroke scale (NIHSS) on admission (0.15 [0.07∼0.23]) were associated with poor outcome. In the two Least Absolute Shrinkage and Selection Operator regression models, model 1 using age, duration from onset to reperfusion, Alberta stroke program early CT score (ASPECTS), NIHSS on admission, modified thrombolysis in cerebral infarction (mTICI) and total cSVD burden as variables perform well on predicting short-term outcome in area under curve (AUC) of 0.90. Model 2, including all of the variables above except cSVD, showed less predictive capability than model 1 (AUC 0.90 vs. 0.82, p = 0.045). CONCLUSIONS: The total cSVD burden score was independently associated with the clinical outcomes of AIS patients after IAT treatment and it may be a reliable predictor for poor outcomes of AIS patients after IAT treatment.

Cerebral small vessel disease and intracranial bleeding risk: Prognostic and practical significance.

Balancing the risks of recurrent ischemia and antithrombotic-associated bleeding, particularly intracranial hemorrhage (ICH), is a key challenge in the secondary prevention of ischemic stroke and transient ischemic attack. In hyperacute ischemic stroke, the use of acute reperfusion therapies is determined by the balance of anticipated benefit and the risk of ICH. Cerebral small vessel disease (CSVD) causes most spontaneous ICH. Here, we review the evidence linking neuroimaging markers of CSVD to antithrombotic and thrombolytic-associated ICH, with emphasis on cerebral microbleeds (CMB). We discuss their role in the prediction of ICH, and practical implications for clinical decision making. Although current observational data suggest CMB presence should not preclude antithrombotic therapy in patients with ischemic stroke or TIA, they are useful for improving ICH risk prediction with potential relevance for determining the optimal secondary prevention strategy, including the use of left atrial appendage occlusion. Following ICH, recommencing antiplatelets is probably safe in most patients, while the inconclusive results of recent randomized controlled trials of anticoagulant use makes recruitment to ongoing trials (including those testing left atrial appendage occlusion) in this area a high priority. Concern regarding CSVD and ICH risk after hyperacute stroke treatment appears to be unjustified in most patients, though some uncertainty remains regarding patients with very high CMB burden and other risk factors for ICH. We encourage careful phenotyping for underlying CSVD in future trials, with the potential to enhance precision medicine in stroke.

Meta-analysis of the efficacy of acupuncture in the treatment of the vascular cognitive impairment associated with cerebral small vessel disease.

OBJECTIVE: To systematically evaluate the efficacy and safety of acupuncture in the treatment of the vascular cognitive impairment (VCI) associated with cerebral small vessel disease (CSVD-VCI) and to provide a theoretical basis for clinical acupuncture treatment for CSVD-VCI. METHOD: Various databases, including China National Knowledge Infrastructure, Wanfang Data, Chinese Science and Technology Journal Database, Chinese BioMedical Literature Service System, PubMed, the Cochrane Library, and EBSCOhost, were searched for randomized controlled trials (RCTs) related to acupuncture treatment for CSVD-VCI. The quality of the included trials was evaluated, and a meta-analysis was conducted using the Review Manager 5.4 software. RESULTS: Ten articles on RCTs were included, involving 761 patients, i.e., 381 in the acupuncture group and 380 in the control group. The meta-analysis results indicated that the use of acupuncture alone and acupuncture alongside other therapies for CSVD-VCI could improve the overall clinical response rate [odds ratio = 3.51, 95% confidence interval (CI) = (2.05, 6.00), P < 0.00001], increase the patients' Montreal Cognitive Assessment scores [mean difference (MD) = 3.33, 95%CI (2.98, 3.68), P < 0.00001], Mini-Mental State Examination scores [MD = 2.78, 95%CI (2.51, 3.06), P < 0.00001], and activities of daily living scores [MD = 6.30, 95%CI (4.22, 8.37), P < 0.00001], and shorten the latency of auditory evoked potential P300 [MD = -14.67, 95%CI (-19.54, -9.80), P < 0.00001]. CONCLUSION: Acupuncture alone and acupuncture alongside other therapies are superior to non-acupuncture-based therapies in the treatment of CSVD-VCI. However, due to the small number of relevant available articles and their general low quality, this conclusion may be biased. More clinical RCTs with a larger sample size and higher quality are needed to support this theory.

Evidence-based evaluation of adjuvant therapy with Chinese medicine for cerebral small vessel disease: A systematic review and meta-analysis.

