Search Results for: Identificata la causa della progressione dell’Alzheimer nel cervello

Stroke, Volume 56, Issue Suppl_1, Page ATMP119-ATMP119, February 1, 2025. Background:Vascular cognitive impairment (VCI) is the second most frequent subtype of dementia following Alzheimer’s disease. However, the underlying mechanism has not been fully understood and there is no effective treatment for VCI. MicroRNAs (miRNAs) play critical roles in the pathologies of cerebral ischemia and dementia. This study aims to identify key miRNAs that may mediate cognitive outcomes using multiple microinfarction (MMI), a VCI model.Methods:MMI was induced by the administration of cholesterol crystals (70-100µm) into the internal carotid artery. Male Wistar rats (10-12 month) subjected to MMI or sham operation were euthanized 28 days after MMI (n=8/group). Total RNAs were isolated from the striatal tissues and miRNA-sequencing was performed. AAV-PHP.Eb carrying miR-145-5p sponge was delivered by the Intracerebroventricular injection at 2 days prior to MMI to knockdown miR-145-5p. The mNSS (modified Neurological Severity Score) and cognition tests were examined at 2 weeks after MMI.Results:MiRNA-sequencing analysis showed that compared to sham rats, MMI significantly up- and down-regulated 4 and 9 miRNAs respectively. Bioinformatics analysis revealed that these miRNAs were highly associated with the oligodendrocytes/myelination (miR-210 and miR-125), BBB (miR-665 and miR-29), and inflammation (miR-322), etc. Amongst them, miR-145 was the top upregulated miRNA in the striatum after MMI. In situ hybridization demonstrated that miR-145 expression was highly upregulated in the smooth muscle cells, which was negatively correlated with the decrease of contraction marker of smooth muscle cells (SMCs). Treatment of MMI rats with AAV-miR-145 sponge significantly reduced sensorimotor deficits assayed by lower mNSS score. Furthermore, MMI rats administered AAV-miR-145 spent less time on the closed arm in the EPM (AAV-miR-145 VS control AAV: 182±28 VS 263±9 (s), P=0.01) and showed less freezing time in the OFT (AAV-miR-145 VS control AAV: 205±9 VS 246±11 (s), P=0.015), compared with those treated with control AAV. These data indicate that inhibition of miR-145 reduces depression-like behavior and cognitive deficit induced by MMI.Conclusion:Our results uncovered the deregulated miRNAs associated with myelination, white matter and vascular damage after MMI. Also, our data suggest that miR-145 could be a potential therapeutic target by the regulation of SMCs against VCI. Thus, our data provides new insights into the molecular mechanisms underlying VCI.

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 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 ATP378-ATP378, February 1, 2025. Introduction:The molecular and metabolic changes that occur after acute ischemic stroke (AIS) are not fully understood. One mechanism known to trigger systemic inflammatory responses and neuronal death during ischemic stroke cascades the rapid increase in Reactive Oxygen Species (ROS). Accumulation of oxidative stress has been shown to trigger the initiation and progression of cognitive deficits, including mild cognitive impairment (MCI) and Alzheimer’s Dementia (AD). One emerging biomarker able to reliably measure oxidative stress is Malondialdehyde (MDA), a reactive carbonyl compound originating from polyunsaturated fatty acid oxidation and lipid peroxidation. Due to its composition, MDA readily reacts with lipid membranes, making it a sensitive oxidative stress biomarker. This study assessed MDA levels in the plasma of AIS patients to evaluate its ability to predict cognitive impairment and long-term functional outcomes.Hypothesis:We hypothesized that oxidative stress correlates with long-term functional outcomes in AIS patients and varies based on non-modifiable risk factors such as sex and race.Methods:In this study, we used peripheral blood plasma from healthy volunteers (HV, N=24), and from ischemic stroke patients (N=27) at 3d and 7d post-stroke to capture the temporal profile of MDA after injury. Cognitive impairment was assessed during hospitalization with the Brief Neurocognitive Screening Test (BNST), with a score of 8 or below denoting cognitive impairment.Results:AIS patients had an increase in MDA levels compared to the control group, as seen in prior literature. There was a significant correlation with increase age of stroke patients and higher levels of MDA (p

