Cortical Superficial Siderosis Research Articles

Occult Amyloid-β-Related Angiitis: Neuroimaging Findings at 1.5T, 3T, and 7T MRI.

Cerebral amyloid angiopathy (CAA) is a progressive neurodegenerative small vessel disease that is associated with intracranial hemorrhage and cognitive impairment in the elderly. The clinical and radiographic presentations have many overlapping features with vascular cognitive impairment, hemorrhagic stroke, and Alzheimer disease (AD). Amyloid-β-related angiitis (ABRA) is a form of primary CNS vasculitis linked to CAA, with the development of spontaneous autoimmune inflammation against amyloid in the vessel wall with resultant vasculitis. The diagnosis of ABRA and CAA is important. ABRA is often fatal if untreated and requires prompt immunosuppression. Important medical therapies such as anticoagulation and antiamyloid agents for AD are contraindicated in CAA. Here, we present a biopsy-proved case of ABRA with underlying occult CAA. Initial 1.5T and 3T MR imaging did not suggest CAA per the Boston Criteria 2.0. ABRA was not included in the differential diagnosis due to the lack of any CAA-related findings on conventional MR imaging. However, a follow-up 7T MR imaging revealed extensive cortical/subcortical cerebral microbleeds, cortical superficial siderosis, and intragyral hemorrhage in extensive detail throughout the supratentorial brain regions, which radiologically supported the diagnosis of ABRA in the setting of CAA. This case suggests an increased utility of high-field MR imaging to detect occult hemorrhagic neuroimaging findings with the potential to both diagnose more patients with CAA and diagnose them earlier.

Combined effect of cortical superficial siderosis and cerebral microbleed on short-term and long-term outcomes after intracerebral haemorrhage

Background and purposeCortical superficial siderosis (cSS) and cerebral microbleed (CMB) have distinct effects on intracerebral haemorrhage (ICH). We aim to investigate the combined effect of cSS and CMB on outcomes...

Cerebral Amyloid Angiopathy-Related Inflammation and Biopsy-Positive Primary Angiitis of the CNS: A Comparative Study.

Cerebral amyloid angiopathy-related inflammation (CAA-RI) and biopsy-positive primary angiitis of the CNS (BP-PACNS) have overlapping clinicoradiologic presentations. It is unknown whether clinical and radiologic features can differentiate CAA-RI from BP-PACNS and whether both diseases have different relapse rates. The objectives of this study were to compare clinicoradiologic presentations and relapse rates in patients with CAA-RI vs BP-PACNS. Patients with CAA-RI and BP-PACNS were enrolled from 2 retrospective multicenter cohorts. Patients with CAA-RI were biopsy-positive or met probable clinicoradiologic criteria. Patients with BP-PACNS had histopathologic confirmation of CNS angiitis, with no secondary etiology. A neuroradiologist read brain MRIs, blinded to the diagnosis of CAA-RI or BP-PACNS. Clinicoradiologic features were compared using univariable logistic regression models. Relapse rates were compared using a univariable Fine-Gray subdistribution hazard model, with death as a competing risk. This study enrolled 104 patients with CAA-RI (mean age 73 years, 48% female sex) and 52 patients with BP-PACNS (mean age 45 years, 48% female sex). Patients with CAA-RI more often had white matter hyperintense lesions meeting the probable CAA-RI criteria (93% vs 51%, p < 0.001), acute subarachnoid hemorrhage (15% vs 2%, p = 0.02), cortical superficial siderosis (27% vs 4%, p < 0.001), ≥1 lobar microbleed (94% vs 26%, p < 0.001), past intracerebral hemorrhage (17% vs 4%, p = 0.04), ≥21 visible centrum semiovale perivascular spaces (34% vs 4%, p < 0.01), and leptomeningeal enhancement (70% vs 27%, p < 0.001). Patients with BP-PACNS more often had headaches (56% vs 31%, p < 0.01), motor deficits (56% vs 36%, p = 0.02), and nonischemic parenchymal gadolinium enhancement (82% vs 16%, p < 0.001). The prevalence of acute ischemic lesions was 18% in CAA-RI and 22% in BP-PACNS (p = 0.57). The features with the highest specificity for CAA-RI were acute subarachnoid hemorrhage (98%), cortical superficial siderosis (96%), past intracerebral hemorrhage (96%), and ≥21 visible centrum semiovale perivascular spaces (96%). The probable CAA-RI criteria had a 71% sensitivity (95% CI 44%-90%) and 91% specificity (95% CI 79%-98%) in differentiating biopsy-positive CAA-RI from BP-PACNS. The rate of relapse in the first 2 years after remission was lower in CAA-RI than in BP-PACNS (hazard ratio 0.46, 95% CI 0.22-0.96, p = 0.04). Clinicoradiologic features differed between patients with CAA-RI and those with BP-PACNS. Specific markers for CAA-RI were hemorrhagic signs of subarachnoid involvement, past intracerebral hemorrhage, ≥21 visible centrum semiovale perivascular spaces, and the probable CAA-RI criteria. A biopsy remains necessary for diagnosis in some cases of CAA-RI. The rate of relapse in the first 2 years after disease remission was lower in CAA-RI than in BP-PACNS.

