Proportion of Community-Dwelling Individuals Older Than 70 Years Eligible for Lecanemab Initiation: The Gothenburg H70 Birth Cohort Study.

OBJECTIVES: To determine the prevalence of individuals with Alzheimer disease (AD) eligible for treatment with the recently FDA-approved lecanemab based on data from a population-based sample of 70-year-olds and extrapolate an estimation of individuals eligible in Europe and the United States. METHODS: Participants from the Gothenburg H70 Birth Cohort Study with clinical data, CSF-amyloid beta 42, and brain MRI analysis were evaluated for eligibility to receive lecanemab treatment according to FDA-approved recommendations, noting factors requiring special consideration. Results were used to extrapolate the number of eligible individuals in Europe and the United States using public demographic data. RESULTS: Thirty (10.3%) of 290 participants met the indication for treatment of whom 18 (6.2%) were eligible and did not present factors requiring special consideration. Our estimate that 6.2% of all 70-year-olds in the full cohort are eligible for treatment extrapolates to an approximation that around 5.9 million Europeans and 2.2 million US residents could be eligible. DISCUSSION: Information on proportion of individuals eligible for AD treatment with lecanemab in the general public is limited. We provide information on 70-year-olds in Sweden and extrapolate these data to Europe and the United States. This study opens for larger studies on this proportion and implementation of lecanemab treatment.

Effects of swimming in cold water on lipolysis indicators via fibroblast growth factor-21 in male Wistar rats.

This study aimed to investigate the effects of swimming in cold water on the release of FGF21 from various tissues and its impact on fat metabolism. Twenty Wistar rats were randomly divided into three groups: untrained (C), trained in thermo-neutral water (TN, 30 °C) and trained in cold water (TC, 15 °C). The training groups swam intervals (2-3 min) until exhaustion, 1 min rest, three days a week for six weeks, with 3-6% bodyweight load. The mRNA expression of variables was determined in white fat tissue (WAT), and FGF21 protein was also measured in the liver, brown fat tissue (BAT), serum, and muscle. The experimental protocols resulted in lower body weight gain, associated with reduced WAT volume; the most remarkable improvement was observed in the TC group. Swimming significantly increased FGF21 protein levels in WAT, BAT, and muscle tissues compared to the C group; substantial increases were in the TC group. Changes in FGF21 were highly correlated with the activation of genes involved in fat metabolisms, such as CPT1, CD36, and HSL, and with glycerol in WAT. The findings indicate a positive correlation between swimming in cold water and the activation of genes involved in fat metabolism, possibly through FGF21 production, which was highly correlated with fat-burning genes.

Validation of a deep learning model for traumatic brain injury detection and NIRIS grading on non-contrast CT: a multi-reader study with promising results and opportunities for improvement.

PURPOSE: This study aimed to assess and externally validate the performance of a deep learning (DL) model for the interpretation of non-contrast computed tomography (NCCT) scans of patients with suspicion of traumatic brain injury (TBI). METHODS: This retrospective and multi-reader study included patients with TBI suspicion who were transported to the emergency department and underwent NCCT scans. Eight reviewers, with varying levels of training and experience (two neuroradiology attendings, two neuroradiology fellows, two neuroradiology residents, one neurosurgery attending, and one neurosurgery resident), independently evaluated NCCT head scans. The same scans were evaluated using the version 5.0 of the DL model icobrain tbi. The establishment of the ground truth involved a thorough assessment of all accessible clinical and laboratory data, as well as follow-up imaging studies, including NCCT and magnetic resonance imaging, as a consensus amongst the study reviewers. The outcomes of interest included neuroimaging radiological interpretation system (NIRIS) scores, the presence of midline shift, mass effect, hemorrhagic lesions, hydrocephalus, and severe hydrocephalus, as well as measurements of midline shift and volumes of hemorrhagic lesions. Comparisons using weighted Cohen's kappa coefficient were made. The McNemar test was used to compare the diagnostic performance. Bland-Altman plots were used to compare measurements. RESULTS: One hundred patients were included, with the DL model successfully categorizing 77 scans. The median age for the total group was 48, with the omitted group having a median age of 44.5 and the included group having a median age of 48. The DL model demonstrated moderate agreement with the ground truth, trainees, and attendings. With the DL model's assistance, trainees' agreement with the ground truth improved. The DL model showed high specificity (0.88) and positive predictive value (0.96) in classifying NIRIS scores as 0-2 or 3-4. Trainees and attendings had the highest accuracy (0.95). The DL model's performance in classifying various TBI CT imaging common data elements was comparable to that of trainees and attendings. The average difference for the DL model in quantifying the volume of hemorrhagic lesions was 6.0 mL with a wide 95% confidence interval (CI) of - 68.32 to 80.22, and for midline shift, the average difference was 1.4 mm with a 95% CI of - 3.4 to 6.2. CONCLUSION: While the DL model outperformed trainees in some aspects, attendings' assessments remained superior in most instances. Using the DL model as an assistive tool benefited trainees, improving their NIRIS score agreement with the ground truth. Although the DL model showed high potential in classifying some TBI CT imaging common data elements, further refinement and optimization are necessary to enhance its clinical utility.

