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Stroke, Volume 56, Issue Suppl_1, Page ATP395-ATP395, February 1, 2025. Introduction:Ischemic stroke is one of the leading causes of death in the United States and is a known risk factor for Alzheimer’s Disease (AD) development. One of the characterizations of AD is the accumulation of β-amyloid peptide due to the proteolysis of Amyloid Precursor Protein (APP) by the protein Presenilin 1 (PS1) among others. In APP/PS1 mice, which contain an additional human copy of APP and PS1, a 15-minute Middle Cerebral Artery Occlusion (MCAO) model was developed. Here we investigate the effects of increased β-amyloid peptide on motor coordination when subjected to local ischemia.Methods:APP/PS1or Wt male mice are initially subjected to either a 15-minute MCAO or Sham surgery. Injury volume using MRI is assessed at 3-days using T2 imaging. To test motor coordination the mice went through a tapered beam analysis at the 7-day time point. Following the tapered beam test, Cresyl Violet was used to stain brain slices. All mice were 8-12 weeks old at the time of surgery. Differences between groups were determined by Welch’s T-Test. Significance was determined as p < 0.05.Results:No significant difference in infarct volume was observed between the APP/PS1-MCAO and Wt-MCAO groups. In the hind legs, it was observed that there is a significant difference in the number of slips off the tapered beam in the APP/PS1-MCAO group when compared to the Wt-MCAO group (9.4 ± 3.356, n=7, p < 0.05 and 2.5 ± 0.289, n=4, p < 0.05 respectively). No significant difference was found in the Cresyl Violet staining.Conclusions:Our study shows motor deficit in the APP/PS1-MCAO experimental group when compared to the Wt-MCAO group as measured on hind-limb coordination. Therefore, further studies are warranted to assess the interaction between ischemia and β-amyloid peptide on histological injury and functional recovery.

Stroke, Volume 56, Issue Suppl_1, Page ATP393-ATP393, February 1, 2025. Dysregulation of the immune system is a contributing factor in the progression of Alzheimer’s Disease (AD), likely by increased vascular inflammation triggered by brain or peripheral inflammation. Our research has demonstrated that neutrophils play a role in causing hypoperfusion by adhering to and obstructing blood vessels, as seen in both mouse models for and patients with AD. Notably, protein glycosylation of membrane proteins is essential for regulating the adhesion properties of neutrophils to immune cells and the vasculature.Here, we utilize lectin blots to show that sialic acid residues, which are the terminal caps of glycosylation chains, are increased on neutrophil membrane proteins from an amyloidosis Alzheimer’s mouse model. Furthermore, we evaluated the efficacy of the sialyltransferase inhibitor alpha 2,3 sialyltransferase-IN-1 by lectin blot analyses, identifying it to be an effective compound for removing sialic acid from neutrophil membrane proteins. Notably, we performedin vivomultiphoton imaging of cerebral blood flow and capillary stalling in AD mice injected with alpha 2,3 sialyltransferase-IN-1. Our findings demonstrated that reducing sialic acid residues on neutrophils improved cerebral blood flow and capillary stalling.This work suggests that the altered glycosylation pattern, specifically aberrant sialylation residues of neutrophil glycoproteins, are a significant contributing factor to the hypoperfusion observed in AD mouse models and patients. Modulating the glycosylation profile may present a potential therapeutic approach for improving the vascular dysfunction associated with AD pathogenesis.

