Clinical Stroke Research Articles

Fried-Breadstick sign: A novel marker for healthy vasculature in magnetic resonance angiography

The Fried-Breadstick sign is characterized as a continuous signal loss at the center of the intracranial internal carotid artery (ICA) on time-of-flight magnetic resonance angiography (TOF-MRA). In this study, we present a novel imaging marker on TOF-MRA and investigate its potential association with ICA-middle cerebral artery (ICA-MCA) atherosclerosis and ischemic stroke. Vessel wall magnetic resonance imaging data were obtained from patients with recent clinical stroke or asymptomatic patients with suspected middle cerebral artery (MCA) atherosclerosis, covering the period from January 2007 to August 2015. We conducted a comparative analysis of ICA stenosis, MCA atherosclerosis and stenosis degree, and the terminal ICA bifurcation angle between ICA-MCAs with and without the Fried-Breadstick sign, involving a total of 1,005 ICA-MCAs from 553 patients. The Fried-Breadstick sign exhibited a higher prevalence in non-to-mild stenotic ICAs (57.5% vs. 9.8% in severely stenotic ICA, P < 0.001) and plaque-free MCAs (53.2% vs. 26.6% in MCAs with plaque, P < 0.001). Factors independently associated with the presence of the Fried-Breadstick sign included MCA stenosis degree (odds ratio [OR]: 0.85/10% increase, 95% confidence interval [CI]: 0.80 – 0.90), ICA stenosis (compared to non-to-mild stenosis, moderate stenosis: OR: 0.39, 95% CI: 0.28 – 0.54, severe stenosis: OR: 0.10, 95% CI: 0.06 – 0.17), and terminal ICA bifurcation angle (OR: 0.86/10° increase, 95% CI: 0.79 – 0.93). In atherosclerotic MCAs without luminal narrowing, the Fried-Breadstick sign was also less frequently observed than in plaque-free MCAs (34.6% vs. 53.2%, P = 0.012). In conclusion, the presence of the Fried-Breadstick sign is associated with healthier ICA-MCAs devoid of stenosis or plaque. The Fried-Breadstick sign may signify healthy ICA-MCA hemodynamics, serving as a potential screening tool for intracranial atherosclerosis without incurring additional cost or risk.

APOE4 Carriers with Perivascular Spaces Exhibit Altered Cerebral Blood Flow

AbstractBackgroundPerivascular spaces (PVS) are fluid‐filled spaces surrounding arterioles, capillaries and venules in the brain, which support metabolic waste clearance. Enlarged PVS are associated with increased dementia risk. Changes in arterial pulsatility are hypothesized to be associated with accumulation of toxic solutes and PVS widening. However, few prior studies have examined whether cerebral blood flow (CBF) is linked to PVS.MethodIndependently living older adults (N = 60, mean age = 68.1 years; SD = 7.5; age range 55‐88 years; 30.0% male) free of dementia or clinical stroke were recruited from the community and underwent brain MRI and venipuncture. Pseudo‐continuous arterial spin labeling was utilized to determine CBF in gray matter CBF (mL/100g tissue/min). Regional mean values were determined for regions of interest. PVS were qualitatively scored in the basal ganglia (BG), and centrum semiovale (CS). APOE genotyping was conducted on the blood cell pellet fraction.ResultAfter accounting for age and sex, multiple linear regression analysis revealed a significant negative association between BG‐PVS and CBF in the left inferior occipital gyrus (B = ‐.07, 95% CI (‐.13, ‐.01), p = .022), right inferior occipital gyrus (B = ‐.06, 95% CI (‐.12, ‐.001), p = .048), left middle occipital gyrus (B = ‐.05, 95% CI (‐.10, ‐.001), p = .047), right middle occipital gyrus (B = ‐.08, 95% CI (‐.13, ‐.02), p = .007), and right inferior temporal gyrus (B = ‐.05, 95% CI (‐.09, ‐.01), p = .025) as well as a positive association in the left precuneus (B = .05, 95% CI (.01, .08), p = .022). When stratified by APOE4 status, all associations were significant only in APOE4 carriers. CS‐PVS were not associated with CBF.ConclusionThese findings indicate altered CBF in older adults with BG‐PVS but not CS‐PVS. Resting CBF was altered in specific brain regions, predominantly in APOE4 carriers. APOE4 is known to convey both vascular risk and risk for Alzheimer’s disease (AD). Additional longitudinal studies are warranted to explore the association between PVS and CBF in individuals at risk for dementia to further understand vascular contributions to the development of AD and other dementias.

Proteomic‐based Biological Aging Clock and MRI Markers of Cerebrovascular Disease: Atherosclerosis Risk in Community Study

