Cerebral circulation - cognition and behavior最新文献

{"title":"Associations between metabolic syndrome and markers of brain pathology: the role of sex- differences","authors":"Anna Marseglia ,&nbsp;Alexandra Cooper ,&nbsp;Lina Ryden ,&nbsp;Silke Kern ,&nbsp;Sara Shams ,&nbsp;Olof Lindberg ,&nbsp;Kaj Blennow ,&nbsp;Henrik Zetterberg ,&nbsp;Anna Zettergren ,&nbsp;Ingmar Skoog ,&nbsp;Eric Westman ,&nbsp;Henrik Zetterberg ,&nbsp;Anna Zettergren ,&nbsp;Ingmar Skoog ,&nbsp;Eric Westman","doi":"10.1016/j.cccb.2024.100241","DOIUrl":"10.1016/j.cccb.2024.100241","url":null,"abstract":"<div><h3>Introduction</h3><p>Cardiovascular and metabolic disorders rarely occur alone in old age but often cluster together in the so-called metabolic syndrome (MetS). While individual components of MetS, such as obesity, hypertension, and diabetes, have been linked to dementia and brain atrophy, their combined impact on cognitive and brain aging remains poorly explored. Our current study aims to investigate the relationship between MetS and markers of neurodegenerative and cerebrovascular pathologies while also considering potential differences between sexes.</p></div><div><h3>Methods</h3><p>We included 741 cognitively intact septuagenarians from the Gothenburg H70-Birth cohort 1944 with available brain MRI (286 had cerebrospinal fluid [CSF] sampling). MetS was defined by standard criteria (at least three among adiposity, raised blood pressure, blood glucose, reduced HDL-cholesterol, elevated triglycerides). MRI markers of brain pathology included overall (mean cortical thickness) and Alzheimer's disease (AD; average cortical thickness in signature areas) neurodegeneration, cerebral small vessel disease (SVD; markers such as white matter hyperintensity, lacunes, microbleeds, and perivascular spaces, and SVD score) and DTI's white- matter microstructural changes (fractional anisotropy). CSF biomarkers included t-tau, neurofilament light, neurogranin (overall neurodegeneration), Aβ42 and p-tau (AD), and CSF/serum albumin ratio (blood-brain barrier integrity). Analyses included regression models and stratification by sex.</p></div><div><h3>Results</h3><p>Overall, 410 participants (53%, n=196 women) had MetS. MetS was associated with increased odds of overall (OR=2.0, 95%CI 1.4–2.9) and AD-related (OR=1.8, 95%CI 1.4–2.6) neurodegeneration, high SVD burden (presence of ≥3 SVD compared to none: OR=2.1, 95%CI 1.1–4.3), and white-matter microstructural changes. Within the SVD markers, MetS was particularly related to white matter hyperintensities, lacunes, and perivascular spaces in basal ganglia. Furthermore, MetS was associated with alterations of blood-brain barrier integrity in the CSF subsample. Sex differences showed increased SVD burden in men with MetS, especially enlarged perivascular spaces (OR=2.9, 95%CI 1.7–5.0), while no differences were observed in women. No associations were detected with amyloid and tau.</p></div><div><h3>Discussion</h3><p>MetS in late life is linked to neurodegenerative and cerebrovascular pathologies, with SVD more prominent in men with MetS, but not in women.</p></div>","PeriodicalId":72549,"journal":{"name":"Cerebral circulation - cognition and behavior","volume":"6 ","pages":"Article 100241"},"PeriodicalIF":1.9,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2666245024000424/pdfft?md5=dd4e4c9de92b887cf5a511a0b8ec59d2&pid=1-s2.0-S2666245024000424-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142121669","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Role of apelin-13 in ischemic stroke under high-fat diet-induced metabolic disturbances at middle- age","authors":"Maud Petrault,&nbsp;Olivier Petrault,&nbsp;Vincent Berezows Ki,&nbsp;Patrick Gele,&nbsp;Michèle Bastide","doi":"10.1016/j.cccb.2024.100244","DOIUrl":"10.1016/j.cccb.2024.100244","url":null,"abstract":"<div><h3>Introduction</h3><p>Visceral fat gain and the progressive onset of metabolic disorders in middle-aged mice induce alteration of the cerebral vascular tree in association with mild cognitive impairment. This precipitates stroke risk and might prompt the middle-aged population to cognitive decline. In this context, an endogenous peptide named apelin-13 and its receptor APJ are suspected to link metabolic disorders at middle age to the consequences of ischemic stroke on brain tissue, as well as vasomotor and cognitive functions. Apelin-13 induces neuroprotection after experimental ischemic stroke, but this action has not been examined under metabolic disturbances. The aim of our study is to evaluate the role of apelin-13 as a new therapeutic target in ischemic stroke under high-fat diet-induced metabolic disturbances at middle-age.