Cerebral circulation - cognition and behavior最新文献

Introduction

Magnetic resonance imaging of the brain reveals age-related pathologies like white matter hyperintensities (WMH), cerebral microbleeds (CMB), lacunar infarcts (LAC) and grey- and white matter atrophy. The term cerebral small vessel disease (CSVD) has been used to collectively describe these changes, believed to emanate from small vessel endothelial dysfunction, although pathophysiological mechanisms are still largely unknown. We hypothesized that an explorative investigation of the plasma biomarker profile in affected subjects might shed some light on underlying mechanisms involved in CSVD and brain atrophy.

Methods

In a cross-sectional design, we investigated 401 subjects aged 70-86 from the randomized population study Good Aging in Skåne Study (GÅS) with brain MRI and OLINK immune- assay proteomics of 257 serum proteins previously associated with cardiovascular disease (CVD II and CVD III) and inflammation. The Benjamini-Yekutieli correction was used for keeping the false discovery rate (FDR) at 5%.

Results

We could see no significant difference in protein expression in the individual markers of CSVD (WMH, CMB or LAC). We observed a significant association between CSVD severity score (including white and grey matter atrophies, WMH, CMB and LAC) and the elevation of 11 serum proteins (CTSL1, PGF, NTpBNP, TNFr2, GDF15, TNFr1, IL4RA, ADM, CXCL9, TFF3, BNP). Furthermore, 11 proteins were significantly associated with Cortical Atrophy (CDH5, IL4RA, TNFr1, PGF, TF, TNFr2, CD93, CTSL1, LTBR, TNFRSF11A, TNFRSF10A). Five of the proteins were significant in both models. We found an association between moderate/severe medial temporal lobe atrophy (MTA) according to Scheltens scale and overexpression of PI3. Atrophy of presumed non-vascular origin was significantly associated with a greater abundance of IL4RA. All models were corrected for FDR and entered into a multivariable model with age and sex as covariates.

Discussion

In a general population cohort of older adults, proteomic analysis of serum identified several proteins associated with MRI-markers of CSVD and brain atrophy. Many of the identified protein biomarkers have previously been associated with hypertension, metabolic disease, or chronic kidney failure. This emphasizes the importance of systemic vascular health on cerebral pathological changes.

Introduction

In healthy adults, 15-20% of cardiac output is distributed to the brain. During aging, absolute cerebral blood flow (CBF) values show significant decline across most parts of the brain, approximately 0.38 ∼ 0.45% per year. CBF decline is suggested to be associated with reduction in neuronal activity and degeneration in microvasculature. However, there was no significant association between global CBF and several vascular risk factors. We examined therefore if Cardiac output, a hemodynamic measure of left ventricular pump capacity, is associated with regional CBF during aging.

Methods

A population based randomised cohort of older adults (n=341), aged 73-87 years (mean 77.4; SD 3.8), took part in a Swedish GÅS study. The regional CBF was examined with arterial spin labelling MRI. The CBF-maps were directly obtained from the MRI-system without any additional processing and regions (ROIs) were positioned upon anatomical preferences. Hemodynamic measures were obtained with Finometer within 6 months from MRI examination, and Cardiac Output was calculated through waveforms recorded from the middle finger and brachial level. Pulsatility Index was calculated (PSV-EDV/MeanV) in both Common Carotid Arteries using ultrasound. Aortic stiffness has been estimated by carotid-femoral pulse wave velocity (cfPWV) (table 1).

Results

Age was associated with Pulsatility indexes (Right r=0.21; left r=0.19), cfPWV (r=0.16), and cardiac output (r= −0.16), but not with mean blood pressure, heart rate or regional CBF.

Cardiac Output was associated with regional CBF in a majority of areas in left and right hemisphere. A linear regression unstandardized coefficients (B) are presented in Table 2 , adjusted for: age, gender, heart rate, mean blood pressure, pulsatility index of corresponding carotid, and cfPWV. Strongest associations were observed in posterior and cerebellar areas, as well as border zone /watershed areas. Gender was a significant confounder in several ROIs, indicating stronger association in females.

