Rescue therapy of early neurological deterioration in lacunar stroke.

BACKGROUND: Early neurological deterioration (END) occurs in many patients with acute ischemic stroke due to a variety of causes. Although pharmacologically induced hypertension (PIH) and anticoagulants have been investigated in several clinical trials for the treatment of END, the efficacy and safety of these treatments remain unclear. Here, we investigated whether PIH or anticoagulation is better as a rescue therapy for the progression of END in patients with lacunar stroke. METHODS: This study included patients with lacunar stroke who received rescue therapy with END within 3 days of symptom onset between April 2014 and August 2021. In the PIH group, phenylephrine was administered intravenously for 24 h and slowly tapered when symptoms improved or after 5 days of PIH. In the anticoagulation group, argatroban was administered continuously intravenously for 2 days and twice daily for next 5 days. We compared END recovery, defined as improvement in NIHSS from baseline, excellent outcomes (0 or 1 mRS at 3 months), and safety profile. RESULTS: Among the 4818 patients with the lacunar stroke, END occurred in 147 patients. Seventy-nine patients with END received PIH (46.9%) and 68 patients (46.3%) received anticoagulation therapy. There was no significant difference in age (P = 0.82) and sex (P = 0.87) between the two groups. Compared to the anticoagulation group, the PIH group had a higher incidence of END recovery (77.2% vs. 51.5%, P < 0.01) and excellent outcomes (34.2% vs. 16.2%, P = 0.04). PIH was associated with END (HR 2.49; 95% CI 1.06-5.81, P = 0.04). PIH remained associated with END recovery (adjusted HR 3.91; 95% CI 1.19-12.90, P = 0.02). Safety outcomes, like hemorrhagic conversion and mortality, were not significantly different between the two groups. CONCLUSIONS: As a rescue therapy for the progression of END in lacunar stroke patients, PIH with phenylephrine was more effective with similar safety compared to anticoagulation with argatroban.

Exercise transiently increases the density of incipient blood clots in antiplatelet-treated lacunar stroke patients.

INTRODUCTION: Older individuals and, in particular, individuals at risk of recurrent stroke, may be susceptible to thrombosis when participating in exercise, however, this aspect has not been well investigated. METHODS: Clot microstructure and conventional markers of thrombotic risk were determined in twenty lacunar stroke patients and fifteen healthy age-matched controls before, immediately after and 1 h after a bout of moderate intensity cycling exercise. Data were analyzed using a linear mixed model approach. RESULTS: At rest, clot microstructure (1.69 ± 0.07 vs. 1.64 ± 0.05, corresponding to a difference of ~ 50% in normalized clot mass; p = 0.009) and thrombocyte count (73%; p < 0.0001) were higher, and activated partial thromboplastin time was lower (18%; p = 0.0001) in stroke patients compared to age-matched controls. Acute exercise increased thrombogenic markers similarly in the two groups: incipient clot microstructure (1.69 ± 0.07 vs. 1.74 ± 0.05; p = 0.0004 and 1.64 ± 0.05 vs. 1.71 ± 0.04; p < 0.0001, for stroke and controls respectively), plasma fibrinogen (12%; p < 0.0001 and 18%; p < 0.0001, for stroke and controls respectively) and the combined coagulation factors II, VII and X (p = 0.0001 and p < 0.0001, for stroke and controls respectively). CONCLUSION: The results show that exercise transiently increases the risk of blood clot formation in both stroke patients and controls, however, due to the higher baseline thrombogenicity in stroke patients, the post exercise risk of forming blood clots may be higher in this group. TRIAL REGISTRATION: Registered at ClinicalTrials.gov (NCT03635177).

FLAIR signal intensity ratio predicts small subcortical infarct early neurologic deterioration: a cross-sectional study.