AbstractBackgroundBiological aging state can be quantified by composite metrics called aging clocks using proteomics. Proteomic aging clocks (PACs) are accurate, easily measured, and are associated with age‐related diseases including Alzheimer’s Disease and Related Dementias. We aim to investigate whether an accelerated biological aging (a discrepancy between chronological age and PAC) is associated with subclinical cerebrovascular structural changes.Method1494 participants from the Atherosclerosis Risk in Communities (ARIC) Study with proteomics and 3T brain MRI data at ARIC visit 5 in 2011‐13 (mean age 76, 59% female, 25% Black) were included. Nearly 5000 plasma proteins were measured using the SomaScan assay. PAC was developed using elastic net regression model and was internally validated. Age acceleration was calculated as residuals after regressing PAC on chronological age (positive value indicates biological age is higher than the person’s chronological age). Linear and logistic regression models were used to assess the associations of age acceleration with white matter hyperintensity volume (in cm3, log2 transformed, median [IQR]: 11[6‐20]) and the presence of: subcortical (n = 281), lacunar (n = 263), and cortical infarcts (n = 150), and microbleeds (n = 355).ResultAccelerated age (median [IQR]:‐0.04[‐1.4,1.3]; correlation with chronological age = 0) was associated with MRI markers of cerebrovascular disease after adjusting for demographic, cardiovascular risk factors, education, and kidney function. Every five years higher age acceleration was associated with larger white matter hyperintensity volume (Difference:0.34[95%CI 0.19,0.49]), higher odds of lacunar (OR:1.61[1.13,2.30]), subcortical (OR:1.63[1.15, 2.32]), and cortical infarcts (OR:1.72[1.11,2.67]). There was no association with presence of microbleeds (OR:1.25[0.91,1.73]) (Figure). Findings were consistent after excluding participants with clinical stroke and there was no difference between APOEe4+ and APOEe4‐ participants.ConclusionHigher accelerated age is cross‐sectionally associated with a greater prevalence of MRI markers of cerebrovascular disease. Understanding this relation has potential to help with risk stratification and personalized prevention and treatment strategies to promote brain health.

Extending understanding of the genetic architecture of cerebral small vessel disease using advanced imaging measures in UK Biobank

AbstractCerebral small vessel disease (cSVD) is a leading cause of stroke and a major contributor to cognitive decline and dementia in the population (Debette JAMA Neurol 2019). Covert cSVD, which is detectable with brain MRI but does not manifest as clinical stroke, is highly prevalent in the general population, particularly with increasing age. Large collaborative genomic studies through consortia like CHARGE or ISGC have led to substantial progress in the identification of common genetic variants that are associated with cSVD. In this presentation, we will provide an overview of such collaborative studies, prominently involving the unique UK Biobank resource, that have recently extended our understanding of the genetic architecture of cSVD, revealing over 70 independent loci associated with this condition, especially with MRI‐markers of cSVD (Bordes, Nat Rev Neurol 2022; Duperron, Nat Med AIP). In silico functional explorations of the observed genetic associations point to a major role of blood pressure‐related pathways, but also mechanisms independent of vascular risk factors, such as extracellular matrix, membrane transport, vascular development, myelination, and blood‐brain barrier. Leveraging next‐generation sequencing data in UK Biobank and other resources, these studies also shed new light on the continuum between monogenic and multifactorial cSVD, with several genes (HTRA1, COLA4) harboring both rare mutations and common variants contributing to the disease (Mishra, Brain 2019). Further, we recently showed that MRI‐cSVD risk loci identified in middle‐ and older age in UK Biobank and other cohorts are associated with white matter microstructure on diffusion imaging (DTI, NODDI) and perivascular space burden already in young adults in their twenties (e.g. at VCAN, OPA1, SLC13A3) suggesting that processes contributing to cSVD may find their root much earlier in life than previously thought (Duperron, Nat Med AIP; Sargurupremraj, Nat Commun. 2020). We provide preliminary insights on how these association patterns change across the adult lifespan and discuss how this can inform dementia prevention, including, in combination with other omics resources, for proof‐of‐concept genomics‐driven drug discovery (Duperron, Nat Med AIP; Mishra, Nature. 2022; Mishra, Brain. 2022).

APOE4 Carriers with Perivascular Spaces Exhibit Altered Cerebral Blood Flow

AbstractBackgroundPerivascular spaces (PVS) are fluid‐filled spaces surrounding arterioles, capillaries and venules in the brain, which support metabolic waste clearance. Enlarged PVS are associated with increased dementia risk. Changes in arterial pulsatility are hypothesized to be associated with accumulation of toxic solutes and PVS widening. However, few prior studies have examined whether cerebral blood flow (CBF) is linked to PVS.MethodIndependently living older adults (N = 60, mean age = 68.1 years; SD = 7.5; age range 55‐88 years; 30.0% male) free of dementia or clinical stroke were recruited from the community and underwent brain MRI and venipuncture. Pseudo‐continuous arterial spin labeling was utilized to determine CBF in gray matter CBF (mL/100g tissue/min). Regional mean values were determined for regions of interest. PVS were qualitatively scored in the basal ganglia (BG), and centrum semiovale (CS). APOE genotyping was conducted on the blood cell pellet fraction.ResultAfter accounting for age and sex, multiple linear regression analysis revealed a significant negative association between BG‐PVS and CBF in the left inferior occipital gyrus (B = ‐.07, 95% CI (‐.13, ‐.01), p = .022), right inferior occipital gyrus (B = ‐.06, 95% CI (‐.12, ‐.001), p = .048), left middle occipital gyrus (B = ‐.05, 95% CI (‐.10, ‐.001), p = .047), right middle occipital gyrus (B = ‐.08, 95% CI (‐.13, ‐.02), p = .007), and right inferior temporal gyrus (B = ‐.05, 95% CI (‐.09, ‐.01), p = .025) as well as a positive association in the left precuneus (B = .05, 95% CI (.01, .08), p = .022). When stratified by APOE4 status, all associations were significant only in APOE4 carriers. CS‐PVS were not associated with CBF.ConclusionThese findings indicate altered CBF in older adults with BG‐PVS but not CS‐PVS. Resting CBF was altered in specific brain regions, predominantly in APOE4 carriers. APOE4 is known to convey both vascular risk and risk for Alzheimer’s disease (AD). Additional longitudinal studies are warranted to explore the association between PVS and CBF in individuals at risk for dementia to further understand vascular contributions to the development of AD and other dementias.