Association of Chronic Kidney Disease With Plasma NfL and Other Biomarkers of Neurodegeneration: The H70 Birth Cohort Study in Gothenburg.

BACKGROUND AND OBJECTIVES: Studies associate chronic kidney disease (CKD) with neurodegeneration. This study investigated the relationship between kidney function, blood, CSF, and structural brain MRI markers of neurodegeneration in a sample including individuals with and without CKD. METHODS: Participants from the Gothenburg H70 Birth Cohort Study, with data on plasma neurofilament light (P-NfL), estimated glomerular filtration rate (eGFR), and structural brain MRI were included. Participants were invited to also have the CSF collected. The primary endpoint of this study was to determine any association between CKD and P-NfL. Secondary endpoints included cross-sectional associations between CKD, eGFR, and CSF-derived and MRI-derived markers of neurodegeneration and Alzheimer disease (AD) pathology (MRI: cortical thickness, hippocampal volume, lateral ventricle volume, and white matter lesion volume; CSF: ß-amyloid (Aß) 42, Aß42/40, Aß42/p-tau, t-tau, p-tau, and NfL). Participants with P-NfL and eGFR at baseline were re-examined on eGFR, 5.5 (5.3-6.1) years (median; IQR) after the first visit, and the predictive value of P-NfL levels on incident CKD was estimated longitudinally, using a Cox proportional hazards model. RESULTS: We included 744 participants, 668 without CKD (age 71 [70-71] years, 50% males) and 76 with CKD (age 71 [70-71] years, 39% males). Biomarkers from the CSF were analyzed in 313 participants. A total of 558 individuals returned for a re-examination of eGFR (75% response rate, age 76 [76; 77] years, 48% males, 76 new cases of CKD). Participants with CKD had higher P-NfL levels than those with normal kidney function (median; 18.8 vs 14.1 pg/mL, p < 0.001), while MRI and CSF markers were similar between the groups. P-NfL was independently associated with CKD after adjustment for confounding variables, including hypertension and diabetes (OR; 3.231, p < 0.001), in a logistic regression model. eGFR and CSF Aß 42/40: R = 0.23, p = 0.004 correlated in participants with Aß42 pathology. P-NfL levels in the highest quartile were associated with incident CKD at follow-up (HR; 2.39 [1.21: 4.72]). DISCUSSION: In a community-based cohort of 70-year olds, P-NfL was associated with both prevalent and incident CKD, while CSF and/or imaging measures did not differ by CKD status. Participants with CKD and dementia presented similar levels of P-NfL.

Associations between dietary patterns and dementia-related neuroimaging markers.

