Cerebral circulation - cognition and behavior最新文献

Cerebrovascular dysfunction, leading to inadequate brain perfusion and oxygenation, is a major contributor to cognitive decline and dementia. Chronic hypoxia is a putative mechanism of vascular-mediated brain damage, particularly in relation to white matter lesions, as demonstrated by human neuroimaging and histopathology studies. Moreover, increasing evidence suggests that microglia, the primary immune cells of the brain parenchyma, may play a key role in modulating cerebrovascular disease outcomes. Indeed, unpublished work from our lab using a model of chronic cerebral hypoperfusion found greater vascular and white matter abnormalities concomitant with reduced microglial-vascular interactions in mice lacking the microglial immunoreceptor triggering receptor expressed on myeloid cells 2 (TREM2). However, the underlying mechanisms remain incompletely understood. Therefore, this project aims to further investigate whether microglial TREM2 signalling contributes to cerebrovascular resilience, and specifically vasculoprotection, focusing on the context of hypoxia. To address this, we are housing mice at 8%O2 to achieve chronic mild hypoxia (CMH). As corroborated by our studies, CMH induces cerebral microbleeds associated with parenchymal fibrinogen leakage in both grey and white matter regions (Figure 1), and is thus a reductionist approach well-suited for examining microglial mechanisms conferring vasculoprotection. Ongoing studies in young (5-6 months) and aged (15-18 months) cohorts are utilising histology and immunostaining to determine the impact of TREM2 deficiency and ageing on CMH-induced phenotypes, with particular focus on profiling microbleed burden, BBB integrity and interactions between microglia and other cell types within the neurovascular unit. Given that TREM2 is a key regulator of microglial metabolism and lipid processing, future work will utilise flow cytometry and spatial lipidomics to characterise microglia and brain lipid metabolism during CMH, thus providing insight into immunometabolic changes that may underpin microglial vasculoprotection in hypoxia. Findings from these studies will increase our understanding of microglia-vascular interactions, which can ultimately be exploited to promote resilience to cerebrovascular and other hypoxia- related pathologies.

Introduction

Cerebral microbleeds (CMB) are predictive of increased risk of dementia and stroke. Although commonly regarded as vascular markers, CMB can also stem from non-vascular aetiologies like head injuries or traumatic brain injury (TBI), although these are often overlooked. Therefore, this study examines CMB in relation to TBI, and their differential causes (i.e., risk factors) and consequences (i.e., clinical outcomes).

Methods

In 605 healthy middle-aged adults (aged 40-59), CMB were rated on 3T susceptibility weighted imaging (SWI) MRI. TBI was assessed using the Brain Injury Screening Questionnaire (BISQ). TBI+ was defined as at least one blow to the head resulting in loss of consciousness (36.0%; n=217). Memory was assessed using the COGNITO battery. Interaction analyses examined TBI*CMB interactions on hypertension, gait, and memory. Dominance analysis examined the relative contribution of TBI and vascular risk factors on predicting gait disturbances and memory. All models adjusted for sex, age, education, and study site.

Results

TBI was related to higher CMB count (t=2.06, p=.039), and were more common in males (48.3%) than females (28.0%) (χ2=28.91, p<.001). Number of TBI events related to poorer memory (t=-2.62, p=.009) and gait disturbances (t=3.54, p<.001). Interaction analyses demonstrated that hypertension (t=-2.26, p=.024), memory (t=2.70, p=.007) and gait (t=-2.29, p=.023) were less closely related to CMB in individuals with greater number of TBI events, relative to those with fewer TBIs. Regionally, these interactions were significant for lobar CMB, but not deep subcortical CMB. Within the TBI+ group, dominance analysis demonstrated that number of TBI events outperformed vascular risk factors in predicting gait disturbances (Contribution to R2: TBI=52.9%, vascular risk=32.6%) and memory (TBI=28.7%, vascular risk=1.2%).

Discussion

CMB appeared to differ aetiologically and clinically in those with and without TBI. In individuals with TBI, TBI itself was the dominant driver of clinical deficits. While vascular CMB may appear more detrimental than traumatic CMB at baseline, longitudinal analysis is required to determine how traumatic CMB differ in clinical trajectory and downstream pathologies. This study highlights the importance of differentiating between CMB of vascular origins vs. TBI in both research and clinically to aid prognosis and treatment decisions.