BACKGROUND: As the population ages, the prevalence of cerebral small vessel disease (CSVD) steadily increases, resulting in a significant economic burden on society. In East Asian nations, Chinese medicine has been used extensively to teat CSVD and has been reported to improve the cognitive function of patients. The present study aimed to comprehensively assess the efficacy and safety of Chinese medicine as adjuvant therapy for CSVD. METHODS: A literature search of the CNKI, Wanfang, VIP, SinoMed, Medline, Cochrane Library, and ChiCTR databases were searched for RCTs investigating the use of TCM as an adjuvant in the treatment of CSVD, published up to July 27, 2023, was performed. Based on the Cochrane Collaboration Network bias risk assessment criteria, Review Manager version 5.3 was used to perform a meta-analysis. RESULTS: Meta-analysis of 27 RCTs, including 2554 subjects, revealed that the majority of the RCTs exhibited risk for ambiguous bias. The findings demonstrated that the use of Chinese medicine as an adjuvant treatment for CSVD effectively enhanced the cognitive function, as evidenced by improvements in the MMSE score (mean difference (MD) = 2.42, 95% confidence interval (CI) [1.79,3.17], P < .00001), MoCA score (MD = 2.39, 95% CI [1.78,2.99], P < .00001) and ADL score (MD = 4.13, 95% CI [1.74,6.51], P = .0007). Furthermore, the study also demonstrated the advantages of Chinese medicine adjuvant therapy in enhancing the Chinese medicine syndrome score (MD = -2.57, 95% CI [-3.31, -1.83], P < .00001), CRP (MD = -1.35, 95% CI [-2.27, -0.43], P = .004), Hcy (MD = -3.44,95% CI [-4.05, -2.83], P < .00001), and blood flow velocity (CBV) (MD = 1.37,95% CI [0.24,2.50], P = .02). Moreover, there was no statistical difference in the incidence of adverse reactions between the 2 groups. CONCLUSION: Findings of the present study indicate that the Chinese medicine, as an adjuvant to conventional treatment, appeared to be efficacious in enhancing cognitive function, reducing Chinese medicine syndrome score, improving blood biochemical markers, and improving cerebral blood flow perfusion in patients with CSVD, without any notable adverse reactions. However, it is imperative to validate these conclusions in future high-quality investigations.

Mesenchymal Stem Cell-Derived Extracellular Vesicles as Proposed Therapy in a Rat Model of Cerebral Small Vessel Disease.

Mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) have been employed in the past decade as therapeutic agents in various diseases, including central nervous system (CNS) disorders. We currently aimed to use MSC-EVs as potential treatment for cerebral small vessel disease (CSVD), a complex disorder with a variety of manifestations. MSC-EVs were intranasally administrated to salt-sensitive hypertension prone SBH/y rats that were DOCA-salt loaded (SBH/y-DS), which we have previously shown is a model of CSVD. MSC-EVs accumulated within brain lesion sites of SBH/y-DS. An in vitro model of an inflammatory environment in the brain demonstrated anti-inflammatory properties of MSC-EVs. Following in vivo MSC-EV treatment, gene set enrichment analysis (GSEA) of SBH/y-DS cortices revealed downregulation of immune system response-related gene sets. In addition, MSC-EVs downregulated gene sets related to apoptosis, wound healing and coagulation, and upregulated gene sets associated with synaptic signaling and cognition. While no specific gene was markedly altered upon treatment, the synergistic effect of all gene alternations was sufficient to increase animal survival and improve the neurological state of affected SBH/y-DS rats. Our data suggest MSC-EVs act as microenvironment modulators, through various molecular pathways. We conclude that MSC-EVs may serve as beneficial therapeutic measure for multifactorial disorders, such as CSVD.

Framework for Clinical Trials in Cerebral Small Vessel Disease (FINESSE): A Review.

Importance: Cerebral 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. Observations: To 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 Relevance: The 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.

Cerebral Small-Vessel Diseases: A Look Back from 1991 to Today.

BACKGROUND: Cerebral small-vessel diseases (cSVDs) encompass a number of causes involving, but not limited to, alterations in the intracranial microvasculature, leading to the accumulation of brain tissue damage and the development of various degrees of cognitive impairment, behavioral alterations, gait instability, and localization signs, often associated with the occurrence of ischemic or hemorrhagic strokes. SUMMARY: In 2021, although key questions remain unanswered, there is general agreement on the construct, its main pathophysiological bases, and the terms used to describe its main clinical and radiological features. However, this has not always been the case, and the 30th anniversary of Cerebrovascular Diseases is an opportunity to look back from 1991 to the present to understand how a number of features, sometimes considered independent, have been progressively brought together by successive scientific breakthroughs, gradually leading to the definition of the now widely accepted concept of cSVDs. KEY MESSAGES: In the course of this journey, we will detail with particular attention the role of what we consider 2 crucial events: the advent of cerebral MRI and the building of large cohorts with monogenic forms of small-vessel disease of the brain.