Tumefactive cerebral amyloid angiopathy - related inflammation.

Cerebral amyloid angiopathy-related inflammation (CAA-ri) derives from inflammatory response to β-amyloid (Aβ) protein deposition within the cerebral blood vessel walls. We report a case that accentuates those clinical and imaging features that can contribute to raise suspicion for the condition and lead to early treatment initiation. A 72-year-old man was referred with one-month history of cognitive decline along with behavioral alterations. Brain MRI showed fluid attenuated inversion recovery (FLAIR) asymmetrical multifocal white matter hyperintensities (WMHs) along with multiple cerebral microbleeds (CMBs) and cortical superficial siderosis (cSS) on T2*-weighted gradient-recalled echo (T2*-GRE) images. Metabolic, infectious, and neoplastic causes were excluded, and subsequently corticosteroids were administered to the patient resulting in clinical recovery. Imaging on follow-up disclosed remission of WMHs, while CMBs load increased significantly. Clinical neurologists' acquaintance with the clinical and imaging features of CAA-ri allows prompt diagnosis and medication initiation, that is essential for a conceivably treatable condition.

Application of artificial intelligence-based magnetic resonance imaging in diagnosis of cerebral small vessel disease.

Cerebral small vessel disease (CSVD) is an important cause of stroke, cognitive impairment, and other diseases, and its early quantitative evaluation can significantly improve patient prognosis. Magnetic resonance imaging (MRI) is an important method to evaluate the occurrence, development, and severity of CSVD. However, the diagnostic process lacks quantitative evaluation criteria and is limited by experience, which may easily lead to missed diagnoses and misdiagnoses. With the development of artificial intelligence technology based on deep learning, the extraction of high-dimensional features in imaging can assist doctors in clinical decision-making, and it has been widely used in brain function and mental disorders, and cardiovascular and cerebrovascular diseases. This paper summarizes the global research results in recent years and briefly describes the application of deep learning in evaluating CSVD signs in MRI imaging, including recent small subcortical infarcts, lacunes of presumed vascular origin, vascular white matter hyperintensity, enlarged perivascular spaces, cerebral microbleeds, brain atrophy, cortical superficial siderosis, and cortical cerebral microinfarct.

Pathophysiology, Diagnosis, Prognosis, and Prevention of Poststroke Epilepsy: Clinical and Research Implications.

Poststroke epilepsy (PSE) is associated with higher mortality and poor functional and cognitive outcomes in patients with stroke. With the remarkable development of acute stroke treatment, there is a growing number of survivors with PSE. Although approximately 10% of patients with stroke develop PSE, given the significant burden of stroke worldwide, PSE is a significant problem in stroke survivors. Therefore, the attention of health policymakers and significant funding are required to promote PSE prevention research. The current PSE definition includes unprovoked seizures occurring more than 7 days after stroke onset, given the high recurrence risks of seizures. However, the pathologic cascade of stroke is not uniform, indicating the need for a tissue-based approach rather than a time-based one to distinguish early seizures from late seizures. EEG is a commonly used tool in the diagnostic work-up of PSE. EEG findings during the acute phase of stroke can potentially stratify the risk of subsequent seizures and predict the development of poststroke epileptogenesis. Recent reports suggest that cortical superficial siderosis, which may be involved in epileptogenesis, is a promising marker for PSE. By incorporating such markers, future risk-scoring models could guide treatment strategies, particularly for the primary prophylaxis of PSE. To date, drugs that prevent poststroke epileptogenesis are lacking. The primary challenge involves the substantial cost burden due to the difficulty of reliably enrolling patients who develop PSE. There is, therefore, a critical need to determine reliable biomarkers for PSE. The goal is to be able to use them for trial enrichment and as a surrogate outcome measure for epileptogenesis. Moreover, seizure prophylaxis is essential to prevent functional and cognitive decline in stroke survivors. Further elucidation of factors that contribute to poststroke epileptogenesis is eagerly awaited. Meanwhile, the regimen of antiseizure medications should be based on individual cardiovascular risk, psychosomatic comorbidities, and concomitant medications. This review summarizes the current understanding of poststroke epileptogenesis, its risks, prognostic models, prophylaxis, and strategies for secondary prevention of seizures and suggests strategies to advance research on PSE.

