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Background and ObjectivesPerivascular spaces (PVS) visible on MRI scans may represent key aspects in the pathophysiology of stroke and dementia, including cerebral small vessel disease and glymphatic dysfunction. This study aimed to determine the association between MRI-visible PVS burden and the risk of incident dementia.MethodsThis study included community-dwelling Framingham Heart Study Original and Offspring cohort participants with available brain MRI-PVS ratings, free of stroke and dementia. Multivariable Cox proportional hazard regression was used to obtain hazard ratios (HRs) and 95% CIs of the association between MRI-visible PVS and incident dementia. PVS were rated using validated methods in the basal ganglia (BG) and centrum semiovale (CSO). The outcomes included all-cause dementia, Alzheimer dementia (AD), and vascular dementia (VaD).ResultsOne thousand four hundred forty-nine participants 50 years or older (46% male) were included. Over a median follow-up period of 8.3 years, the incidence of all-cause dementia, AD, and VaD was 15.8%, 12.5%, and 2.5%, respectively. In models that adjusted for vascular risk factors and cardiovascular disease, the hazard for dementia increased steadily as PVS burden increased, rising 2-fold for those with grade II PVS (HR 2.44, 95% CI 1.51–3.93) to 5-fold in participants with grade IV (HR 5.05, 95% CI 2.75–9.26) compared with grade I PVS in CSO. In the BG, hazards increased 1.6-fold (HR 1.62, 95% CI 1.15–2.27) for grade II to 2.6-fold (HR 2.67, 95% CI 1.04–6.88) for grade IV compared with grade I PVS. The association remained significant for CSO but not for BG, after adjustment for white matter hyperintensity volume (WMHV), covert infarcts, and total brain volume. Similar findings were observed for AD, but VaD, limited by a small number of events, was not statistically significant.DiscussionHigher burden of PVS in CSO was associated with increased risk of developing dementia, independent of vascular risk factors, total brain volume, WMHVs, and covert infarcts. This finding supports a role for PVS as a subclinical MRI marker to identify individuals in subclinical stages at high risk of developing dementia who may benefit from early intervention.

Background and Purpose: Although most strokes present with mild symptoms, these have been poorly represented in clinical trials. The objective of this study is to describe multidimensional outcomes, identify predictors of worse outcomes, and explore the effect of thrombolysis in this population. Methods: This prospective observational study included patients with ischemic stroke or transient ischemic attack, a baseline National Institutes of Health Stroke Scale (NIHSS) score 0 to 5, presenting within 4.5 hours from symptom onset. The primary outcome was a 90-day modified Rankin Scale score of 0 to 1; secondary outcomes included good outcomes in the Barthel Index, Stroke Impact Scale-16, and European Quality of Life. Multivariable models were created to determine predictors of outcomes and the effect of alteplase. Results: A total of 1765 participants were included from 100 Get With The Guidelines-Stroke participating hospitals (age, 65±14; 42% women; final diagnosis of ischemic stroke, 90%; transient ischemic attack, 10%; 57% received alteplase). At 90 days, 37% were disabled and 25% not independent. Worse outcomes were noted for older individuals, women, non-Hispanic Blacks and Hispanics, Medicaid recipients, smokers, those with diabetes, atrial fibrillation, prior stroke, higher baseline NIHSS, visual field defects, and extremity weakness. Similar outcomes were noted for the alteplase-treated and untreated groups. Alteplase-treated patients were younger (64±13 versus 67±1.4) with higher NIHSS (2.9±1.4 versus 1.7±1.4). After adjusting for age, sex, race/ethnicity, and baseline NIHSS, we did not identify an effect of alteplase on the primary outcome but did find an association with Stroke Impact Scale-16 in the restricted sample of baseline NIHSS score 3–5. Few symptomatic intracerebral hemorrhages were recorded ( Conclusions: A large proportion of stroke patients presenting with low NIHSS have a disabled outcome. Baseline predictors of worse outcomes are described. An effect of alteplase on outcomes was not identified in the overall cohort, but a suggestion of efficacy was noted in the NIHSS 3–5 subgroup. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT02072681.