Subclinical Vascular Risk Composites Predict Cardiovascular Disease, Stroke, and Dementia: The Multi‐Ethnic Study of Atherosclerosis (MESA)

AbstractBackgroundSubclinical cardiovascular disease (CVD) measures may reflect biological pathways that contribute to increased risk for CVD events and dementia beyond conventional risk scores. Therefore, we examined whether subclinical CVD biomarkers: 1) dissociate into composites representing distinct pathologic pathways that 2) predict future risk of clinical CVD, stroke, and dementia‐related outcomes in a diverse longitudinal cohort.MethodMESA followed 6,814 participants (45‐84 years of age) from baseline in 2000‐2002 to 2018 over 6 clinical examinations and annual follow‐up interviews. Baseline subclinical CVD biomarkers were transformed into z‐scores before factor analysis to derive composite factor scores. Time to clinical CVD events (coronary heart disease (CHD) and stroke) and dementia were modeled using Cox proportional hazards models reported as area under the curve (AUC) with 95% Confidence Intervals (95%CI). Global cognitive decline was measured by change in the Cognitive Abilities Screening Instrument from 2010‐12 to 2019‐2021, modeled by linear mixed models, and reported as beta estimates and standard error (SE). Cognitive status was adjudicated in 2019‐2021 as cognitively normal, mild cognitive impairment (MCI) and dementia from Uniform Data Set v3 tests and informant interview and modeled with multinomial logistic regression reported as odds ratios (OR). All models included all factor scores together and adjustment for conventional risk scores: Framingham risk scores for CVD or stroke or Cardiovascular Risk Factors, Aging, and Incidence of Dementia (CAIDE) for dementia.ResultSubclinical CVD measures aggregated into four distinct factors representing: blood pressure, arterial stiffness, atherosclerosis, and cardiac remodeling (Table 1). Each factor significantly predicted CVD events and dementia independent of each other and conventional risk scores (Figure). Atherosclerosis best predicted time to clinical events of CHD [AUC(95%CI) = 0.73(0.71‐0.75)], stroke [AUC(95%CI) = 0.75(0.70‐0.78)], and dementia [AUC(95%CI) = 0.74(0.71‐0.77)]. Arterial stiffness was the only the factor significantly associated with both cognitive decline (b = ‐0.95, SE = 0.11, p<0.0001), a higher odds of MCI [OR(95%CI) = 1.10(1.01‐1.21)] and dementia [OR(95%CI) = 1.79(1.37‐2.35)] (Table 2). These results were consistent across sex and racial/ethnic groups.ConclusionSubclinical vascular factor composites of arterial stiffness and atherosclerosis shown to independently predict both CVD events and dementia may be useful biomarkers to inform the vascular pathways contributing to Alzheimer’s disease and related dementia etiologies.

Cognitive status modifies the association between elevated cerebrospinal fluid phosphorylated tau and longitudinal cerebral blood flow changes over a 7‐year follow‐up period

AbstractBackgroundAlzheimer’s disease (AD) is associated with widespread reductions in cerebral blood flow (CBF), but the precise link between AD pathology and CBF is unclear. Hypoperfusion is a late‐stage event associated with tau, but not amyloid, pathology. We assessed whether baseline levels of cerebrospinal fluid (CSF)‐measured core AD pathology [β‐amyloid42 (Aβ42), phosphorylated tau (p‐tau)] related to CBF changes over a 7‐year period and if associations differed by baseline cognitive status.MethodsVanderbilt Memory and Aging Project participants free of clinical dementia or stroke at enrollment [n = 153, 72±6 years, 37% mild cognitive impairment (MCI), 33% female] underwent lumbar puncture to obtain CSF at study entry and serial multimodal 3T brain magnetic resonance imaging over a 7‐year follow‐up period (mean = 5.4 years). Enzyme‐linked immunosorbent assays quantified CSF Aβ42 and p‐tau181. Pseudo‐continuous arterial spin‐labeling captured CBF in total and lobar grey matter regions of interest (ROI). Linear mixed‐effects models related biomarker x time to longitudinal CBF variables adjusting for baseline age and cognitive status, sex, race/ethnicity, education, Framingham Stroke Risk Profile (minus age), ROI volume, APOE‐ε4 status, and time. Models were repeated testing a cognitive status x biomarker x time interaction term.ResultsIn main effect models, neither CSF Aβ42 (p‐values>0.31) nor p‐tau (p‐values>0.28) related to CBF outcomes. Aβ42 did not interact with cognitive status on CBF outcomes (p‐values>0.37), but p‐tau interacted with baseline cognitive status on longitudinal frontal, temporal, parietal, occipital, and total grey matter CBF trajectories (p‐values<0.005). Among cognitively unimpaired participants, higher p‐tau was associated with slower reductions in frontal (β = 0.01, p = 0.03), parietal (β = 0.01, p = 0.04), occipital (β = 0.01, p = 0.02), and total grey matter CBF (β = 0.01, p = 0.04). Among individuals with MCI, higher p‐tau was associated with faster reductions in frontal (β = ‐0.03, p = 0.008), temporal (β = ‐0.02, p = 0.01), parietal (β = ‐0.04, p = 0.002), occipital (β = ‐0.03, p = 0.0004), and total grey matter CBF (β = ‐0.03, p = 0.005).ConclusionsResults linking CSF p‐tau to CBF decline in MCI support the theory that grey matter hypoperfusion is a later‐stage event tied to neurofibrillary tangle pathology. Associations between higher p‐tau and slower rates of CBF decline among cognitively unimpaired individuals warrants further investigation. Funding: R01‐AG034962, K24‐AG046373, F31‐AG079640, T32‐AG058524, P20‐AG068082

