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

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Stroke, Ahead of Print. As awareness of dementia increases, more individuals with minor cognitive complaints are requesting clinical assessment. Neuroimaging studies frequently identify incidental white matter hyperintensities, raising patient concerns about their brain health and future risk for dementia. Moreover, current US demographics indicate that ≈50% of these individuals will be from diverse backgrounds by 2060. Racial and ethnic minority populations bear a disproportionate burden of vascular risk factors magnifying dementia risk. Despite established associations between white matter hyperintensities and cognitive impairment, including dementia, no study has comprehensively and prospectively examined the impact of individual and combined magnetic resonance imaging measures of white matter injury, their risk factors, and comorbidities on cognitive performance among a diverse, nondemented, stroke-free population with cognitive complaints over an extended period of observation. The Diverse VCID (Diverse Vascular Cognitive Impairment and Dementia) study is designed to fill this knowledge gap through 3 assessments of clinical, behavioral, and risk factors; neurocognitive and magnetic resonance imaging measures; fluid biomarkers of Alzheimer disease, vascular inflammation, angiogenesis, and endothelial dysfunction; and measures of genetic risk collected prospectively over a minimum of 3 years in a cohort of 2250 individuals evenly distributed among Americans of Black/African, Latino/Hispanic, and non-Hispanic White backgrounds. The goal of this study is to investigate the basic mechanisms of small vessel cerebrovascular injury, emphasizing clinically relevant assessment tools and developing a risk score that will accurately identify at-risk individuals for possible treatment or clinical therapeutic trials, particularly individuals of diverse backgrounds where vascular risk factors and disease are more prevalent.

Neurologi: ‘si apre una nuova storia per i pazienti’

Circulation, Volume 150, Issue Suppl_1, Page A4147625-A4147625, November 12, 2024. Background:Cardiometabolic syndrome (CMS) poses a significant public health concern. The study aimed to investigate the predictive value of age and CMS for incident Alzheimer’s disease (AD) in women aged≥50.Methods:A cohort of women aged 50-79 (n= 63,117) who participated in the Women’s Health Initiative Observational Study (WHIOS) in 1993-1998, without baseline AD and followed through to March 1, 2019, were analyzed. CMS was defined as having ≥3 of five CMS components: large waist circumference, HBP, elevated triglycerides, elevated glucose, and low HDL-cholesterol. AD was classified by physician-diagnoses of incident AD. Hazards ratios (HR) of AD risk associated with CMS by age were analyzed using Cox’s proportional hazards regression analysis. Machine learning (ML)-XGBoost and Lasso Cox models clustered individuals with low, mild, moderate, and severe risk of incident AD.Results:During a median follow-up of 20 years (range: 3.36 to 23.36 years), 8340 developed incident AD. The incident rate (95%CI) of AD was 8.6 (8.1-9.1) per 1000 person-years (PY) in women with CMS, and 7.0 (6.9-7.2) per 1000 PY in those without CMS (p

Circulation, Volume 150, Issue Suppl_1, Page A4122290-A4122290, November 12, 2024. Background:Sodium-glucose cotransporter 2 inhibitors (SGLT2i) have demonstrated to reduce the risk of hospitalizations from heart failure and cardiovascular mortality. However, SGLT2i therapy’s potential effects on the risks of dementia and Parkinson’s disease are not well established, with conflicting results based on observational studies.Objective:We sought to evaluate the association between SGLT2i and the risk of dementia and Parkinson’s disease in patients with type 2 diabetes mellitus (T2DM), heart failure, or chronic kidney disease.Methods:We performed a systematic literature search on PubMed, Scopus, and Clinicaltrial.gov for relevant randomized controlled trials (RCTs) from inception until March 2024 without any language restrictions. Odds ratios (OR) and 95% confidence intervals (CI) were pooled using a random-effect model.Results:A total of 12 RCTs with 74, 442 patients (40784 in the SGLT2i group and 33658 in the control group) were included in the analysis. The mean age of patients in SGLT2i and control was 65.3 and 65.2 years respectively. The mean follow-up duration was 2.9 years. Pooled analysis showed that there is no significant association between SGLT2i and the risk of dementia (OR, 1.37 (95%CI: 0.70-2.69),P=0.36, I2=0%), dementia Alzheimer’s type (OR, 2.62 (95%CI: 0.47-14.49),P=0.27, I2=0), vascular dementia (OR, O.52 (95%CI: 0.09-2.98),P=0.46, I2=0%), and Parkinson’s disease (OR, 0.75 (95%CI: 0.25-2.25),P=0.61, I2=0%) was comparable between SGLT2i and control groups.Conclusion:Our study suggest that there is no significant association between SGLT2i and the risk of dementia, its subtypes, and Parkinson’s disease. Further large-power randomized trials are needed to strengthen the understanding of neuropsychiatric beneficial effects of SGLT2i.