PURPOSE: Prior studies have used the fluid-attenuated inversion recovery sequence signal intensity ratio (FLAIR-SIR) to predict those with an incomplete infarct that may safely receive acute thrombolytics. Clinical early neurologic deterioration (END) of small subcortical infarcts (SSIs) is suspected to occur due to delayed infarct completion. We aimed to understand if a lower FLAIR-SIR, suggestive of an incomplete infarct, would have a higher likelihood of SSI-related END. METHODS: A cross-sectional retrospective study was performed of those with an acute SSI (anterior or posterior circulation) without significant parent vessel steno-occlusive disease. END was defined as a new or worsened disabling neurologic deficit during the index hospitalization. Standard-of-care brain MRIs were reviewed from the hospitalization, and a FLAIR-SIR cutoff of ≤ 1.15 was used based on prior studies. Adjusted logistic regression models were used for analysis. RESULTS: We identified 252 patients meeting inclusion criteria: median (IQR) age 68 (12) years, 38.5% (97/252) female, and 11% (28/252) with END. Tobacco use was more common in those without END (32%) compared with END (55%, p = 0.03). In adjusted analyses, a FLAIR-SIR cutoff of ≤ 1.15 yielded an odds ratio of 2.8 (95% CI 1.23-6.13, p = 0.012) of early neurological deterioration. CONCLUSION: Those with a FLAIR-SIR ≤ 1.15 are nearly threefold more likely to develop SSI-related END.

CT Perfusion imaging as prognostic factor for outcome of lacunar stroke.

BACKGROUND: Early neurological deterioration (END) affects 20-30% of patients with lacunar stroke within 48 h despite optimal treatment. Previously established markers included infection and infarct location on imaging. We studied the utility of measuring global cerebral blood flow (gCBF) measured by CT-Perfusion (CTP) as an early predictor of END in patients with lacunar strokes. METHODS: 162 patients with lacunar stroke were measured for gCBF including both cerebral hemispheres and cerebellum. We stratified patients by normal gCBF (> 40 ml/100 mg/min) vs. low gCBF (< 40 ml/100 mg/min). Stroke location, vascular risk factors, age and gender were assessed. The primary outcome was the change in the NIHSS score after 48 h from index stroke. RESULTS: Mean gCBF of the overall cohort was 37.72 ml/100 mg/min. Both groups had a baseline NIHSS score of 4.2 with similar standard deviations. The NIHSS score decreased by 1.3 points in normal gCBF group and increased by 1.1 points in the low gCBF group. All stroke sites deteriorated in the low gCBF group, particularly the capsula interna, corona radiata, and lateral pontine area. END occurred in 37.8% in low gCBF compared to 3.1% in the normal gCBF patients. In contrast, clinical improvement after 48 h occurred in 64.2% of patients with normal gCBF but only 6.1% with low gCBF. CONCLUSION: Our study supports measurement of gCBF by CTP as a potential imaging biomarker for END. Additionally, it adds evidence to the body of supporting the vulnerability of capsula interna and pontine infarctions to END.

Posterior reversible encephalopathy syndrome and acute ischemic stroke: an underreported association.

INTRODUCTION: Posterior reversible encephalopathy syndrome (PRES) is a rare and complex disorder with variable clinical presentation and a typical magnetic resonance imaging (MRI) pattern of vasogenic edema with typical and atypical locations. It is often triggered by other diseases and drugs and the most prototypical association is with persistently elevated arterial pressure values. Among the potential cerebrovascular complications, intracranial bleeding has been described, but ischemic stroke is uncommonly reported. METHODS: We are presenting a case of a male patient with prolonged and sustained arterial hypertension acutely presenting with lacunar ischemic stroke involving the right corona radiata and composite MRI findings with the association of chronic small vessel disease (SVD) markers, acute symptomatic lacunar stroke, and atypical, central variant, posterior fossa dominant PRES. In the MRI follow-up, the white matter hyperintensities in T2-fluid attenuated inversion recovery (FLAIR sequences) due to PRES. DISCUSSION: The pathophysiology of PRES is not yet fully known, but the association with markedly increased values of arterial pressure is typical. In this context, ischemic stroke has not been considered in the clinical and neuroradiological manifestations of PRES and it has been only occasionally reported in the literature. In this case, the main hypothesis is that sustained hypertension may have triggered both manifestations, PRES, and ischemic stroke and the last one allowed to diagnose the first one. CONCLUSIONS: Atypical variants of PRES are not so rare and it may also occur in typical triggering situations. The association with ischemic stroke is even rarer and it may add some clues to the pathomechanisms of PRES.