Arterial spin‐labeling spatial coefficient of variation is associated with cerebral small vessel disease

AbstractBackgroundCerebral small vessel disease (SVD) is the most common pathology to co‐occur with Alzheimer’s disease but pathophysiologic mechanisms leading to SVD are poorly understood. The arterial spin‐labeling (ASL) spatial coefficient of variation (sCoV), a proxy marker of arterial transit time (ATT), may better reflect SVD‐related hemodynamic disturbances than ASL‐derived cerebral blood flow (CBF). We investigated whether grey matter CBF and grey matter sCoV each related to neuroimaging markers of SVD, including white matter hyperintensities (WMHs), basal ganglia enlarged perivascular spaces (ePVS), cerebral microbleeds (CMBs), and lacunes.MethodsVanderbilt Memory and Aging Project participants free of clinical dementia and stroke at study entry (n = 312, 73±7 years, 39% mild cognitive impairment, 41% female) underwent multimodal 3T brain magnetic resonance imaging to quantify ASL parameters and SVD burden. Pseudo‐continuous ASL assessed CBF in total grey matter. Grey matter sCoV was calculated as σ(CBFGrey Matter)/μ(CBFGrey Matter). WMHs and ePVS volumes were quantified using automated methods and ePVS volumes were standardized to basal ganglia volume. CMBs and lacune counts were quantified by an expert rater. Ordinary least squares regression models cross‐sectionally related grey matter CBF and sCoV individually to log‐transformed burden of each SVD marker. Models were adjusted for age, sex, race/ethnicity, education, cognitive status, Framingham Stroke Risk Profile (minus age), intracranial volume, grey matter volume, and apolipoprotein E‐ε4 status.ResultsGrey matter CBF was unrelated to all SVD outcomes (p‐values>0.25). Higher grey matter sCoV was associated with greater WMHs (β = 2.1, p = 0.001), ePVS (β = 0.004, p = 0.0003), and lacunar infarcts (β = 1.4, p = 0.0006) but not CMBs (β = 1.0, p = 0.06).ConclusionsOur findings align with previous results showing that grey matter sCoV is a valuable marker of SVD. In contrast to previous work, we found an association between higher grey matter sCoV and higher basal ganglia ePVS burden. Potentially, our use of volumetric ePVS quantification rather than qualitative ePVS burden increased our ability to detect this association. As sCoV is a proxy marker of ATT, future work should consider quantifying sCoV or ATT in addition to CBF to better characterize SVD‐related hemodynamic disturbances. Funding: R01‐AG034962, K24‐AG046373, F31‐AG079640, P20‐AG068082

Combining plasma p‐tau231 and glial fibrillary acidic protein produces higher discriminative accuracy for amyloid positivity than other blood‐based biomarker combinations

AbstractBackgroundPlasma phosphorylated tau (p‐tau)231 is an emerging blood‐based biomarker that has shown great promise for early identification of individuals at risk of Alzheimer’s disease (AD). However, it is unclear if this biomarker is sufficient as a standalone test or if diagnostic classification improves when simultaneously considering other plasma biomarkers. We investigated various plasma biomarkers, individually and in combination, in relation to cerebrospinal fluid (CSF) amyloid positivity.MethodVanderbilt Memory and Aging Project participants free of clinical dementia and stroke (n = 155, 72±6 years, 33% female) underwent fasting lumbar puncture and blood draw. CSF β‐amyloid42 (Aβ42) and β‐amyloid40 (Ab40) and plasma p‐tau231, glial fibrillary acidic protein (GFAP), Aβ42, Aβ40, and neurofilament light chain (NfL) were analyzed in batch. The Aβ42/40 ratio was used for all analyses and CSF amyloid positivity was defined as Aβ42/40 ratio <0.072. Logistic regression models related each biomarker to amyloid positivity, adjusting for age, sex, race/ethnicity, apolipoprotein E‐ε4 status, and cognitive status. Subsequent models included p‐tau231 as the predictor in a base model with other biomarkers being added individually and then in combination with other biomarkers to the base model. Models were compared using likelihood ratio test (LRTest) and Akaike Information Criterion (AIC) values.ResultIn single predictor models, p‐tau231 (C‐index = 0.87, p = 0.005) and GFAP (C‐index = 0.87, p = 0.01) were associated with amyloid positivity, while other biomarkers were not (p‐values>0.35). In models including p‐tau231 and various biomarker combinations, p‐tau231 remained significant in each model (p‐values<0.02). In comparison to the base model with p‐tau231 only, models adding GFAP (AIC = 143.8, LRTest p = 0.008), GFAP and NfL (AIC = 145.5, LRTest p = 0.02), and GFAP and Aβ42/40 (AIC = 145.8, LRTest p = 0.03) improved prediction of amyloid positivity. The model including plasma p‐tau231 and GFAP was the best fitting model (C‐index = 0.89).ConclusionIn this sample of community‐dwelling older adults free of clinical dementia, we found plasma p‐tau231 and GFAP were associated with amyloid positivity. Models including both p‐tau231 and GFAP performed best, and adding additional plasma biomarkers to this combination did not produce a better fitting model. Taken together, these findings highlight the utility of plasma p‐tau231 for screening for amyloid status and suggest that including plasma GFAP will improve discriminative accuracy.

Does tumoral cavernous carotid stenosis predict an increased risk of future stroke in skull base meningiomas?