Quantitative electroencephalography in cerebral amyloid angiopathy

ObjectiveWe investigated whether quantitative electroencephalography (qEEG) correlates with cognition and cortical superficial siderosis (cSS) in cerebral amyloid angiopathy. MethodsWe included patients with sporadic (sCAA) and hereditary Dutch-type CAA (D-CAA). Spectral measures and the phase lag index (PLI) were analyzed on qEEG. Cognition was assessed with the MoCA and cSS presence was scored on 3T-MRI. Linear regression analyses were performed to investigate these qEEG measures and cognition. Independent samples T-tests were used to analyze the qEEG measure differences between participants with and without cSS. ResultsWe included 92 participants (44 D-CAA; 48 sCAA). A lower average peak frequency (β[95 %CI] = 0.986[0.252–1.721]; P = 0.009) and a higher spectral ratio (β[95 %CI] = −0.918[−1.761–−0.075]; P = 0.033) on qEEG correlated with a lower MoCA score, irrespective of a history of symptomatic intracerebral hemorrhage (sICH). The PLI showed no correlation to the MoCA. qEEG slowing was not different in those with or without cSS. ConclusionsSpectral qEEG (but not PLI) reflects cognitive performance in patients with CAA with and without a history of sICH. We found no association between qEEG slowing and cSS. SignificanceqEEG could be a valuable biomarker, especially in challenging cognitive testing situations in CAA, and a potential predictive tool in future studies.

Clinical characteristics of cerebral amyloid angiopathy and risk factors of cerebral amyloid angiopathy related intracerebral hemorrhage.

There is limited understanding of the differences between cerebral amyloid angiopathy (CAA) with and without intracerebral hemorrhage (ICH). This article aimed to describe the characteristics of CAA and identify the risk factors of CAA-ICH in a multicenter cohort. Patients consecutively enrolled in the national multicenter prospective Cerebral Small Vessel Disease Cohort Study who met the Boston diagnostic criteria for CAA or CAA-related inflammation were included in this study. The demographic characteristics and clinical data were collected. The clinical and radiographic differences between CAA with and without ICH were compared to identify the risk factors for CAA-ICH. A total of 219 CAA patients were included, with an average age of 67.12 ± 9.93. Of all patients, 26.0% were CAA with ICH. Univariate analysis showed that CAA-ICH is associated with carrying more APOE ε2 allele, less lobar cerebral microbleeds (CMBs), cortical superficial siderosis (cSS), lower Fazekas scale, a tendency of gait disorder, and acute onset (P < 0.05). The generalized linear mixed model yielded statistically significant associations between CAA with ICH and carrying the APOE ε2 allele, cSS, the lower number of lobar CMBs, and the lower Fazekas scale (P < 0.05). It is meaningful to classify CAA with and without ICH, as there may be different mechanisms between the two. CAA with ICH has a susceptibility to carrying APOE ε2, cSS, and a relatively small number of CMBs. Fewer CMBs do not mean lower susceptibility to ICH in CAA. Larger prospective cohort studies are necessary to further clarify these conclusions.

Sex differences in histopathological markers of cerebral amyloid angiopathy and related hemorrhage.

