Risultati per: Gestione delle complicanze psichiatriche e cognitive nel Parkinson

Stroke, Volume 56, Issue Suppl_1, Page ATP181-ATP181, February 1, 2025. Introduction:The mechanisms of cognitive dysfunction following ischemic cerebellar stroke (CS) are not well understood. Furthermore, traditional clinical stroke MRI protocols often cannot identify subtle and early changes in normal appearing tissue of the cerebellum. We aimed to implement an advanced MRI protocol in subacute CS patients to better understand outcomes.Hypothesis:The MRI markers for tissue microstructure and cerebrovascular function (CVF) in the cerebellum will provide mechanistic insight into post-stroke cognitive dysfunction.Methods:After 4 weeks of stroke onset, 13 first-time subacute mildly-impaired ischemic stroke participants (PPT) were imaged on a 3T Siemens Prisma MRI scanner with an advanced multi-shell diffusion-weighted protocol to map of Non-Gaussian Diffusion (NGD) and a multi-echo resting-state functional protocol with a breath-hold task (rs+BH-fMRI) to map CVF. PPT demographics: 62.6(11.44) years, sex (11 males), race (1 Latino, 2 Asian, 4 black, 6 white), NIHSS median = 1 (IQR 0-3), Montreal Cognitive Assessment (MoCA) median = 25 (IQR 21-28). 3 PPTs were diagnosed with right cerebellar stroke (CS), and 10 PPTs were diagnosed with non-cerebellar subcortical stroke (NCS). Statistical analyses were performed to: 1) identify the group differences between the CS PPTs versus the NCS PPTs for both NGD and rs+BH-fMRI metrics in the normal appearing white and gray matter of the infarcted cerebellum, and 2) for all PPTs, correlate the NGD metrics in the left ‘unaffected’ cerebellum white matter versus MoCA score.Results:Fig. 1 shows the group comparison for significantly increased NGD (p

Stroke, Volume 56, Issue Suppl_1, Page AWMP41-AWMP41, February 1, 2025. Introduction:Post-stroke cognitive decline (PSCD) is a common complication of strokes, and early assessment is crucial. However, outpatient cognitive assessment protocols are inconsistent, leading to missed diagnoses of PSCD. A potential solution is the XpressO application, introduced in 2023 by the creators of the Montreal Cognitive Assessment (MoCA). Because XpressO is self-paced, it can be completed by patients while waiting for an appointment and hence can assess cognition without impacting clinic workflow.Hypothesis:This study aims to investigate the feasibility of using the XpressO online self-administered cognitive assessment and compare its ability to detect PSCD with the MoCA short form (MoCA-sf) at our out-patient stroke clinic.Methods:Patients at the clinic with a history of ischemic or hemorrhagic strokes were included. We used

Stroke, Volume 56, Issue Suppl_1, Page AWP44-AWP44, February 1, 2025. Background:Patent foramen ovale (PFO) is an independent risk factor for neurovascular injury such as stroke. We previously found that large PFO shunt is associated with increased long-term risk of vascular dementia. However, the mechanism underlying this association remains poorly understood. Our previous research revealed that PFO shunt enables the accumulation of homocysteine in circulation (Deng, Neurology 2021). It is thus possible that homocysteine may mediate the effect of PFO shunt on cognitive decline. This study aims to explore the relationship among PFO shunt, total homocysteine (tHcy) levels and the risk of vascular cognitive impairment and dementia (VCID).Method:A total of 1282 PFO patients were prospectively recruited and followed for over 11 years post their PFO closure in accordance with IRB protocol. All the patients were cognitively normal at the time of PFO diagnosis. Residual shunt post PFO closure was assessed using transthoracic echocardiogram (TTE) with saline contrast. Cognitive function was evaluated using Montreal Cognitive Assessment (MoCA). tHcy levels in peripheral venous blood was measured using mass spectrometry.ResultAmong the patients, 67 (5.2%) developed VCID as measured by MoCA < 26 and NINDS AIREN criteria. The risk of VCID was significantly high in patients with residual shunt, particularly those with large shunt size (no shunt: 5.0%; small shunt: 6.4%; large shunt: 11.5%), suggesting a dose effect of PFO shunt (OR: 1.53; 95% CI: 1.09 ~ 2.16; p = 0.014) (Figure 1A, Table 1). Moreover, residual PFO shunt also contributed to tHcy elevation in circulation (β: 0.44; 95% CI: 0.19 ~ 0.69; p < 0.001) (Figure 1B, Table 1), and high tHcy levels were linked to increased risk of VCID (OR: 1.87; 95% CI: 1.14 ~ 3.07; p = 0.013) (Figure 1C, Table 1). Further mediation analyses revealed a significant indirect effect of PFO shunt on VCID through tHcy (OR: 1.29; 95% CI: 1.01 ~ 1.66; p = 0.047) (Figure 1D, Table 1). tHcy mediated 40% (95% CI: 6% ~ 74%; p = 0.021) of the total association between PFO shunt and VCID risk (Figure 1D, Table 1). These findings remained robust after adjusting for other VCID risk factors, such as age, diabetes, hyperlipidemia and hypertension (Table 1).Conclusion:Our study suggested that that PFO shunt may contribute to the development of VCID by promoting circulatory tHcy elevation. Further mechanistic investigation of neurovascular injury and cognitive decline associated with PFO shunt is ongoing.