The impact of pre-stroke aspirin exposure on radiographic appearance and disability outcomes: A post-hoc analysis of the SPS3 trial: Aspirin Use and Small Subcortical Stroke.

OBJECTIVES: The effect of pre-stroke use of aspirin on small subcortical infarct dimensions or outcomes is not well described. We aimed to bridge this knowledge gap amongst a well-described and heterogeneous patient population. MATERIALS AND METHODS: We performed a post-hoc analysis of the Secondary Prevention of Small Subcortical Stroke (SPS3) trial. The primary exposure was aspirin use ≤7 days of index stroke. The primary outcomes were infarct dimensions. Functional outcomes by modified Rankin Scale (mRS) was a secondary outcome. Age restricted (≥55 years) subgroup analyses were performed as a sensitivity analysis. Descriptive statistical and regression modeling were performed for data analysis. RESULTS: We included 1423 participants of which 453(31.8 %) used aspirin. Aspirin use was associated with more cardiovascular risk diagnoses. Maximal infarct diameter did not differ with pre-stroke aspirin use (11.3±4.2 mm versus 11.8±4.1 mm, p=0.057) however infarct area was smaller with exposure (126.4±90.0 mm2 versus 137.4±97.0 mm2, p=0.037) regardless of aspirin strength. Participants ≥55 years had smaller infarct diameters (11.1±4.2 mm versus 11.9±4.4 mm, p=0.019) and area (123.4±87.1 mm2 versus 130.6±93.2 mm2, p=0.037) with aspirin use. mRS did not significantly differ in our analyses. CONCLUSIONS: In this post-hoc analysis of the SPS3 trial, pre-stroke aspirin use was associated with a smaller infarct area regardless of aspirin strength and without impact on functional outcomes. These findings were more pronounced in participants ≥55 years. REGISTRATION: https://clinicaltrials.gov/study/NCT00059306?term= %22sps3 %22&rank=1.

Changes in Cardiovascular Health Across Midlife and Late-Life and Magnetic Resonance Imaging Markers of Cerebral Vascular Disease in Late-Life.

BACKGROUND: Cardiovascular health may be used for prevention of cerebral vascular disease; however, data on the association of cardiovascular health across midlife and late-life with late-life cerebral vascular disease are lacking. Our aim was to examine whether midlife or late-life cardiovascular health as well as changes of cardiovascular health within midlife and between midlife and late-life were associated with prevalence of magnetic resonance imaging markers of cerebral vascular disease at late-life. METHODS: Prospective cohort study including 1638 participants from the Atherosclerosis Risk in Communities Study who took part in 2 visits at midlife (mean ages, 53 and 59 years), and a late-life visit (mean age, 76 years). A cardiovascular health Life's Simple 7 score (range, 0-12/0-14, depending on diet availability) including 6 out of 7 items was calculated at each visit, with weight assigned to each item as poor (0), intermediate (1), or ideal (2). Participants underwent 3T brain magnetic resonance imaging scans in late-life visit. Outcomes were white matter hyperintensity volume, microbleeds, and lacunar, subcortical, and cortical infarcts at late-life. Linear and logistic regression models were used to assess the associations of cardiovascular health in midlife and late-life, and improvement of cardiovascular health within midlife, and from midlife to late-life with magnetic resonance imaging markers of cerebral vascular disease, adjusting for potential confounders. RESULTS: A higher cardiovascular health in midlife, improvement of cardiovascular health within midlife, higher cardiovascular health at late-life, and improvement of cardiovascular health from midlife to late-life were associated with a lower prevalence of cerebral vascular disease markers. For example, improvement in cardiovascular health (per point) from midlife to late-life was associated with smaller white matter hyperintensity volume (ß, -0.07 [95% CI, -0.10 to -0.04]) and lower odds of microbleeds (odds ratio, 0.93 [0.90-0.97]), lacunar (odds ratio, 0.93 [0.89-0.97]), subcortical (odds ratio, 0.93 [0.89-0.97]), and cortical infarcts (odds ratio, 0.92 [0.87-0.97]). CONCLUSIONS: Improving cardiovascular health within midlife and from midlife to late-life may prevent development of cerebral vascular disease.