Men with cerebral amyloid angiopathy (CAA) may have an earlier onset of intracerebral hemorrhage and a more hemorrhagic disease course compared to women. In this cohort study, we investigated sex differences in histopathological markers associated with amyloid-β burden and hemorrhage in cognitively impaired individuals and patients with CAA, using neuropathological data from two autopsy databases. First, we investigated presence of parenchymal (Thal score) and vascular amyloid-β (CAA severity score) in cognitively impaired individuals from the National Alzheimer's Coordinating Center (NACC) neuropathology database. Next, we examined sex differences in hemorrhagic ex vivo magnetic resonance imaging (MRI) markers and local cortical iron burden and the interaction of sex on factors associated with cortical iron burden (CAA percentage area and vessel remodeling) in patients with pathologically confirmed clinical CAA from the Massachusetts General Hospital (MGH) CAA neuropathology database. In 6120 individuals from the NACC database (45% women, mean age 80 years), the presence of parenchymal amyloid-β (odds ratio (OR) (95% confidence interval (CI)) =0.68 (0.53-0.88)) but not vascular amyloid-β was less in men compared to women. In 19 patients with definite CAA from the MGH CAA database (35% women, mean age 75 years), a lower microbleed count (p < 0.001) but a higher proportion of cortical superficial siderosis and a higher local cortical iron burden was found in men (p < 0.001) compared to women. CAA percentage area was comparable in men and women (p = 0.732). Exploratory analyses demonstrated a possible stronger negative relation between cortical CAA percentage area and cortical iron density in men compared to women (p = 0.03). Previously observed sex differences in hemorrhage onset and progression in CAA patients are likely not due to differences in global CAA severity between men and women. Other factors, such as vascular remodeling, may contribute, but future studies are necessary to replicate our findings in larger data sets and to further investigate the underlying mechanisms behind these complex sex differences.

Hemorrhagic Transformation in Noncardioembolic Acute Ischemic Stroke: MRI Analysis From PACIFIC-STROKE.

In the phase 2 PACIFIC-STROKE trial (Proper Dosing and Safety of the Oral FXIa Inhibitor BAY 2433334 in Patients Following Acute Noncardioembolic Stroke), asundexian, an oral factor XIa inhibitor, did not increase the risk of hemorrhagic transformation (HT). In this secondary analysis, we aimed to investigate the frequency, types, and risk factors of HT on brain magnetic resonance imaging (MRI). This was a secondary analysis of the PACIFIC-STROKE trial. Patients with mild-to-moderate acute noncardioembolic ischemic stroke were randomly assigned to asundexian or placebo plus guideline-based antiplatelet therapy. Brain MRIs were required at baseline (≤120 hours after stroke onset) and at 26 weeks or end-of-study. HT was defined using the Heidelberg classification and classified as early HT (identified on baseline MRI) or late HT (new HT by 26 weeks) based on iron-sensitive sequences. Multivariable logistic regression models were used to test factors that are associated with early HT and late HT, respectively. Of 1745 patients with adequate baseline brain MRI (mean age, 67 years; mean National Institutes of Health Stroke Scale score, 2.8), early HT at baseline was detected in 497 (28.4%). Most were hemorrhagic infarctions (hemorrhagic infarction type 1: 15.2%; HI2: 12.7%) while a few were parenchymal hematomas (parenchymal hematoma type 1: 0.4%; parenchymal hematoma type 2: 0.2%). Early HT was more frequent with longer symptom onset-to-MRI interval. Male sex, diabetes, higher National Institutes of Health Stroke Scale large (>15 mm) infarct size, cortical involvement by infarct, higher number of acute infarcts, presence of chronic brain infarct, cerebral microbleed, and chronic cortical superficial siderosis were independently associated with early HT in the multivariable logistic regression model. Of 1507 with follow-up MRI, HT was seen in 642 (42.6%) overall, including 361 patients (23.9%) with late HT (new HT: 306; increased grade of baseline HT: 55). Higher National Institutes of Health Stroke Scale, large infarct size, cortical involvement of infarct, and higher number of acute infarcts predicted late HT. About 28% of patients with noncardioembolic stroke had early HT, and 24% had late HT detectable by MRI. Given the high frequency of HT on MRI, more research is needed on how it influences treatment decisions and outcomes.

Temporal Ordering of Biomarkers in Dutch-Type Hereditary Cerebral Amyloid Angiopathy.