Stroke, Volume 56, Issue Suppl_1, Page AWP310-AWP310, February 1, 2025. Background:Vascular risk factors, particularly in midlife, are associated with an increased risk of dementia, and smoking has been inversely associated with Parkinson’s disease (PD) risk, but the role of these factors in PD-dementia (PDD) is less clear. This study explores whether midlife vascular risk factors are associated with risk of PDD in the community-based ARIC cohort.Methods:ARIC participants were evaluated for vascular risk factors (hypertension, diabetes, hypercholesterolemia, smoking, and obesity) in 1987-1989 (ages 44-64) and followed through 2016. PD cases were identified using participant medications, self-reported physician diagnosis, hospitalization and death surveillance, and PD diagnostic data provided by participants and physicians. Dementia was defined by in-person and phone-based cognitive assessment, informant interviews, and hospitalization codes. PDD was defined as having both a PD and dementia diagnosis, with the PD diagnosis occurring first. We excluded participants with missing covariates, on neuroleptic medications, or with PD or dementia at baseline. Adjusted Cox proportional hazards models examined the associations between midlife vascular risk factors (combined in one model) and incident PDD, PD/no dementia, and dementia/no PD, vs no PD/no dementia. We explored effect modification by race.Results:Of 13,875 participants (25% Black, 54% female), 179 developed PD at a mean age of 73.4 yo, 94 devleoped PDD at a mean age of 79.2 yo, and 1,791 developed dementia/no PD at a mean age of 79.7 yo. Midlife current smoking (HR 0.41, 95% CI 0.18-0.95, Figure) was signficantly associated with a lower risk of PDD; other vascular risk factors had nonsignficiant associations. Older age, APOEe4, male sex, and low education were significantly assoiated with an increased risk of PDD. Smoking, diabetes, hypertension, obesity, Black race, age, low education, male sex, and APOEe4 were associated with an increased risk of dementia/no PD. There was effect modification by race for smoking and obesity, which were significant risk factors for dementia/no PD in White but not Black participants (Table).Conclusions:Smoking in midlife was significantly associated with a lower rate of PDD vs no PD/no dementia. Other vascular risk factors were not associated with PDD, but demographic associations were similar to dementia. Future studies should evaluate these vascular risk factors over the life course and the mechanisms underlying 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 AWP45-AWP45, February 1, 2025. Introduction:Perivascular Spaces (PVS) visible on brain MRI are fluid-filled compartments surrounding cerebral blood vessels. They are key indicators of cerebral small vessel disease (CSVD) and are associated with mild cognitive impairment (MCI) and dementia. This study aims to measure the effect of PVS location and severity on cognitive performance in adults from a community-based population.Methods:Framingham Heart Study participants from all cohorts with available MRI scans and neuropsychological (NP) test data within one year of each other were included in a cross-sectional analysis. PVS burden in the basal ganglia (BG) and centrum semiovale (CSO) was categorized into grades I-IV based on PVS counts. PVS burden was further dichotomized into high burden (Grades III&IV) vs low (Grades I&II). NP tests included were the Boston Naming Test (BNT30), Hooper Visual Organization Test (HVOT), Visual Reproduction-Delayed (VRD), Logical Memory-Delayed (LMD), and Trials B (TRB). Multiple linear regression models tested associations between PVS burden and each NP test, adjusting for age, sex, smoking, diabetes, hypertension, and education.Results:Among 3777 participants (mean age 60.6 ± 14.5, 46.4% male, 49% college educated, 17.5% CSO high burden, 9.8% BG high burden), we observed a general trend toward an inverse relationship between PVS burden and cognitive performance, although this trend was not significant in every model. Subjects with either high CSO or BG burden had slower completion time on TRB (β estimate 0.135, 95% Confidence Interval (CI): [0.036, 0.234], p-value: 0.008, and β: 0.346, 95% CI: [0.218, 0.475], p:

Stroke, Volume 56, Issue Suppl_1, Page AWMP15-AWMP15, February 1, 2025. Introduction:Stroke can contribute to age-related cognitive decline, directly affecting the quality of life and post-stroke functioning. While cognitive impairment is usually associated with chronological age, the association between biological/electrocardiographic age (ECG-age) and cognition is unclear. We used a machine learning model to predict the ECG-age of participants directly from their ECG waveform data in the UK Biobank. We determined the association between participants’ ECG-age and their scores on various digital cognitive tests.Methods:In the UK Biobank, about 500,000 participants aged between 40 and 69 were recruited from across the United Kingdom. Electrocardiogram data was collected using a 12-lead ECG at rest. Deep neural network (DNN) was used to predict the ECG-age of participants from their raw ECG waveform data. In our main analysis, participants with available ECG data and cognitive test scores were selected (n=63800). Δage was defined as the difference between ECG-age and reported age. We used a multivariable linear regression model to evaluate the association between Δage and digital cognitive tests adjusted for reported age, sex, and education. Additionally, we defined aging according to these 3 categories: decelerated aging: participants with Δage below -5, normal aging: participants with an absolute value of Δage below mean absolute error, and accelerated aging: participants with Δage above 5.Results:Compared to the normal aging group, the accelerated aging group (Δage >5) showed a significant decline in cognitive performance, whereas the decelerated aging group (Δage

Stroke, Volume 56, Issue Suppl_1, Page AWP119-AWP119, February 1, 2025. Background:Given the growing number of stroke survivors in the US, especially among women, understanding contemporary sex-specific trajectories of outcomes after stroke is crucial. Yet, such data are rare. We estimated sex-specific functional, neurological, cognitive, and quality of life outcomes at 3, 6, and 12 months post-stroke in a population-based study.Methods:First-ever ischemic strokes (IS) were ascertained between January 1, 2014 and December 31, 2019 from the Brain Attack Surveillance in Corpus Christi (BASIC) Project in South Texas. Data were collected from medical records and patient or proxy interviews (baseline, 3, 6, and 12 months after stroke). Sex-specific trajectories in functional (activities of daily living/instrumental activities of daily living score, ADL/IADL), neurological (National Institutes of Health Stroke Scale, NIHSS), cognitive (Modified Mini-Mental State Examination), and quality of life (QOL) outcomes (12-domain Stroke-specific Quality of Life scale) were estimated using multivariable-adjusted linear mixed effect models accounting for within-subject correlations. Interactions between sex and time were included to examine sex differences at each time point.Results:Among the 1,440 IS (median age 68, 48.4% women), women had significantly worse functional outcomes (0.11 points higher in ADL/IADL score) but better neurological outcomes (0.33 points lower in NIHSS score) than men at 3 months (Table 1). There were no sex differences in quality of life and cognitive outcomes. Throughout the one year following stroke, functional and neurological outcomes among both sexes improved, primarily driven by the improvement between 3 to 6 months, with small changes in the outcomes on the absolute scale (Table 2). Improvement in quality of life was only seen among women between 3 to 6 months, while worsening of cognitive outcome between 6 to 12 months was seen among both sexes. There were no significant sex differences for all outcomes at 6 or 12 months and no significant interactions between sex and time.Conclusions:Functional and neurological outcomes were at their worst at 3 months after stroke for both sexes and sex differences were small throughout the one-year poststroke, suggesting early assessment and intervention to improve these outcomes in both sex groups. The considerable worsening of cognition after 6 months post-stroke in both sexes suggests that longer-term monitoring of cognitive outcome may be needed.