Circulation, Volume 150, Issue Suppl_1, Page A4124039-A4124039, November 12, 2024. Background:Age is the most important risk factor for coronary artery disease (CAD), independent of traditional risk factors such as hypertension, diabetes (DM), hyperlipidemia and smoking, through poorly understood mechanisms. Medin, a cleavage product of MFGE8 protein that forms the most common human amyloid, accumulates in the vasculature with age, including the coronary arteries. Although medin amyloid has been implicated in various diseases such as Alzheimer’s disease, vascular dementia and aortic aneurysms, its role in CAD remains unknown. Medin was shown to induce changes characteristic of vascular aging, such as endothelial and smooth muscle dysfunction in human donor cerebral arteries. Medin also induced proinflammatory activation of human brain microvascular endothelial cells through NFκB activation .Aims:To determine the effects of medin on pro-inflammatory and prothrombotic activation of human coronary artery endothelial cells (HCAECs).Methods:Primary HCAECs (passages 6-8) were exposed for 20 hours to physiologic doses of recombinant medin (0.5, 1 and 5 µM) and gene expression of pro-inflammatory proteins (IL-6, IL-8, IL-1b and intercellular adhesion molecule (ICAM)-1), prothrombotic protein (plasminogen activator inhibitor (PAI)-1) and anticoagulant membrane protein thrombomodulin were quantified using rtPCR and compared. Separately, HCAECs were exposed to medin (0.5, 1 and 5 µM) with or without small molecule specific inhibitor of NFκB (RO106-9920, 10 uM) for 20 hours and protein expression of IL-6 in conditioned media was measured using ELISA.Results:Medin caused dose-dependent increases in gene expressions of pro-inflammatory cytokines IL-6, IL-8, IL-1b, ICAM-1 (Figure 1 A-D). Medin caused a dose-dependent increase in PAI-1 and a dose-dependent decrease in thrombomodulin (Fig. 1 E-F). Co-treatment with RO106-9920 prevented medin-induced increase in IL-6 protein expression (Fig. 1G).Conclusions:Medin induces pro-inflammatory and prothrombotic activation of human coronary artery endothelial cells. The proinflammatory activation is likely NFκB-dependent. Medin is a promising potential novel mediator of CAD and vascular aging.

Circulation, Volume 150, Issue Suppl_1, Page A4144467-A4144467, November 12, 2024. Previous studies have linked plasma levels of high-density lipoprotein cholesterol (HDL-C) with impaired cognitive function. However, few studies have investigated the associations between plasma HDL functionality and brain structure and function. Thus, our study aimed to elucidate the associations between plasma HDL measures and brain structure/function in a multiethnic cohort of middle-aged adults.Accordingly, we conducted a cross-sectional study in 1,826 adults (mean age 51.0±9.7 years, 58% female, 47% Black adults) without preexisting cardiovascular disease or stroke who participated in the Dallas Heart Study to determine associations between HDL measures and brain structure/function. Whole brain white matter hyperintensities (WMH) and grey matter volume (GMV) was measured using a 3-T MRI scanner and normalized to total cranial volume (TCV), and the Montreal Cognitive Assessment (MoCA) was used to measure cognition. HDL cholesterol efflux capacity (HDL-CEC) was assessed using fluorescence-labeled cholesterol efflux from J774 macrophages and was expressed in arbitrary units. HDL particle measures were assessed using NMR spectroscopy. Adjusted multivariable linear regression models were performed with standardized beta estimates reported.Higher HDL-CEC and small HDL particles (HDL-P) were positively associated with GMV/TCV after adjustment for relevant risk factors (β=0.078 [95% CI: 0.029, 0.126],Figure, and β=0.063 [95% CI: 0.014, 0.111], respectively, all p0.05). Associations of HDL-CEC and small HDL-P with GMV were not modified by race/ethnicity or ApoE-ε4 status.In conclusion, higher HDL function and small HDL-P were associated with higher GMV after adjustment for traditional risk factors and were not modified by race/ethnicity or ApoE-ε4 carrier status. As such, these findings suggest that better HDL functionality is linked with larger brain GM volume in middle-aged adults. Since GMV loss has been linked to the development of mild cognitive impairment (MCI) and conversion of MCI to Alzheimer’s disease, our study may have implications for prevention of age-related decline in cognitive function.