Dual Antiplatelet Therapy With Cilostazol for Secondary Prevention in Lacunar Stroke: Subanalysis of the CSPS.com Trial.

BACKGROUND: The effectiveness of long-term dual antiplatelet therapy (DAPT) to prevent recurrent strokes in patients with lacunar stroke remains unclarified. Therefore, this study aimed to compare and to elucidate the safety and effectiveness of DAPT and single antiplatelet therapy (SAPT) in preventing recurrence in chronic lacunar stroke. METHODS: CSPS.com (Cilostazol Stroke Prevention Study for Antiplatelet Combination) was a prospective, multicenter, randomized controlled trial. In this prespecified subanalysis, 925 patients (mean age, 69.5 years; 69.4% men) with lacunar stroke were selected from 1884 patients with high-risk noncardioembolic stroke, enrolled in the CSPS.com trial after 8 to 180 days following stroke. Patients were randomly assigned to receive either SAPT or DAPT using cilostazol and were followed for 0.5 to 3.5 years. The primary efficacy outcome was the first recurrence of ischemic stroke. The safety outcomes were severe or life-threatening bleeding. RESULTS: The DAPT group receiving cilostazol and either aspirin or clopidogrel and SAPT group receiving aspirin or clopidogrel alone comprised 464 (50.2%) and 461 (49.8%) patients, respectively. Ischemic stroke occurred in 12 of 464 patients (1.84 per 100 patient-years) in the DAPT group and 31 of 461 patients (4.42 per 100 patient-years) in the SAPT group, during follow-up. After adjusting for multiple potential confounding factors, ischemic stroke risk was significantly lower in the DAPT group than in the SAPT group (hazard ratio, 0.43 [95% CI, 0.22-0.84]). The rate of severe or life-threatening hemorrhage did not differ significantly between the groups (2 patients [0.31 per 100 patient-years] versus 6 patients [0.86 per 100 patient-years] in the DAPT and SAPT groups, respectively; hazard ratio, 0.36 [95% CI, 0.07-1.81]). CONCLUSIONS: In patients with lacunar stroke, DAPT using cilostazol had significant benefits in reducing recurrent ischemic stroke incidence compared with SAPT without increasing the risk of severe or life-threatening bleeding. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT01995370. URL: https://www.umin.ac.jp/ctr; Unique identifier: UMIN000012180.

Intracranial carotid artery calcification morphology differs in patients with lacunar and nonlacunar acute ischemic strokes.

BACKGROUND AND PURPOSE: Intracranial carotid artery calcifications (ICACs) are a common finding on noncontrast computed tomography (NCCT) and have been associated with an increased risk of ischemic stroke. However, no data are available about the association between ICAC patterns and stroke etiology. We investigated the association between ICAC patterns and etiological subtypes of ischemic stroke. METHODS: We retrospectively analyzed a single center cohort of patients admitted for ischemic stroke with known etiology. Each carotid artery was evaluated separately on NCCT scans to define the ICAC pattern (intimal, medial, mixed). The association between ICAC patterns and stroke etiology was investigated using logistic regression models adjusting for relevant confounders. RESULTS: A total of 485 patients were included (median age = 78 [interquartile range (IQR) = 70-85] years, 243 [50%] female, median National Institutes of Health Stroke Scale = 6 [IQR = 3-12]). Frequencies of ICAC patterns were: intimal, n = 96 (20%); medial, n = 273 (56%); mixed, n = 51 (11%), indistinct/absent, n = 65 (13%) patients. Intimal pattern was more frequent in lacunar compared with nonlacunar (33% vs. 16%, p < 0.001) stroke etiology, whereas medial pattern was less frequent in lacunar compared with nonlacunar stroke (36% vs. 62%, p < 0.001). After adjustment for confounders, intimal ICAC predominant pattern remained associated with lacunar stroke etiology in two multivariate models (Model 1: adjusted odds ratio [aOR] = 2.08, 95% confidence interval [CI] = 1.20-3.56; Model 2: aOR = 2.01, 95% CI = 1.16-3.46). CONCLUSIONS: Our study suggests that intimal ICAC pattern is associated with lacunar stroke and may serve as a marker for lacunar stroke etiology, possibly strengthening the relation between endothelial dysfunction and lacunar stroke.