Stroke, Volume 56, Issue Suppl_1, Page AWP115-AWP115, February 1, 2025. Background:Cognitive factors influence motor performance, but often this is not considered when testing motor function. Here we examined this issue using 3 versions of the Box and Blocks Test (BBT), a measure of arm motor function. First, we developed 2 new, briefer versions of BBT and then tested their validity. Second, we hypothesized that cognitive factors would be more strongly related to versions of the BBT that require a longer period of testing.Methods:In 71 patients

Stroke, Volume 56, Issue Suppl_1, Page AWP377-AWP377, February 1, 2025. Background and Purpose:Aged patients experience more cognitive dysfunction than young patients after stroke. Brain astrocytes and microglia causes excessive removal of synapses at the early stage of stroke. Inhibition of their phagocytosis improved neurobehavioral outcomes. Long-term post-stroke cognitive dysfunction in aged subjects may be associated with increased synapse pruning by astrocytes, as increased reactive astrocytes are present in and around the atrophic region.Hypothesis:Excessive synapse pruning by reactive astrocytes contributes to the long-lasting post-stroke memory dysfunction in aged mice.Methods:pMCAO was induced in young (2-month-old) and aged (15-18-month-old) mice. Memory performance was tested weekly for 8 weeks by Y-maze, and at 8 weeks post-stroke by novel objective recognition (NOR) tests. Brains were collected 8 weeks after pMCAO. Gene expressions were analyzed by RNAseq and western blot. Atrophic volume, CD68+cells, GFAP+cells, and synaptophysin (SYP) were analyzed histologically.Results:In Y-maze test, aged stroke mice made fewer spontaneous alternations from 3 to 8 weeks after pMCAO than young stroke and sham operated aged mice. In NOR test, aged stroke mice spent shorter time on the novel objects than young stroke and sham aged mice. RNAseq data showed up-regulation of inflammation, and down-regulation of axon growth and synaptic transmission pathways in the aged ipsilateral than young ipsilateral cortex and aged contralateral cortex. Glutamatergic and cholinergic synapses were decreased in aged ipsilateral cortex and hippocampus. GABAergic presynapse protein was increased in the aged ipsilateral hippocampus compared to the young mice. All support reduced activity in the cortex and hippocampus of aged stroke mice. Aged mice showed larger atrophic volumes, more CD68+and GFAP+cells in the peri-atrophic and hippocampi regions than young mice. About 10-fold more GFAP+cells were detected in aged peri-atrophic and ipsilateral hippocampi regions than CD68+cells; 57% GFAP+and 37% CD68+cells were SYP+in the ipsilateral hippocampi, 53% GFAP+and 39% CD68+cells were SYP+in the peri atrophic region of aged stroke brain, indicating that reactive astrocytes contributed more than microglia on synapse pruning in aged mice.Conclusions:Reactive astrocytes contribute more than microglia to synapse pruning at the chronic stage of stroke, which is involved in long-lasting post-stroke memory dysfunction in the aged mice.