Skull base meningiomas (SBMs) involving the cavernous sinus encase the internal carotid artery (ICA) and may lead to stenosis of the vessel. Although ischemic stroke has been reported in the literature, there are to the authors' knowledge no reported studies quantifying the risk of stroke in these patients. The authors aimed to determine the frequency of arterial stenosis in patients with SBMs that encase the cavernous ICA and to estimate the risk of ischemic stroke in these patients. Records of all patients with SBM encasing the ICA whose cases were managed by the skull base multidisciplinary team at Salford Royal Hospital between 2011 and 2017 were reviewed using a two-stage approach: 1) clinical and radiological strokes were identified from electronic patient records, and 2) cases were reviewed to examine the correlation between ICA stenosis associated with SBM encasement and anatomically related stroke. Strokes that were caused by another pathology or did not occur in the perfusion territory were excluded. In the review of patient records the authors identified 118 patients with SBMs encasing the ICA. Of these, 62 SBMs caused stenosis. The median age at diagnosis was 70 (IQR 24) years, and 70% of the patients were female. The median follow-up was 97 (IQR 101) months. A total of 13 strokes were identified in these patients; however, only 1 case of stroke was associated with SBM encasement, which occurred in the perfusion territory of a patient without stenosis. Risk of acute stroke during the follow-up period for the entire cohort was 0.85%. Acute stroke in patients with ICA encasement by SBMs is rare despite the propensity of these tumors to stenose the ICA. Patients with ICA stenosis secondary to their SBM did not have a higher incidence of stroke than those with ICA encasement without stenosis. The results of this study demonstrate that prophylactic intervention to prevent stroke is not necessary in ICA stenosis secondary to SBM.

Blood pressure variability and functional network connectivity in older adults

AbstractBackgroundBlood pressure variability is an emerging risk indicator for cerebrovascular disease and Alzheimer’s disease, independent of traditionally studied mean blood pressure levels. Recent studies suggest elevated blood pressure variability in older adults is also associated with attenuated cerebrovascular reactivity, which may have implications for functional hyperemia underpinning brain network connectivity. However, it remains unclear whether blood pressure variability is related to functional network connectivity. We examined relationships between beat‐to‐beat blood pressure variability in older adults and functional connectivity in multiple brain networks vulnerable to Alzheimer’s disease and related disorders (AD/ADRD).Method32 community‐dwelling older adults (mean [SD] age = 69.6 [7.5] years) without history of dementia or clinical stroke underwent continuous blood pressure monitoring during a 5‐minute period of rest and resting state fMRI. Blood pressure variability was calculated as variability independent of mean, an increasingly used index of variability uncorrelated with mean blood pressure levels. Functional connectivity was determined by resting state fMRI for several brain networks: default mode, salience, dorsal attention, fronto‐parietal, and language. Multiple linear regression examined relationships between blood pressure variability and functional network connectivity, controlling for age, sex, and mean blood pressure. Associations with mean blood pressure were also explored to directly compare potential effects with blood pressure variability.ResultElevated blood pressure variability was associated with lower functional connectivity in the default mode network (ß = ‐.55 [‐1.02, ‐.08]; p = .02). There were no significant associations between blood pressure variability and connectivity in other functional networks (p’s = .10 ‐ .62). Mean blood pressure was not related to functional connectivity in any network (p’s = .08 ‐ .98).ConclusionOlder adults with elevated blood pressure variability exhibit resting state functional connectivity deficits in the default mode network. Findings add to literature supporting the role of blood pressure variability in neurovascular dysfunction and AD/ADRD. Blood pressure variability may represent an important but understudied early vascular risk factor for neurovascular dysfunction relevant to AD/ADRD, with potential therapeutic implications.

Validation of a German-language modified Rankin Scale structured telephone interview at 3 months in a real-life stroke cohort

BackgroundThe modified Rankin scale (mRS) at 3 months is established as the primary outcome measure in clinical stroke trials. Traditionally, the mRS is assessed through an unstructured face-to-face interview. This approach can be labor-intensive and lead to suboptimal inter-rater reliability. Recently, the Covid-19 pandemic made face-to-face contact even more challenging. To address these issues, we developed and validated a structured German-language questionnaire for mRS testing by telephone.MethodsIn this prospective cohort study, we compared the mRS testing results of the standard face-to-face interview with those obtained in a structured interview by telephone using Cohen’s Kappa.ResultsAt our tertiary care stroke center, we included 108 patients who underwent both assessments. In 80.6% of cases (87/108) face-to-face and telephone interview reached identical scores. Linear weighted Kappa was 0.82 (p < 0.001). Unweighted Kappa for dichotomized mRS between fair (0–2) and poor (3–6) functional outcome was κ = 0.97 (p < 0.001).ConclusionsOur study validates the use of the German-language structured telephone interview as a reliable instrument for the use in clinical trials. We encourage others to utilize the questionnaire. It is available as an Appendix (Additional file 1) to this publication.

Pulmonary vein isolation versus PVI + adjunctive strategy (substrate modification and renal denervation therapy) for the reduction of 12-month AF recurrence