</p></div><div><h3>Methods</h3><p>C57Bl/6 mice were fed for 6 months with normal diet (ND) or high-fat diet (HFD) before 30-minute middle cerebral artery occlusion (MCAO). Metabolic parameters, as well as circulating apelin-13 levels were evaluated every 3 months before MCAO. APJ brain expression and plasmatic apelin rate were assess at acute phase (24h post-stroke) and after behavioral (motor and cognitive) evaluation at chronic phase (10 days after MCAO).</p></div><div><h3>Results</h3><p>Mice under HFD developed overweight, hyperglycemia and hypercholesterolemia. Plasmatic apelin slowly decreased with age and was different between overweight and lean mice, but not between HFD and ND. The onset of MCAO under HFD induced 49% higher mortality than under ND. At acute phase, mice under HFD had a 25% decreased plasmatic apelin rate whereas mice under ND had a 2.5% of reduction. APJ brain expression in HFD mice was 59% reduced compared to ND. After 10 days, worsened behavioral impairment was observed in HFD mice compared to ND mice. Plasmatic apelin levels were reduced whatever the diet.</p></div><div><h3>Discussion</h3><p>These first results highlight the contribution of the apelinergic system to the influence of metabolic disturbances on stroke severity, that should be considered in therapeutic studies.</p></div>","PeriodicalId":72549,"journal":{"name":"Cerebral circulation - cognition and behavior","volume":"6 ","pages":"Article 100244"},"PeriodicalIF":1.9,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S266624502400045X/pdfft?md5=0976ed8fbb064eaae747131d9c678082&pid=1-s2.0-S266624502400045X-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142121672","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cardiovascular Risk Management in Persons with Dementia","authors":"Charlotte Nijskens ,&nbsp;Marieke Henstra ,&nbsp;Hanneke Rhodius-Meester ,&nbsp;Sevil Yasar ,&nbsp;Eveline van Poelgeest ,&nbsp;Mike Peters ,&nbsp;Majon Muller","doi":"10.1016/j.cccb.2024.100245","DOIUrl":"10.1016/j.cccb.2024.100245","url":null,"abstract":"<div><p>The number of people living with dementia, such as Alzheimer's disease, is increasing worldwide. Persons with dementia often have a high risk of atherosclerotic cardiovascular disease and they are therefore theoretically eligible for treatment of hypertension and hyperlipidemia. However, in this population, beneficial and harmful effects of cardiovascular risk management (CVRM) may be different compared to older persons without cognitive impairment. Current CVRM guidelines are based on trials from which persons with dementia were excluded. In this narrative review, we will discuss how current guidelines can be translated to persons with dementia and which aspects should be taken into account when treating hypertension and hyperlipidemia to prevent major adverse cardiovascular events (MACE). Survival time is significantly shorter in persons with dementia. We therefore suggest that since the main goal of CVRM is prevention of MACE, first of all, the patient's life expectancy and treatment wishes should be evaluated. Risk assessment tools are to be used with care, as they tend to overestimate the 5- and 10-year risk of MACE and benefit from CVRM in the prevention of MACE in persons with dementia. When the clinician and patient have decided that treatment is initiated or intensified, patients should be closely monitored since they are at high risk for adverse drugs events and overtreatment due to the natural course of blood pressure in persons with dementia. In the event of intolerance or side effects, medication should be switched or withdrawn. For persons with dementia and limited life expectancy, deprescribing should be part of usual care.