Research Design: In this study, we describe patients from a tertiary care safety-net hospital endocarditis registry with tricuspid valve infective endocarditis (TVIE), and concomitant acute or subacute ischemic stroke predominantly associated with injection drug use (IDU). We retrospectively obtained data pertinent to neurologic examinations, history of injection drug use (IDU), blood cultures, transthoracic/transesophageal echocardiography (TTE/TEE), neuroimaging, and Modified Rankin Scale (mRS) scores at discharge. Only those patients with bacteremia, tricuspid valve vegetations, and neuroimaging consistent with acute to subacute ischemic infarction and microhemorrhages in two cases were included in this series. Results: Of 188 patients in the registry, 66 patients had TVIE and 10 of these were complicated by ischemic stroke. Neurologic symptoms were largely non-specific, eight patients had altered mental status and only 3 had focal deficits. Nine cases were associated with IDU. Two patients had evidence of a patent foramen ovale on echocardiography. Blood cultures grew S. aureus species in 9 of the patients, all associated with IDU. Three patients died during hospitalization. The mRS score at discharge for survivors ranged 0-4. Conclusions: Patients with strokes from TVIE had heterogeneous presentations and putative mechanisms. We noted that robust neuroimaging is lacking for patients with TVIE from IDU and that such patients may benefit from neuroimaging as a screen for strokes to assist peri-operative management. Further inquiry is needed to elucidate stroke mechanisms in these patients.

ImportanceEnlarged perivascular spaces (ePVSs) have been associated with cerebral small-vessel disease (cSVD). Although their etiology may differ based on brain location, study of ePVSs has been limited to specific brain regions; therefore, their risk factors and significance remain uncertain.ObjectiveToperform a whole-brain investigation of ePVSs in a large community-based cohort.Design, Setting, and ParticipantsThis cross-sectional study analyzed data from the Atrial Fibrillation substudy of the population-based Multi-Ethnic Study of Atherosclerosis. Demographic, vascular risk, and cardiovascular disease data were collected from September 2016 to May 2018. Brain magnetic resonance imaging was performed from March 2018 to July 2019. The reported analysis was conducted between August and October 2022. A total of 1026 participants with available brain magnetic resonance imaging data and complete information on demographic characteristics and vascular risk factors were included.Main Outcomes and MeasuresEnlarged perivascular spaces were quantified using a fully automated deep learning algorithm. Quantified ePVS volumes were grouped into 6 anatomic locations: basal ganglia, thalamus, brainstem, frontoparietal, insular, and temporal regions, and were normalized for the respective regional volumes. The association of normalized regional ePVS volumes with demographic characteristics, vascular risk factors, neuroimaging indices, and prevalent cardiovascular disease was explored using generalized linear models.ResultsIn the 1026 participants, mean (SD) age was 72 (8) years; 541 (53%) of the participants were women. Basal ganglia ePVS volume was positively associated with age (β = 3.59 × 10−3; 95% CI, 2.80 × 10−3 to 4.39 × 10−3), systolic blood pressure (β = 8.35 × 10−4; 95% CI, 5.19 × 10−4 to 1.15 × 10−3), use of antihypertensives (β = 3.29 × 10−2; 95% CI, 1.92 × 10−2 to 4.67 × 10−2), and negatively associated with Black race (β = −3.34 × 10−2; 95% CI, −5.08 × 10−2 to −1.59 × 10−2). Thalamic ePVS volume was positively associated with age (β = 5.57 × 10−4; 95% CI, 2.19 × 10−4 to 8.95 × 10−4) and use of antihypertensives (β = 1.19 × 10−2; 95% CI, 6.02 × 10−3 to 1.77 × 10−2). Insular region ePVS volume was positively associated with age (β = 1.18 × 10−3; 95% CI, 7.98 × 10−4 to 1.55 × 10−3). Brainstem ePVS volume was smaller in Black than