Circulation, Volume 150, Issue Suppl_1, Page A4144534-A4144534, November 12, 2024. Background:Anxiety, depression, and cognitive changes are common adverse outcomes after acute coronary syndromes (ACS). These challenges also predict increased risk of adverse cardiac outcomes. While it is known that females have higher rates of psychological symptoms generally, data on sex differences in onset following an acute cardiac event are scarce, especially among older adults.Goal:Our goal was to determine if sex differences exist in mental health and cognitive outcomes after acute coronary syndrome in older adults.Hypothesis:Females are more likely to have new psychological and cognitive issues within one year of ACS compared to male patients.Methods:We conducted a retrospective analysis using Texas Medicare claims data from 2017-2020. The study population consisted of those 65 and older, diagnosed with ACS (either STEMI or NSTEMI). Eligible participants had continuous enrollment in Medicare Part A and B for at least one year before and after the index event, were not part of any Health Maintenance Organization, and had no prior diagnosis of the outcomes of interest (anxiety, depression, amnesia, and dementia). Data were extracted on demographic characteristics, clinical variables, and intervention (i.e. PCI/CABG). Descriptive statistics were used to summarize the data.Results:Our study included 56,325 patients (23,911, 42.4% female), 13,078 with STEMI and 43,247 with NSTEMI. In STEMI and NSTEMI patients respectively, the prevalence of onset of the following outcomes was significantly higher among females compared to males: anxiety (14.8% vs. 9.3%; 16.2% vs. 11.3%), depression (11.5% vs. 7.9%; 14.1% vs. 9.9%), and dementia/Alzheimer’s (2.5% vs. 1.7%; 3.5% vs. 2.5%). No differences were observed in amnesia by sex. Differences by sex persisted by treatment type for anxiety and depression (Table). Additionally, rates of new diagnoses were higher across sexes for CABG compared to PCI.Conclusion:Significant sex differences exist in cognitive and mental health outcomes after ACS. Females are more likely to have worse outcomes following ACS as compared to men. Additionally, across sexes, psychological outcomes are worse following CABG as compared to PCI.

Circulation, Volume 150, Issue Suppl_1, Page A4146396-A4146396, November 12, 2024. Introduction/Background:By 2050, the U.S. will see a demographic shift where individuals over 65 outnumber those under 65. This change underscores a rising prevalence of neurodegenerative diseases, particularly Alzheimer’s disease and various vascular dementias. Over the past 20 years, dementia cases have increased by 20% and are expected to triple in the next 30 years due to aging. The cerebral vasculature becomes increasingly stiff and blood-brain barrier molecules degenerate during aging, leading to accumulation of T cells in the aged brain. The role of T cells on neuroinflammation and dementia during aging is a key unanswered question.Research questions/Hypothesis:How does vascular impairment impact immune cells and inflammation in the brain?How does aging impact immune cells and inflammation in the brain?Goals/Aims:To quantify and characterize T cells within the brain during aging and in a model of vascular contributions to cognitive impairment and dementia (VCID).To determine interactions between brain-resident immune cells (glia) and T cells in aging and a model of VCID.Methods/Approach:We isolated T cells and microglia from 3-month old and 21-month old brains in a model of vascular contributions to cognitive impairment and dementia (VCID). We performed single-cell RNA sequencing to identify and characterize peripheral and resident immune cells in the brain in the setting of typical aging and a model of VCID.Results:We identified a substantial increase inGzmk+ expressing effector memory CD8+ T cells in the brains of 21-month-old mice compared to 3-month-old mice. These cells were distinguished by their unique transcriptome, cytokine secretion profiles, and accumulation patterns. We also found a significant shift of microglia from an anti-inflammatory expression pattern toward a pro-inflammatory profile in the VCID group compared to control.Conclusions:We found a significant accumulation of age-associated T cells which may promote dementias. This study highlights the importance of using aged animal models to understand the cellular dynamics of chronic inflammatory diseases and dementias, potentially guiding the development of targeted therapeutic strategies.