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 AWP49-AWP49, February 1, 2025. Cerebral small vessel disease, particularly characterized by white matter hyperintensities (WMHs), is a prominent contributor to cognitive impairment. The concurrent role of Alzheimer’s disease (AD) pathology, as measured by hyperphosphorylated tau species (pTau), in vascular cognitive impairment remains unclear. While plasma pTau217 is an established biomarker for AD, its relevance in vascular disease-enriched populations has not been extensively studied. This study investigates plasma pTau217 as a biomarker for distinguishing cognitive impairment and dementia in a cohort de-enriched for AD but enriched for vascular disease, focusing on its relationship with cognitive status and Fazekas scores. A cohort of 72 participants (mean age: 70.4, SD 7.9, 58% female) from the MarkVCID Consortium study were selected with 75% having a Fazekas score ≥ 2. pTau217 levels were quantified using the Meso Scale Discovery S Plex assay. Individuals were classified based on their cognitive status into cognitively normal, mild cognitive impairment (MCI), or dementia. Receiver operating characteristic (ROC) curve analysis was performed to assess the ability of pTau217 to distinguish between these groups. Linear regression models were used to examine the association between pTau217 levels and Clinical Dementia Rating (CDR) global scores. Plasma pTau217 levels were found to be elevated in individuals with MCI and dementia. The ROC curve analysis showed pTau217 could distinguish between patients with MCI (AUC: 0.74) and dementia (AUC: 0.72), suggesting moderate diagnostic accuracy in this vascular disease-enriched cohort. No significant relationship was observed between pTau217 levels and Fazekas scores. Regression analysis revealed plasma pTau217 levels were significantly associated with CDR global scores (β=0.337; p=0.0007), a correlation that remained significant after adjusting for sex, age, and education, underscoring pTau217 as an independent predictor of cognitive decline. Additionally, 75% of participants with an AD diagnosis (6/8) had pTau217 levels >10 pg/mL (consistent with prior studies) ranging from 12.2 to 35.3 pg/mL. In conclusion, for this cohort enriched for vascular disease and de-enriched for AD, plasma pTau217 exhibited accuracy in distinguishing patients with MCI and dementia, independent of Fazekas scores. These findings support the utility of plasma pTau217 as a biomarker for cognitive impairment, even in populations with a significant vascular pathology.

Stroke, Volume 56, Issue Suppl_1, Page AWP346-AWP346, February 1, 2025. Dementia is associated with respiratory dysfunction. In mice models of dementia, there is increased astrogliosis in the brain stem retro-trapezoid nucleus (RTN), which is crucial for breathing control. Our previous work using a genetic approach suggested that increased transforming growth factor beta receptor (TGFβR) signaling may be responsible for RTN astrogliosis and contribute to respiratory and cognitive dysfunctions. Here we tested our hypothesis that pharmacological inhibition of TGFβR2 in mice models of dementia may reduce RTN gliosis, breathing disorder and cognitive impairment.We used male 16-month-old Tg-2576 and Tg-SwDI mice that model Alzheimer’s Disease (AD) and Cerebral Amyloid Angiopathy (CAA), respectively with WT controls. LY2109761, a selective TGF-β receptor inhibitor, was administered orally every day for 6 weeks at a 50 mg/kg dose. Barnes Maze and Novel Object Recognition Test (NORT) were used to measure cognitive strength, and plethysmography was used to measure respiratory metrics such as apnea rate after the 6 weeks of treatment. Immunofluorescence was used to quantify gliosis (GFAP) at RTN. All data is presented as Mean±SEM.Tg-2576 mice performed significantly worse than the WTs in the Barnes Maze (escape latency 184±20.99 vs. 119.4±12, p=.039, n=8-9/group), in the NORT (percentage time with the novel object 48.3±2.061 vs. 63.3±2.071, p=.0003, n=8-9/group), and showed increased apneas per minute (9±.9 vs 4.33±.81, p=.001, n=8-9/group). Similarly, Tg-SwDI mice showed impaired breathing and cognition function. In Tg-2576 mice, TGFβR2 inhibition improved performances in Barnes Maze (112±18.6 vs. 184±20.9, p= .02 n=8-9/group) and NORT (57.7±2.54 vs. 48.3±2.06, p=.023, n=8-9/group), and reduced apneas per minute (4.88±.058 vs. 9.0±.98, p=.004, n=8-9/group) compared with vehicle treatment. In Tg-SwDI mice, TGFβR2 inhibition also improved performance in Barnes Maze (43.8±2.72 vs. 58.2±5.16, p=.03 n=7/group) and NORT (59.1±3.28 vs. 46.6±3.32, p=.02, n=7/group), and reduced apneas per minute (5±1.06 vs. 9.71±1.71, p=.038 n=7/group) compared with vehicle group. TGFβR2 pharmacological inhibition additionally reduced astrogliosis in the RTN of Tg-2576 mice (drug 53.62±4.8 vs. vehicle 70.9±3.38, p=.018, n= 4/group).In conclusion, pharmacological inhibition of TGFβR2 improved cognition in AD and CAA mice. Improving breathing control via reducing gliosis at breathing center RTN may be the underlying mechanisms of the improvement.