in White participants (β = −5.34 × 10−3; 95% CI, −8.26 × 10−3 to −2.41 × 10−3). Frontoparietal ePVS volume was positively associated with systolic blood pressure (β = 1.14 × 10−4; 95% CI, 3.38 × 10−5 to 1.95 × 10−4) and negatively associated with age (β = −3.38 × 10−4; 95% CI, −5.40 × 10−4 to −1.36 × 10−4). Temporal region ePVS volume was negatively associated with age (β = −1.61 × 10−2; 95% CI, −2.14 × 10−2 to −1.09 × 10−2), as well as Chinese American (β = −2.35 × 10−1; 95% CI, −3.83 × 10−1 to −8.74 × 10−2) and Hispanic ethnicities (β = −1.73 × 10−1; 95% CI, −2.96 × 10−1 to −4.99 × 10−2).Conclusions and RelevanceIn this cross-sectional study of ePVSs in the whole brain, increased ePVS burden in the basal ganglia and thalamus was a surrogate marker for underlying cSVD, highlighting the clinical importance of ePVSs in these locations.

El presente trabajo de investigacion muestra un estudio experimental y exploratorio de un modelo de techo verde a escala. Esto con el fin de estimar los parametros para la disminucion de la escorrentia en areas tropicales y su correspondiente aplicacion en sistemas de drenaje urbano sostenible, como los son los techos verdes en edificios para uso residencial. El estudio se baso en la construccion de dos modelos fisicos de un (1) m2 cada uno, que luego de su preparacion fueron sometidos a diferentes eventos de precipitacion definidos para tres periodos de retorno (5, 10 y 25 anos), tres pendientes de techos (5%, 10% y 12%) y una condicion de humedad antecedente a capacidad de campo. Para recrear la intensidad de la lluvia se construyo un simulador, utilizando un sistema de bombeo y aspersores. Se utilizaron orificios de salida en los techos para las mediciones de volumen, ubicados a cada lado del mismo. Se calcularon las tasas de flujo maximo para cada modelo y los hidrogramas de escorrentia.Se demostro que a traves del uso de estos techos verdes es posible una reduccion en las tasas de flujo maximas en un 16%, incluso cuando la matriz del suelo esta saturada.

Background and aims: Combining biologically related traits in genome-wide association studies (GWAS) increases the power for genetic discovery. Given the established relationship between lobar intracerebral hemorrhage (ICH) and cerebral amyloid angiopathy (CAA), and between the latter and levels of cerebrospinal fluid amyloid-β 42 (CSF-Aβ42), we leveraged genetic predisposition for lower CSF-Aβ42 levels as a proxy phenotype for CAA to identify new genes associated with lobar ICH. Methods: We used publicly available GWAS data for CSF-Aβ42 levels (n = 3146) and for lobar ICH (n = 2094). First, we evaluated the association between lobar ICH risk and CSF-Aβ42 in lobar ICH patients using a polygenic risk score (PRS) for CSF-Aβ42. Next, we conducted multi-trait analysis of GWAS (MTAG) for pleiotropy analysis of lobar ICH and CSF-Aβ42. MTAG results were further tested using Expression Quantitative Trait Locus and Differential Gene Expression Analyses. Results: CSF-Aβ42 PRS was associated with lobar ICH risk (p = 0.04). MTAG analysis identified a novel association within CDH9 (rs1007589; minor allele frequency = 0.09; MTAG p = 5.4 × 10−8; lobar ICH odds ratio = 1.4 and p = 2.4 × 10−3; CSF-Aβ42 β = −0.03 and p = 4.5 × 10−6). rs1007589 was significantly associated with the expression levels of CDH9 in temporal and occipital cortices, regions known to preferentially accumulate microhemorrhages in CAA. Conclusion: Our pleiotropy analysis suggested a variant possibly implicated with lobar ICH driven by amyloid-related mechanisms in CDH9 and associated with differential expression in brain regions characteristically affected by CAA. CDH9 is one subtype of the cadherin superfamily, which regulates intercellular adhesion, is involved in blood-brain barrier integrity, and is elevated in Alzheimer’s disease patients. Further analyses are warranted to understand the effects of the variant on the pathogenesis of ICH and its clinical significance.

