Cerebrovascular Disease*

Date/Time: Monday, September 11, 2023 - 4:15 PM – 5:45 PM
Track: Special Interest Group (SIG) Session
Room: Franklin Hall 1 (4th Floor)
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Session Evaluation Form: https://myana.org/form/ana2023-session-evaluation-cereb

Chair: Michelle C. Johansen, MD, PhD

Co-Chair: Peter Kang, MD, MSCI

This stroke special interest group (SIG) session aims to bring the most important Cerebrovascular Science updates to the attendees of the ANA meeting regarding Stroke Epidemiology, Stroke Clinical Trials, and Advanced MRI imaging in Stroke. 

Learning Objectives:

  • Understand the objective contributions of vascular risk factors common in stroke patients to brain health, and the risk of dementia over time. Learners will have the knowledge to effectively counsel patients regarding the importance of proper early risk factor management. 
  • Interpret the latest MRI imaging techniques, the limitations implicit to these techniques, and the power of applying them in future research and clinical applications. 
  • Understand the pathophysiology and recovery trajectory of patients with mild disabling strokes, using the latest evidence to guide clinical decision making.

Ischemic Stroke, Vascular Risk Factors and Cognition over the Decades

Speaker: Deborah Levine, MD, MPH

The presentation will discuss how our understanding of vascular cognitive impairment including post-stroke dementia has changed over time. 

Mild Stroke: From Prevention to Recovery

Speaker: Pooja Khatri, MD, MSc

Ischemic stroke of milder severity presents some unique considerations.  It offers the chance to prevent the next potentially more severe stroke.  Its symptoms can be disabling , or can quickly worsen especially in the setting of large vessel occlusion, and the acute treatment options present challenges and limitations.  Finally, it requires special considerations during the recovery phase.  This presentation will review the evidence base and its clinical practice implications, and include discussion of  recent updates and ongoing trials.

From Diffusion to Perfusion: The latest developments in MRI imaging in Stroke across the lifespan

Speaker: Richard Leigh, MD, FANA

The gold standard for diagnosing stroke is diffusion weighted imaging (DWI) which, when combined with perfusion weighted imaging (PWI), is able to approximate the ischemic penumbra, the salvage of which is the purpose of all acute stroke treatments. However, these modalities can do much more. Diffusion tensor imaging (DTI) can not only measure connectivity but also quantify interstitial free water (edema). PWI source images can be used to map out disruption of the blood-brain barrier (BBB) and estimate risk of hemorrhagic conversion. Newer MRI methods are being used to measure pH and oxygen extraction fraction (OEF). These modalities are also informative in the subacute and chronic phases of cerebrovascular disease providing targets for treatment in post-stroke inflammation, vascular cognitive impairment and sickle cell disease.

Association of Cerebral Blood Flow with Microstructural Injury in Periventricular and Whole Brain White Matter

Oral Abstract Presenter: Banafsheh Shakibajahromi, MD, MPH

Periventricular white matter (PVWM), perfused exclusively by small arteries, has the lowest cerebral blood flow (CBF) in the brain and a high load of white matter hyperintensities (WMH) in aging and dementia. Accordingly, PVWM tissue may be particularly sensitive to hypoperfusion and white matter injury. We evaluated the association of CBF and microstructural white matter integrity measured by DTI metrics in normal-appearing periventricular white matter (NAPVWM) and normal-appearing white matter (NAWM) as a whole. Methods: Multimodal MRI data from N=168 subjects in the Penn Alzheimer’s Disease Research Center were analyzed. We categorized participants into 3 groups: cognitively normal (CN) adults, mild cognitive impairment (MCI), and dementia (including Alzheimer’s disease (AD) and non-AD) based on consensus designation. WMH lesion masks were obtained from FLAIR MRI to calculate total WMH volume and to exclude WMH voxels from WM and PVWM regions. Mean values for ASL-derived CBF and DTI metrics (fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD)) were extracted in NAWM and NAPVWM through an established CBF-based PVWM mask. We used multiple linear regression to assess the association of CBF and group as independent variables with each DTI metric as the dependent variable in regions of interest (ROIs) considering age, sex, and WMH volume as the covariates. We selected the models with the highest R2 to show the strongest associations in each region. Results: 168 subjects, including 124 CN, and 28 MCI and 16 dementia subjects were included. The mean (SD) age was 68(15) with 55% females. In NAWM, the multivariate model with the highest R2 (0.542) suggested that CBF was significantly associated with MD (Beta=-0.206, P=0.001) whereas in NAPVWM, CBF was significantly associated with RD in the model with the highest R2(0.641) (Beta= -0.212, P<0.001). In both models, group differences (CN> MCI> dementia) were associated with MD in NAWM (Beta=0.212, p<0.001) and RD in NAPVWM (Beta=0.224, P<0.001). Conclusion: Lower CBF is correlated with DTI evidence of microstructural injury in both NAWM and NAPVWM and across clinical phenotypes. The finding of lower CBF with higher RD in the NAPVWM suggests that hypoperfusion in this region might be primarily associated with myelin injury.