Emerging Concepts in Vascular Dementia: A Review.

OBJECTIVE: Vascular dementia (VaD) is the second most common cause of dementia and a major health concern worldwide. A comprehensive review on VaD is warranted for better understanding and guidance for the practitioner. We provide an updated overview of the epidemiology, pathophysiological mechanisms, neuroimaging patterns as well as current diagnostic and therapeutic approaches. MATERIALS AND METHODS: A narrative review of current literature in VaD was performed based on publications from the database of PubMed, Scopus and Google Scholar up to January, 2021. RESULTS: VaD can be the result of ischemic or hemorrhagic tissue injury in a particular region of the brain which translates into clinically significant cognitive impairment. For example, a cerebral infarct in the speech area of the dominant hemisphere would translate into clinically significant impairment as would involvement of projection pathways such as the arcuate fasciculus. Specific involvement of the angular gyrus of the dominant hemisphere, with resultant Gerstman's syndrome, could have a pronounced effect on functional ability despite being termed a "minor stroke". Small vessel cerebrovascular disease can have a cumulate effect on cognitive function over time. It is unfortunately well recognized that "good" functional recovery in acute ischemic or haemorrhagic stroke, including subarachnoid haemorrhage, does not necessarily translate into good cognitive recovery. The victim may often be left unable to have gainful employment, drive a car safely or handle their affairs independently. CONCLUSIONS: This review should serve as a compendium of updated information on VaD and provide guidance in terms of newer diagnostic and potential therapeutic approaches.

Cerebral small vessel disease and vascular cognitive impairment: from diagnosis to management.

PURPOSE OF REVIEW: We present recent developments in the field of small vessel disease (SVD)-related vascular cognitive impairment, including pathological mechanisms, updated diagnostic criteria, cognitive profile, neuroimaging markers and risk factors. We further address available management and therapeutic strategies. RECENT FINDINGS: Vascular and neurodegenerative pathologies often co-occur and share similar risk factors. The updated consensus criteria aim to standardize vascular cognitive impairment (VCI) diagnosis, relying strongly on cognitive profile and MRI findings. Aggressive blood pressure control and multidomain lifestyle interventions are associated with decreased risk of cognitive impairment, but disease-modifying treatments are still lacking. Recent research has led to a better understanding of mechanisms leading to SVD-related cognitive decline, such as blood-brain barrier dysfunction, reduced cerebrovascular reactivity and impaired perivascular clearance. SUMMARY: SVD is the leading cause of VCI and is associated with substantial morbidity. Tackling cardiovascular risk factors is currently the most effective approach to prevent cognitive decline in the elderly. Advanced imaging techniques provide tools for early diagnosis and may play an important role as surrogate markers for cognitive endpoints in clinical trials. Designing and testing disease-modifying interventions for VCI remains a key priority in healthcare.

Association of Plasma Neurofilament Light With Small Vessel Disease Burden in Nondemented Elderly: A Longitudinal Study.

BACKGROUND AND PURPOSE: Neurofilament light chain (NfL) is a promising predictive biomarker of active axonal injury and neuronal degeneration diseases. We aimed to evaluate if an increase in plasma NfL levels could play a monitoring role in the progression of cerebral small vessel disease (CSVD) among the nondemented elders, which are highly prevalent in elderly individuals and associated with an increased risk of stroke and dementia. METHODS: The study included 496 nondemented participants from the Alzheimer disease neuroimaging initiative database. All participants underwent plasma NfL measurements and 3.0-Tesla magnetic resonance imaging of the brain; 387 (78.0%) underwent longitudinal measurements. The number of cerebral microbleeds, lacunar infarcts, and volumetric white matter hyperintensities, as well as Fazekas scores, were measured. Cross-sectional and longitudinal associations between CSVD burden and NfL levels were evaluated using multivariable-adjusted models. RESULTS: Plasma NfL was higher in the moderate-severe CSVD burden group (45.2±16.0 pg/mL) than in the nonburden group (34.3±15.1 pg/mL; odds ratio [OR]=1.71 [95% CI, 1.24-2.35]) at baseline. NfL was positively associated with the presence of cerebral microbleeds (OR=1.29 [95% CI, 1.01-1.64]), lacunar infarcts (OR=1.43 [95% CI, 1.06-1.93]), and moderate-severe white matter hyperintensities (OR=1.67 [95% CI, 1.24-2.25]). Longitudinally, a higher change rate of NfL could predict more progression of CSVD burden (OR=1.38 [95% CI, 1.08-1.76]), white matter hyperintensities (OR=1.41 [95% CI, 1.10-1.79]), and lacunar infarcts (OR=1.99 [95% CI, 1.42-2.77]). CONCLUSIONS: Plasma NfL level is a valuable noninvasive biomarker that supplements magnetic resonance imaging scans and possibly reflects the severity of CSVD burden. Furthermore, high plasma NfL levels tend to represent an increased CSVD risk, and dynamic increases in NfL levels might predict a greater progression of CSVD.