Abstract Background of the Study This meta-analysis assessed the latest evidence on the use of adjunct ablation strategies to standard pulmonary vein isolation (PVI) for treating atrial fibrillation (AF). Adjunct treatments were further classified as substrate modification (posterior wall isolation, linear ablation and ablation of complex fractionated atrial electrograms) or renal denervation (RDN). Purpose While ablation maintains sinus rhythm more effectively than antiarrhythmic drug therapy, recurrent AF remains common after 12 months, occurring in up to 40-60% of patients undergoing standard PVI ablation. Treatment strategies have diversified in a response to these challenges. These include reduction of the arrhythmogenic substrate, modulation of autonomic inputs and improvement of risk factors, such as hypertension. Methods A systematic literature search from MEDLINE and PubMed electronic databases was performed until November 2022. The primary outcome was 12-month AF recurrence defined as AF lasting ≥30 seconds on follow-up. The secondary outcome was incidence of procedure-related major adverse events (MAEs), defined as death, clinical strokes, acute heart failure decompensation, pericardial effusion causing tamponade, arteriovenous fistulas, and atrioesophageal fistulas. Results Nine studies comprising 1686 patients were included in the final analysis. AF recurrence was 487/1082 (45%) in the PVI + Adjunct group and 204/604 (33.8%) in PVI Alone. Pooled analysis showed that PVI + adjunct was inconclusively associated with less incidence of 12-month AF recurrence (RR 0.79, 95% CI 0.60–1.04, I2 = 70%, p-value 0.09). Subgroup analyses of six RCTs under the PVI with substrate modification arm showed non-significant increase in 12-month AF recurrence in PVI + substrate modification (RR 0.85, 95% CI 0.6-1.21, p-value 0.38). Subgroup analyses of the 3 RCTs on hypertensive AF patients showed strong evidence of decreased 12-month AF recurrence in PVI + RDN compared to PVI alone (RR 0.65, 95% CI 0.48-0.89, p-value 0.007). Secondary outcome of major adverse procedure-related events in overall pooled analysis showed 8 events in 604 patients undergoing PVI alone, and 23 events in 1082 patients undergoing PVI + adjunct ablation. There is no significant difference in the number of reported MAE in PVI alone over PVI + adjunct (RR 1.16 [0.49-2.75], p = 0.73). Conclusion Overall, PVI with adjunctive strategies did not significantly reduce 12-month AF recurrence after ablation. Among these strategies, RDN demonstrated a significant reduction in the primary endpoint, whereas substrate modification did not. There was no significant difference in MAEs reported between standard therapy versus those with adjunctive treatment. We conclude that PVI ablation strategies should be individualized, and modification of both triggers and risk factors for AF show better rhythm control on follow-up.

Patent foramen ovale: high-risk echocardiographic features related to secondary stroke prevention

Abstract Introduction Patent foramen ovale (PFO) closure has long been a matter of debate concerning the impact of such procedure on preventing ischemic events recurrence. Recent reports support this strategy raising the issue of optimal patient selection based on anatomical high-risk characteristics evaluated by transoesophageal echocardiography (TEE) that may be associated with an increased risk of recurrence. Purpose Characterize PFO-related echocardiographic findings and clinical features of a cohort of Embolic Stroke of Undetermined Source (ESUS) patients (pts). Methods Unicentric, retrospective analysis of pts with ESUS diagnosis who underwent TEE between 1/2014 and 11/2019. Excluded pts aged older than 70 years. Clinical stroke characteristics and echocardiographic PFO features were analysed. Results A total of 124 pts were included in the analysis, presenting a mean age of 50±1.6 [20;68] years and female gender predominance (58.9%). 48.4% of ESUS pts had PFO (53% female). Regarding PFO pts, 38 (62.3%) had significant right-to-left shunt on TEE, which was statistically associated with cortical infarcts (78.9 vs 56.5%,p=0.037). 35pts (58.3%) had shunt occurring at rest and during the Valsalva manoeuvre; when associated to significant shunt there was a correlation with cortical located infarcts (82.1 vs 60.0%, p&amp;lt;0.001). 33 PFOs (54.1%) had tunnel-like morphology. Tunnel-like PFOs were associated with significant right-to-left shunt (78.8 vs 42.9%, p&amp;lt;0.001), atrial septum aneurysm (ASA) presence (68.8 vs 50.0%, p&amp;lt;0.001) and with haemorrhagic transformation of ischemic stroke (15.2 vs 3.6%, p=0.031). 34 PFO pts (60.7%) had ASA. Mean PFO length was 6.42±5.0mm and mean height was 3.2±2.0mm. Conclusion In this cohort, there was a similar number of pts with and without PFO. Regarding ESUS pts with PFO, the majority had significant right-to-left shunt that occurred at rest and during Valsalva manoeuvre and were associated with cortical located infarcts. Tunnel-like morphology and ASA were also frequent. Tunnel-like morphology were associated with haemorrhagic transformation of ischemic strokes. These findings support the proposal that PFO characterization should have an additional role in stratifying pts with ESUS and selecting them for device closure.

Abstract 12485: Cardiovascular Disease Risk, Cognitive Function, and Serum Biomarkers in Older Women Participating in a Lifestyle Intervention

Background: Cardiovascular disease (CVD), including atherosclerotic CVD (ASCVD) and stroke, increase risk of cognitive dysfunction. Serum biomarkers, including brain-derived neurotrophic factor (BDNF), vascular endothelial growth factor (VEGF), and insulin-like growth factor 1 (IGF-1) may be associated with elevated CVD risk and are also emerging as early indicators of cognitive dysfunction. Yet, few studies have investigated associations among all three: CVD risk, cognitive function, and serum biomarkers. Aims: We examined associations between CVD risk, cognitive function, and serum biomarkers in older women with CVD. Methods: Baseline data from an ongoing lifestyle intervention trial for the prevention of cognitive decline in older women with CVD (NCT04556305) were analyzed. Women ( N =253) aged ≥65 years were recruited from ambulatory cardiology clinics. At baseline, CVD risk factors, including blood pressure, body mass index (BMI), waist circumference, and step test (cardiorespiratory fitness) were assessed. ASCVD and CHA 2 DS 2 -VASc scores were calculated to estimate clinical ASCVD and stroke risk, respectively. Serum biomarkers included BDNF, VEGF, and IGF-1. Neurocognitive tests for global cognition, including episodic memory, executive function, semantic memory, and working memory domains, were administered. Linear regression models adjusted for age, education, and race or ethnicity were used to evaluate associations of individual CVD risk factors, ASCVD and CHA 2 DS 2 -VASc scores with cognitive function and serum biomarkers, separately. Results: Of CVD risk factors, waist circumference and BMI were associated with cognition: waist circumference with global cognition, episodic memory, and executive function ( β = -.14 - -.20); BMI with executive function ( β = -.13). ASCVD and CHA2DS2-VASc scores were associated with semantic memory ( β = -.23 and -.16, respectively). Only the ASCVD risk score was associated with BDNF ( β = .18) and VEGF ( β = .24) levels. Conclusion: In older women with CVD, body composition and CVD risk scores appear to be correlated with cognitive function. Future studies should explore associations prospectively and consider serum biomarkers as mediators of the relation of CVD risk to cognitive dysfunction.