The temporal ordering of biomarkers for cerebral amyloid angiopathy (CAA) is important for their use in trials and for the understanding of the pathological cascade of CAA. We investigated the presence and abnormality of the most common biomarkers in the largest (pre)symptomatic Dutch-type hereditary CAA (D-CAA) cohort to date. We included cross-sectional data from participants with (pre)symptomatic D-CAA and controls without CAA. We investigated CAA-related cerebral small vessel disease markers on 3T-MRI, cerebrovascular reactivity with functional 7T-MRI (fMRI) and amyloid-β40 and amyloid-β42 levels in cerebrospinal fluid. We calculated frequencies and plotted biomarker abnormality according to age to form scatterplots. We included 68 participants with D-CAA (59% presymptomatic, mean age, 50 [range, 26-75] years; 53% women), 53 controls (mean age, 51 years; 42% women) for cerebrospinal fluid analysis and 36 controls (mean age, 53 years; 100% women) for fMRI analysis. Decreased cerebrospinal fluid amyloid-β40 and amyloid-β42 levels were the earliest biomarkers present: all D-CAA participants had lower levels of amyloid-β40 and amyloid-β42 compared with controls (youngest participant 30 years). Markers of nonhemorrhagic injury (>20 enlarged perivascular spaces in the centrum semiovale and white matter hyperintensities Fazekas score, ≥2, present in 83% [n=54]) and markers of impaired cerebrovascular reactivity (abnormal BOLD amplitude, time to peak and time to baseline, present in 56% [n=38]) were present from the age of 30 years. Finally, markers of hemorrhagic injury were present in 64% (n=41) and only appeared after the age of 41 years (first microbleeds and macrobleeds followed by cortical superficial siderosis). Our results suggest that amyloid biomarkers in cerebrospinal fluid are the first to become abnormal in CAA, followed by MRI biomarkers for cerebrovascular reactivity and nonhemorrhagic injury and lastly hemorrhagic injury. This temporal ordering probably reflects the pathological stages of CAA and should be taken into account when future therapeutic trials targeting specific stages are designed.

Superficial small cerebellar infarcts in cerebral amyloid angiopathy on 3 T MRI: A preliminary study

BackgroundStrictly superficial cerebellar microbleeds and cerebellar superficial siderosis have been considered markers of advanced cerebral amyloid angiopathy (CAA), but there are few studies on cerebellar ischemic lesions in CAA. We investigated the presence of superficial small cerebellar infarct (SCI) ≤15 mm and its relation to magnetic resonance imaging (MRI) markers in patients with probable CAA. MethodsEighty patients with probable CAA were retrospectively evaluated. The presence of superficial SCIs was examined, along with cerebellar microbleeds and cerebellar superficial siderosis, using 3-T MRI. Lobar cerebral microbleeds, cortical superficial siderosis (cSS), enlargement of the perivascular space in the centrum semiovale, and white matter hyperintensity were assessed and the total CAA-small vessel disease (SVD) score was calculated. ResultsNine of the 80 patients (11.3%) had a total of 16 superficial SCIs. By tentatively defining SCI <4 mm as cerebellar microinfarcts, 8 out of 16 (50%) superficial SCIs corresponded to cerebellar microinfarcts. The total CAA-SVD score was significantly higher in patients with superficial SCIs (p = 0.01). The prevalence of cSS (p = 0.018), cortical cerebral microinfarct (p = 0.034), and superficial cerebellar microbleeds (p = 0.006) was significantly higher in patients with superficial SCIs. The number of superficial cerebellar microbleeds was also significantly higher in patients with superficial SCIs (p = 0.001). ConclusionsOur results suggest that in patients with CAA, superficial SCIs (including microinfarcts) on MRI may indicate more severe, advanced-stage CAA. These preliminary findings should be verified by larger prospective studies in the future.

Cardiovascular Management in Asymptomatic (Silent) Cerebral Microbleeds and Suspected Cerebral Amyloid Angiopathy.

Cerebral microbleeds (CMBs) detected on blood-sensitive magnetic resonance imaging sequences are usually a sign of an underlying cerebral small vessel disease such as sporadic cerebral amyloid angiopathy or sporadic nonamyloid small vessel pathology (eg, arteriolosclerosis). Much of the enduring interest in CMBs relates to their high prevalence (partly due to the widespread use of magnetic resonance imaging) in the context of stroke, cognitive impairment and in healthy individuals, and the clinical uncertainties created about the safety of antithrombotic medications due to their association with both future hemorrhagic and ischemic stroke. Historically, the research literature overwhelmingly emphasized the future hemorrhagic risk associated with CMBs, potentially leading to unnecessary withholding of treatments proven effective at preventing thrombosis, such as anticoagulants in patients with atrial fibrillation who happened to have some microbleeds. The lack of strong guidelines in this area contributes to wide variation in clinical practice. In this article, we critically review and discuss the implications of silent CMBs and cortical superficial siderosis (ie, without symptomatic intracerebral hemorrhage) in different clinical settings: the general population, patients with ischemic stroke, and the memory clinic. Emerging evidence, albeit not from randomized controlled trials, suggests that in most patients, CMBs alone should not prevent the use of antithrombotics or anticoagulants for stroke prevention, when they are otherwise indicated. Where possible, we provide specific suggestions for clinical care grounded in both the limited available literature and our personal clinical practice.