Evaluation of eight-style Tai chi on cognitive function in patients with cognitive impairment of cerebral small vessel disease: study protocol for a randomised controlled trial.

INTRODUCTION: Cerebral small vessel disease (CSVD) is a critical factor that causes cognitive decline and progresses to vascular dementia and acute cerebrovascular events. Tai chi has been proven to improve nerve plasticity formation and directly improve cognitive function compared with other sports therapy, which has shown its unique advantages. However, more medical evidence needs to be collected in order to verify that Tai chi exercises can improve cognitive impairment due to CSVD. The main purposes of this study are to investigate the effect of Tai chi exercise on neuropsychological outcomes of patients with cognitive impairment related to CSVD and to explore its mechanism of action with neuroimaging, including functional MRI (fMRI) and event-related potential (P300). METHODS AND ANALYSIS: The design of this study is a randomised controlled trial with two parallel groups in a 1:1 allocation ratio with allocation concealment and assessor blinding. A total of 106 participants will be enrolled and randomised to the 24-week Tai chi exercise intervention group and 24-week health education control group. Global cognitive function and the specific domains of cognition (memory, processing speed, executive function, attention and verbal learning and memory) will be assessed at baseline and 12 and 24 weeks after randomisation. At the same time, fMRI and P300 will be measured the structure and function of brain regions related to cognitive function at baseline and 24 weeks after randomisation. Recruitment is currently ongoing (recruitment began on 9 November 2020). The approximate completion date for recruitment is in April 2021, and we anticipate to complete the study by December 2021. ETHICS AND DISSEMINATION: Ethics approval was given by the Medical Ethics Committee of the Affiliated People's Hospital of Fujian University of Traditional Chinese Medicine (approval number: 2019-058-04). The findings will be disseminated through peer-reviewed publications and at scientific conferences. TRIAL REGISTRATION NUMBER: ChiCTR2000033176; Pre-results.

Recurrent Pontine Strokes in a Young Male.

A 34-year-old patient presented to the emergency department with recurrent neurologic symptoms of sudden onset. MRI showed white matter hyperintensities consistent with small vessel disease, predominantly in the pons. There were no known cardiovascular risk factors (CVRF) and extensive workup for vasculitis was negative. The preliminary diagnosis was small vessel primary central nervous system vasculitis, but immunosuppressive treatment did not stop a progression of the disease over 6 months. Repeated negative diagnostic workup for vasculitis, lack of response to therapy, young age, and predominant involvement of the pons were compatible with pontine autosomal dominant microangiopathy and leukoencephalopathy (PADMAL), which is a very rare monogenic cause of cerebral small vessel disease due to upregulation of collagen type-IV. Correspondingly, a COL4A1 mutation was found. Therapy was immediately stopped in favour of more strict adjustment of the CVRF including lowering of LDL < 70 mg/dl and extensive monitoring of blood-pressure.

Clinical management of cerebral small vessel disease: a call for a holistic approach.

ABSTRACT: Cerebral small vessel disease (SVD) is a common global brain disease that causes cognitive impairment, ischemic or hemorrhagic stroke, problems with mobility, and neuropsychiatric symptoms. The brain damage, seen as focal white and deep grey matter lesions on brain magnetic resonance imaging (MRI) or computed tomography (CT), typically accumulates "covertly" and may reach an advanced state before being detected incidentally on brain scanning or causing symptoms. Patients have typically presented to different clinical services or been recruited into research focused on one clinical manifestation, perhaps explaining a lack of awareness, until recently, of the full range and complexity of SVD.In this review, we discuss the varied clinical presentations, established and emerging risk factors, relationship to SVD features on MRI or CT, and the current state of knowledge on the effectiveness of a wide range of pharmacological and lifestyle interventions. The core message is that effective assessment and clinical management of patients with SVD, as well as future advances in diagnosis, care, and treatment, will require a more "joined-up"' approach. This approach should integrate clinical expertise in stroke neurology, cognitive, and physical dysfunctions. It requires more clinical trials in order to improve pharmacological interventions, lifestyle and dietary modifications. A deeper understanding of the pathophysiology of SVD is required to steer the identification of novel interventions. An essential prerequisite to accelerating clinical trials is to improve the consistency, and standardization of clinical, cognitive and neuroimaging endpoints.