</p></div>","PeriodicalId":72549,"journal":{"name":"Cerebral circulation - cognition and behavior","volume":"6 ","pages":"Article 100245"},"PeriodicalIF":1.9,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2666245024000461/pdfft?md5=0d3a46a72145d86c8878a51dc912a36c&pid=1-s2.0-S2666245024000461-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142121673","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cerebrospinal Fluid Neurofilament Light Chain and Soluble Amyloid Precursor Protein - β in the Subcortical Small Vessel Type of Dementia","authors":"Elin Axelsson Andrén ,&nbsp;Petronella Kettunen ,&nbsp;Maria Bjerke ,&nbsp;Sindre Rolstad ,&nbsp;Henrik Zetterberg ,&nbsp;Kaj Blennow ,&nbsp;Anders Wallin ,&nbsp;Johan Svensson","doi":"10.1016/j.cccb.2024.100268","DOIUrl":"10.1016/j.cccb.2024.100268","url":null,"abstract":"<div><h3>Introduction</h3><p>The subcortical small vessel type of dementia (SSVD) is a common form of vascular dementia. There is a lack of disease-specific cerebrospinal fluid (CSF) biomarkers. We investigated whether CSF concentrations of neurofilament light chain (NFL), soluble amyloid precursor protein-α (sAPP-α), sAPP-β, and CSF/serum albumin ratio could separate SSVD from healthy controls, Alzheimer's disease (AD) and mixed dementia (combined AD and SSVD).</p></div><div><h3>Methods</h3><p>Patients with SSVD (n = 38), AD (n = 121), mixed dementia (n = 62), and healthy controls (n = 96) were included. The CSF biomarkers were measured using immunoassays, and their independent contribution to the separation between groups were evaluated using the Wald test. Then, the area under the receiver operating characteristics curve (AUROC) and 95% confidence intervals (CIs) were calculated.</p></div><div><h3>Results</h3><p>Elevated NFL concentrations and decreased sAPP-β concentrations independently separated SSVD from controls, and sAPP-β also distinguished SSVD from AD and mixed dementia. Furthermore, the combination of NFL and sAPP-β discriminated SSVD from controls with high accuracy (AUROC 0.903, 95% CI: 0.834 – 0.972). Additionally, sAPP-β combined with the core AD biomarkers (β-amyloid1-42, total tau, and phosphorylated tau181) had a high ability to separate SSVD from AD (AUROC 0.886, 95% CI: 0.830 – 0.942) and mixed dementia (AUROC 0.903, 95% CI: 0.838 – 0.968).</p></div><div><h3>Discussion</h3><p>The high accuracy of NFL and sAPP-β to separate SSVD from controls supports that SSVD is a specific diagnostic entity. Moreover, sAPP-β in combination with the core AD biomarkers distinguished SSVD from AD and mixed dementia.</p></div>","PeriodicalId":72549,"journal":{"name":"Cerebral circulation - cognition and behavior","volume":"6 ","pages":"Article 100268"},"PeriodicalIF":1.9,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2666245024000692/pdfft?md5=2fdc2069a8e13463f04ef78341115725&pid=1-s2.0-S2666245024000692-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142121679","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Diabetes and Dementia in 3 H-70 cohorts in Gothenburg","authors":"Roland Haase ,&nbsp;Xin Xin Guo ,&nbsp;Valter Sundh ,&nbsp;Ingmar Skoog","doi":"10.1016/j.cccb.2024.100317","DOIUrl":"10.1016/j.cccb.2024.100317","url":null,"abstract":"<div><p>A total number of 2498 individuals 70 years old were randomly elicited in Gothenburg, n=966 in 1971, n=1028 in 1976 and n=504 in 2000. Blood glucose levels in the 3 cohorts were 5.53 mmol/l for 1971 cohort, 5.30 mmol/l for 1976 and 5.83 mmol/l for 2000. Blood glucose levels declined when the cohorts were examined again with 75 years and 79 years. Looking at DM individuals, blood glucose levels at age 70 for the cohort 1971 was 8,90 mmol/l (n=54), for cohort 1976 of 8,91 mmol/l (n=64) and for cohort 1930 of 8,45 mmol/l (n=57). A strong correlation between Diabetes mellitus (DM) and body mass index (BMI) existed: BMI &lt;25 had a frequency of DM in 6,0%, for BMI =25&lt;30 had 6,4% DM, for BMI =30&lt;35 had 10,6% and BMI &gt;=35 had 23,1% DM. HbA1c mean was 40,68 (median 38,0) for all participants and 53,12 (median 51,0) in DM. The correlation of HbA1c with BMI did not reach statistical significance (p=0,09). In 2009 in DM individuals HbA1c was considerably higher in cerebrovascular dementia (62,3 mmol/l) than in DM with Alzheimer dementia (52,3 mmol/l) or in non-dementia (52,5 mmol/l) but numbers were too small for significance (rank test pooled 0,14; Satterthwaite 0,22). The proportion of DM was higher in the cerebrovascular group (8 of 18; 44%) than in the Alzheimer dementia (9 of 38; 27%) or in non-dementia (83 of 600; 13,8%). This prospective study showed an association between DM with cerebrovascular dementia, whereas the association with Alzheimer dementia was weaker.