Stroke, Volume 56, Issue Suppl_1, Page AWP383-AWP383, February 1, 2025. Background and purpose:Vascular dementia (VaD) is one of the most common causes of cognitive decline, primarily resulting from cerebrovascular damage. Central to the pathogenesis of VaD are cerebrovascular endothelial cell (CEC) dysfunction, blood-brain barrier (BBB) disruption, and neuroinflammation. CD38, an enzyme involved in neuroinflammation and cellular senescence, has recently been implicated in these processes. However, its specific role in CEC dysfunction within the context of VaD remains poorly understood. We hypothesize that CD38 contributes to CEC dysfunction, BBB disruption, and cognitive decline in VaD, and that inhibiting CD38 could mitigate these pathological effects and improve cognitive outcomes.Method:We used a mouse model of VaD induced by bilateral carotid artery stenosis (BCAS). Mice were treated with the selective CD38 inhibitor 78c (10 mg/kg, twice daily for 1 month) to assess its therapeutic potential. CBF, BBB permeability, and cognitive function were evaluated. The expression of CD38, pro-inflammatory cytokines (IL-1β, IL-6, TNF-α), and CEC tight junction proteins were analyzed. In vitro experiments were conducted using CECs to investigate the effects of 78c on TNF-α-induced CD38 expression and inflammatory responses, focusing on the NOX4/eNOS signaling pathway.Result:Our results demonstrated that BCAS significantly reduced CBF, increased BBB permeability, and induced cognitive deficits, all of which were accompanied by elevated CD38 expression in CECs and heightened levels of pro-inflammatory cytokines. Treatment with the CD38 inhibitor 78c effectively mitigated these effects, resulting in reduced white matter damage, improved CBF, enhanced expression of CEC tight junction proteins, and decreased neuroinflammation and BBB disruption. In vitro studies further revealed that 78c attenuates TNF-α-induced CD38 expression and inflammatory responses in CECs, likely via the NOX4/eNOS signaling pathway.Conclusion:This study identifies CD38 as a crucial mediator of CEC dysfunction in VaD, linking chronic cerebral hypoperfusion to neurovascular damage. Targeting CD38 with the selective inhibitor 78c presents a promising therapeutic strategy for restoring vascular integrity and alleviating cognitive impairment in VaD. These findings not only highlight a novel molecular mechanism underlying VaD progression but also open new avenues for the development of targeted treatments for this debilitating condition.

Stroke, Volume 56, Issue Suppl_1, Page AWMP97-AWMP97, February 1, 2025. Background:The advancement of age is associated with an increased incidence of both cerebral small vessel disease (CSVD) and sleep disorders, which are recognized as risk factors for cognitive decline. Recent studies suggest that the glymphatic system may play an important role in these relationships.Methods:In this cross-sectional and longitudinal study, participants from Shanghai Aging Study underwent multi-modal MRI, Pittsburgh Sleep Quality Index (PSQI) and neuropsychological assessment. Diffusion tensor image analysis along the perivascular space (DTI-ALPS) index was employed to evaluate the function of glymphatic system. Spearman correlation and partial correlation analyses were used to explore the relationships between CSVD burden/sleep disorders, glymphatic dysfunction, and cognition. Furthermore, mediation analysis was conducted to investigate the potential mediating effects of DTI-ALPS in the association between CSVD/PSQI and cognition. We further examined the interaction effects between CSVD burden and sleep disorders on cognitive outcomes.Results:258 participants were included in this study (average age, 68.5 years), among which 133 participants were followed up after a 7-year interval. At baseline, DTI-ALPS was significantly correlated with PSQI (r = -0.174, p = 0.005) and various imaging biomarkers of CSVD after adjusting for age, gender, vascular risk factors, and ApoE4. Additionally, DTI-ALPS was significantly correlated with executive function (r = -0.237, p < 0.001), memory (r = 0.146, p = 0.02), and visuospatial ability (r = 0.154, p = 0.014). Mediation analysis indicated that DTI-ALPS simultaneously mediated the association between CSVD burden/sleep disorders and cognitive decline, with a complete mediation effect of 19.22% between CSVD burden and executive function, 13.03% between PSQI and memory. Interaction analysis showed that the impacts of sleep disorders on general cognitive function and executive function were more significant among older adults at high risk of CSVD. Longitudinally, classic imaging biomarkers of CSVD as well as DTI-ALPS were significantly related to long-term changes in cognition.Conclusion:The study reveals that glymphatic dysfunction serves as a link to closely connect sleep disorders/CSVD with cognitive decline in community-dwelling older adults. Moreover, the interaction effect between two risk factors emphasizes the importance of individualized sleep management in the elderly at high risk of CSVD.