BACKGROUND: Cerebral amyloid angiopathy (CAA) is an age-related small vessel disease, characterised pathologically by progressive deposition of amyloid β in the cerebrovascular wall. The Boston criteria are used worldwide for the in-vivo diagnosis of CAA but have not been updated since 2010, before the emergence of additional MRI markers. We report an international collaborative study aiming to update and externally validate the Boston diagnostic criteria across the full spectrum of clinical CAA presentations.METHODS: In this multicentre, hospital-based, retrospective, MRI and neuropathology diagnostic accuracy study, we did a retrospective analysis of clinical, radiological, and histopathological data available to sites participating in the International CAA Association to formulate updated Boston criteria and establish their diagnostic accuracy across different populations and clinical presentations. Ten North American and European academic medical centres identified patients aged 50 years and older with potential CAA-related clinical presentations (ie, spontaneous intracerebral haemorrhage, cognitive impairment, or transient focal neurological episodes), available brain MRI, and histopathological assessment for CAA diagnosis. MRI scans were centrally rated at Massachusetts General Hospital (Boston, MA, USA) for haemorrhagic and non-haemorrhagic CAA markers, and brain tissue samples were rated by neuropathologists at the contributing sites. We derived the Boston criteria version 2.0 (v2.0) by selecting MRI features to optimise diagnostic specificity and sensitivity in a prespecified derivation cohort (Boston cases 1994-2012, n=159), then externally validated the criteria in a prespecified temporal validation cohort (Boston cases 2012-18, n=59) and a geographical validation cohort (non-Boston cases 2004-18; n=123), comparing accuracy of the new criteria to the currently used modified Boston criteria with histopathological assessment of CAA as the diagnostic standard. We also assessed performance of the v2.0 criteria in patients across all cohorts who had the diagnostic gold standard of brain autopsy.FINDINGS: The study protocol was finalised on Jan 15, 2017, patient identification was completed on Dec 31, 2018, and imaging analyses were completed on Sept 30, 2019. Of 401 potentially eligible patients presenting to Massachusetts General Hospital, 218 were eligible to be included in the analysis; of 160 patient datasets from other centres, 123 were included. Using the derivation cohort, we derived provisional criteria for probable CAA requiring the presence of at least two strictly lobar haemorrhagic lesions (ie, intracerebral haemorrhages, cerebral microbleeds, or foci of cortical superficial siderosis) or at least one strictly lobar haemorrhagic lesion and at least one white matter characteristic (ie, severe visible perivascular spaces in centrum semiovale or white matter hyperintensities in a multispot pattern). The sensitivity and specificity of these criteria were 74·8% (95% CI 65·4-82·7) and 84·6% (71·9-93·1) in the derivation cohort, 92·5% (79·6-98·4) and 89·5% (66·9-98·7) in the temporal validation cohort, 80·2% (70·8-87·6) and 81·5% (61·9-93·7) in the geographical validation cohort, and 74·5% (65·4-82·4) and 95·0% (83·1-99·4) in all patients who had autopsy as the diagnostic standard. The area under the receiver operating characteristic curve (AUC) was 0·797 (0·732-0·861) in the derivation cohort, 0·910 (0·828-0·992) in the temporal validation cohort, 0·808 (0·724-0·893) in the geographical validation cohort, and 0·848 (0·794-0·901) in patients who had autopsy as the diagnostic standard. The v2.0 Boston criteria for probable CAA had superior accuracy to the current Boston criteria (sensitivity 64·5% [54·9-73·4]; specificity 95·0% [83·1-99·4]; AUC 0·798 [0·741-0854]; p=0·0005 for comparison of AUC) across all individuals who had autopsy as the diagnostic standard.INTERPRETATION: The Boston criteria v2.0 incorporate emerging MRI markers of CAA to enhance sensitivity without compromising their specificity in our cohorts of patients aged 50 years and older presenting with spontaneous intracerebral haemorrhage, cognitive impairment, or transient focal neurological episodes. Future studies will be needed to determine generalisability of the v.2.0 criteria across the full range of patients and clinical presentations.FUNDING: US National Institutes of Health (R01 AG26484).