Cerebral tau pathology in cerebral amyloid angiopathy.

Tau, a hallmark of Alzheimer's disease, is poorly characterized in cerebral amyloid angiopathy. We aimed to assess the clinico-radiological correlations between tau positron emission tomography scans and cerebral amyloid angiopathy. We assessed cerebral amyloid and hyperphosphorylated tau in patients with probable cerebral amyloid angiopathy (n = 31) and hypertensive small vessel disease (n = 27) using 11C-Pittsburgh compound B and 18F-T807 positron emission tomography. Multivariable regression models were employed to assess radio-clinical features related to cerebral tau pathology in cerebral amyloid angiopathy. Cerebral amyloid angiopathy exhibited a higher cerebral tau burden in the inferior temporal lobe [1.25 (1.17-1.42) versus 1.08 (1.05-1.22), P < 0.001] and all Braak stage regions of interest (P < 0.05) than hypertensive small vessel disease, although the differences were attenuated after age adjustment. Cerebral tau pathology was significantly associated with cerebral amyloid angiopathy-related vascular markers, including cortical superficial siderosis (β = 0.12, 95% confidence interval 0.04-0.21) and cerebral amyloid angiopathy score (β = 0.12, 95% confidence interval 0.03-0.21) after adjustment for age, ApoE4 status and whole cortex amyloid load. Tau pathology correlated significantly with cognitive score (Spearman's ρ=-0.56, P = 0.001) and hippocampal volume (-0.49, P = 0.007), even after adjustment. In conclusion, tau pathology is more frequent in sporadic cerebral amyloid angiopathy than in hypertensive small vessel disease. Cerebral amyloid angiopathy-related vascular pathologies, especially cortical superficial siderosis, are potential markers of cerebral tau pathology suggestive of concomitant Alzheimer's disease.

Advances in Cerebral Small Vessel Disease: Sandra E. Black Lecture to the Canadian Neurological Sciences Federation.

Cerebral small vessel diseases (CSVDs) are among the most common age-related pathologies of the brain. Arteriolosclerosis and cerebral amyloid angiopathy (CAA) are the most common CSVDs. In addition to causing stroke and dementia, CSVDs can have diverse covert radiological manifestations on computed tomography and magnetic resonance imaging including lacunes, T2-weighted white matter hyperintensities, increased density of visible perivascular spaces, microbleeds and cortical superficial siderosis. Because they cannot be visualized directly, research on the pathophysiology of CSVD has been difficult. However, advances in quantitative imaging methods, including physiological imaging such as measurement of cerebrovascular reactivity and increased vascular permeability, are beginning to allow investigation of the early effects of CSVD in living people. Furthermore, genomics, metabolomics and proteomics have the potential to illuminate previously unrecognized pathways to CSVD that could be important targets for new clinical trials.

Abstract WP158: Cortical Superficial Siderosis is Associated With Ischemia After Intracerebral Hemorrhage

Background: Ischemia on diffusion weighted imaging (DWI) after intracerebral hemorrhage (ICH) increases the risk of future ischemic stroke. Radiographic markers of small vessel disease, including cerebral microbleeds (CMB), are associated with DWI lesions. Though cortical superficial siderosis (cSS) is also a hemorrhagic small vessel disease subtype, it is unclear if cSS similarly relates to DWI lesions. We hypothesized that cSS would represent a more severe phenotype of small vessel disease and would associate with DWI lesions after ICH independent to other small vessel disease markers. Methods: Using the Intracerebral Hemorrhage Outcomes Project (ICHOP), we included all cases of spontaneous ICH who underwent DWI and susceptibility imaging/gradient echo. DWI hyperintensities were identified if &gt;10mm from the hematoma with decreased ADC signal. cSS were identified as subarachnoid hemosiderin deposition without acute subarachnoid hemorrhage. The relationship of cSS with DWI lesion presence as the outcome was assessed with logistic regression adjusted for ICH score, blood pressure change within 24 hours, and small vessel disease markers (CMB and white matter hyperintensity). Sensitivity analyses were performed to adjust for demographics and ICH location. A secondary analysis using linear regression assessed the association with the number of DWI lesions adjusted for similar covariates. Results: Of 198 patients analyzed, DWI lesions were observed in 31.3% and cSS in 10.6%. The presence of cSS was associated with DWI lesions (adjusted OR 3.72, CI: 1.29-10.72), independent of other small vessel disease markers. Separate sensitivity analyses adjusting for sex, race, and ICH location did not change the association of cSS with DWI lesions. In secondary analyses, cSS was not associated with greater number of DWI lesions counts (b 0.213, CI -0.53-0.63). Discussion: cSS is associated with the presence of DWI lesions, independent to other small vessel disease markers. cSS may represent a severe phenotype of small vessel disease with a risk of ICH recurrence and ischemia. Further work is required to investigate underlying mechanisms and optimal strategies to mitigate competing risks of future hemorrhage and ischemic events in these patients.