Antiplatelet therapy for secondary prevention of lacunar stroke: a systematic review and network meta-analysis.

PURPOSE: To comprehensively compare the efficacy of different antiplatelet therapies for secondary prevention of lacunar stroke (LS). METHODS: The relevant studies were identified by searching PubMed, EMBASE, Web of Science, and Cochrane Collaboration Database up to May 2022. Cardiovascular and cerebrovascular events were chosen to evaluate the efficacy of antiplatelet therapy for secondary prevention. Loop-specific approach and node-splitting analysis were used to evaluate consistency and inconsistency, respectively. The value of the surface under the cumulative ranking (SUCRA) was calculated and ranked. Funnel-plot symmetry was used to evaluate publication bias. The meta-analysis was performed by using STATA 16.0. RESULTS: Thirteen studies with a total of 33,011 subjects were included in this network meta-analysis. Compared with placebo, aspirin, clopidogrel, cilostazol, ticlopidine, aspirin plus dipyridamole, and aspirin plus clopidogrel were associated with reducing cardiovascular and cerebrovascular events. The SUCRA estimated relative ranking of treatments showed that cilostazol may be the most effective (RR 0.56, 95% CI 0.42-0.74, SUCRA 95.8). No significant inconsistency or publication bias was found in the study. CONCLUSIONS: This meta-analysis suggests that cilostazol may be a priority option for secondary prevention of patients with LS. These findings still need further study in the future.

Frailty and outcomes in lacunar stroke.

BACKGROUND: Lacunar strokes (LS) are ischemic strokes of the small perforating arteries of deep gray and white matter of the brain. Frailty has been associated with greater mortality and attenuated response to treatment after stroke. However, the effect of frailty on patients with LS has not been previously described. OBJECTIVE: To analyze the association between frailty and outcomes in LS. METHODS: Patients with LS were selected from the National Inpatient Sample (NIS) 2016-2019 using the International Classification of Disease, 10th edition (ICD-10) diagnosis codes. The 11-point modified frailty scale (mFI-11) was used to group patients into severely frail and non-severely frail cohorts. Demographics, clinical characteristics, and complications were defined. Health care resource utilization (HRU) was evaluated by comparing total hospital charges and length of stay (LOS). Other outcomes studied were discharge disposition and inpatient death. RESULTS: Of 48,980 patients with LS, 10,830 (22.1%) were severely frail. Severely frail patients were more likely to be older, have comorbidities, and pertain to lower socioeconomic status categories. Severely frail patients with LS had worse clinical stroke severity and increased rates of complications such as urinary tract infection (UTI) and pneumonia (PNA). Additionally, severe frailty was associated with unfavorable outcomes and increased HRU. CONCLUSION: Severe frailty in LS patients is associated with higher rates of complications and increased HRU. Risk stratification based on frailty may allow for individualized treatments to help mitigate adverse outcomes in the setting of LS.

High-intensity training in patients with lacunar stroke: A one-year follow-up.

