Search Results for: La scansione cerebrale può diagnosticare il morbo di Alzheimer

Objectives
Alzheimer’s disease (AD) poses a significant challenge for individuals aged 65 and older, being the most prevalent form of dementia. Although existing AD risk prediction tools demonstrate high accuracy, their complexity and limited accessibility restrict practical application. This study aimed to develop a convenience, efficient prediction model for AD risk using machine learning techniques.

Design and setting
We conducted a cross-sectional study with participants aged 60 and older from the National Alzheimer’s Coordinating Center. We selected personal characteristics, clinical data and psychosocial factors as baseline predictors for AD (March 2015 to December 2021). The study utilised Random Forest and Extreme Gradient Boosting (XGBoost) algorithms alongside traditional logistic regression for modelling. An oversampling method was applied to balance the data set.

Interventions
This study has no interventions.

Participants
The study included 2379 participants, of whom 507 were diagnosed with AD.

Primary and secondary outcome measures
Including accuracy, precision, recall, F1 score, etc.

Results
11 variables were critical in the training phase, including educational level, depression, insomnia, age, Body Mass Index (BMI), medication count, gender, stenting, systolic blood pressure (sbp), neurosis and rapid eye movement. The XGBoost model exhibited superior performance compared with other models, achieving area under the curve of 0.915, sensitivity of 76.2% and specificity of 92.9%. The most influential predictors were educational level, total medication count, age, sbp and BMI.

Conclusions
The proposed classifier can help guide preclinical screening of AD in the elderly population.

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Stroke, Volume 56, Issue Suppl_1, Page A96-A96, February 1, 2025. Background:White Matter Hyperintensities (WMH) are a radiographic manifestation of cerebral small vessel disease (CSVD), representing myelin and axonal loss. Currently, no drugs specifically target or reduce the burden of WMH. Integrating genomic and proteomic data may identify proteins as potential targets to slow WMH progression. Particularly promising are proteins that serve as pathway-level hubs through which polygenic effects converge.Methods:We analyzed data from 53,014 participants enrolled in the UK Biobank. The analytical pipeline involved (Figure 1): 1) linear regression analyses between a polygenic risk score of WMH (from 27 independent variants) and normalized levels of 2,923 proteins ascertained at baseline, adjusting for age, sex, and genetic principal components; 2) evaluation of proteins selected in step 1 for association with WMH volume, ascertained through dedicated research MRIs; 3) mediation analyses to confirm that proteins with significant and directionally concordant associations with both the polygenic score and WMH are indeed mediators of the polygenic score-WMH relationship; 4) Mendelian Randomization using cis-protein quantitative trait loci as instruments to evaluate the causality between selected proteins and WMH and other clinical manifestation of CSVD. Each step was adjusted for multiple testing using Bonferroni correction.Results:Our analyses identified two proteins (Cathepsin B and ECHDC3) that met all the criteria to mediate the polygenic effect of CSVD on WMH. However, only one of these, Cathepsin B, was confirmed by Mendelian Randomization (Beta: -0.092, SE: 0.003, P

Stroke, Volume 56, Issue Suppl_1, Page AWP178-AWP178, February 1, 2025. Background and Objective:Cerebral amyloid angiopathy (CAA) is a major cause of lobar intracerebral hemorrhage and cognitive dysfunction in the elderly, and frequently coexists with Alzheimer’s disease (AD) and tau pathology. Dual-phase11C-PiB PET can determine amyloid deposition and cerebral perfusion changes, and may have diagnostic value for detecting tau in CAA. This study aimed to assess the diagnostic utility of combining early- and late-phase PiB PET images in predicting tau pathology in CAA.Methods:We prospectively enrolled patients with probable CAA for dynamic PiB and AV1451 scans. Tau positivity was defined as a standardized uptake value ratio (SUVR) > 1.26 in the meta-temporal region on static AV1451 PET. We compared early-stage (0-6 minutes after tracer injection) and late-phase (40-70 minutes) PiB PET between the tau(+) and tau(-) groups. Relationships between PiB PET parameters and tau burden were assessed using a linear regression model. Receiver operating characteristic (ROC) analysis was performed to evaluate the diagnostic value of PET parameters.Results:No significant differences in age, sex, educational years,ApoE2orApoE4carrier status were observed between the CAA/tau(+) vs. CAA/tau(-) groups. As expected, the CAA/tau(+) group had lower MMSE scores (p=0.021) and was associated with a lower hippocampal volume (p=0.036). On PET analysis, CAA/tau(+) was associated with lower early-phase temporal lobe PiB uptake than CAA/tau(-) (SUVR 0.87 [0.81-0.93] vs. 0.92 [0.89-0.98],p=0.014) and higher late-phase PiB uptake in the whole cortex and temporal and parietal lobes (allp

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 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 A15-A15, February 1, 2025. Background:Ischemic stroke (IS) is a multifactorial disease with a significant genetic component contributing about 40% of the risk. Current prevention strategies focus on risk factor control, but integrating genomic and proteomic data could uncover key molecular targets for more effective treatments based on genetic insights.Objective:To utilize a comprehensive multi-omic approach to identify novel drug targets that mediate the genetic risk of IS.Methods:We analyzed genomic and proteomic data from 53,014 UK Biobank participants. Using a polygenic risk score (PRS) for IS from 43 independent risk variants, we deployed four analytical steps (Fig. 1, all steps corrected for multiple testing): (1) linear regression between PRS and 2,923 standardized protein levels measured at baseline, adjusted for age, sex, and genetic principal components; (2) association between selected proteins and IS; (3) Mendelian Randomization to assess causality for the proteins from (1+2), and (4) mediation to quantify the intermediary role of causal proteins in the PRS-stroke relationship. To provide clinical context, we conducted a proof-of-concept analysis using Alzheimer’s disease (AD) given APOE’s established role in AD risk.Results:We found 15 proteins that causally mediate the association between polygenic risk and IS (Fig. 2). The identified proteins are involved in cell adhesion (e.g. CD34, CD48, PODXL), inflammatory pathways (e.g. CD28, CD300A, NCR1), angiogenesis (FGF5, MET), and protein glycosylation (GALNT10, GCNT1), influencing vascular integrity, immune response, and blood vessel formation. Mediated effects range from 1-5% per protein and two proteins served as targets for existing or developing drugs (Tab. 1). As proof-of-concept, we discovered five proteins with significant mediation in AD, the strongest effect seen in APOE (10% mediated effect) and MENT (5%), confirming their known roles in neurodegenerative processes.Conclusion:This multi-omic strategy successfully identified 15 proteins mediating polygenic risk of IS, highlighting crucial pathways such as cell adhesion, inflammation, angiogenesis, and glycosylation. These findings can advance targeted therapies for stroke risk in primary prevention. Our proof-of-concept study illustrates the clinical meaning of the proteins in comparison with the known impact of APOE on AD. Future work should focus on validating these targets in clinical settings and exploring drug repurposing opportunities.