BACKGROUND: The exploration of associations between dietary patterns and dementia-related neuroimaging markers can provide insights on food combinations that may impact brain integrity. METHODS: Data were derived from the Swedish Gothenburg H70 Birth Cohort Study (n = 610). Three dietary patterns were obtained using principal component analysis. Magnetic resonance imaging markers included cortical thickness, an Alzheimer's disease (AD) signature score, small vessel disease, and white matter microstructural integrity. Adjusted linear/ordinal regression analyses were performed. RESULTS: A high-protein and alcohol dietary pattern was negatively associated with cortical thickness in the whole brain (Beta: -0.011; 95% confidence interval [CI]: -0.018 to -0.003), and with an Alzheimer's disease cortical thickness signature score (Beta: -0.013; 95% CI: -0.024 to -0.001). A positive association was found between a Mediterranean-like dietary pattern and white matter microstructural integrity (Beta: 0.078; 95% CI: 0.002-0.154). No associations were found with a Western-like dietary pattern. DISCUSSION: Dietary patterns may impact brain integrity through neurodegenerative and vascular pathways. HIGHLIGHTS: Certain dietary patterns were associated with dementia-related neuroimaging markers. A Mediterranean dietary pattern was positively associated with white matter microstructure. A high-protein and alcohol pattern was negatively associated with cortical thickness.

Swimming in cold water upregulates genes involved in thermogenesis and the browning of white adipose tissues.

The purpose of this study was to investigate whether there is an interacting effect of six weeks of swimming in cold water on the gene expression of browning markers in adipose tissue in rodents. Twenty male Wistar rats were randomly divided into four groups: Control (C, 25 °C), Cold Exposure (CE, 4 °C), Swimming in tepid Water (STW, 30 °C), and Swimming in Cold Water (SCW, 15 °C). The swimming included 2-3 min intervals, 1 min rest, until exhaustion, three days a week for six weeks, with 3 to 6% of bodyweight overload. Rats from CE were exposed to cold for 2 h per day, five days per week. After the experimental protocol, interscapular brown (BAT) and inguinal subcutaneous white (WAT) fat tissues were excised, weighed, and processed for beiging and mitochondrial biogenesis markers gene expression. The experimental protocols resulted in an apparent increase in the number of brown adipocytes (per mm2) in the adipose deposits compared to the C group; substantial changes were observed in the SCW group. Compared to other groups, cold exposure alone increased significantly serum norepinephrine, and also ß2-adrenergic receptor expression was upregulated in the adipocytes compared to the C group. The STW group increased the expression of peroxisome proliferator-activated receptor-γ (PPAR-γ) coactivator-1 alpha (PGC-1α), ß2-adrenergic receptor, and CCAAT/enhancer-binding proteins-α(c/EBP-α) in WAT in comparison with the C group(p < 0.05). In both adipocytes, the SCW intervention significantly upregulated the expression of PGC-1α, PPAR-γ, and c/EBP-α genes in comparison with the C and CE groups. In addition, the expression of TFAM and UCP1 was upregulated substantially in the SCW group compared to other groups. Our data demonstrate that swim training and cold exposure present additive effects in the expression of genes involved in the beiging process and mitochondrial biogenesis markers in BAT and WAT. In addition, it seems that the upregulation of these genes is related to the activation of ß2-adrenergic receptors.

Association of Cerebrovascular and Alzheimer Disease Biomarkers With Cholinergic White Matter Degeneration in Cognitively Unimpaired Individuals.

BACKGROUND AND OBJECTIVES: Several pathologic processes might contribute to the degeneration of the cholinergic system in aging. We aimed to determine the contribution of amyloid, tau, and cerebrovascular biomarkers toward the degeneration of cholinergic white matter (WM) projections in cognitively unimpaired individuals. METHODS: The contribution of amyloid and tau pathology was assessed through CSF levels of the Aß42/40 ratio and phosphorylated tau (p-tau). CSF Aß38 levels were also measured. Cerebrovascular pathology was assessed using automatic segmentations of WM lesions (WMLs) on MRI. Cholinergic WM projections (i.e., cingulum and external capsule pathways) were modeled using tractography based on diffusion tensor imaging data. Sex and APOE ε4 carriership were also included in the analysis as variables of interest. RESULTS: We included 203 cognitively unimpaired individuals from the H70 Gothenburg Birth Cohort Studies (all individuals aged 70 years, 51% female). WM lesion burden was the most important contributor to the degeneration of both cholinergic pathways (increase in mean square error [IncMSE] = 98.8% in the external capsule pathway and IncMSE = 93.3% in the cingulum pathway). Levels of Aß38 and p-tau also contributed to cholinergic WM degeneration, especially in the external capsule pathway (IncMSE = 28.4% and IncMSE = 23.4%, respectively). The Aß42/40 ratio did not contribute notably to the models (IncMSE<3.0%). APOE ε4 carriers showed poorer integrity in the cingulum pathway (IncMSE = 21.33%). Women showed poorer integrity of the external capsule pathway (IncMSE = 21.55%), which was independent of amyloid status as reflected by the nonsignificant differences in integrity when comparing amyloid-positive vs amyloid-negative women participants (T201 = -1.55; p = 0.123). DISCUSSION: In cognitively unimpaired older individuals, WMLs play a central role in the degeneration of cholinergic pathways. Our findings highlight the importance of WM lesion burden in the elderly population, which should be considered in the development of prevention programs for neurodegeneration and cognitive impairment.