Stroke, Volume 56, Issue Suppl_1, Page AWP340-AWP340, February 1, 2025. Background:Acute hyperglycemia is common post ischemic stroke, and is a robust predictor of poor stroke outcome. Even transient glucose elevation substantially increases the risk of mortality and long-term disability. Tight glucose control with insulin is effective in correcting hyperglycemia, but lacks efficacy in improving patient outcome, suggesting the presence of early hyperglycemic injuries that are resistant to later glucose control. Our recent clinical research revealed that abnormal red blood cells (RBCs) could be a novel mediator of the adverse effect of acute hyperglycemia on stroke outcome. Here, using in vitro and ex vivo models, we aim the explore the underlying mechanism.Method:RBCs were isolated from healthy C57BL6 mice (10~12 wk) and exposed to in vitro normal glucose (NG: 5 mM) or high glucose (HG: 15 mM) for 24 hr. HG-exposed RBCs were also treated with ROS scavenger TEMPOL (HG+TEMPOL). The treated RBCs were then incubated with mouse brain blood vessels for additional 24 hr. Changes in vascular gene expression were profiled via RNA sequencing.Result:HG exposure increased reactive oxygen species (ROS) production within RBCs, which was mitigated by TEMPOL (Figure 1A). Importantly, HG-challenged RBCs (HG-RBCs) led to a significant shift in brain vascular gene expression and function (Figure 1B-D). Specifically, the expression of endothelial nitric oxide synthase (eNOS), the enzyme responsible nitric oxide (NO) production, was decreased by HG-RBCs treatment, potentially reducing NO availability and compromising cerebral blood flow (Figure 2A). These changes were further validated by immunohistochemistry (Figure 2B, 2C). Moreover, RBCs affected vascular pathways linked to Alzheimer’s disease (Figure 1D). HG-RBCs suppressed Adam10 (α-secretase)-mediated non-amyloidogenic process and activated Bace1 (β-secretase)-mediated amyloidogenic process, potentially contributing to β-amyloid accumulation (Figure 2D, 2E). Most of these detrimental effects could be reversed by TEMPOL pretreatment (Figure 2A-E), and the overall vascular gene expression pattern was closer to those treated by NG-RBCs (Figure 1B, 1C), suggesting that hyperglycemia-induced RBC oxidative stress play a causal role in brain vascular dysfunction.Conclusion:RBCs, beyond their oxygen transport role, are crucial regulators of vascular function and could be a previously overlooked contributor to vascular dysfunction in acute hyperglycemia post stroke (Figure 3).