Stroke, Volume 56, Issue Suppl_1, Page ATP284-ATP284, February 1, 2025. Enrichment is the prospective use of any patient characteristic to select a study population at higher risk in which detection of a drug effect is more likely than it would be in an unselected population. Patients with post-stroke cognitive impairment (PSCI) found to have higher risk of stroke recurrence in a recently completed meta-analysis. The goal of this study is to test whether PSCI based patient selection may represent enrichment strategy for secondary stroke prevention clinical trial. This is a subgroup analysis of Insulin Resistance Intervention after Stroke (IRIS) trial. In IRIS trial, patients were randomized to receive pioglitazone vs. placebo and had a baseline Modified Mini-Mental State Examination (3MS, where 3MS ≤ 88 was indicative of global PSCI. The primary endpoint of the study was recurrent stroke or MI. We estimated the hazard ratio (HR) for the effect of pioglitazone among those with global PSCI. To determine the sample size for a subsequent trial enriched by including only subjects with global PSCI, we make the following assumptions: (1) time to event follows an exponential distribution in both the pioglizone and placebo groups where the hazard rate for the placebo group is assumed to be the same as in the IRIS trial among those with global PSCI; (2) hazards for the pioglitizon and placebo groups are proportional over the course of the study; and (3) subjects are randomized to pioglitazone or placebo in equal proportions.Data on n = 3,338 patients of original cohort of n = 3,876 were analyzed, and n = 473 among them had PSCI at baseline. During 5-years of follow-up, n=246 patients experienced recurrent stroke, and n = 118 had MI. In patients with PSCI HR was 0.56 (95% CI 0.34 – 0.92) suggesting a 44% reduction in the hazard rate for secondary stroke or MI after 5 years of follow-up in the pioglitizone group compared to the placebo. If we conservatively assume that the true HR = 0.56 (closer to the null of HR = 1 than what was observed in the IRIS trial), then a total sample size of n= 967 willl proivde 90% power using a two-sided log-rank test at the 5% significance level. This conservative sample size corresponds to a 75% reduction in the sample size that was required for the IRIS Trial. PSCI screening may represent enrichment strategy for secondary stroke prevention clinical trial potentially reducing sample size by 75%. PSCI screening-based enrichment can be tested in phase 2 secondary stroke prevention trial.

Stroke, Volume 56, Issue Suppl_1, Page ADP14-ADP14, February 1, 2025. Background:PCSK9, a key regulator of cholesterol metabolism, has been implicated in atherosclerosis. However, its potential role in vascular cognitive impairment and dementia (VCID) remains elusive. We hypothesized that PCSK9 overexpression, exacerbated by a high-fat diet (HFD), would promote neurovascular inflammation and recapitulate VCID pathology.Methods:C57 mice were stratified into control, PCSK9 overexpression, HFD, and PCSK9+HFD groups. PCSK9 overexpression was induced via AAV injection, and mice were subjected to either a normal diet or HFD for 4 months. Laser speckle contrast imaging was employed to assess CBF response to whisker stimulation. Immunofluorescence analyses were conducted to evaluate neurovascular alterations, encompassing microvascular density, glial activation, neuronal density, arteriosclerosis, and blood-brain barrier integrity. Light sheet microscopy was utilized to provide ultra-high resolution 3D imaging of the cerebrovascular architecture. Cognitive function and exploratory behavior were investigated using novel object recognition and open field tests.Results:PCSK9+HFD mice exhibited significantly compromised neurovascular coupling, as evidenced by attenuated CBF response to whisker stimulation. Immunofluorescence revealed profound neurovascular alterations, including markedly reduced microvascular density, exacerbated astrogliosis and microglial activation, diminished neuronal density, heightened arteriosclerosis and inflammation, and severe blood-brain barrier disruption. These changes were most pronounced in the PCSK9+HFD group, followed by the HFD and PCSK9 groups, highlighting the synergistic detrimental effects of PCSK9 overexpression and HFD. Notably, light sheet fluorescence microscopy (LSFM) unveiled a dramatically sparser and less complex 3D cerebrovascular network in PCSK9+HFD mice. Moreover, PCSK9+HFD mice displayed the most severe neurocognitive changes, as shown by impaired recognition memory and reduced exploration.Conclusions:This study demonstrates that metabolic syndrome induced by PCSK9 overexpression and HFD synergistically converge upon neuroinflammatory mediators to recapitulate VCID pathology. Microglial and astrocytic activation in PCSK9 overexpression and HFD is strongly associated with altered cerebral blood flow regulation. Our findings provide a preclinical platform for discovery of new therapeutic approaches for neuroinflammatory and cerebrovascular alterations associated with VCID pathology.