MRI Markers of Small Vessel Disease and the APOE Allele in Cognitive Impairment.

Objective: The apolipoprotein E (APOE) ε4 allele is the main genetic risk factor for dementia and Alzheimer's disease (AD), but the underlying mechanism for the increased risk is not well understood. Cerebral small vessel disease (SVD) is prevalent among patients with cognitive impairment and is thought to play an important role in the pathophysiology of dementia. We aimed to investigate the association between the APOE ε genotype and magnetic resonance imaging (MRI) markers of SVD in a memory clinic population. Material and Methods: This is a cross-sectional study with a total of 520 patients undergoing dementia investigation, including an MRI brain scan and APOE genotyping in all patients enrolled, and cerebrospinal fluid (CSF) analysis for routine AD biomarkers in 399 patients. MR images were assessed for markers of SVD: cerebral microbleeds (CMBs), cortical superficial siderosis, intracerebral hemorrhage, white matter hyperintensities, lacunar infarcts, and enlarged perivascular spaces. Results: Apolipoprotein E carriers with AD had a higher number of CMBs when looking at all brain regions and lobar brain regions (p < 0.001). A lower number of CMBs were seen in APOE ε2 (p < 0.05), ε3 and ε3/3 carriers (p < 0.001) when looking at all brain regions. A higher number of CMBs in deep and infratentorial regions were seen in APOE ε2 and ε3 (p < 0.05). In APOE ε4/4 carriers, CMBs, cortical superficial siderosis, white matter hyperintensities, and enlarged perivascular spaces were associated with lower levels of CSF amyloid ß (Aß) 42 in the whole cohort, and in individuals with AD and mild cognitive impairment (p < 0.05). Conclusion: Apolipoprotein E ε4 is associated with MRI markers of SVD related to amyloid pathology, specifically CMBs and Aß42 plaque formation in the brain, as reflected by decreased CSF Aß42 levels, whereas APOE ε3 and ε2 are associated with the markers of hypertensive arteriopathy, as reflected by the association with CMBs in deep and infratentorial brain regions.

Plasma and CSF NfL are differentially associated with biomarker evidence of neurodegeneration in a community-based sample of 70-year-olds.

Neurofilament light protein (NfL) in cerebrospinal fluid (CSF) and plasma (P) are suggested to be interchangeable markers of neurodegeneration. However, evidence is scarce from community-based samples. NfL was examined in a small-scale sample of 287 individuals from the Gothenburg H70 Birth cohort 1944 study, using linear models in relation to CSF and magnetic resonance imaging (MRI) biomarker evidence of neurodegeneration. CSF-NfL and P-NfL present distinct associations with biomarker evidence of Alzheimer's disease (AD) pathology and neurodegeneration. P-NfL was associated with several markers that are characteristic of AD, including smaller hippocampal volumes, amyloid beta (Aß)42, Aß42/40, and Aß42/t-tau (total tau). CSF-NfL demonstrated associations with measures of synaptic and neurodegeneration, including t-tau, phosphorylated tau (p-tau), and neurogranin. Our findings suggest that P-NfL and CSF-NfL may exert different effects on markers of neurodegeneration in a small-scale community-based sample of 70-year-olds.

Effect of different recovery modes during resistance training with blood flow restriction on hormonal levels and performance in young men: a randomized controlled trial.