Background and Purpose: Clinical fluctuations in ischemic stroke symptoms are common, but fluctuations before hospital arrival have not been previously characterized. Methods: A standardized qualitative assessment of fluctuations before hospital arrival was obtained in an observational study that enrolled patients with mild ischemic stroke symptoms (National Institutes of Health Stroke Scale [NIHSS] score of 0–5) present on arrival to hospital within 4.5 hours of onset, in a subset of 100 hospitals participating in the Get With The Guidelines–Stroke quality improvement program. The number of fluctuations, direction, and the overall improvement or worsening was recorded based on reports from the patient, family, or paramedics. Baseline NIHSS on arrival and at 72 hours (or discharge if before) and final diagnosis and stroke subtype were collected. Outcomes at 90 days included the modified Rankin Scale, Barthel Index, Stroke Impact Scale 16, and European Quality of Life. Prehospital fluctuations were examined in relation to hospital NIHSS change (admission to 72 hours or discharge) and 90-day outcomes. Results: Among 1588 participants, prehospital fluctuations, consisting of improvement, worsening, or both were observed in 35.5%: 25.1% improved once, 5.3% worsened once, and 5.1% had more than 1 fluctuation. Those who improved were less likely and those who worsened were more likely to receive alteplase. Those who improved before hospital arrival had lower change in the hospital NIHSS than those who did not fluctuate. Better adjusted 90-day outcomes were noted in those with prehospital improvement compared to those without any fluctuations. Conclusions: Fluctuations in neurological symptoms and signs are common in the prehospital setting. Prehospital improvement was associated with better 90-day outcomes, controlling for admission NIHSS and alteplase treatment. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT 02072681.

Background: Insulin-like growth factor 1 (IGF-1), reduces progression of atherosclerosis and in cross-sectional studies low circulating IGF-1 is associated with increased carotid intima-media thickness. Yet, prospective data linking IGF-1 levels to development of stroke remain sparse and inconsistent. We related circulating IGF-1 levels to risk of incident stroke in a community-dwelling sample. Methods: Serum IGF-1 levels were assayed in 757 stroke-free participants (age 79+5 years, 62% women) from the Framingham original cohort (1990-1994), and related to prospectively ascertained, incident all-stroke and ischemic stroke using Cox models. Results: During a mean follow-up of 10.2 years in 757 participants, 119 developed stroke including 99 with ischemic stroke. After adjustment for age and sex, higher log-IGF1 levels were associated with a lower risk of incident ischemic stroke [hazard ratio (HR): 0.79, 95% confidence interval (CI): 0.63- 0.99, p=0.043]. There was a threshold effect with subjects in the lowest quintile of IGF-1 levels having 2.56-fold higher risk of incident ischemic stroke (95% CI: 1.20, 5.45, p=0.015) compared to all others. We observed significant interaction between diabetes and IGF1 in their relation to ischemic stroke (p=0.016). In pre-specified subgroup analyses the effect was restricted to persons with diabetes and central obesity (waist-to-hip ratio in top quartile) in whom each SD increase in IGF-1 was associated with a 61% (HR: 0.39, 95%CI: 0.20-0.78, p=0.007), and 41% (HR: 0.59, 95%CI: 0.37- 0.95, p=0.031) lower risk of incident ischemic stroke, respectively. Results were similar for all-stroke. Conclusions: IGF-1 may have a protective role in the pathogenesis of ischemic stroke among persons with insulin resistance as manifested by diabetes and/or obesity.

