Relationships of Hematocrit With Chronic Covert and Acute Symptomatic Lacunar Ischemic Lesions.

BACKGROUND AND OBJECTIVES: Red blood cell (RBC) concentrations are known to associate with ischemic stroke. It is unclear whether RBC concentrations associate specifically with small vessel disease lacunar infarcts. We investigated the hypothesis that RBC concentrations associate with both chronic covert and acute symptomatic brain MRI lacunar infarcts. METHODS: A cross-sectional observational analysis was performed across 2 cohorts with available hematocrit (as the assessment of RBC concentration exposure) and MRI outcome data. The primary setting was a population-based cohort of stroke-free, older adult (>50 years) participants from the Northern Manhattan Study (NOMAS) enrolled between 2003 and 2009. A second replication sample consisted of patients admitted with acute stroke and enrolled into the Columbia Stroke Registry (CSR) between 2005 and 2020. Associations of hematocrit with (1) chronic, covert lacunar infarcts and (2) symptomatic (i.e., acute) lacunar strokes were separately assessed from the NOMAS and CSR cohorts, respectively, using general additive models after adjusting for relevant covariates. RESULTS: Of 1,218 NOMAS participants analyzed, 6% had chronic, covert lacunar infarcts. The association between hematocrit and these covert lacunar infarcts was U-shaped (χ2 = 9.21 for nonlinear associations; p = 0.03), with people with hematocrit extremes being more likely to have covert lacunar infarcts. Of the 1,489 CSR patients analyzed, 23% had acute lacunar strokes. In this sample, only the relationships of increased hematocrit concentrations and lacunar strokes were replicated (adjusted coefficient ß = 0.020; SE = 0.009; p = 0.03). DISCUSSION: We identified relationships of hematocrit with MRI lacunar infarcts in both stroke-free and ischemic stroke cohorts, respectively. The relationship between increased hematocrit concentrations with lacunar infarcts was replicated in both cohorts. Further studies are required to clarify the mechanisms behind the relationships of hematocrit with ischemic cerebral small vessel disease.

Epidemiology, Pathophysiology, and Imaging of Atherosclerotic Intracranial Disease.

Intracranial atherosclerotic disease (ICAD) is one of the most common causes of stroke worldwide. Among people with stroke, those of East Asia descent and non-White populations in the United States have a higher burden of ICAD-related stroke compared with Whites of European descent. Disparities in the prevalence of asymptomatic ICAD are less marked than with symptomatic ICAD. In addition to stroke, ICAD increases the risk of dementia and cognitive decline, magnifying ICAD societal burden. The risk of stroke recurrence among patients with ICAD-related stroke is the highest among those with confirmed stroke and stenosis ≥70%. In fact, the 1-year recurrent stroke rate of >20% among those with stenosis >70% is one of the highest rates among common causes of stroke. The mechanisms by which ICAD causes stroke include plaque rupture with in situ thrombosis and occlusion or artery-to-artery embolization, hemodynamic injury, and branch occlusive disease. The risk of stroke recurrence varies by the presumed underlying mechanism of stroke, but whether techniques such as quantitative magnetic resonance angiography, computed tomographic angiography, magnetic resonance perfusion, or transcranial Doppler can help with risk stratification beyond the degree of stenosis is less clear. The diagnosis of ICAD is heavily reliant on lumen-based studies, such as computed tomographic angiography, magnetic resonance angiography, or digital subtraction angiography, but newer technologies, such as high-resolution vessel wall magnetic resonance imaging, can help distinguish ICAD from stenosing arteriopathies.

Chromosome 10q24.32 Variants Associate With Brain Arterial Diameters in Diverse Populations: A Genome-Wide Association Study.

BACKGROUND: Brain arterial diameters (BADs) are novel imaging biomarkers of cerebrovascular disease, cognitive decline, and dementia. Traditional vascular risk factors have been associated with BADs, but whether there may be genetic determinants of BADs is unknown. METHODS AND RESULTS: The authors studied 4150 participants from 6 geographically diverse population-based cohorts (40% European, 14% African, 22% Hispanic, 24% Asian ancestries). Brain arterial diameters for 13 segments were measured and averaged to obtain a global measure of BADs as well as the posterior and anterior circulations. A genome-wide association study revealed 14 variants at one locus associated with global BAD at genome-wide significance (P<5×10-8) (top single-nucleotide polymorphism, rs7921574; ß=0.06 [P=1.54×10-8]). This locus mapped to an intron of CNNM2. A trans-ancestry genome-wide association study meta-analysis identified 2 more loci at NT5C2 (rs10748839; P=2.54×10-8) and AS3MT (rs10786721; P=4.97×10-8), associated with global BAD. In addition, 2 single-nucleotide polymorphisms colocalized with expression of CNNM2 (rs7897654; ß=0.12 [P=6.17×10-7]) and AL356608.1 (rs10786719; ß=-0.17 [P=6.60×10-6]) in brain tissue. For the posterior BAD, 2 variants at one locus mapped to an intron of TCF25 were identified (top single-nucleotide polymorphism, rs35994878; ß=0.11 [P=2.94×10-8]). For the anterior BAD, one locus at ADAP1 was identified in trans-ancestry genome-wide association analysis (rs34217249; P=3.11×10-8). CONCLUSIONS: The current study reveals 3 novel risk loci (CNNM2, NT5C2, and AS3MT) associated with BADs. These findings may help elucidate the mechanism by which BADs may influence cerebrovascular health.