Greater Albumin Concentration in Serum May Be Protective against Stroke: The Northern Manhattan Study

Oral Abstract Presenter: Adomas Bunevicius, MD, PhD

Introduction: Higher albumin concentrations can be associated with lower risk of stroke. However, the role of diet in this association remains unclear. We investigated the association of serum albumin concentration with incident cerebrovascular and cardiovascular diseases considering dietary factors. Methods: Participants from the Northern Manhattan Study (NOMAS; n=2407; mean age: 68.65±10.21 years) free of stroke and myocardial infarction at baseline were followed for incident cerebrovascular and cardiovascular events for a median of 14.8 years (range from 0 to 28 years). Cox proportional hazard models were used to estimate the hazard ratios (HRs) and 95% confidence intervals (CIs) of baseline serum albumin concentration for the risk of ischemic stroke, intracerebral hemorrhage, myocardial infarction and vascular death adjusting for traditional vascular risk factors, and diet, including daily calorie intake and gram intake of legumes, vegetables, fruits, cereals, fish, meat and dairy. Results: The mean baseline serum albumin concentration was 4.22±0.32 g/dL. There were 347 (14%) incident strokes, 738 (31%) vascular deaths and 999 (42%) cases of ischemic stroke, intracerebral hemorrhage, myocardial infarction or vascular death. Higher albumin concentration was associated with lower risk of stroke (HR = 0.59; 95%CI 0.41 - 0.85; p = 0.0046), vascular death (HR = 0.62; 95% CI 0.48 - 0.81; p = 0.0004) and ischemic stroke, intracerebral hemorrhage, myocardial infarction or vascular death (HR = 0.66; 95%CI 0.00- 0.82; p =0.0002) independent of traditional vascular risk factors and diet. Conclusions: Higher serum albumin concentration is protective from incident stroke, vascular death and composite outcome of stroke, ischemic stroke, intracerebral hemorrhage, myocardial infarction or vascular death.

Analysis of the Plasma Proteome in Early CADASIL Reveals Dysregulations in Angiogenesis

Oral Abstract Presenter: Steven Fitzsimons, PhD

Background: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), is a genetic form of Vascular Cognitive Impairment and Dementia (VCID) caused by mutations in NOTCH3. There are currently no therapies for CADASIL. A better molecular understanding of CADASIL could help to advance therapeutic developments for this disease and for the more common sporadic forms of VCID, which are difficult to detect and model. Here, we analyzed the plasma proteome of patients with early CADASIL to understand the molecular pathways dysregulated prior to the onset of severe symptoms. Methods: We collected plasma from patients with CADASIL (n=25), enrolled in VascBrain, our longitudinal study of genetic and sporadic VCID. We selected age/sex matched controls (n=28) from the UCSF Memory and Aging Center biobank. Plasma samples were analyzed using aptamer-based technology via the SomaScan Assay (version 4.1) from Somalogic. Pathway analysis (IPA and PANTHER) and correlation analysis was performed. Results: 439 proteins were significantly upregulated in the CADASIL group while 98 were significantly downregulated (Fold change cut off +/- 1.2, uncorrected p<0.05). Several proteins previously shown to be altered in brain tissue from patients with CADASIL, including NOTCH3, BGN and COL6A1, were differentially expressed in the plasma. In silico pathway analysis on the 537 differentially expressed proteins (DEPs) showed that angiogenesis and VEGF signaling were among the pathways predicted to be activated. Fibrotic and inflammatory pathways were also predicted to be activated. Intersection of plasma proteomics with a publicly available dataset of blood vessel proteomics from patients with CADASIL (Zellner et al. 2018) identified 15 overlapping DEPs . Upstream regulators, LONP1 and TNFA, were predicted to be dysregulated. Critically, in plasma, 64% of DEPs correlated with Jagged1 (JAG1) in the CADASIL cohort only. JAG1, a known ligand of NOTCH3 and a pro-angiogenic regulator, correlated with the angiogenic regulators, EDIL3 and SHMT2, and other proteins associated with angiogenesis including FLT4, WNT5B and GRB2. Intersection with existing single cell seqRNA analysis on healthy blood vessels (Winkler et al. 2022) showed that many of the DEPs were also highly expressed in smooth muscle cells (SMCs) and correlated also with JAG1 expression. Conclusion: This study found that CADASIL plasma is reflective of known disease pathology. In addition, this study identified dysregulations in angiogenesis associated proteins alongside proteins related to fibrosis and inflammation, in early-stage CADASIL. The angiogenic activity, potentially driven by JAG1-related SMC dysfunction, may provide insights into therapeutically treating disease progression.