Stroke, Volume 56, Issue Suppl_1, Page AWP61-AWP61, February 1, 2025. Background:Retinal vasculopathy had been reported across the continuum of neurodegeneration. Retinal color fundus photography coupled with automated retinal vascular analysis offers potential to non-invazively screen for Alzheimer’s disease (AD) neurodegeneration. Amyloid positron emission tomography (PET) and apolipoprotein 4 (APOE4) carrier status are known biomarkers of AD risk. Herein, we examined the relationship between retinal vascular fractal dimensions in non-mydriatic color fundus photographs, amyloid-PET burden and APOE4 carrier status in a cohort of cognitively intact individuals.Methods:Our dataset included 91 macula-centered and 39 optic disc-centered images from 96 cognitively intact participants (29% male). 25 (26%) were amyloid-PET positive, defined as amyloid-PET standardized uptake value ratio centiloid cut-off > 20. AutoMorph software automatically determined retinal arteriolar and venular density, tortuosity and width, among other fractal dimensions. To test the effect of amyloid-PET status on the retinal vascular parameters, we used a generalized linear model compensated for age, sex and the interaction between APOE4 carrier and amyloid-PET status. We also compared amyloid-PET positive and negative subjects for vascular fractal dimensions correcting for age and gender. We adjusted for multiple comparisons using the False Discovery Rate correction and reported significant P values less than 0.05.Results:Compared to amyloid-PET negative, cognitively intact amyloid-PET positive cohort had greater mean age (71 vs 66 years, P=0.06), more males (60% vs 35%, P=0.02), more APOE4 carriers (P0.05 for all) and significantly lower macular vessel tortuosity density (P=0.019). The amyloid-PET positive status had a significant effect on the retinal artery distance tortuosity (corrected P=8.75E-04, β=13.9, 95% CI [7.75-19.99]) and artery squared curvature tortuosity (corrected P=8.91E-10, β=464, 95% CI [359.10-569.15]).Conclusions:Automatically determined retinal vascular fractal dimension on non-mydriatic color fundus photographs predicts amyloid-PET burden in cognitively intact individuals. Future longitudinal studies should asssess the utility of automated quantitative retinal vasculopathy analysis to screen for presymptomatic AD.

Stroke, Volume 56, Issue Suppl_1, Page A36-A36, February 1, 2025. Background:Intracranial atherosclerotic disease (ICAD), a common cause of stroke, is associated with cerebral atrophy and cognitive impairment, but the underlying pathophysiology remains unknown. We sought to determine if common age-related neuropathologies modified the association between ICAD and cerebral atrophy.Methods:This cross-sectional analysis included deceased participants from the National Alzheimer’s Coordinating Center database who had MRI morphometry and autopsy assessments for vascular pathologies and Alzheimer’s disease (AD). We represented ICAD, arteriolosclerosis, and AD dichotomously based on autopsy-determined Circle of Willis atherosclerosis (none-mild vs moderate-severe), arteriolosclerosis (none-mild vs moderate-severe), and National Institute of Aging-Alzheimer’s Association ABC score (none-low vs intermediate-high likelihood of AD), respectively. Our primary outcome of interest was total cortical thickness (mm) on MRI. We conducted adjusted linear regression to determine the association between ICAD and cortical thickness, then tested for multiplicative interaction between arteriolosclerosis and AD substrata.Results:Among 449 included participants (age at enrollment 77 years [interquartile range 70-83], 45% female, 87% non-Hispanic white), 39% had ICAD, 56% had arteriolosclerosis, and 72% had AD. In fully adjusted models, we found ICAD and AD to be independently associated with cortical thinning (ICAD β-estimate [95% confidence interval, CI] = -2.89 [GJD1] [-5.65, -0.13]; AD β-estimate [95% confidence interval, CI] = -5.61 [-8.44, -2.78]). In interactions models, we found significant associations between ICAD and cortical thickness only in subgroups with coexistent arteriolosclerosis or AD pathology, [GJD2] but we did not detect a significant multiplicative interaction (arteriolosclerosis, p = 0.50, AD, p = 0.35).Conclusion:In this cross-sectional study, we found ICAD to be independently associated with cortical thinning. Coexistent arteriolosclerosis and AD pathologies did not seem to modify the effect of ICAD on cortical thickness, but we may have been limited by sample size.