</p></div>","PeriodicalId":72549,"journal":{"name":"Cerebral circulation - cognition and behavior","volume":"6 ","pages":"Article 100317"},"PeriodicalIF":1.9,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2666245024001181/pdfft?md5=2e21e99c85afcc3254f2a97a5297c183&pid=1-s2.0-S2666245024001181-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142121692","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"TREM2-regulated microglial reactivity confers resilience against vascular contributions to white matter injury and cognitive decline","authors":"Stefan Szymkowiak ,&nbsp;Mila Redzic ,&nbsp;Anirudh Patir ,&nbsp;Clare Latta ,&nbsp;Michael Daniels ,&nbsp;Jack Barrington ,&nbsp;Katie Askew ,&nbsp;Jessica Duncombe ,&nbsp;Karen Horsburgh ,&nbsp;Barry McColl","doi":"10.1016/j.cccb.2024.100318","DOIUrl":"10.1016/j.cccb.2024.100318","url":null,"abstract":"<div><p>Cerebrovascular disease is a major contributor to subcortical white matter pathology, vascular cognitive impairment (VCI) and dementia. Although the precise pathophysiological mechanisms remain unclear, it is increasingly evident that microglial responses may be critical to the development and progression of cerebrovascular disease and its cognitive consequences. To investigate this further, we assessed microglial reactivity in white matter regions of human post- mortem tissue with pathologically confirmed cerebrovascular injury. In parallel, we implemented a mouse model of VCI induced by bilateral carotid artery stenosis (BCAS) and determined the impact of genetically deleting the microglial immunoreceptor triggering receptor expressed on myeloid cells 2 (TREM2), a key regulator of microglial homeostatic and reactive functions. Using immunohistochemistry (IHC) and quantitative polymerase chain reaction (QPCR) we observed increased microglial reactivity and TREM2 expression in our human cohort implicating TREM2 signalling in microglial responses to cerebrovascular. In mice, IHC and flow cytometric analysis revealed Trem2 deficiency blunted microglial reactivity following BCAS (1 month). Transcriptomic analysis of Trem2-/- microglia also demonstrated attenuated induction of gene expression modules associated with inflammation, lysosomal function, lipid processing and metabolic reprogramming following BCAS (data not shown). Importantly, this was associated with greater white matter injury compared to wildtype (WT) counterparts in the absence of overt cognitive changes. Following longer durations of BCAS (6 months), Trem2-/- mice exhibited additional parenchymal and vascular pathologies associated with impairments in spatial learning and memory whilst such changes were largely absent in WT mice. Interestingly, assessment of microglia by IHC demonstrated reduced interaction with white matter cerebrovasculature in Trem2-/- mice. Taken together, these data support a role for microglia in cerebrovascular contributions to cognitive decline and dementia. Therefore, targeting regulators of microglia reactivity may provide means to influence cerebrovascular disease trajectory and associated cognitive changes. While further work is required to delineate the precise function of microglia in this context, our preclinical data suggest TREM2-regulated microglial responses to cerebrovascular insult are important for maintenance of brain health and cognitive resilience. Future work will continue to decipher how TREM2 mediates such resilience with particular focus on interaction with other cell types within the neurogliovascular unit.