OBJECTIVES: Physical inactivity is a major risk factor for stroke. It is a challenge for patients to initiate and adhere to regular exercise post-stroke. Early initiation of home-based high-intensity interval training (HIIT) may engage patients in physical activity, improve cardiorespiratory fitness, and reduce risk of recurrent stroke. MATERIALS AND METHODS: Post-intervention follow-up of patients with lacunar stroke, randomized to three-months HIIT including weekly motivational calls, or usual care. At follow-up (six- and 12-months post-stroke), we investigated changes in cardiorespiratory fitness, physical activity, fatigue, depression, mental well-being, stress, cognition, cardiovascular function, and recurrent stroke. RESULTS: We included 71 patients of whom 59 patients (mean age: 63.9 ± 8.8 years) completed six- and 12-month follow-up. No change was detected in cardiorespiratory fitness between groups from baseline to 12-months follow-up. At six months, vigorous-intensity activity (median hours/week [interquartile range]) was maintained in the intervention group (baseline, 0[0;2]; post-intervention, 2[0;3]; six-month, 2[0;4]) and increased in the usual care group (baseline, 0[0;1]; post-intervention, 1[0;2]; six-month, 1[0;3]), with no difference between groups. Vigorous-intensity activity declined to baseline levels at 12-months in both groups. Secondary outcomes improved from baseline to 12-months with no significant differences between groups. Similar rate of recurrent stroke (n=3) occurred in each group with a three-month delay in the intervention group. CONCLUSIONS: Early initiated HIIT did not increase long-term cardiorespiratory fitness, but increased time spent doing vigorous-intensity activities post-stroke. Decline to baseline activity level at 12 months warrants identification of motivators to initiate and sustain physical activity post-stroke.

A Scoping Review on Biomarkers of Endothelial Dysfunction in Small Vessel Disease: Molecular Insights from Human Studies.

Small vessel disease (SVD) is a highly prevalent disorder of the brain's microvessels and a common cause of dementia as well as ischaemic and haemorrhagic strokes. Though much about the underlying pathophysiology of SVD remains poorly understood, a wealth of recently published evidence strongly suggests a key role of microvessel endothelial dysfunction and a compromised blood-brain barrier (BBB) in the development and progression of the disease. Understanding the causes and downstream consequences associated with endothelial dysfunction in this pathological context could aid in the development of effective diagnostic and prognostic tools and provide promising avenues for potential therapeutic interventions. In this scoping review, we aim to summarise the findings from clinical studies examining the role of the molecular mechanisms underlying endothelial dysfunction in SVD, focussing on biochemical markers of endothelial dysfunction detectable in biofluids, including cell adhesion molecules, BBB transporters, cytokines/chemokines, inflammatory markers, coagulation factors, growth factors, and markers involved in the nitric oxide cascade.

Human adenosine deaminase 2 deficiency: A multi-faceted inborn error of immunity.

Human adenosine deaminase 1 deficiency was described in the 1970s to cause severe combined immunodeficiency. The residual adenosine deaminase activity in these patients was attributed to adenosine deaminase 2. Human adenosine deaminase type 2 deficiency (DADA2), due to biallelic deleterious mutations in the ADA2 gene, is the first described monogenic type of small- and medium-size vessel vasculitis. The phenotype of DADA2 also includes lymphoproliferation, cytopenia, and variable degrees of immunodeficiency. The physiological role of ADA2 is still enigmatic hence the pathophysiology of the condition is unclear. Preliminary data showed that in the absence of ADA2, macrophage differentiation is skewed to a pro-inflammatory M1 subset, which is detrimental for endothelial integrity. The inflammatory phenotype responds well to anti-TNF therapy with etanercept and that is the first-line treatment for prevention of severe vascular events including strokes. The classic immunosuppressive drugs are not successful in controlling the disease activity. However, hematopoietic stem cell transplantation (HSCT) has been shown to be a definitive cure in DADA2 patients who present with a severe cytopenia. HSCT can also cure the vascular phenotype and is the treatment modality for patients' refractory to anti-cytokine therapies. In this review, we describe what is currently known about the molecular mechanisms of DADA2. Further research on the pathophysiology of this multifaceted condition is needed to fine-tune and steer future therapeutic strategies.

Identification of novel proteins for lacunar stroke by integrating genome-wide association data and human brain proteomes.