Stroke, Volume 56, Issue Suppl_1, Page AWMP17-AWMP17, February 1, 2025. Introduction:Intracranial arterial calcifications (IAC) are considered a surrogate for intracranial large artery atherosclerosis but IAC can also represent non-atherosclerotic arterial aging. People with IAC have an increased risk of dementia. Nonetheless, the interplay between IAC, atherosclerosis, luminal stenosis and arterial stiffness as determinants of neurodegeneration remains unclear.Methods:We analyzed 161 brain autopsy cases from the Brain Arterial Remodeling Study. We dissected each of the components of the circle of Willis and stained all arterial segments with H&E, elastic van-Gieson (to semi-quantify elastin content) and trichrome (to semi-quantify collagen content) stains. We rated calcification using H&E as present or absent and classified calcifications as scattered, media calcifications, coalescent or a combination of the above. We obtained ipsilateral brain cuts and stained with H&E to measure the arteriolar wall thickness and lumen. We used immunohistochemistry to stain for beta amyloid, phospho-tau and Iba1, a measure of activated microglia. Each stained slide was processed automatically to quantify the number of amyloid plaques and microglial (Iba1+) cells per 100u2and percentage of tissue area stained positive by phospho-tau. We related calcification in the circle of Willis to parenchymal measure of neurodegeneration using mixed hierarchical models, adjusting for age, demographics and vascular risks.Results:Among 161 cases (mean age 81±16 years), 52% were female, 78% non-Hispanic white, 52% had hypertension, 11% diabetes, and 54% died with diagnosed dementia. Presence of any calcification was associated with increased number of Aβ plaques per 100 µ2, greater percentage of tissue area stained by phospho-tau, higher number of microglial cells and higher lumen to wall ratio (Table 1). The results were most consistent for IAC that had combined scattered and coalescent calcifications. The association between IAC and neurodegeneration markers attenuated after adjusting for elastin loss and collagenosis, both markers of arterial stiffness, but not after adjusting for atherosclerosis or luminal stenosis.Conclusion:IAC are associated with pathology markers of neurodegeneration, specifically Alzheimer’s disease. The association was independent of atherosclerosis and luminal stenosis, but attenuated partially after adjusting for markers of arterial stiffness. Hemodynamic studies in living persons are needed to replicate these associations.

Stroke, Volume 56, Issue Suppl_1, Page ATP205-ATP205, February 1, 2025. Introduction:Alzheimer’s Disease (AD), characterized by extracellular deposition of amyloid beta (Aβ) plaques in brain tissue, is often comorbid with cerebral amyloid angiopathy, which carries an elevated risk of intracranial hemorrhage. Furthermore, severe hemorrhagic complications have been observed following the use of new Aβ-targeted immunotherapies for AD. However, there are limited population-based data regarding the risk of intracranial hemorrhage associated with AD.Methods:We performed a retrospective cohort study using inpatient and outpatient claims between 2008-2018 from a nationally representative 5% sample of Medicare beneficiaries ≥65 years of age. The exposure variable was AD, defined byICD-9-CMcode 331.0 andICD-10-CMcode G30.x. The primary outcome was non-traumatic intracranial hemorrhage, defined as a composite of intracerebral hemorrhage (ICH), subarachnoid hemorrhage (SAH), and subdural hemorrhage (SDH) using validatedICD-9-CMandICD-10-CMdiagnosis codes. Secondary outcomes were ICH, SAH, and SDH assessed separately. Cox proportional hazards models were used to determine the associations between AD and outcomes after adjustment for demographics, vascular risk factors, and Charlson comorbidities.Results:Of 2,107,151 patients included, 87,751 (4.1%) had a diagnosis of AD. A total of 14,400 (0.7%) patients were diagnosed with ICH, 6,003 with SAH (0.3%), and 6,650 (0.3%) with SDH. In multivariable Cox proportional hazards analysis, AD was associated with an increased risk of intracranial hemorrhage (adjusted hazard ratio [aHR], 1.54, 95% confidence interval [CI], 1.44-1.65). In adjusted analyses of secondary outcomes, AD was associated with an increased risk of ICH (aHR, 1.35; 95% CI, 1.23-1.48), SAH (aHR, 2.59; 95% CI, 2.26-2.97), and SDH (aHR, 2.05; 95% CI, 1.83-2.30).Conclusions:In a nationally representative cohort of Medicare beneficiaries, AD was associated with an increased risk of spontaneous intracranial hemorrhage. This increased risk was also present for ICH, SAH, and SDH when examined separately.