BACKGROUND: Resistance training with blood flow restriction (BFR) results in hypertrophy, and its magnitude depends on various training variables. This study aimed to compare the long-term effect of passive recovery (PR) and active recovery (AR) during low-intensity resistance training with BFR on hormonal levels and performance in young men. METHODS: In the randomized clinical trial, 20 men were randomly divided into PR and AR groups during resistance training with BFR. The intervention consisted of six upper and lower body movements with 30% of one maximum repetition (1RM), three sessions per week for six weeks. Both groups wore pneumatic cuffs on the proximal part of thighs and arms. The cuff pressure was 60% of the calculated arterial blood occlusion and increased 10% every two weeks. The AR group performed seven repetitions in 30 s break between sets by one second for concentric and eccentric phases and two seconds rest, and the other group had passive rest. The blood samples and a series of performance tests were gathered before and after the intervention. A repeated measure ANOVA was used to analyze data. RESULTS: AR and PR interventions significantly improved the C-reactive protein (CRP) (- 38% vs. - 40%), Lactate dehydrogenase (LDH) (- 11% vs. - 3%), Sargent jump (9% vs. 10%), peak power (20% vs.18%), and average power (14% vs. 14%), upper 1RM (8% vs. 8%) and no significant differences were observed between groups. The AR intervention significantly increased growth hormone (GH) (423% vs. 151%, p = 0.03), lower body 1RM (18% vs. 11%) and muscle endurance (34% vs. 22% for the upper body, p = 0.02 and 32% vs. 24% for the lower body, p = 0.04) than the PR group. The PR intervention further increased the minimum power than the AR group (19% vs. 10%). There were no significant changes in testosterone (p = 0.79) and cortisol (p = 0.34) following interventions. CONCLUSION: The findings indicated that by increasing muscle activation and higher metabolic load, AR during resistance training with BFR might cause more remarkable improvements in serum GH, muscle strength, and endurance. Thus, to gain further benefits, AR during training with BFR is recommended. TRIAL REGISTRATION: IRCT20191207045644N1. Registration date: 14/03/2020. URL: https://www.irct.ir/search/result?query=IRCT20191207045644N1.

Glycemic control is not related to cerebral small vessel disease in neurologically asymptomatic individuals with type 1 diabetes.

AIMS: To determine if medium- and long-term blood glucose control as well as glycemic variability, which are known to be strong predictors of vascular complications, are associated with underlying cerebral small vessel disease (cSVD) in neurologically asymptomatic individuals with type 1 diabetes. METHODS: A total of 189 individuals (47.1% men; median age 40.0, IQR 33.0-45.2 years) with type 1 diabetes (median diabetes duration of 21.7, IQR 18.3-30.7 years) were enrolled in a cross-sectional retrospective study, as part of the Finnish Diabetic Nephropathy (FinnDiane) Study. Glycated hemoglobin (HbA1c) values were collected over the course of ten years before the visit including a clinical examination, biochemical sampling, and brain magnetic resonance imaging. Markers of glycemic control, measured during the visit, included HbA1c, fructosamine, and glycated albumin. RESULTS: Signs of cSVD were present in 66 (34.9%) individuals. Medium- and long-term glucose control and glycemic variability did not differ in individuals with signs of cSVD compared to those without. Further, no difference in any of the blood glucose variables and cSVD stratified for cerebral microbleeds (CMBs) or white matter hyperintensities were detected. Neither were numbers of CMBs associated with the studied glucose variables. Additionally, after dividing the studied variables into quartiles, no association with cSVD was observed. CONCLUSIONS: We observed no association between glycemic control and cSVD in neurologically asymptomatic individuals with type 1 diabetes. This finding was unexpected considering the large number of signs of cerebrovascular pathology in these people after two decades of chronic hyperglycemia and warrants further studies searching for underlying factors of cSVD.

Atrial Fibrillation, Stroke, and Silent Cerebrovascular Disease: A Population-based MRI Study.