Circulation, Volume 150, Issue Suppl_1, Page A4132120-A4132120, November 12, 2024. Epidemiological studies indicate that individuals with Down syndrome (DS) have an increased risk of leukemia and neuronal diseases but a significantly reduced incidence of most solid tumors and advanced vascular dysfunction. This suggests that one or a combination of trisomy genes on human chromosome 21 (HSA21) or murine chromosome 16 (Mmu16) may be responsible for protecting against vasculopathy. Our previous research has shown that theDown syndrome critical region (Dscr)-1gene, located on HSA21 orMmu16, encodes a feedback modulator of calcineurin-NFAT signaling in endothelial cells (ECs). Null mutation or overexpression of Dscr-1 has been found to increase or prevent septic mortality, angiogenesis, liver steatosis, and susceptibility of tumor metastasizing to the lung, respectively, demonstrating its significant role in these processes.In a unique approach, we crossed DS model mice withApoE-null mice and fed them a high-fat diet (HFD) for 12 weeks to survey the effects of DS-related genes on atherosclerosis. The results were striking, with HFD-mediated increased LDL and triglyceride levels inApoE-null mice significantly reduced in the combined DS plusApoE-null mice. This innovative method allowed us to observe a remarkable (~35%) reduction in ApoE-null mediated atheroma formation in the DS model. This finding was also replicated in EC-specific DSCR-1 transgenic (DSCR-1ECTg) mice.Furthermore, to test the effect of HSA21, we have collected DS patient-derived trisomy and disomy iPS cells and executed them for the chromatin conformation capture analysis and thein vitroECs differentiation experiments. DS-derived trisomy iPS cells already changed the whole chromatin structure, typically within the X chromosome. Moreover, the trisomy iPS-derived ECs revealed less proliferation compared to the disomy. RNA-seqs indicated trisomy iPS derived ECs dramatically (21-fold) increasedDSCR-1, but some HSA21 genes, Alzheimer’s relatedAppandBace2, e.g., were inversely reduced the expression.Our comprehensive studies not only shed new light on the mechanisms of atherosclerosis in vascular pathology but also offer potential therapeutic strategies. The discovery of theDscr-1gene on the DS chromosome, which could be a powerful tool in combating lifestyle-related vascular diseases, underscores the significance of our research.

Circulation, Volume 150, Issue Suppl_1, Page A4142250-A4142250, November 12, 2024. Introduction:Circulating progenitor cells (CPC’s) are mononuclear stem cells which originate in the bone marrow, and circulate in the blood, playing a role in promoting vascular regeneration and healing. Previous studies have shown associations between lower levels of CPC’s and increased all-cause mortality, MACE, and atherosclerosis. Additionally, those with cognitive disorders such as Alzheimer’s disease have been shown to have reduced levels of CPC’s, and some association between CPC’s and cognitive decline has been shown. Clinical surrogates for cognitive decline include a lower Montreal Cognitive Assessment (MoCA) score, and an increase in white matter hyperintensities (WMH) on MRI. We hypothesize that reduced circulating EPCs are associated with a lower MoCA score and an increased number of white matter hyperintensities (WMH) on MRI.Methods:In 181 participants (40.3% male, 41.4% Black) with and without mild cognitive impairment, CPCs were enumerated by flow cytometry as CD45medmononuclear cells expressing CD34 and co-expression with either CD133, chemokine CXC motif receptor 4 (CXCR4), or vascular endothelial growth factor receptor-2 (VEGF2R). Participants were followed for four years and underwent neuropsychiatric testing and MRI imaging. MoCA testing was used to evaluate multiple domain cognitive function. Diffusion weighted MRI was used to evaluate for WMH indicating microvascular damage. Linear regression modeling was used to determine the cross-sectional association between CPC’s and both the MoCA score and burden of WMH after adjusting for age, gender, race, body mass index, history of heart failure, and history of chronic kidney disease.Results:Lower levels of CD34/VEGF2R were associated with lower MoCA scores (β=1.31, p=0.025) and more WMH (β= -2109.1, p=0.011) when comparing first and fourth quartile of CPC concentration. Additionally, decreased CD34/133 and CD34/CXCR4 were associated with an increased burden of WMH (β=-3491.1, p=0.029 and β= -2419.8, p=0.012) when first and fourth quartiles were compared.Conclusions:Lower CPC counts of CD34 subsets were associated with worse performance on MoCA and more white matter hyperintensities on MRI, demonstrating that lower endothelial regenerative capacity may lead to decreased cognition and cognitive decline.