Discussion

The variability of regional CBF increases in elderly population and cardiac output is decreasing with age. In older adults, Cardiac Output is strongly associated with regional CBF, especially in posterior and watershed brain areas, independently of central or peripheral arterial stiffness. Sex-related difference observed in younger elderly is still present in aging.

Introduction

Alzheimer's disease (AD) and cerebral small vessel disease (SVD) frequently coexist, and increasing evidence suggest that microvascular changes may be related to AD pathology. SVD is however heterogeneously expressed on magnetic resonance imaging (MRI), and several novel methods can determine different aspects of vascular pathology. These methods need to be explored properly in clinical AD cohorts to better understand the link between AD and SVD, and could possibly be included in the staging and diagnostics of AD.

Methods

588 subjects were included from the Norwegian Dementia Disease initiation (DDI) cohort, longitudinal data was available for 285 subjects. Subjects underwent clinical examination including lumbar puncture, and were classified according to the A/T/N-system into the following groups: A-/T-/N- (N=208), A-/T+/N± (N=11), A+/T-/N- (N=75)and A+/T+/N±(N=157) according to positive (+) or negative (-) values of cerebrospinal fluid (CSF) amyloid-β42/40-ratio (A), phosphorylated-tau (T) and total-tau (N)). We used Peak width of skeletonized mean diffusivity (PSMD), a novel MRI Diffusion Tensor Imaging (DTI) method for determination of global SVD-burden based on an automated algorithm (5). We used a mixed linear regression model to determine baseline and longitudinal differences in PSMD across A/T/N-classified subjects in a predementia cohort, adjusted for subject and scanner as a random effect.

Results

Compared to A-/T-/N- at baseline, we found significantly larger SVD burden in A+/T-/N- compared to A-/T-/N- (p<0.05). Longitudinally, we found a significantly greater increase in SVD burden measured by PSMD in A+/T+/N± compared to A-/T-/N- (p<0.001).

Discussion

Our findings indicate that PSMD reflects AD-related SVD. Notably, SVD burden increased markedly in in A+/T+/N± subjects, compared to biomarker-negative subjects. These microvascular alterations may be subsequent events following the formation of amyloid and neurofibrillary tangle pathology. Our findings thereby contribute to the growing body of evidence linking AD pathology and SVD. Further exploration of this connection via CSF candidate biomarkers reflecting vascular pathology is warranted for a deeper understanding of these intertwined pathologies.

Introduction

Arterial spin labeling (ASL) MRI, a non-invasive technique for imaging perfusion, now allows studying BBB permeability. The DEveloping BBB-ASL as a non-Invasive Early biomarker of Alzheimer's Disease (DEBBIE-AD) multi-cohort study integrates this modified BBB-ASL technique in several healthy and diseased populations (Table 1) to study methodological and clinical research questions (Table 2) on the ability of BBB-ASL as an early AD biomarker.

Methods

DEBBIE-AD will enroll various cohorts with subjective cognitive decline, mild cognitive impairment, and AD dementia, as well as age-matched healthy controls, at seven sites (Table 1). Our newly developed BBB-ASL sequence — implemented with the vendor-independent MRI framework gammaSTAR — will be added to multiple MRI protocols. The BBB-ASL sequence combines time-encoded multi-post labeling delay pseudo-continuous ASL with a multi-echo 3D GRASE readout, allowing estimating CBF, ATT, and the BBB time of exchange (Tex). Data analyses will be conducted using ExploreASL. Beyond MRI standard sequences, including T1w, T2w, FLAIR, DWI, the DEBBIE clinical outcomes include amyloid-PET and blood and CSF fluid biomarkers (Table 1).