BACKGROUND AND OBJECTIVES: Atrial fibrillation (AF) has been associated with cognitive decline and dementia. However, the mechanisms behind these associations are not clear. Examination of cerebrovascular pathology on MRI may shed light on how AF affects the brain. This study aimed to determine whether AF is associated with a broad range of cerebrovascular diseases beyond the well-known association with symptomatic stroke, including silent infarcts and markers of small vessel disease, i.e., cerebral microbleeds (CMBs), white matter hyperintensities (WMHs), and lacunes, in a population-based sample of 70-year-olds. METHODS: Data were obtained from the Gothenburg H70 Birth Cohort Studies, in which individuals are invited based on birthdate. This study has a cross-sectional design and includes individuals born in 1944 who underwent structural brain MRI in 2014 to 2017. AF diagnoses were based on self-report, ECG, and register data. Symptomatic stroke was based on self-report, proxy interviews, and register data. Brain infarcts and CMBs were assessed by a radiologist. WMH volumes were measured on fluid-attenuated inversion recovery images with the Lesion Segmentation Tool. Multivariable logistic regression was used to study the association between AF and infarcts/CMBs, and multivariable linear regression was used to study the association between AF and WMHs. RESULTS: A total of 776 individuals were included, and 65 (8.4%) had AF. AF was associated with symptomatic stroke (odds ratio [OR] 4.5, 95% confidence interval [CI] 2.1-9.5) and MRI findings of large infarcts (OR 5.0, 95% CI 1.5-15.9), lacunes (OR 2.7, 95% CI 1.2-5.6), and silent brain infarcts (OR 3.5; 95% CI 1.6-7.4). Among those with symptomatic stroke, individuals with AF had larger WMH volumes (0.0137 mL/total intracranial volume [TIV], 95% CI 0.0074-0.0252) compared to those without AF (0.0043 mL/TIV, 95% CI 0.0029-0.0064). There was no association between AF and WMH volumes among those without symptomatic stroke. In addition, AF was associated to CMBs in the frontal lobe. DISCUSSION: AF was associated with a broad range of cerebrovascular pathologies. Further research is needed to establish whether cerebrovascular MRI markers can be added to current treatment guidelines to further personalize anticoagulant treatment in patients with AF and to further characterize the pathogenetic processes underlying the associations between AF and cerebrovascular diseases, as well as dementia.

Cerebral small-vessel disease is associated with the severity of diabetic retinopathy in type 1 diabetes.

INTRODUCTION: Cerebral small-vessel disease is common in neurologically asymptomatic individuals with type 1 diabetes. The retinal vasculature is thought to mirror the brain's vasculature, but data on this association are limited in type 1 diabetes. Our aim was to study associations between diabetic retinopathy severity and cerebral small-vessel disease in type 1 diabetes. RESEARCH DESIGN AND METHODS: For this cross-sectional study, we enrolled 189 participants with type 1 diabetes (median age 40 (33-45) years; 53% female; diabetes duration 21.6 (18.2-30.7) years) and 29 healthy age-matched and sex-matched controls as part of the Finnish Diabetic Nephropathy Study. Participants underwent a clinical investigation, brain MRI, and fundus imaging. Signs of cerebral small-vessel disease in brain MRIs were analyzed in relation to diabetic retinopathy severity (Early Treatment Diabetic Retinopathy Study (ETDRS) score). RESULTS: In type 1 diabetes, participants with cerebral small-vessel disease had higher ETDRS scores (35 (20-61) vs 20 (20-35), p=0.022) and a higher prevalence of proliferative diabetic retinopathy than those without cerebral small-vessel disease (25% vs 9%, p=0.002). In adjusted analysis, proliferative diabetic retinopathy was associated with cerebral small-vessel disease (OR 2.57 (95% CI 1.04 to 6.35)). Median ETDRS score (35 (20-65) vs 20 (20-35), p=0.024) and proliferative diabetic retinopathy prevalence were higher (29% vs 13%, p=0.002) in participants with versus without cerebral microbleeds. ETDRS scores increased by number of cerebral microbleeds (p=0.001), both ETDRS score (OR 1.05 (95% CI 1.02 to 1.09)) and proliferative diabetic retinopathy (8.52 (95% CI 1.91 to 37.94)) were associated with >2 cerebral microbleeds in separate multivariable analysis. We observed no association with white matter hyperintensities or lacunar infarcts. CONCLUSIONS: Presence of cerebral small-vessel disease on brain MRI, particularly cerebral microbleeds, is associated with the severity of diabetic retinopathy.