Association of brain arterial diameters with demographic and anatomical factors in a multi-national pooled analysis of cohort studies.

BACKGROUND AND PURPOSE: Brain arterial diameters are markers of cerebrovascular disease. Demographic and anatomical factors may influence arterial diameters. We hypothesize that age, sex, height, total cranial volume (TCV), and persistent fetal posterior cerebral artery (fPCA) correlate with brain arterial diameters across populations. METHODS: Participants had a time-of-flight MRA from nine international cohorts. Arterial diameters of the cavernous internal carotid arteries (ICA), middle cerebral arteries (MCA), and basilar artery (BA) were measured using LAVA software. Regression models assessed the association between exposures and brain arterial diameters. RESULTS: We included 6,518 participants (mean age: 70 ± 9 years; 41% men). Unilateral fPCA was present in 13.2% and bilateral in 3.2%. Larger ICA, MCA, and BA diameters correlated with older age (Weighted average [WA] per 10 years: 0.18 mm, 0.11 mm, and 0.12 mm), male sex (WA: 0.24 mm, 0.13 mm, and 0.21 mm), and TCV (WA: for one TCV standard deviation: 0.24 mm, 0.29 mm, and 0.18 mm). Unilateral and bilateral fPCAs showed a positive correlation with ICA diameters (WA: 0.39 mm and 0.73 mm) and negative correlation with BA diameters (WA: -0.88 mm and -1.73 mm). Regression models including age, sex, TCV, and fPCA explained on average 15%, 13%, and 25% of the ICA, MCA, and BA diameter interindividual variation, respectively. Using height instead of TCV as a surrogate of head size decreased the R-squared by 3% on average. CONCLUSION: Brain arterial diameters correlated with age, sex, TCV, and fPCA. These factors should be considered when defining abnormal diameter cutoffs across populations.

The role of intracranial artery calcification (IAC) in stroke subtype and risk of vascular events.

OBJECTIVE: To test the hypothesis that intracranial arterial calcification (IAC) is associated with intracranial large artery stenosis (ILAS) and a higher risk of vascular events and mortality. METHOD: We leveraged data from two cohorts, the New York-Presbyterian Hospital/Columbia University Irving Medical Center Stroke Registry Study (NYP/CUIMC-SRS) and the Northern Manhattan Study (NOMAS) to test our hypotheses. We measured IAC using CT scans of participants in both cohorts and expressed IAC as present (vs not) and in tertiles. For the CUIMC-SRS, demographic, clinical and ILAS status was collected retrospectively. In NOMAS, we used research brain MRI and MRA to define asymptomatic ILAS and covert brain infarcts(CBI). We built models adjusted for demographics and vascular risk factors for cross-sectional and longitudinal analyses. RESULTS: Cross-sectionally, IAC was associated with ILAS in both cohorts (OR 1.78, 95% CI: 1.16-2.73 for ILAS-related stroke in the NYP/CUIMC-SRS and OR 3.07, 95%CI 1.13-8.35 for ILAS-related covert brain infarcts in NOMAS). In a meta-analysis of both cohorts, IAC in the upper (HR 1.25, 95%CI 1.01-1.55) and middle tertile (HR 1.27, 95%CI 1.01-1.59) was associated with higher mortality compared with participants with no IAC. There were no longitudinal associations between IAC and risk of stroke or other vascular events. CONCLUSION: In these multiethnic populations, IAC is associated with symptomatic and asymptomatic ILAS as well as higher mortality. IAC may be a useful marker of higher mortality, the role of IAC as an imaging marker of risk of stroke is less certain.

Chromosome 10q24.32 Variants Associate with Brain Arterial Diameters in Diverse Populations: A Genome-Wide Association Study.