Expected Results

Preliminary testing of the BBB-ASL has been conducted on 3T systems (different Siemens Heathineers scanners) in different cohorts at multiple sites. Data processing with ExploreASL includes FSL-FABBER4 for quantification, allowing harmonized image processing. An example of the mean and standard deviation Tex maps of two DEBBIE cohorts is shown in Figure 1 to illustrate the similarities of the Tex patterns from two cohorts of similar-aged healthy adults from different sites.

Discussion

The DEBBIE-AD study aims to provide evidence on the ability of BBB-ASL to measure BBB permeability and demonstrate its utility in AD-related pathologies. The presented sequence may provide novel and unique insights into the staging of BBB permeability changes in groups at greater risk of developing AD, which may, in turn, provide new targets for treatment.

Introduction

Diagnosis of acute ischemic stroke (AIS) as based on clinical examination and neuroimaging has limitations in determining subgroup aetiology and subsequent long-term motor and cognitive impairment. Identification of high-risk patients enables personalised prophylaxis and rehabilitation strategies. This study explores the clinical value of plasma brain-derived tau (BD-tau) and phosphorylated-tau217 (p-tau217), primarily associated with neurodegeneration, in identifying patients at risk of sequela after AIS.

Methods

We analysed a cohort of 193 patients admitted to the stroke unit at Akershus University Hospital in Oslo, Norway. Each patient received a diagnosis of AIS (n=102), transient ischemic attack (TIA, n=63) or stroke mimic (n=31). Patient characteristics were collected from hospital records. Biomarkers were quantified using Simoa HDX in venous blood sampled obtained the day after admission. Inpatient short-term outcomes, including stroke diameter on magnetic resonance imaging (MRI, n=134) and mini mental state examination (MMSE, n=153), were assessed prior to discharge. Non-parametric statistics, including Kruskal-Wallis and Kendall´s tau-b correlation tests were applied. Backwards stepwise linear regression analysis was used to determine the association between stroke diameter or MMSE and the biomarkers. A full model was fitted with explanatory variables as listen in table 1.

Results

BD-tau was significantly increased in AIS patients as compared to mimics (p=.004), whereas p- tau217 did not differentiate between the diagnostic groups. MRIs were available for 66 (64.7%) of AIS patients, of whom n=36 were diagnosed with cortical and n=30 with subcortical stroke. Cortical stroke diameter showed a strong correlation with BD-tau (fig. 1, <.001) and p-tau217 (=.003). In regression analysis, only BD-tau was found to be significantly associated with stroke diameter (table 1). Subcortical strokes were mot associated with any of the biomarkers. Furthermore, MMSE score correlated with BD-tau (fig. 2, <.001) and p-tau217 (<.001). In regression analysis, age was the strongest predictor of MMSE score, followed by p-tau217.

Discussion

Our findings suggest that blood-based BD-tau and p-tau217 have clinical potential in determining AIS subgroup aetiology and provide insights into cognitive impairment in AIS patients. These findings may have implications for rehabilitation and secondary prophylaxis after stroke.

Introduction

The mechanistic associations between small vessel disease (SVD) and dementia are still poorly understood. The APOE ε4 allele, recognised as the strongest genetic risk factor for Alzheimer's disease, has been previously implicated in SVD, although it remains unclear whether this association is gene-dose dependent. An emerging neuroimaging biomarker of SVD is Peak Width of Skeletonised Mean Diffusivity (PSMD), obtained from histogram analyses of diffusion weighted imaging (DWI) datasets. Here, we investigated the relationship between APOE ε4 gene dose and PSMD, as a surrogate marker of SVD, in a group of cognitively normal middle-aged adults.

Methods

The study included data from 1954 asymptomatic middle-aged adults from the ALFA (ALzheimer and FAmilies) and PREVENT-Dementia cohorts (See Table 1 for sample characteristics). PSMD was calculated from the DWI datasets using a publicly available script, and harmonised using COMBAT to account for site-related differences. Using non-parametric permutation models, our primary analyses focused on the (a) comparison of group differences (APOE ε4 heterozygotes vs homozygotes vs non-carriers) in PSMD, adjusting for age, sex, years of formal education, and sites; and (b) potential interactions between APOE ε4 gene dose and age on PSMD values. Marginal predictions were used to estimate the earliest age at which differences might emerge between the APOE ε4 groups and non-carriers.