Carotid intima-media thickness and arterial stiffness in relation to cerebral small vessel disease in neurologically asymptomatic individuals with type 1 diabetes.

AIMS: To determine if arterial functional and structural changes are associated with underlying cerebral small vessel disease in neurologically asymptomatic individuals with type 1 diabetes. METHODS: We enrolled 186 individuals (47.8% men; median age 40.0, IQR 33.0-45.0 years) with type 1 diabetes (median diabetes duration of 21.6, IQR 18.2-30.3 years), and 30 age- and sex-matched healthy controls, as part of the Finnish Diabetic Nephropathy (FinnDiane) Study. All individuals underwent a biochemical work-up, brain magnetic resonance imaging (MRI), ultrasound of the common carotid arteries and arterial tonometry. Arterial structural and functional parameters were assessed by carotid intima-media thickness (CIMT), pulse wave velocity and augmentation index. RESULTS: Cerebral microbleeds (CMBs) were present in 23.7% and white matter hyperintensities (WMHs) in 16.7% of individuals with type 1 diabetes. Those with type 1 diabetes and CMBs had higher median (IQR) CIMT 583 (525 - 663) µm than those without 556 (502 - 607) µm, p = 0.016). Higher CIMT was associated with the presence of CMBs (p = 0.046) independent of age, eGFR, ApoB, systolic blood pressure, albuminuria, history of retinal photocoagulation and HbA1c. Arterial stiffness and CIMT were increased in individuals with type 1 diabetes and WMHs compared to those without; however, these results were not independent of cardiovascular risk factors. CONCLUSIONS: Structural, but not functional, arterial changes are associated with underlying CMBs in asymptomatic individuals with type 1 diabetes.

Sex differences in CSF biomarkers for neurodegeneration and blood-brain barrier integrity.

INTRODUCTION: As cerebrospinal fluid (CSF) neurofilament light protein (NfL) and the CSF/serum albumin ratio (QAlb) are used in the clinical routine, the impact of demographic factors on these biomarkers is important to understand. METHODS: Participants were derived from two Swedish samples: the population-based H70 Study (n = 308, age 70) and a clinical routine cohort (CSF NfL, n = 8995, QAlb, n = 39252, age 0 to 95). In the population-based study, QAlb and NfL were examined in relation to sex, cardiovascular risk factors, and cerebral white matter lesions (WMLs). In the clinical cohort, QAlb and NfL sex differences were tested in relation to age. RESULTS: Men had higher QAlb and NfL concentrations and had higher QAlb and NfL concentrations from adolescence throughout life. NfL was not related to WML, but QAlb correlated positively with WMLs. DISCUSSION: The CSF NfL sex difference could not be explained by vascular pathology. Future studies should consider using different reference limits for men and women.

Cerebrospinal Fluid Biomarkers, Brain Structural and Cognitive Performances Between Normotensive and Hypertensive Controlled, Uncontrolled and Untreated 70-Year-Old Adults.

Background: Hypertension is an important risk factor for Alzheimer's disease (AD). The pathophysiological mechanisms underlying the relationship between AD and hypertension are not fully understood, but they most likely involve microvascular dysfunction and cerebrovascular pathology. Although previous studies have assessed the impact of hypertension on different markers of brain integrity, no study has yet provided a comprehensive comparison of cerebrospinal fluid (CSF) biomarkers and structural brain differences between normotensive and hypertensive groups in a single and large cohort of older adults in relationship to cognitive performances. Objective: The aim of the present work was to investigate the differences in cognitive performances, CSF biomarkers and magnetic resonance imaging (MRI) of brain structure between normotensive, controlled hypertensive, uncontrolled hypertensive, and untreated hypertensive older adults from the Gothenburg H70 Birth Cohort Studies. Methods: As an indicator of vascular brain pathology, we measured white matter hyperintensities (WMHs), lacunes, cerebral microbleeds, enlarged perivascular space (epvs), and fractional anisotropy (FA). To assess markers of AD pathology/neurodegeneration, we measured hippocampal volume, temporal cortical thickness on MRI, and amyloid-ß42, phosphorylated tau, and neurofilament light protein (NfL) in cerebrospinal fluid. Various neuropsychological tests were used to assess performances in memory, attention/processing speed, executive function, verbal fluency, and visuospatial abilities. Results: We found more white matter pathology in hypertensive compared to normotensive participants, with the highest vascular burden in uncontrolled participants (e.g., lower FA, more WMHs, and epvs). No significant difference was found in any MRI or CSF markers of AD pathology/neurodegeneration when comparing normotensive and hypertensive participants, nor among hypertensive groups. No significant difference was found in most cognitive functions between groups. Conclusion: Our results suggest that good blood pressure control may help prevent cerebrovascular pathology. In addition, hypertension may contribute to cognitive decline through its effect on cerebrovascular pathology rather than AD-related pathology. These findings suggest that hypertension is associated with MRI markers of vascular pathology in the absence of a significant decline in cognitive functions.