Stroke, Volume 56, Issue Suppl_1, Page A111-A111, February 1, 2025. Background:Neutrophil infiltration plays a pivotal role in exacerbating brain injury following subarachnoid hemorrhage (SAH). Integrin α9, highly expressed on activated neutrophils, facilitates their adhesion and transendothelial migration. Once infiltrated, neutrophils aggravate inflammatory response and can impair microglial efferocytosis. Defective efferocytosis may results in accumulation of apoptotic cells, persistent inflammation, and resultant poor recovery following SAH. Despite the known role of integrin α9 in promoting cerebral inflammation, the impact neutrophil integrin α9 on microglial efferocytosis and subsequent SAH outcomes remains unknown.Hypothesis:Integrin α9 dependent neutrophil transendothelial migration impedes microglial efferocytosis, promotes cerebral inflammation, and mediates poor SAH recovery.Methods:Neutrophil specific integrin α9 knockout mice (α9fl/flMrp8Cre+/-) and littermate controls (α9fl/flMrp8Cre-/-) were subjected to the endovascular perforation model to induce SAH. Sensorimotor tests (modified neurological severity score, corner, and cylinder test) and cognitive function tests (Y-maze and novel object recognition test) were performed up to 4-weeks. Neutrophil infiltration, inflammation, apoptosis, and blood brain barrier (BBB) disruption were quantified 24-hr post-SAH. In vitro and in vivo functional assays were carried out to assess the neutrophil integrin α9-dependent effects on microglial efferocytosis.Results:Mice with SAH exhibited increased integrin α9 levels on infiltrated neutrophils as compared to mice with sham-surgery.α9fl/flMrp8Cre+/-mice showed improved sensorimotor and cognitive recovery (up to 4-weeks) (Fig 1), reduced neutrophil infiltration, BBB damage, neuronal apoptosis as compared to controls.α9fl/flMrp8Cre+/-mice exhibited reduced brain neutrophil elastase levels along with enhanced microglial efferocytosis of apoptotic neurons. In vitro mechanistic studies revealed that reduced transendothelial migration ofα9-/-neutrophils directly contributed to the enhanced microglial efferocytosis of apoptotic neurons (Fig 2). Pharmacological targeting of integrin α9 with macitentan significantly improved SAH outcomes, reduced neutrophil infiltration, BBB damage, neuronal apoptosis, and showed enhanced microglial efferocytosis (Fig 3).Conclusions:Our study uncovered a previously unrecognized role of neutrophil integrin α9 in microglial efferocytosis and post-SAH sensorimotor and cognitive recovery.

Stroke, Volume 56, Issue Suppl_1, Page ADP11-ADP11, February 1, 2025. Introduction:We examined whether prestroke cardiovascular risk is associated with faster cognitive decline and higher dementia risk after stroke independent of prestroke cognition.Methods:We included 1,808 dementia-free individuals with incident stroke (91% ischemic, 7% hemorrhagic, 2% other; 52% women, 38% Black, median age 75) from 4 cohorts (1971-2019): Atherosclerosis Risk In Communities Study, Cardiovascular Health Study, Framingham Offspring Study, and REasons for Geographic And Racial Differences in Stroke. We assessed prestroke atherosclerotic cardiovascular disease (ASCVD) risk with the American Heart Association’s Predicting Risk of cardiovascular disease EVENTs (PREVENT) 10-year ASCVD risk score, which has age and sex as risk factors. Outcomes were global cognition (primary), executive function, memory, and dementia. Linear mixed-effects and Cox regression models examined continuous and categorical (quintiles) 10-year ASCVD risk scores and adjusted for mean prestroke cognition, race, education, and cohort. Median (IQR) follow-up was 4.4 (2.0, 7.9) years for global cognition and 5.1 (2.4, 8.8) for dementia. Dementia cases totaled 142 at 5 years and 182 at 10 years.Results:Median (IQR) 10-year prestroke ASCVD risk was 14.0% (9.9%, 18.5%). Higher prestroke 10-year ASCVD risk was associated with lower adjusted initial poststroke global cognition, memory, and executive function (changes to intercept, Table 1). The quintile analysis showed a dose-response relationship between higher prestroke ASCVD risk and lower initial poststroke cognition scores (changes to intercept, Table 1). The overall stroke survivor group had unadjusted mean declines of -0.59 points/year (95%CI, -0.66 to -0.52 points/year; P