BACKGROUND: Previous genome-wide association studies (GWAS) have identified numerous risk genes for lacunar stroke, but it is challenging to decipher how they confer risk for the disease. We employed an integrative analytical pipeline to efficiently transform genetic associations to identify novel proteins for lacunar stroke. METHODS: We systematically integrated lacunar stroke genome-wide association study (GWAS) (N=7338) with human brain proteomes (N=376) to perform proteome-wide association studies (PWAS), Mendelian randomization (MR), and Bayesian colocalization. We also used an independent human brain proteomic dataset (N=152) to annotate the new genes. RESULTS: We found that the protein abundance of seven genes (ICA1L, CAND2, ALDH2, MADD, MRVI1, CSPG4, and PTPN11) in the brain was associated with lacunar stroke. These seven genes were mainly expressed on the surface of glutamatergic neurons, GABAergic neurons, and astrocytes. Three genes (ICA1L, CAND2, ALDH2) were causal in lacunar stroke (P < 0.05/proteins identified for PWAS; posterior probability of hypothesis 4 ≥ 75 % for Bayesian colocalization), and they were linked with lacunar stroke in confirmatory PWAS and independent MR. We also found that ICA1L is related to lacunar stroke at the brain transcriptome level. CONCLUSIONS: Our present proteomic findings have identified ICA1L, CAND2, and ALDH2 as compelling genes that may give key hints for future functional research and possible therapeutic targets for lacunar stroke.

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.

Clinical features and imaging markers of small vessel disease in symptomatic acute subcortical cerebral microinfarcts.

BACKGROUND: As currently defined, recent small subcortical infarcts (RSSI) do not have a lower size boundary, and the smallest diffusion-weighted imaging (DWI) infarcts, which we term acute subcortical cerebral microinfarcts (As-CMI) with lesion diameter less than 5 mm, might have clinical implications distinct from RSSI. We aimed to investigate the distinct characteristics of As-CMI as compared to the larger size of RSSI regarding vascular risk factors, clinical manifestation, radiological markers of SVD distribution, and outcomes. METHODS: In a consecutive cohort, patients were selected with a magnetic resonance DWI-confirmed RSSI between January 2010 and November 2020. We measured axial infarct diameter and classified patients into two groups: The As-CMI group (diameter < 5 mm) versus the Larger RSSI group (diameter 5-20 mm). Clinical variables, including vascular risk factors, clinical symptoms/signs, lesion locations, and radiological markers of cerebral small vessel disease (SVD) on MRI were analyzed between the two groups. Patients were followed up for 12 months and functional outcomes were measured by the modified ranking scale (mRS). RESULTS: In a total of 584 patients with RSSI, 23 (3.9%) were defined as As-CMI. The most common neurological deficits with As-CMI were hemiparalysis (n = 20), followed by central facial/lingual palsy (n = 10) and hemidysesthesia (n = 10). Most As-CMIs were located in the basal ganglia (n = 11), followed by the thalamus (n = 5) and centrum semiovale (n = 4). No different regional distributions and symptoms/signs frequencies were found between the two groups except for a lower percentage of dysarthria in the As-CMI group (p = 0.008). In a multivariate analysis, patients with As-CMI were independently associated with the presence of lacunes (adjusted odds ratio [aOR] 2.88; 95% confidence interval [CI] 1.21-6.84), multiple lacunes (aOR 3.5, CI 1.29-9.48) and higher total SVD burden (aOR 1.68, CI 1.11-2.53). Patients with As-CMI did not show a better functional outcome after 12 months of follow-up. CONCLUSIONS: Patients with As-CMI had a non-specific clinical profile but a higher burden of SVD, indicating As-CMI might be s sign of more severe small vascular injury. Whether its vascular features are associated with worse cognitive outcomes requires further investigation.

Microglial activation and blood-brain barrier permeability in cerebral small vessel disease.