Abstract WMP22: Higher Burden of Cerebral Small Vessel Disease is Associated With Risk of Incident Stroke in Community-Dwelling Individuals

Background: Mild manifestations of individual cerebral small vessel disease (CSVD) markers are common and may not denote increased risk, but high CSVD burden identifies individuals at increased risk of stroke and dementia. Scores incorporating multiple CSVD markers may better identify a person’s risk, but it remains unclear if they offer benefit beyond tools based on clinical factors alone such as the revised Framingham Stroke Risk Profile (FSRP). Therefore, we related a multi-marker CSVD score to risk of incident stroke and compared the findings with the FSRP in community-dwelling individuals. Methods: Framingham Heart Study (FHS) participants aged ≥55 years, free of stroke and dementia and with brain magnetic resonance imaging (MRI) ratings of CSVD markers were included. A multi-marker CSVD score reflecting increasing CSVD burden was used (one point each for presence of cerebral microbleeds, severe perivascular spaces, extensive white matter hyperintensities, covert brain infarcts, and cortical superficial siderosis, ranging 0-5). Multivariable Cox proportional hazards regression analyses were used to relate CSVD score to incident stroke. Results: Among 1,154 participants (46% male, mean age 70.9±8.7), 590 (51%) had score 0, 352 (31%) had score 1, 164 (14%) had score 2, and 48 (4%) had score ≥ 3. Over a median follow-up of 8.2 years (Q1-Q3: 5.1-12.5) from the time of MRI, 92 (8%) developed stroke. In models adjusting for time interval between clinic exam and MRI, FHS cohort, and FSRP score, number of CSVD manifestations was associated with increased risk of stroke in a dose-dependent manner: score 1 (HR: 1.73; 95% CI 1.05-2.84), score 2 (HR 1.83; 95% CI: 1.01-3.30), and score ≥ 3 (HR: 3.31; 95% CI: 1.50-7.28) in relation to participants with no CSVD markers. In comparison, a 5-percent increase in FSRP alone was associated with increased risk of stroke (HR: 1.25; 95% CI 1.15-1.36). Interpretation: Higher CSVD burden is associated with increased risk of stroke, beyond the effect explained by risk factors in the FSRP. These findings support consideration of CSVD burden to identify risk of stroke in community-dwelling individuals.

Abstract TP39: Multi-Marker Cerebral Small Vessel Disease Score and Risk of Incident Depression: The Framingham Heart Study

Introduction: The vascular depression hypothesis postulates that cerebral small vessel disease (CSVD) contributes to the development of depression. A multi-marker CSVD score based on brain magnetic resonance imaging (MRI) could serve as a valuable tool for predicting the risk of developing vascular depression. This is important as depression can mimic cognitive impairment, dementia and is treatable. This study aimed to determine the relation of a MRI multi-marker CSVD score with incident depression in community-dwelling individuals. Methods: Framingham Heart Study participants from the Original and Offspring cohorts free of stroke, dementia and depression with available data on depression and CSVD ratings on MRI were included. Depression was defined as Center for Epidemiological Studies Depression scale score ≥16 or use of antidepressant medication. The multi-marker CSVD score was calculated by summing 1 point for individual CSVD markers present (covert brain infarcts, cerebral microbleeds, extensive white matter hyperintensities, high burden perivascular spaces, cortical superficial siderosis), ranging 0-5. Multivariable logistic regression models were used to relate the MRI-multi-marker CSVD score and incident depression in a primary analysis and individual CSVD biomarkers and depression in an exploratory analysis. Models were adjusted for age, sex, FHS cohort, time interval between MRI and clinic exam, body mass index, smoking, prevalent hypertension and diabetes. Results: In 1768 participants included (mean age 54.4±12.4 years, 54% male), the incidence of depression was 11% (median follow-up 6.0 years, IQR: 5.3-6.7). No CSVD score group had a statistically significant association with incident depression, however a CSVD score 3+ showed a trend towards increased odds of developing incident depression (OR 2.65 [0.87, 8.06], p =0.09). Among the individual CSVD markers, visible perivascular spaces had the highest odds for incident depression (OR 1.55 [0.96, 2.51] p =0.07). Conclusion: A higher multi-marker CSVD score might be associated with increased odds of incident depression. Further studies with a larger sample may help elucidate a potential association between this CSVD burden and onset of depression.