</p></div>","PeriodicalId":72549,"journal":{"name":"Cerebral circulation - cognition and behavior","volume":"6 ","pages":"Article 100318"},"PeriodicalIF":1.9,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2666245024001193/pdfft?md5=f38710d7ba93681190ddec3dec12c2b7&pid=1-s2.0-S2666245024001193-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142121694","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Association between angiogenic factors and vascular risk, white matter hyperintensities and CSF amyloid beta","authors":"Lene Pålhaugen ,&nbsp;Berglind Gísladóttir ,&nbsp;Jonas Alexander Jarholm ,&nbsp;Bjørn-Eivind Kirsebom ,&nbsp;Per Selnes ,&nbsp;Tormod Fladby","doi":"10.1016/j.cccb.2024.100304","DOIUrl":"10.1016/j.cccb.2024.100304","url":null,"abstract":"<div><h3>Introduction</h3><p>Angiogenic mediators like placental growth factor (PlGF) and vascular endothelial growth factors (VEFG-C and VEFG-A) in cerebrospinal fluid (CSF) are suggested markers of cerebral small vessel disease (SVD). SVD is a cause of vascular cognitive impairment and dementia (VCID), but studies have shown that both non-amyloid SVD related to vascular risk factors and cerebral amyloid angiopathy (CAA) often exist in patients with Alzheimer's Disease (AD). CSF amyloid beta (Abeta) 42 is reduced in AD due to trapping in parenchymal plaques. Abeta40 is mainly deposited in the vasculature, and low CSF concentrations are seen in CAA. In this cross-sectional study, we examine the associations between these angiogenic factors, vascular risk and white matter hyperintensities (WMH) on MRI, as well as Abeta peptides in CSF.</p></div><div><h3>Methods</h3><p>We recruited non-demented participants from the Norwegian Dementia Disease Initiation cohort. We measured PlGF, VEGF-C and VEGF-A in CSF. Vascular risk was assessed with the Framingham Risk Score (FRS) for cardiovascular disease. WMH volumes were calculated by an automated algorithm. We used linear regression to examine associations between angiogenic markers and FRS, CSF levels of Abeta42 and Abeta40. Associations with WMH load were assessed in models without (Model 1) and with (Model 2) correction for amyloid status. Continuous variables were standardized. Age and sex were covariates.</p></div><div><h3>Results</h3><p>In total, 240 individuals (mean age 63.4 years, 128 female/112 male, 124 cognitively normal/116 cognitively impaired) were included. Reduced VEGF-C was associated with higher FRS (B=-0.292, p&lt;0.001) and reduced Abeta42 (B=0.261, p&lt;0.001) and Abeta40 (B=0.574, p&lt;0.001). We also found a negative association between WMH load and VEGF-C (B=-0.233, p&lt;0.001), that remained significant after correction for amyloid status. Increased PlGF was associated with higher FRS (B=0.186, p&lt;0.001), lower Abeta40 (B=-0.111, p=0.029) and increased WMH load (B=0.188, p=0.026), the latter remaining significant after correction for amyloid status.</p></div><div><h3>Discussion</h3><p>Both angiogenic factors VEGF-C and PlGF are associated with vascular risk, Abeta40 and WMH load, suggesting a role in both SVD and AD pathogenesis. These factors should be included in longitudinal studies to further confirm their impact on disease processes and elucidate mechanisms involved in the interaction between SVD and AD.</p></div>","PeriodicalId":72549,"journal":{"name":"Cerebral circulation - cognition and behavior","volume":"6 ","pages":"Article 100304"},"PeriodicalIF":1.9,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2666245024001053/pdfft?md5=4ceab7c6227e5c2d0cc95fda8a291c28&pid=1-s2.0-S2666245024001053-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142121696","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Angiotensin-converting enzyme 2 (ACE-2) is dysregulated in Alzheimer's disease but not Vascular dementia","authors":"Ozge Guzel,&nbsp;Hannah Mary Tayler,&nbsp;James Scott Miners,&nbsp;Patrick Gavin Kehoe","doi":"10.1016/j.cccb.2024.100298","DOIUrl":"10.1016/j.cccb.2024.100298","url":null,"abstract":"<div><h3>Introduction</h3><p>The brain renin-angiotensin system (RAS) is dysregulated in dementia. We have previously shown that ACE-2, a central regulator of the protective counter-regulatory arm of RAS, is inversely associated with disease pathology in Alzheimer's disease (AD). We have investigated whether ACE-2 is similarly deficient in Vascular dementia (VaD) and mixed dementia (AD-VaD), in addition to AD. We also investigated whether ACE-2 is related to vascular pathology including CAA and SVD and explored whether ACE-2 varies according to gender, hypertension status, and ACE-2 genotype.