Results

There were no significant differences in PSMD values across the non-carriers (n=1,197), heterozygous carriers (n=659), and homozygous APOE ε4 carriers (n=98) (p = 0.6; Figure 1). However, there was a statistically significant interaction between APOE ε4 gene dose and age on PSMD. Specifically, homozygous APOE ε4 carriers exhibited a steeper increase in PSMD with age compared to non-carriers and heterozygous carriers (T = 4.7, p<0.01; Figure 2). Marginal effect analyses revealed higher PSMD values in homozygous APOE ε4 carriers at the estimated age of 57 relative to non-carriers and heterozygous carriers.

Discussion

Homozygosity for APOE ε4 could hasten dementia onset by accelerating age-dependent increases in PSMD. Future studies with a longitudinal design are warranted to clarify the molecular mechanisms through which the APOE ε4 allele influences PSMD and if this contributes to the contributes to the development of dementia.

Introduction

Reduced cerebral blood flow has been associated with cognitive decline and incident dementia, with oxidative stress and reduced beta-amyloid clearance as possible mechanisms for neurodegeneration. Transcranial doppler sonography is a non-invasive tool for measuring cerebrovascular hemodynamics, including mean cerebral blood flow velocity. A systematic review and meta-analysis was performed to study mean cerebral blood flow velocity in the middle cerebral artery in persons with mild cognitive impairment and dementia compared to cognitively normal elderly.

Methods

We searched Pubmed, Embase, Cochrane Library, Epistemonikos, PsychINFO, and CINAHL according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. In total, 33439 titles and abstracts were screened, 86 articles were reviewed in full text, and 35 were included.

Results

Mean cerebral blood flow velocity in the middle cerebral artery was significantly lower in Alzheimer's disease (mean difference = 8.42; 95% confidence interval, -10.56 to -6.28), vascular dementia (mean difference = 11.75; 95% confidence interval, -14.68 to -8.82) and mild cognitive impairment (mean difference = 4.19; 95% confidence interval, -5.52 to -2.85) compared to cognitively normal elderly, see figures 1 – 3. Reduction in blood flow was equally pronounced in Alzheimer's disease and vascular dementia (mean difference = 2.79; 95% confidence interval, -0.78 to 6.35).

Discussion

Cerebral blood flow velocity is reduced in Alzheimer's disease, vascular dementia and MCI, with more pronounced disturbances in dementia.

Blood pressure variability (BPV) impacts brain health by influencing brain structure and cerebrovascular pathologies, though the mechanisms are poorly understood. Changes in the cerebrovasculature may lead to late-onset depression, cognitive impairment, and dementia, however the relationship between BPV with depression and anxiety remains unclear, due to methodological differences and inconsistencies in past research. This review aims to clarify the association between BPV with depression and anxiety in adults to inform understandings of the mechanisms implicating BPV in cognitive health. A systematic search from inception through to January 2024 was performed on Embase, PubMed, PsycINFO, and Web of Science. Studies that assessed BPV quantified by beat-to-beat, 24-hour, or visit-to-visit were eligible if the standardised assessment of depression and/or anxiety were reported as a linear association, or mean differences across control and affect groups. A total of 14 articles reporting on 13 samples and N = 5055 persons met the inclusion criteria (median female proportion = 61 %, range 0 % - 76 %). A meta-analysis was not possible due to methodological heterogeneity in BPV measurements and metrics across studies. Mixed results were observed across depression studies with inconsistencies and variation in the direction, strength of association, and BPV metric. There was weak evidence from only three studies to support a linear association between systolic coefficient of variation and anxiety. Collectively, the findings contribute to understanding the association between BPV and brain health, suggesting that any relationship between BPV and brain structures critical for cognitive function are independent of depression and only modestly implicate anxiety.