Circulation, Volume 150, Issue Suppl_1, Page A4146706-A4146706, November 12, 2024. Background:The endothelium plays a major role in preventing thrombosis. Aging leads to a hypercoagulable state with increased procoagulant factors without accompanying rise in anticoagulant factors, shifting the balance to a prothrombotic profile. This increases the risk for conditions such as stroke or myocardial infarction. The mediator/s of this change remains unknown. Medin is a 50 amino acid cleavage product of MFGE8, accumulates in the vasculature with aging and is the most common human amyloid. Vascular medin burden is increased in vascular dementia, Alzheimer’s disease and aortic aneurysms. Medin was shown to induce endothelial and smooth muscle dysfunction and endothelial pro-inflammatory activation. Its role in aging-associated prothrombotic activation is unknown.Aim:To determine the effect of medin on human brain microvascular endothelial cells (HBMVECs) expression and function of thrombomodulin (a transmembrane glycoprotein that is a major anticoagulant through its interaction with thrombin leading to activation of protein C and S which in turn degrades factors Va and VIIIa) and HBMVEC expression of plasminogen activator inhibitor-1 (PAI-1) and tissue factor (major procoagulant proteins).Methods:Primary HBMVECs (passages 6-8) were exposed for 20 hours to physiologic doses of recombinant human medin (1 or 5 uM) and gene and protein expression of thrombomodulin, PAI-1 and tissue factor were measured using rtPCR or Western blot, respectively. In separate experiments, assessment of thrombomodulin function was determined by exposing HBMVECs for 20 hours to medin, after which human protein C (0.2 uM) and α-thrombin (10 nM) were added for 1 hour and amount of activated protein C in media was measured using ELISA.Results:Physiologic dose of medin (5 uM) given to HBMVECs resulted in reduced gene and protein expression of thrombomodulin (Fig. 1), increased gene and protein expression of PAI-1 (Fig. 2), and modest increased protein, but not gene expression of tissue factor (Fig. 3). Medin exposure also reduced HBMVEC ability to convert protein C to activated protein C in the presence of thrombin.Conclusions:Medin reduced HBMVEC production of anticoagulant protein thrombomodulin and increased protein expression of procoagulant proteins PAI-1 and tissue factor. Medin is a potential novel mediator of aging-associated hypercoagulability and could be a promising target in thrombotic diseases such as stroke.

Circulation, Volume 150, Issue Suppl_1, Page A4136600-A4136600, November 12, 2024. Background:Hypertensive disorders of pregnancy (HDP) are associated with maternal adverse cardiovascular outcomes. However, their association with maternal Dementia and Alzheimer’s disease is not well established with limited and conflicting results to date.Objective:We sought to evaluate the association between HDP and risk of incidence of Dementia, and Alzheimer’s disease.Methods:We performed a systematic review and meta-analysis of available literature that enrolled women with HDP and women without HDP groups. PubMed, Embase and ClinicalTrials.gov were systematically searched from inspection till May 2024 without any language restrictions. Adjusted hazard ratios (aHR) and 95% confidence intervals (CI) were pooled using a random-effect model.Results:A total of 8 studies with 2503538 patients (1,51,905 in women with HDP and 23,51,633 in the women without HDP group) were included. Pooled analysis shows that HDP women were having 37% higher risk of dementia (aHR, 1.37(95%CI: 1.27-1.46), P