Abstract WMP16: Multi-Marker Cerebral Small Vessel Disease Score and Risk of Incident Dementia in the Framingham Heart Study

Background: Individual magnetic resonance imaging (MRI) markers of cerebral small vessel disease (CSVD) are associated with impaired cognition and dementia but may not reflect the overall burden of CSVD. It is unclear whether these markers provide additional value in evaluating the risk of dementia beyond assessments based solely on clinical risk factors. Thus, we aimed to determine whether the association of additive burden of multiple CSVD markers was independent of vascular risk factors and the Framingham Stroke Risk Profile (FSRP) and to also compare results with the FSRP. Methods: We included 1,152 Framingham Heart Study (FHS) participants over the age of 55, free of stroke and dementia, from the Original and Offspring cohorts with available MRI and FSRP data. CSVD score was calculated by summing the number of CSVD features detected in the MRI: cerebral microbleeds, cerebral brain infarcts, extensive white matter hyperintensities, severe perivascular spaces, and cortical superficial siderosis. Two Cox proportional hazards regression models were used to relate the multi-marker CSVD score to incident all-cause dementia and Alzheimer’s dementia. The first model adjusted for education, cohort, and clinical risk factors while the second adjusted for education, cohort, and FSRP. Results: Mean age was 70.9 years (SD: 8.7), 527 (46%) were male, and 211 (18%) had score ≥ 2. Over a median follow-up time of 6.4 years (Q1-Q3: 4.6-11.3), participants with score ≥ 2 had elevated risk of all-cause dementia compared to those with no CSVD markers after adjustment for FSRP (HR: 2.32; 95% CI: 1.46-3.69; p&lt;0.001) and vascular risk factors (HR: 1.76; 95% CI: 1.10-2.81; p=0.02). Score ≥ 2 was also significantly associated with AD after adjustment for FSRP (HR: 2.05; 95% CI: 1.19-3.62; p&lt;0.01), but not vascular risk factors (HR: 1.50; 95% CI: 0.87-2.60; p=0.15). In addition, a 5-percent increase in FSRP was independently associated with incident dementia after adjustment for education and FHS cohort (HR: 1.21; 95% CI: 1.13-1.30; p&lt;0.001). Conclusions: Our results support the use of CSVD score as an indicator for dementia risk and it may be as robust as the FSRP. Further studies are necessary to validate the use of CSVD score in quantifying dementia risk.

Association of enlarged perivascular spaces with cognitive function in dementia-free older adults: A population-based study.

We sought to characterize cognitive profiles associated with enlarged perivascular spaces (EPVS) among Chinese older adults. This population-based study included 1191 dementia-free participants (age ≥60 years) in the MIND-China MRI Substudy (2018-2020). We visually evaluated EPVS in basal ganglia (BG) and centrum semiovale (CSO), white matter hyperintensities (WMHs), lacunes, cerebral microbleeds (CMBs), and cortical superficial siderosis. We used a neuropsychological test battery to assess cognitive function. Data were analyzed using general linear models. Greater BG-EPVS load was associated with lower z-scores in memory, verbal fluency, and global cognition (p<0.05); these associations became non-significant when controlling for other cerebral small vessel disease (CSVD) markers (e.g., WMHs, lacunes, and mixed CMBs).Overall, CSO-EPVS load was not associated with cognitive z-scores (p>0.05); among apolipoprotein E (APOE) -ε4 carriers, greater CSO-EPVS load was associated with lower verbal fluency z-score, even when controlling for other CSVD markers (p<0.05). The associations of BG-EPVS with poor cognitive function in older adults are largely attributable to other CSVD markers. The association of enlarged perivascular spaces (EPVS) with cognitive function in older people is poorly defined.The association of basal ganglia (BG)-EPVS with poor cognition is attributed to other cerebral small vessel disease (CSVD) markers.In apolipoprotein E (APOE) ε4 carriers, a higher centrum semiovale (CSO)-EPVS load is associated with poorer verbal fluency.