Background: Brain arterial diameters are novel imaging biomarkers of cerebrovascular disease, cognitive decline and dementia. Traditional vascular risk factors have been associated with brain arterial diameters but whether there may be genetic determinants of brain arterial diameters is unknown. Results: We studied 4150 participants from six geographically diverse population-based cohorts (40% European, 14% African, 22% Hispanic, 24% Asian ancestries). We measured brain arterial diameters for 13 segments and averaged them to obtain a global measure of brain arterial diameters as well as the posterior and anterior circulations. A genome-wide association study (GWAS) revealed 14 variants at one locus associated with global brain arterial diameter at genome-wide significance (P<5×10-8) (top SNP, rs7921574; ß =0.06, P=1.54×10-8). This locus mapped to an intron of CNNM2. A trans-ancestry GWAS meta-analysis identified two more loci at NT5C2 (rs10748839; P=2.54×10-8) and at AS3MT (rs10786721; P=4.97×10-8), associated with global brain arterial diameter. In addition, two SNPs co-localized with expression of CNNM2 (rs7897654, ß=0.12, P=6.17×10-7) and AL356608.1 (rs10786719, ß =-0.17, P=6.60×10-6) in brain tissue. For the posterior brain arterial diameter, two variants at one locus mapped to an intron of TCF25 were identified (top SNP, rs35994878; ß =0.11, P=2.94×10-8). For the anterior brain arterial diameter, one locus at ADAP1 was identified in trans-ancestry genome-wide association analysis (rs34217249; P=3.11×10-8). Conclusion: Our study reveals three novel risk loci (CNNM2, NT5C2 and AS3MT) associated with brain arterial diameters. Our finding may elucidate the mechanisms by which brain arterial diameters influence the risk of stroke and dementia.

Serum inflammation markers associated with altered brain white matter microstructure in people with HIV on antiretroviral treatment.

BACKGROUND: Many studies have reported reduced brain white matter fractional anisotropy (FA) and increased mean diffusivity (MD) on diffusion tensor imaging (DTI) of people with HIV (PWH). Few, however, have linked individual blood inflammatory markers with white matter tract-specific FA and MD. METHODS: PWH 50 years old or older from New York, NY, USA, were invited to a cross-sectional study. Demographic data, blood samples, and brain DTI were obtained. Least absolute shrinkage and selection operator (LASSO) regression was used to examine associations between biomarkers and white matter tract-specific FA and MD. All models included age, sex, race, ethnicity, diabetes, hypertension, smoking, and viral load as control variables. RESULTS: Seventy-two cases were analyzed. Mean age was 60 ± 6 years, 47% were women, 21% were Hispanic, and 78% were black. All had asymptomatic HIV infection and were on antiretroviral therapy. Eighty-nine percent had CD4 count >200 cell/mm3 and 78% were virally suppressed. Vascular endothelial growth factor (VEGF) and macrophage inflammatory proteins (MIP) 1ß and 1α were consistently associated with lower FA and higher MD across white matter tracts. CONCLUSIONS: Elevated serum VEGF, MIP-1α, and MIP-1ß were associated with altered white matter microstructure. These blood biomarkers may help predict HIV-associated white matter damage.

Role of Brain Arterial Remodeling in HIV-Associated Cerebrovascular Outcomes.

As the life expectancy of people living with HIV (PLWH) on combination antiretroviral therapy (cART) increases, so does morbidity from cerebrovascular disease and neurocognitive disorders. Brain arterial remodeling stands out as a novel investigational target to understand the role of HIV in cerebrovascular and neurocognitive outcomes. We therefore conducted a review of publications in PubMed, EMBASE, Web of Science and Wiley Online Library, from inception to April 2021. We included search terms such as HIV, cART, brain, neuroimmunity, arterial remodeling, cerebrovascular disease, and neurocognitive disorders. The literature shows that, in the post-cART era, PLWH continue to experience an increased risk of stroke and neurocognitive disorders (albeit milder forms) compared to uninfected populations. PLWH who are immunosuppressed have a higher proportion of hemorrhagic strokes and strokes caused by opportunistic infection and HIV vasculopathy, while PLWH on long-term cART have higher rates of ischemic strokes, compared to HIV-seronegative controls. Brain large artery atherosclerosis in PLWH is associated with lower CD4 nadir and higher CD4 count during the stroke event. HIV vasculopathy, a form of non-atherosclerotic outward remodeling, on the other hand, is associated with protracted immunosuppression. HIV vasculopathy was also linked to a thinner media layer and increased adventitial macrophages, suggestive of non-atherosclerotic degeneration of the brain arterial wall in the setting of chronic central nervous system inflammation. Cerebrovascular architecture seems to be differentially affected by HIV infection in successfully treated versus immunosuppressed PLWH. Brain large artery atherosclerosis is prevalent even with long-term immune reconstitution post-cART. HIV-associated changes in brain arterial walls may also relate to higher rates of HIV-associated neurocognitive disorders, although milder forms are more prevalent in the post-cART era. The underlying mechanisms of HIV-associated pathological arterial remodeling remain poorly understood, but a role has been proposed for chronic HIV-associated inflammation with increased burden on the vasculature. Neuroimaging may come to play a role in assessing brain arterial remodeling and stratifying cerebrovascular risk, but the data remains inconclusive. An improved understanding of the different phenotypes of brain arterial remodeling associated with HIV may reveal opportunities to reduce rates of cerebrovascular disease in the aging population of PLWH on cART.