Stroke, Volume 56, Issue Suppl_1, Page A101-A101, February 1, 2025. Introduction:Previous studies have shown an association between vascular disease and Alzheimer’s disease, but there are few studies have considered a relationship between brain arterial remodeling and biomarkers of Alzheimer’s disease. Our study aims to find the association between specific arterial characteristics in brain arterial remodeling and Alzheimer’s pathology.Method:We analyzed 132 brain autopsy cases from the Brain Arterial Remodeling Study (BARS), a collection of brains from multiple brain banks in the United States and abroad. Brain sections were obtained systematically by each brain bank, and the anatomical location was harmonized across the banks. The brain slides were stained with LH&E to measure the lumen and wall thickness of the pial, CSF-floating small arteries, parenchymal arteries, and arterioles. Then lumen area, wall thickness, lumen-to-wall ratio (LWR), and wall proportion (which serves as a measure of vessel stenosis) were calculated. We used immunohistochemistry to stain for beta-amyloid, phospho-tau, and Iba1, a measure of microglia. Each stained slide was processed automatically using Visiopharm (version 2021.12) by color thresholding and pattern detection to quantify the number of amyloid plaques and microglial (Iba1+ cells) per 100 µm2and the percentage of tissue area stained positive by phospho-tau, and the number of microglial cells per 100 µm2.Results:Overall, a thicker arterial wall was associated with a greater area of tau staining and a lower lumen-to-wall ratio (suggestive of inward remodeling) was associated with a higher number of microglial cells (table 1). There was a statistical interaction between measures of arterial remodeling by anatomical location (pial vs. parenchymal, P

Stroke, Volume 56, Issue Suppl_1, Page ATP252-ATP252, February 1, 2025. Alzheimer’s Disease (AD) is the most common form of dementia and is characterized by progressive neurodegeneration and cognitive decline. Cardiovascular risk factors in AD lead to decreased cerebral blood flow (CBF), particularly in capillaries, which play a crucial role in the exchange of oxygen and nutrients in response to neuronal activity. Deficits in capillary-level cerebral blood flow are likely to induce vascular inflammation and disrupt the shear forces associated with blood flow, both of which are hallmarks of Alzheimer’s disease and aging. The Piezo1 channel has been shown to be a crucial mechanosensor in brain capillaries that mediates mechanically induced endothelial cell Ca2+transients, suggesting a possible role for Piezo1 in CBF regulation. Here, we investigated the contribution of mechanosensitive Piezo1 ion channels to capillary stalling and CBF reductions in the 5xFAD mouse model of AD. We performed cranial window implantation on twelve 4-month-old 5xFAD mice and twelve age-matched wild-type controls. Usingin vivomultiphoton imaging, we measured cerebral blood flow and capillary stalling in 5xFAD mice following injection with Yoda1, a Piezo1 agonist, before, 24 hrs and one week after Piezo1 activation. Our findings demonstrated that modulating Piezo1 activity reduced capillary stalling and improved CBF in response to Piezo1 activation. Further, Yoda1 injection for one week improved functional hyperemia, measured using laser speckle contrast imaging, in 7-month-old 5xFAD mice. These results suggest the crucial implication of Piezo1 in vascular dysfunction during AD. Importantly, this work highlights the potential therapeutic targeting of Piezo1 to mitigate the effects of impaired cerebral perfusion in AD.