Abstract 18296: Insights From the LURIC Study: Decoding the Peripheral Immune Cell Composition in Atherosclerosis Through Single Cell RNA-Sequencing

Introduction: Atherosclerosis and its clinical sequelae, myocardial infarction and stroke, represent the main causes of death worldwide. Although preclinical evidence has suggested the existence of a sustained inflammatory and immune response driving disease and complications, the extend of cellular alterations in human atherosclerosis remains enigmatic. Hypothesis: Here, we employ single cell RNA-sequencing (scRNA-seq) on peripheral blood mononucleated cells (PBMCs) in a well-defined cardiovascular risk cohort from the Ludwigshafen Risk and Cardiovascular Health (LURIC) trial to define changes in the immune cell landscape in atherosclerotic patients Methods: Of 3317 patients enrolled in the LURIC trial, we selected individuals with stable coronary-artery disease (CAD) (n=31) and healthy patients (no CAD) (n=16) by propensity score matching, adjusted for CRP, NT-proBNP, Troponin T, LDL-C, and Cystatin-C, in a case-control design. scRNA-seq was performed by droplet sequencing on PBMCs stored in liquid nitrogen. Individual data sets were integrated and changes between healthy individuals and patients with CAD were evaluated on numeric and transcriptional levels. Results: We identified several regulated leukocyte populations that were differentially regulated between both conditions. Interestingly, small cell populations like Tregs (&gt;1.4-fold more), platelets (&gt;10-fold more), stem cells (&gt;3-fold more), and proliferating cells (&gt;2-fold-more) were significantly increased in PBMCs from patients suffering from CAD. On the contrary, naïve B cell and T cell populations were considerably overrepresented in healthy control patients (&gt;1.4-fold more). Pathway analyses of distinct clusters in patients with CAD revealed increased signalling for cellular exhaustion, response to stress, and leukocyte activation, which strikingly resembles the underlying pathology in atherosclerosis. Conclusions: Employing scRNAseq, we demonstrate that atherosclerosis is associated with a profound change in the circulating immune cell landscape even in the absence of measurable differences in inflammatory biomarkers. These findings propose the usage of scRNAseq for the discovery of outcome-relevant cellular biomarkers in the future.

Abstract 11433: Elevated Vascular Endothelial Growth Factor A is Associated With Disruption of Default Network Connectivity

Introduction: Vascular Endothelial Growth Factor A (VEGF-A) is an angiogenic signaling protein involved in the maintenance of the cerebral vasculature. VEGF-A may play a role in the pathogenesis of Alzheimer’s disease and vascular dementia; however, whether elevated VEGF-A levels indicate a pathophysiolocal response or protective mechanism remains unclear. No prior study has explored whether VEGF-A levels may be associated with changes in functional connectivity among brain regions prior to the development of cognitive decline. Hypothesis: Disruption of the default network often precedes the development of cognitive changes. In a sample of older adults, we hypothesized that VEGF-A levels may be associated with default network connectivity, indicating early involvement of VEGF-A in disease processes. Methods: Forty-six independently living older adults (mean age = 72.0 years; SD = 6.4; 34.8% male) free of dementia or clinical stroke underwent venipuncture and brain MRI. Plasma was assayed for VEGF-A. Using resting state functional MRI, blood-oxygen level dependent (BOLD) time series from all voxels in each region of interest (ROI) was averaged to determine mean ROI activity. Medial prefrontal cortex, lateral parietal cortex and precuneus cortex ROIs comprised the default network. Results: Accounting for age and sex, multiple linear regression analysis revealed a significant negative association between VEGF-A levels and default mode network connectivity (B =-.0007, 95% CI (-.0012, -.0002), p = .0096). This association persisted after adjusting for APOE4 carrier status and Framingham score. A significant association was present in both APOE4 carriers (p = .019) and non-carriers (p = .029). Conclusions: Prior studies evaluating the association between VEGF-A levels and cognition have been conflicted. This study is the first to examine whether VEGF-A may be linked to early changes in brain network connectivity which precede cognitive decline. These findings suggest that VEGF-A may be elevated early in the progression of neurocognitive disorders. Whether higher levels of VEGF-A contribute to the pathogenesis of neurocognitive disorders or play a protective role in persevering cognitive function warrants further investigation.