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 ATP214-ATP214, February 1, 2025. Background:Amyloid-related Imaging Abnormalities (ARIA) are adverse effects that occur during amyloid beta monoclonal antibody treatment for Alzheimer’s disease, including edema-type ARIA and hemorrhage-type ARIA. Few retrospective analysis have compared ARIA-H incidence among individual monoclonal antibodies, and a comprehensive comparison is currently lacking. After the approval of these antibodies, research has mainly focused on dosing frequency and drug dosage, leaving it unclear whether ARIA-H is associated with the specific characteristics of different monoclonal antibodies.Methods:1. For monoclonal antibodies targeting Aβ clearance, we selected seven: Aducanumab, Bapineuzumab, Crenezumab, Donanemab, Gantenerumab, Lecanemab, and Solanezumab. Our data is derived from systematic reviews and meta-analyses of Phase III clinical trials for these seven monoclonal antibodies. Data from Jeremic D et al. include six monoclonal antibodies (mAbs), while data from Qiao Y et al. include four mAbs. 2. For the evaluation variables, we selected the following factors: the form of monoclonal antibody binding to Aβ protein, binding affinity, binding epitope, Fc subtype of the monoclonal antibody, and the Aβ clearance rate. ARIA-H occurrence was used as a categorical variable for differential analysis. The odds ratio (OR) was utilized for data assessment, with an OR not equal to 1 and a 95% confidence interval excluding 1 used as the criterion for statistical significance. 3. We standardized the data for the seven monoclonal antibodies (mAbs). We compared the ARIA-H occurrence rates for the mAbs, taking into account other dimensional variables.Results:The risk of ARIA-H, from highest to lowest, is as follows: Donanemab, Aducanumab, Bapineuzumab, Lecanemab, Gantenerumab, Crenezumab, Solanezumab. Besides, ARIA-H is associated with the characteristics of mAb. (1)More mature Aβ clearance is associated with a higher risk of ARIA-H.(2)Lower clearance of Aβ oligomers is associated with a higher risk of ARIA-H.(3)Aβ clearance closer to the N-terminus is associated with a higher risk of ARIA-H.(4)mAb with an IgG4 structure are more likely to cause ARIA-H than those with an IgG1 structure.(5)Faster achievement of Aβ clearance thresholds is associated with a higher risk of ARIA-H.Conclusion:This research enhances our understanding of ARIA-H and may guide future monoclonal antibody drug development, which may improve the cognition and overall prognosis of Alzheimer’s disease patients.

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.

Stroke, Volume 56, Issue Suppl_1, Page ATP28-ATP28, February 1, 2025. Cognitive impairment following acute stroke significantly impacts patient outcomes and rehabilitation. Early detection is crucial, yet comprehensive assessments are often impractical in acute settings. Digital clock drawing and recall (DCR) offers a rapid 5-minute cognitive screening by assessing clock drawing and three-word recall. While previously shown effective in early Alzheimer’s detection, its utility in stroke patients has been underexplored. This study investigates the feasibility and validity of DCR compared to the Montreal Cognitive Assessment (MoCA) in stroke patients.The study involved 80 acute ischemic stroke patients who completed both DCR and MoCA during hospitalization. DCR was implemented on the Linus Health platform. DCR data included DCR scores, battery duration, demographic variables, and recorded NIH Stroke Scale scores. Cognitive impairment was defined using a MoCA threshold of ≤24. Leave-One-Out Cross-Validation and XGBoost were used for analysis. Optuna-optimized hyperparameters and model performance were evaluated via AUC, accuracy, F1-score, sensitivity, and specificity. SHAP analysis provided insights into feature importance.The median time from stroke to cognitive screening was 3 days [1.0, 2.0]. The impaired group (MoCA ≤ 24) was older (mean 63.2 vs. 53.2 years, p = 0.271), had lower education levels (mean 13.4 vs. 15.8 years, p = 0.005), longer battery durations (median 288.0 vs. 232.0 seconds, p = 0.017), and lower DCR scores (median 1.0 vs. 3.0, p < 0.001). NIHSS scores were higher but not statistically significant (median 4.0 vs. 2.0, p = 1.). Gender, race, and ethnicity were insignificant predictors excluded from the final model.The XGBoost model demonstrated strong predictive performance, with an AUC of 0.8114, an F1-score of 0.8916, and an accuracy of 0.9. At the threshold of 0.5656 (Youden’s J statistic), the model achieved high sensitivity 0.9841 and moderate specificity 0.5882. SHAP analysis identified DCR score, education level, and battery duration as the most important features.DCR screening proves to be an effective, rapid cognitive screening tool in acute ischemic stroke care. It demonstrates high sensitivity in detecting subtle cognitive impairments and correlates well with MoCA scores. While further validation is needed, this tool offers a rapid and reliable method for cognitive assessment in acute settings, potentially enhancing personalized treatment approaches and improving patient outcomes in stroke care.