Cerebral small vessel disease (SVD) is a major cause of stroke and dementia. The underlying pathogenesis is poorly understood, but both neuroinflammation and increased blood-brain barrier permeability have been hypothesized to play a role, and preclinical studies suggest the two processes may be linked. We used PET magnetic resonance to simultaneously measure microglial activation using the translocator protein radioligand 11C-PK11195, and blood-brain barrier permeability using dynamic contrast enhanced MRI. A case control design was used with two disease groups with sporadic SVD (n = 20), monogenic SVD (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, CADASIL), and normal controls (n = 20) were studied. Hotspots of increased glial activation and blood-brain barrier permeability were identified as values greater than the 95th percentile of the distribution in controls. In sporadic SVD there was an increase in the volume of hotspots of both 11C-PK11195 binding (P = 0.003) and blood-brain barrier permeability (P = 0.007) in the normal appearing white matter, in addition to increased mean blood-brain barrier permeability (P < 0.001). In CADASIL no increase in blood-brain barrier permeability was detected; there was a non-significant trend to increased 11C-PK11195 binding (P = 0.073). Hotspots of 11C-PK11195 binding and blood-brain barrier permeability were not spatially related. A panel of 93 blood biomarkers relating to cardiovascular disease, inflammation and endothelial activation were measured in each participant; principal component analysis was performed and the first component related to blood-brain barrier permeability and microglial activation. Within the sporadic SVD group both hotspot and mean volume blood-brain barrier permeability values in the normal appearing white matter were associated with dimension 1 (ß = 0.829, P = 0.017, and ß = 0.976, P = 0.003, respectively). There was no association with 11C-PK11195 binding. No associations with blood markers were found in the CADASIL group. In conclusion, in sporadic SVD both microglial activation and increased blood-brain barrier permeability occur, but these are spatially distinct processes. No evidence of increased blood-brain barrier permeability was found in CADASIL.

Progressive Lacunar Strokes: A Predictive Score.

BACKGROUND AND PURPOSE: Progressive lacunar syndromes (PLS) occur in up to 20-30% of patients with lacunar strokes, increasing the risk of long term dependency. Our aim is to develop a predictive score to identify patients at high risk of presenting PLS. METHODS: We derived a risk score for PLS in a cohort of consecutive patients (n=187) presenting with one of the five classic lacunar syndromes (LS) and absence of vascular occlusion, perfusion deficit or symptomatic stenosis. A risk score was developed using the coefficients from the logistic regression model, and receiver operating characteristic (ROC) analysis was conducted to assess the prognostic value of the risk score. Sensitivity, specificity and accuracy were estimated for each total point score. RESULTS: Out of 187 patients included in our sample, 52 (27.8%) presented PLS. Previous history of diabetes mellitus (1 point), diastolic blood pressure at admission (2 points), clinical deficits consistent with a pure motor syndrome (1 point) and asymptomatic intracranial atheromatosis or stenosis in non-symptomatic territory (1 point) were independent predictors for PLS. The estimated area under the ROC curve for this model was 0.77 (95% CI,0.68 - 0.84). CONCLUSION: This score could be a useful tool in routine clinical practice to predict the occurrence of PLS, allowing the identification of those patients with LS who are at high risk of long term dependency due to early neurological worsening, and who would benefit the most from an intensive treatment.

Quantitative Proteomics of Medium-Sized Extracellular Vesicle-Enriched Plasma of Lacunar Infarction for the Discovery of Prognostic Biomarkers.

Lacunar infarction (LACI), a subtype of acute ischemic stroke, has poor mid- to long-term prognosis due to recurrent vascular events or incident dementia which is difficult to predict using existing clinical data. Herein, we aim to discover blood-based biomarkers for LACI as a complementary prognostic tool. Convalescent plasma was collected from forty-five patients following a non-disabling LACI along with seventeen matched control subjects. The patients were followed up prospectively for up to five years to record an occurrence of adverse outcome and grouped accordingly (i.e., LACI-no adverse outcome, LACI-recurrent vascular event, and LACI-cognitive decline without any recurrence of vascular events). Medium-sized extracellular vesicles (MEVs), isolated from the pooled plasma of four groups, were analyzed by stable isotope labeling and 2D-LC-MS/MS. Out of 573 (FDR < 1%) quantified proteins, 146 showed significant changes in at least one LACI group when compared to matched healthy control. A systems analysis revealed that major elements (~85%) of the MEV proteome are different from the proteome of small-sized extracellular vesicles obtained from the same pooled plasma. The altered MEV proteins in LACI patients are mostly reduced in abundance. The majority of the shortlisted MEV proteins are not linked to commonly studied biological processes such as coagulation, fibrinolysis, or inflammation. Instead, they are linked to oxygen-glucose deprivation, endo-lysosomal trafficking, glucose transport, and iron homeostasis. The dataset is provided as a web-based data resource to facilitate meta-analysis, data integration, and targeted large-scale validation.