Prevention of cerebral thromboembolism by oral anticoagulation with dabigatran after pulmonary vein isolation for atrial fibrillation: the ODIn-AF trial

Background and objectivesLong-term oral anticoagulation (OAC) following successful catheter ablation of atrial fibrillation (AF) remains controversial. Prospective data are missing. The ODIn-AF study aimed to evaluate the effect of OAC on the incidence of silent cerebral embolic events and clinically relevant cardioembolic events in patients at intermediate to high risk for embolic events, free from AF after pulmonary vein isolation (PVI).MethodsThis prospective, randomized, multicenter, open-label, blinded endpoint interventional trial enrolled patients who were scheduled for PVI to treat paroxysmal or persistent AF. Six months after PVI, AF-free patients were randomized to receive either continued OAC with dabigatran or no OAC. The primary endpoint was the incidence of new silent micro- and macro-embolic lesions detected on brain MRI at 12 months of follow-up compared to baseline. Safety analysis included bleedings, clinically evident cardioembolic, and serious adverse events (SAE).ResultsBetween 2015 and 2021, 200 patients were randomized into 2 study arms (on OAC: n = 99, off OAC: n = 101). There was no significant difference in the occurrence of new cerebral microlesions between the on OAC and off OAC arm [2 (2%) versus 0 (0%); P = 0.1517] after 12 months. MRI showed no new macro-embolic lesion, no clinical apparent strokes were present in both groups. SAE were more frequent in the OAC arm [on OAC n = 34 (31.8%), off OAC n = 18 (19.4%); P = 0.0460]; bleedings did not differ.ConclusionDiscontinuation of OAC after successful PVI was not found to be associated with an elevated risk of cerebral embolic events compared with continued OAC after a follow-up of 12 months.Graphical abstract

Management of Postprocedural Conduction Disturbances Using a Prespecified Algorithm in the Optimize PRO Study

BackgroundLack of standardization in posttranscatheter aortic valve replacement (TAVR) conduction disturbance (CD) identification and treatment may affect permanent pacemaker implantation (PPI) rates and clinical outcomes. The safety and efficacy of a standardized TAVR CD algorithm has not been analyzed. This study analyzes the Optimize PRO post-TAVR CD management algorithm with Evolut PRO/PRO+ valves. MethodsOptimize PRO is a prospective, postmarket study implementing 2 strategies to reduce pacemaker rates: TAVR with cusp overlap technique and a post-TAVR CD algorithm. The 2-hour postprocedural electrocardiogram (ECG) stratified patients to early discharge in the absence of new ECG changes or to CD algorithms for (1) ECG changes with preexisting right or left bundle branch block (LBBB), interventricular conduction delay or first-degree atrioventricular block, (2) new LBBB, or (3) high-degree atrioventricular block (HAVB). ResultsThe interim analysis of the CD cohort consisted of 125/400 TAVR recipients. In the CD cohort, the 30-day new PPI rate was higher (28.1% vs 1.5%; P <.001), and 60 (48%) patients were discharged with a 30-day continuous ECG monitor. At 30 days, 90% of patients discharged with a monitor did not require PPI. Clinical outcomes, including mortality, stroke, bleeding, and reintervention, were similar in patients with and without CDs. No patient experienced sudden cardiac death. ConclusionsEffective management of CDs using a standard algorithm following Evolut TAVR provides similar 30-day safety outcomes to patients without CDs who undergo routine next day discharge. The CD algorithm may provide an effective strategy to recognize arrhythmias early, improve PPI utilization, and facilitate safe monitoring of patients after discharge.

32 Elevated Plasma pTau-181 is Associated with Lower Global Cognition and Executive Function in Older Adults

Objective:Aggregation of phosphorylated tau (pTau) is a hallmark feature of Alzheimer’s disease (AD). Novel assays now allow pTau to be measured in plasma. Elevated plasma pTau predicts subsequent development of AD, cortical atrophy and AD-related pathologies in the brain. We aimed to determine whether elevated pTau is associated with cognitive functioning in older adults prior to the development of dementia.Participants and Methods:Independently living older adults (N = 48, mean age = 70.0 years; SD = 7.7; age range 55-88 years; 35.4% male) free of dementia or clinical stroke were recruited from the community and underwent blood draw and neuropsychological assessment. Plasma was assayed using the Quanterix Simoa® pTau-181 V2 Advantage Kit to quantify pTau-181 levels and APOE genotyping was conducted on the blood cell pellet fraction obtained from plasma separation. Global cognition was assessed using the Dementia Rating Scale-2 (DRS-2) and executive function was assessed using the Stroop, D-KEFS-2 Fluency, and Trails Making Test. Diagnosis of mild cognitive impairment (MCI) was determined based on overall neuropsychological performance. Participants were diagnosed as MCI if they scored &gt;1 SD below norm-referenced values on 2 or more tests within a domain (language, executive, memory) or on 3 tests across domains.Results:Multiple linear regression analysis revealed a significant negative association between plasma pTau-181 levels and DRS-2 (B = -2.57, 95% CI (-3.68, -1.47), p &lt;.001), Stroop Color-Word score (B = -2.64, 95% CI (-4.56, - 0.71), p = .009) and Fruits and Vegetables Fluency (B = -1.67, 95% CI (-2.84, -0.49), p = .007), adjusting for age, sex, education and APOE4 status. MCI diagnosis was determined for 43 participants, of which 8 (18.6%) met criteria. Logistic regression analysis revealed that pTau-181 levels are associated with increased odds of MCI diagnosis (OR = 2.18, 95% CI (1.01, 4.68), p = .046), after accounting for age, sex, education and APOE4 status.Conclusions:Elevated plasma pTau-181 is associated with worse cognition, particularly executive function, and predicts MCI diagnosis in older adults. Higher plasma pTau-181 was associated with increased odds of MCI diagnosis. Detection of pTau-181 in plasma allows a novel, non-invasive method to detect burden of one form of AD pathology. These findings lend support to the use of plasma pTau-181 as a valuable marker in detecting even early cognitive changes prior to the development of AD. Additional longitudinal studies are warranted to explore the prognostic value of plasma pTau-181 over time.