Cerebral circulation - cognition and behavior最新文献

As the emerging treatments that target grey matter pathology in Alzheimer's Disease have limited effectiveness, there is a critical need to identify new neural targets for treatments. White matter's (WM) metabolic vulnerability makes it a promising candidate for new interventions. This study examined the age and sex differences in estimates of axonal content, as well the associations of with highly prevalent modifiable health risk factors such as metabolic syndrome and adiposity. We estimated intra-axonal volume fraction (ICVF) using the Neurite Orientation Dispersion and Density Imaging (NODDI) in a sample of 89 cognitively and neurologically healthy adults (20–79 years). We showed that ICVF correlated positively with age and estimates of myelin content. The ICVF was also lower in women than men, across all ages, which difference was accounted for by intracranial volume. Finally, we found no association of metabolic risk or adiposity scores with the current estimates of ICVF. In addition, the previously observed adiposity-myelin associations (Burzynska et al., 2023) were independent of ICVF. Although our findings confirm the vulnerability of axons to aging, they suggest that metabolic dysfunction may selectively affect myelin content, at least in cognitively and neurologically healthy adults with low metabolic risk, and when using the specific MRI techniques. Future studies need to revisit our findings using larger samples and different MRI approaches, and identify modifiable factors that accelerate axonal deterioration as well as mechanisms linking peripheral metabolism with the health of myelin.

Upright posture challenges the cerebrovascular system, leading to changes in middle cerebral artery velocity (MCAv) dynamics which are less evident at supine rest. Chronic alterations in MCAv have been linked to hypoperfusion states and the effect that this may have on cognition remains unclear. This study aimed to determine if MCAv and oscillatory metrics of MCAv (ex. pulsatility index, PI) during upright posture are i) associated with cognitive function and gait speed (GS) to a greater extent than during supine rest, and ii) are different between sexes.

Beat-by-beat MCAv (transcranial Doppler ultrasound) and mean arterial pressure (MAP, plethysmography) were averaged for 30-seconds during supine-rest through a transition to standing for 53 participants (73±6yrs, 17 females). While controlling for age, multiple linear regressions predicting MoCA scores and GS from age, supine MCAv metrics, and standing MCAv metrics, were completed. Simple linear regressions predicting Montreal Cognitive Assessment (MoCA) score and GS from MCAv metrics were performed separately for females and males. Significance was set to p<0.05.

Lower standing diastolic MCAv was a significant (p = 0.017) predictor of lower MoCA scores in participants with mild cognitive impairment, and this relationship only remained significant for males. Lower standing PI was associated with slower GS (p = 0.027, r=-0.306) in both sexes. Our results indicate a relationship between blunted MCAv and altered oscillatory flow profiles during standing, with lower MoCA scores and GS. These relationships were not observed in the supine position, indicating a unique relationship between standing measures of MCAv with cognitive and physical functions.

Introduction

Vascular cognitive impairment (VCI) is heterogeneous in brain atrophy patterns, clinical symptoms, and possibly in the factors affecting resilience to symptoms. The objective of this study was to investigate the heterogeneity of VCI by estimating different atrophy-driven subtypes and use those for identifying resilience factors in each subtype.

Methods

We used cross-sectional data from the Trace-VCI cohort comprising of memory-clinic patients with vascular brain injury on MRI (n=361 all-cause dementia, n=190 MCI, and n=188 SCD). White matter hyper-intensities (WMH) were segmented, and SLF toolbox was used to refill them on the MRIs for accurate parcellation. Freesurfer volumes were used for identifying subtypes with non-negative matrix factorization. Subtype-specific pseudo-timelines of progression were estimated using a previously validated discriminative event-based model. Severity of atrophy (SA) in patients was estimated using cross-validation based on their position on the pseudo-timeline. Using linear-regression, cognition and disability (MMSE, Global deterioration scale, disability assessment for dementia) were modelled to be dependent on SA and its interactions with genetic factors, vascular markers and risk-factors, and co-pathology independently (variables in Figure-3). Resilience factors were identified by testing if the model with the interaction explains the symptoms significantly more than the one without.

Results

The algorithm identified three atrophy-based VCI subtypes: Frontal, Subcortical/Temporal, and Parietal subtype. Their prevalence, vascular and clinical presentations are summarized in Figure-1. The pseudo-timelines of atrophy are shown in Figure-2. SA's interaction with education positively influenced cognition in all subtypes, but negatively influenced disability in subcortical/temporal subtype. In frontal and parietal subtypes, APOE ε4, AD co-pathology resulted in more SA without worsening symptoms. SA's interaction with smoking and microbleeds negatively influenced disability. In the subcortical/temporal subtype, SA's interaction with WMH, lacunes, infarcts negatively impacted disability. In parietal subtype, men have more cognitive resilience than women. SA's interaction with hypercholesterolemia, and smoking were significantly negative for cognition. Lacunes were associated with more SA without affecting cognition. Figure-3 summarizes the interactions for all subtypes.

Discussion

We identified three atrophy-based VCI subtypes where the risk-factors have different influence on atrophy and symptoms highlighting differences in resilience. These results could aid in prognosis and in personalizing patients’ intervention strategy.

Introduction

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.

Methods

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.

Results

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.

Discussion

MetS in late life is linked to neurodegenerative and cerebrovascular pathologies, with SVD more prominent in men with MetS, but not in women.

Introduction

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.

Methods

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).

Results

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.

Discussion

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.

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.