</p></div><div><h3>Methods</h3><p>We studied brain tissue (frontal cortex) from 147 dementia cases (AD (n=94), VaD (n=20) and AD-VaD (n=33)) and 104 age-matched non-demented controls from the South West Dementia Brain Bank, University of Bristol. Amyloid β (Aβ) and tau pathology and levels, had previously been measured by IHC and ELISA, respectively. ACE-2 protein levels were measured by ELISA, and ACE-2 enzyme activity was measured using a fluorometric sensolyte kit (Anaspec). ACE-1 activity was measured using a fluorogenic assay; Ang-II and Ang-(1-7) were measured by in-house direct ELISA. ACE-2 genotypes (rs2285666 and rs4240157) were obtained by PCR.</p></div><div><h3>Results</h3><p>ACE-2 enzyme activity was significantly reduced in AD and AD-VaD cases (p&lt;0.0001 and p=0.0039, respectively) but not VaD. ACE-2 protein levels were unchanged between dementia groups. ACE-2 activity correlated inversely with parenchymal Aβ (r=-0.223, p=0.0005) and tau load (r=-0.294, p&lt;0.0001) and with insoluble Aβ40 and Aβ42 levels (r=-0.267 and r=-0.289, both p&lt;0.0001). ACE-2 activity correlated inversely with ACE-1 activity (r=−0.227, p=0.0004), and the ratio of ACE-1 to ACE-2 was significantly increased in AD and AD-VaD cases (p&lt;0.0001 and p=0.0029, respectively) but not in VaD. ACE-2 activity was lower in females with AD (p=0.0015). There is no relationship with CAA/SVD. ACE-2 activity was higher in people with late-stage hypertension (p=0.044), and females with hypertension have lower enzyme activity than males (p=0.041). ACE-2 levels and activity werenot associated with ACE-2 genotypes.</p></div><div><h3>Discussion</h3><p>These findings indicate that, despite strong vascular properties, changes in ACE-2 function are AD-related and not altered in VaD. The reduction in ACE-2 in females in AD warrants further investigation. We did not find any association with ACE-2 genotypes.</p></div>","PeriodicalId":72549,"journal":{"name":"Cerebral circulation - cognition and behavior","volume":"6 ","pages":"Article 100298"},"PeriodicalIF":1.9,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2666245024000990/pdfft?md5=8b7a017a0f50fecbe251364f6a3fce3a&pid=1-s2.0-S2666245024000990-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142122043","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Baseline levels of soluble amyloid precursor proteins predict conversion to subcortical small-vessel disease","authors":"Petronella Kettunen ,&nbsp;Francesco Locatelli ,&nbsp;Emir Basic ,&nbsp;Maria Bjerke ,&nbsp;Michael Jonsson ,&nbsp;Johan Svensson ,&nbsp;Anders Wallin","doi":"10.1016/j.cccb.2024.100301","DOIUrl":"10.1016/j.cccb.2024.100301","url":null,"abstract":"<div><h3>Introduction</h3><p>The Gothenburg Mild Cognitive Impairment (MCI) study is a longitudinal mono-center study of patients seeking help for cognitive complaints at the memory clinic in Gothenburg, Sweden. The study includes both pre-clinical diagnoses, e.g. subjective cognitive impairment (SCI) and mild cognitive impairment (MCI), as well as patients with manifest dementia, including Alzheimer's disease (AD), subcortical small-vessel disease (SSVD) and mixed AD/SSVD. The International Working Group (IWG) for New Research Criteria for the Diagnosis of AD has proposed a conceptual framework for guiding diagnosis by biomarker analysis. In short, patients with typical AD and mixed AD/SSVD should display decreased amyloid-β (Aβ) 1-42 together with increased total tau or phosphorylated tau in cerebrospinal fluid (CSF).</p></div><div><h3>Methods</h3><p>In this project, we used the IWG-2 criteria to help the exploration of preclinical CSF biomarkers for SSVD. To this end, we investigated the odds of SCI and MCI patients with and without AD pathology converting to SSVD. Moreover, we investigated how CSF biomarker levels at baseline affected risk of converting to SSVD. The applied cut-offs for AD pathology were Aβ-42 &lt; 530 ng/L, t-tau&gt;350 ng/L and p-tau181&gt;59 ng/L. The study cohort consisted of 29 SCI with AD pathology and 173 SCI without AD pathology, and 98 MCI with AD pathology and 203 MCI without AD pathology. CSF biomarkers Aβ-38, Aβ-40 and Aβ-42, and soluble amyloid precursor protein (sAPP) alpha and beta were analyzed at baseline.