Background: Leptin is a major adipokine that regulates weight balance and energy homeostasis. There is some inconsistent evidence linking circulating leptin levels to risk of stroke. We tested the hypothesis that leptin levels are associated with risk of first ever stroke in an elderly community-based population. Methods: Serum leptin levels were assayed in 757 stroke-free individuals (mean age 79 [SD, 5 years], 62% women) from the Framingham Original cohort at the 22nd examination cycle (1990-1994). Incidence of all-stroke and ischemic stroke were prospectively ascertained. Results: During a mean follow-up of 10 years, 119 individuals developed stroke, 99 of whom had ischemic stroke. In multivariable Cox regression models, log-leptin levels were not associated with incidence of all-stroke or ischemic stroke (hazard ratios [HR] per SD increment in log-leptin 0.9 [0.73-1.09] and 0.89 [0.72-1.11], respectively). The results were highly suggestive for effect modification by WHR for the association between leptin and ischemic stroke. Analysis in sub-groups stratified by waist-to-hip ratio (WHR) and adjusting for age, sex and established stroke risk factors revealed a lower incidence of first-ever all-stroke and ischemic stroke associated with higher leptin levels among subjects in the top WHR quartile but not in others (HR, 0.64 [0.43, 0.95] versus 0.98 [0.77, 1.25] for incident all-stroke and 0.61 [0.39, 0.95] versus 0.96 [0.74, 1.26] for ischemic stroke). Conclusions: Our data suggests that leptin may exert protective effects against first ever stroke in obese individuals. Further investigations are required to confirm these findings and explore possible mechanisms for this protective effect.

Objectives: To determine and compare the accuracy of the Boston criteria for the diagnosis of cerebral amyloid angiopathy (CAA) applied to: 1) a large hospital-based cohort; 2) a cohort of community-dwelling individuals. Methods: Among patients seen at a single academic medical center and participants enrolled in the Framingham Heart Study (FHS) we identified all individuals having had brain MRI (including hemosiderin-specific sequences) and pathological assessment of CAA at age ≥55. CAA was defined as Vonsattel degree ≥2, except in non-autopsy studies, where any vascular amloyid deposition was considered diagnostic of CAA. We excluded cases with: 1) non-lobar ICH; 2) alternative clinical diagnosis for the lobar hemorrhage/es; 3) CAA-negative studies based on small brain biopsy samples (greater diameter 1 strictly lobar hemorrhage) in both cohorts. Results: The study included 143 cases: 96 from the hospital cohort (mean age at time of MRI 74.1±8.2 years, 47.9% women, 47.9% autopsy studies, 54.2% cases with any lobar microbleed, 44.8% with any lobar ICH) and 47 from FHS (mean age at time of MRI 83.4±10.9 years, 48.9% women, 100% autopsy studies, 17% cases with any lobar microbleed, no lobar ICH cases). Hospital cohort: CAA prevalence was 72.6%. Specificity/sensitivity of “possible CAA” and “probable CAA” were 78.2%/33.3% and 92%/57.7%. Community cohort: CAA prevalence was 47%. Specificity/sensitivity of “probable CAA” were 88%/3%. Discussion: Specificity of detection of multiple lobar hemorrhages on MRI (“probable CAA”) for moderate-severe CAA is similarly high in both hospital and community cohorts. This increases the opportunity to identify individuals with CAA for observational studies and emerging anti-amyloid therapeutic trials. In view of its poor sensitivity, “probable CAA” diagnosis represents an inadequate screening tool for exclusion of CAA in both populations.