Cerebrospinal Fluid Metals and the Association with Cerebral Small Vessel Disease.

BACKGROUND: Brain metal homeostasis is essential for brain health, and deregulation can result in oxidative stress on the brain parenchyma. OBJECTIVE: Our objective in this study was to focus on two hemorrhagic MRI manifestations of small vessel disease [cerebral microbleeds (CMBs) and cortical superficial siderosis (cSS)] and associations with cerebrospinal fluid (CSF) iron levels. In addition, we aimed to analyze CSF biomarkers for dementia and associations with CSF metal levels. METHODS: This is a cross-sectional study of 196 patients who underwent memory clinic investigation, including brain MRI. CSF was collected and analyzed for metals, amyloid-ß (Aß) 42, total tau (T-tau), and phosphorylated tau (P-tau), and CSF/serum albumin ratios. Statistical analyses were performed using generalized linear models. RESULTS: No significant difference was found between CSF metal levels across diagnostic groups. Higher iron and copper levels were associated with higher CSF levels of Aß42, T-tau, P-tau, and CSF/serum albumin ratios (p < 0.05). Zinc was associated with higher CSF/serum albumin ratios. There was no significant association between CMBs or cSS and CSF iron levels. An increase in CSF iron with the number of CMBs was seen in APOEɛ4 carriers. CONCLUSION: CSF iron levels are elevated with cerebral microbleeds in APOEɛ4 carriers, with no other association seen with hemorrhagic markers of small vessel disease. The association of elevated CSF iron and copper with tau could represent findings of increased neurodegeneration in these patients.

Angiotensin converting enzyme inhibitors and angiotensin receptor blockers have no effect on the outcomes of endovascular revascularization in tibial arterial occlusive disease.

The effects of angiotensin converting enzyme inhibitors and angiotensin receptor blockers (ACEI/ARBs) on angiogenesis, myocardial remodeling and intermittent claudication have been studied. Clinical studies have shown reduced re-intervention after cardiac stenting with the use of ACEI/ARBs. We hypothesized that the use of ACEI/ARBs decreases re-interventions after endovascular revascularization in tibial artery disease (TAD) patients. This is a retrospective study comparing the effects of ACEI/ARBs on the outcomes after endovascular revascularization for TAD. We divided all patients that underwent endovascular revascularization into Angiotensin converting enzyme inhibitor/Angiotensin receptor blockers (ACEI/ARBs) and No Angiotensin converting enzyme inhibitor/Angiotensin receptor blockers (NoACEI/ARBs) groups. A total of 360 patients underwent endovascular intervention for TAD. One hundred and ninety-six (54%) patients, 124 (57%) males, were on ACEI/ARBs after endovascular intervention for TAD, whereas 164(46%) patients, 87 (53%) males were not. The groups were well matched in the demographic variables except higher incidence of congestive heart failure, coronary artery disease and dialysis in the ACEI/ARBs group (p = .001, 0.02, 0.01 respectively). Reintervention rates were not associated with ACEI/ARBs use (p = .097). Even when corrected for statin use and antiplatelet therapy, no difference was seen in the reintervention rates in the two groups (p = .535, 0.547 respectively). Primary patency, assisted primary patency and secondary patency did not differ with the use of ACEI/ARBs (p = .244 0.096,0.060 respectively). No difference was seen in overall survival between the two groups (p = .690). ACEI/ARBs do not appear to affect the patency and reintervention rates for patients undergoing endovascular revascularization for TAD.