</p></div><div><h3>Results</h3><p>While SCI and MCI patients with pathological AD biomarkers were 30 times more likely to convert to AD and 15 times more likely to convert to mixed AD/SSVD, pathological AD biomarkers did not predict conversion to SSVD. Using Cox regression analysis, we found that higher levels of sAPP-α and sAPP-β at baseline were associated with lower risk of converting to SSVD. Moreover, Kaplan- Meier estimations showed that when preclinical subjects were stratified according to baseline levels of sAPP-α or Aβ-40, those with the lower levels of the proteins had increased probability of converting to SSVD. No other biomarkers were associated with conversion to SSVD.</p></div><div><h3>Discussion</h3><p>sAPP-α/-β and Aβ-40 could be used as potential biomarkers to evaluate progression to SSVD.</p></div>","PeriodicalId":72549,"journal":{"name":"Cerebral circulation - cognition and behavior","volume":"6 ","pages":"Article 100301"},"PeriodicalIF":1.9,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2666245024001028/pdfft?md5=82f0f4a80ce5b6c91d1ed94ab6a1b443&pid=1-s2.0-S2666245024001028-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142122046","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Diabetes and MRI Infarction in the Hispanic Community Health Study, Study of Latinos","authors":"Vincent Chen ,&nbsp;Ariana Stickel ,&nbsp;Wassim Tarraf ,&nbsp;Kevin Gonzalez ,&nbsp;Donglin Zeng ,&nbsp;Jianwen Cai ,&nbsp;Carmen Isasi ,&nbsp;Robert Kaplan ,&nbsp;Richard Lipton ,&nbsp;Martha Daviglus ,&nbsp;Fernando Testai ,&nbsp;Melissa Lamar ,&nbsp;Linda Gallo ,&nbsp;Gregory Talavera ,&nbsp;Vladimir Ivanovic ,&nbsp;Stephan Seiler ,&nbsp;Hector Gonzalez ,&nbsp;Charles DeCarli","doi":"10.1016/j.cccb.2024.100289","DOIUrl":"10.1016/j.cccb.2024.100289","url":null,"abstract":"<div><h3>Introduction</h3><p>HCHS/SOL is a representative study of Hispanic/Latinos living in the US. HCHS/SOL participants have a high prevalence of diabetes (1) and diabetic associated cognitive decline (2). Previous studies of predominantly non-Hispanic White populations indicate that silent brain infarcts are associated with incident dementia (3). Given that diabetes is prevalent in HCHS/SOL and associated with cognitive decline, we examined whether diabetes may also lead to infarction on MRI.</p></div><div><h3>Methods</h3><p>SOL-INCA-MRI consists of 2668 individuals of Hispanic/Latino Heritage from 4 centers across the US. Demographics of the cohort are summarized in the Table. The presence or absence of infarction on MRI was determined from review of high resolution T1, T2 and FLAIR imaging as well as gradient echo imaging by a neuroradiologist and a stroke neurologist with a high level of agreement (ICC &gt;0.90). Desperate readings were adjudicated by a neurologist with experience in vascular brain injury. Diabetes based on American Diabetes Association definition of normal, prediabetic and diabetic. This definition used measures serum glucose levels adjusted for fasting time and, if available, post-OGTT glucose levels, A1C percentages, and scanned/transcribed anti- diabetic medication use. General linear model was used to test the associated between the presence or absence of MRI and diabetes adjusting for age, gender, heritage, and center.</p></div><div><h3>Results</h3><p>Subjects were 62.3 + 9.2 years of age at MRI range [35-86], 67% were female and the prevalence of MRI infarction was 7% (Table). Pre-diabetes was present in 45% and diabetes in 22%. Stroke prevalence increased with age ranging from &lt;1% at age 40 to 18% at age 80 (Figure 1). Diabetes or pre-diabetes prevalence also increased with age being 10% at 40 and over 60% at age 80 (Figure 2). Adjusting for age, men were 2 times more likely to be diabetic. In the full model, age, gender, and diabetes were significantly associated with infarction seen on MRI with the likelihood of infarction 1.9 times greater in persons with diabetes.</p></div><div><h3>Discussion</h3><p>These results indicate that the presence of diabetes is strongly associated with infarction on MRI in Hispanic/Latinos in the US. This association may explain, in part, the association between diabetes and cognitive decline.</p></div>","PeriodicalId":72549,"journal":{"name":"Cerebral circulation - cognition and behavior","volume":"6 ","pages":"Article 100289"},"PeriodicalIF":1.9,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2666245024000904/pdfft?md5=f537124251def64cd9c846fc95353e0e&pid=1-s2.0-S2666245024000904-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142122117","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}