Stroke, Volume 56, Issue Suppl_1, Page AWP217-AWP217, February 1, 2025. Background:In CLARITY-AD, lecanemab slowed cognitive decline but increased intracranial hemorrhages (ICHs), particularly with concurrent anticoagulant use. The Alzheimer’s Association’s expert guidance is to avoid co-prescribing; however, CMS and FDA do not restrict or warn against it. We used a microsimulation model to quantify the potential benefits and harms of co-prescribing lecanemab and apixaban in people with atrial fibrillation (AF) experiencing mild cognitive impairment or early Alzheimer’s.Methods:We developed a microsimulation model to estimate the health and cognition-related quality of life among persons 65-90 years with AF and cognitive impairment. We compared 4 strategies over 18 months in a cohort of 100,000 people: apixaban alone, lecanemab and apixaban, lecanemab alone, and neither. The model was populated with the Health and Retirement Study-AF cohort. Monthly model outcomes included ICH, ischemic stroke, cognitive impairment, quality-adjusted life months (QALMs), and survival. Increased ICH risk was a key input: a trial-reported 2.02-fold increase for lecanemab alone, a 1.84-fold increase for apixaban alone (anticoagulant literature), and a trial-reported 9.92-fold increase for lecanemab and anticoagulants together. We assigned quality-of-life estimates and mortality rates for people with cognitive impairment, stroke, and ICH. Background mortality rates increased with cognitive decline and following a stroke or ICH event.Results:For ages 65-74, apixaban alone and lecanemab added to apixaban produced a similar net benefit (13.2 QALM each,Table). Over 100,000 simulated persons aged 65-74 years, adding lecanemab to apixaban would result in greater ICH events (2000 vs. 400) and all-cause deaths (5860 vs. 5180) and slower cognitive decline (mean change in CDR-SB 1.11 vs. 1.53). One-way sensitivity analyses show that the net benefit for people aged 65-74 years is sensitive to the determinants of ICH—lecanemab/anticoagulant interaction, lecanemab effect on ICH, apixaban effect on ICH, baseline ICH risk—and lecanemab effect on CDR-SB (Figure). Apixaban alone was preferred for people 75 years and older.Conclusion:The model-based results suggest equipoise between apixaban alone and lecanemab with apixaban for people with cognitive impairment and AF aged 65-74 years. Improving lecanemab efficacy or reducing its effect on ICH could produce a net benefit for this age group. For people 75 and older, apixaban alone would be preferred.

Stroke, Volume 56, Issue Suppl_1, Page AWP400-AWP400, February 1, 2025. SARS-COV-2 causes neurological and cognitive impairments and aggravates Alzheimer’s Disease-Related Dementia (ADRD). Yet, the molecular mechanism is not fully understood. We have previously shown that SARS-CoV-2 spike protein disturbs the brain’s renin-angiotensin system (RAS) and increases cerebrovascular inflammation. We hypothesize that SARS-CoV-2 spike protein will accelerate hypoxia-induced ADRD via augmenting cerebrovascular inflammation and impairing blood-brain-barrier (BBB) functions. We propose that the pharmacological restoration of the RAS balance using Losartan, an AT1receptor blocker, will improve SARS-CoV-2 spike protein-induced ADRD.Methods:Hypoxia-induced ADRD was produced in humanized ACE2 mice, a COVID-19 mouse model, using a permanent unilateral common carotid artery ligation (UCCL). Cerebral hypoxia was confirmed by laser speckle imaging. hACE-2 mice received either vehicle, SARS-CoV-2 spike protein via jugular vein, or spike protein with Losartan (10 mg/kg) in drinking water after UCCL. ADRD was assessed via Novel Object Recognition at baseline, seven days, and fourteen days after surgery. Cerebrovascular inflammatory markers and tight junction proteins (TNF-α, Il-6, VEGF, MMP-9, and occludin) were measured in brain homogenate using RT-PCR and Western Blots.Results:Blood flow analysis confirmed cerebrovascular hypoxia in all groups. Spike protein further decreased cerebral blood flow, which was prevented with Losartan (P