Circulation, Volume 150, Issue Suppl_1, Page A4119913-A4119913, November 12, 2024. Background:Medin is one of the most common amyloidogenic proteins and accumulates in the vasculature with aging. Vascular medin accumulation is associated with Alzheimer’s disease, vascular dementia and aortic aneurysms.In vitro, medin has been shown to induce endothelial proinflammatory activation and inex vivohuman cerebral arterial tissue, medin induces both endothelial and smooth muscle dysfunction. The role of medin in vascular smooth muscle (VSMC) activation remains unknown.Aim:The aim of the study is to determine using gene transcription assay whether medin induces VSMC activation and phenotypic transformation.Methods:Human brain vascular smooth muscle cells (HBVSMCs, passages 6-10) were exposed to medin at doses observed in human tissues (0, 0.5, 1 and 5 υM) for 20 hours and reverse transcription polymerase chain reaction (rtPCR) was used to quantify gene expression of proinflammatory factors (interleukin (IL)-6, IL-8, IL-1b) and structural and enzyme proteins associated with VSMC phenotypic transformation (ACTA2, MYH11 and NOX4). In separate experiments, HBVSMCs were exposed to vehicle, medin 5 υM without or with small molecule NFκB inhibitor RO106-9920 (10 υM) or NLGM1 nanoliposome (70% phosphatidylcholine, 25% cholesterol, 5% monosialoganglioside, 100 υg/mL, agent shown to reverse medin-induced endothelial dysfunction and proinflammatory activation).Results:Medin induced a dose-dependent increase in gene expression of IL-6, IL-8 and IL-1b but did not alter gene expression of ACTA2, MYH11 and NOX4 (Fig. 1). Co-treatment of medin with RO106-9920 and NLGM1 showed a trend (not statistically significant) of reduced IL-6 and IL-8 (Fig. 2).Conclusions:Physiologic doses of medin induced pro-inflammatory activation of HBVSMCs but did not affect gene expression of structural proteins (ACTA2 and MYH11) and enzyme (NOX4) involved in VSMC phenotypic transformation. Although the mechanisms behind this effect remains to be explored, results suggest that medin may be an important mediator of aging-associated vascular inflammation.

Circulation, Volume 150, Issue Suppl_1, Page A4144008-A4144008, November 12, 2024. Background:Physical activity and cognitive training can improve cognitive health, including related neurotrophic biomarkers, with potential interactive effects. In older women with cardiovascular disease (CVD) who are at increased risk for poor cognitive health, we evaluated the efficacy ofMindMoves, a 24-week multidomain physical activity and cognitive training intervention, on change in serum biomarkers, including brain-derived neurotrophic factor (BDNF), vascular endothelial growth factor (VEGF), insulin-like growth factor 1 (IGF-1), and growth differentiation factor 15 (GDF-15).Methods:This randomized controlled trial (NCT04556305) with a 2×2 factorial design tested independent and combined efficacies ofMind(tablet-based cognitive training) andMove(lifestyle physical activity) on change in serum biomarkers (BDNF, VEGF, IGF-1, GDF-15). Women (n= 253) aged 65 years and older with CVD were randomized toMind,Move,MindMoves, or usual care. Women completed fasting venipunctures at baseline, 24, 48, and 72 weeks. We conducted multilevel linear growth models adjusting for age, education, and racial and ethnic background. To examine intervention effects on linear change in serum biomarkers over 72 weeks, we included main and interaction effects ofMindandMove.Results:Participants were, on average, 72.4 years old at baseline (range= 65–90), primarily of non-Hispanic White (54%) and Black (38%) racial backgrounds, and 60% graduated college. A total of 86% (n= 218) of participants completed the 72-week data collection. Attrition was not a significant function of intervention condition or sociodemographics (allp’s > .05). There were no significant main effects ofMindorMoveon linear change for any of the four serum biomarkers. However, there was a significant interaction effect (Mind*Move) on linear change over all four timepoints for GDF-15, whereby those in the control and combined conditions improved (decreased) relative to those in theMindorMoveconditions (t= -2.20,p= .028).Conclusions:In this cohort of older women with CVD, there were significantMind*Moveinteractive effects on GDF-15, a biomarker that may be associated with risk of Alzheimer’s disease or other conditions related to neuroinflammation. However, there were no significant intervention effects for the other biomarkers. Future analyses should examine other biomarkers related to Alzheimer’s disease and inflammation that may provide more mechanistic insight.