Introduction

The contribution of associated Alzheimer disease to poststroke cognitive impairment has been suggested on clinical grounds. However, the few published studies using amyloid PET have provided a widely ranging prevalence and a questionable relationship with cognitive status.

The main objective of the study was to determine the prevalence of amyloid PET positivity among poststroke patients with at least one impaired cognitive score. The secondary objectives were to determine the association between clinical, cognitive, and imaging characteristics at baseline with amyloid status.

Methods

The IDEA3 cohort included 91 stroke patients (cerebral infarct: 89%; hemorrhage: 11%). They were assessed at 808 ± 589 days poststroke with a cognitive battery, MRI, and florbetapir PET. Clinical, cognitive, and imaging characteristics at baseline were compared according to amyloid status.

Results

Amyloid PET was positive for 14 patients, corresponding to a prevalence of 15.4% (95%CI: 7.97-22.8). Amyloid-positive patients were older (p = 0.0001), did not differ according to the cause of stroke, except for a tendency towards a higher frequency of cerebral amyloid angiopathy in the hemorrhagic subgroup (p = 0.06). Their cognitive performance was lower on both the cognitive screening test (p = 0.023) and battery (p = 0.02), without a specific profile.

Discussion

This study supports the mild prevalence of amyloid burden and shows that it contributes to poststroke cognitive impairment.

Introduction

Due to increasing availability of MRI scans, incidental diffusion-weighted imaging (DWI)-positive lesions are increasingly recognized on brain MRI in individuals with vascular disease. Cerebral small vessel disease (SVD) is a putative cause of these lesions. We investigated the prevalence of incidental DWI-positive lesions in patients with Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL), a genetic form of SVD, which frequently manifests as subcortical infarcts at a younger age and serves as a pure disease model for sporadic SVD. Furthermore, in these patients, we assessed risk factors of incidental DWI-positive lesions, including common vascular risk factors and MRI markers of SVD.

Methods

64 patients with CADASIL and without acute (< 6 months) ischemic stroke were included from the VASCAMY study. Mean age was 51.9 years (SD 10.5) and 63% was female. Patients underwent 3T MRI at baseline, and 43 patients underwent a second MRI at 18 or 36 months. Incidental DWI- positive lesions were assessed by one expert rater on pre-processed trace images derived from diffusion MRI. At follow-up, difference imaging of the trace images was applied to allow systematic identification of new lesions. Rating was done according to STRIVE-2 criteria.

Results

At baseline, incidental DWI-positive lesions were prevalent in 13/64 (20%) patients. In total, 27/107 (25%) scans were DWI-positive, with 19/64 (30%) patients having an incidental DWI- positive lesion at any time point. Most lesions were located subcortically and were either tubular in shape, following the orientation of a perforating arteriole, or ovoid with a small cavitation. A few incidental DWI-positive lesions corresponded to recent microinfarcts. At baseline, incidental DWI- positive lesions were significantly associated with greater white matter hyperintensity volume, and presence and increased volume of lacunes (all p<.05).

Discussion

Cross-sectionally, incidental DWI-positive lesions were detected in a fifth of patients with CADASIL. Incidental DWI-positive lesions were mostly subcortical and significantly associated with MRI markers of SVD. Our findings, obtained in patients with pure SVD, i.e., without age-related co- morbidities, provide supporting evidence that subcortical incidental DWI-positive lesions are common in CADASIL and may be a feature of SVD.

Introduction

Biomarkers of inflammation and brain damage are associated with neurodegeneration and dementia but are scarcely investigated post-stroke. We hypothesized that biomarkers of brain tissue damage and inflammation are associated with i) cognition and imaging markers of brain pathology seven years post-stroke and ii) long-term cognitive deterioration post-stroke.

Methods

All patients with a first-ever stroke or TIA admitted to the stroke unit, Bærum Hospital, Norway, during 2007/2008 were invited to participate in the CAST (Cognition After Stroke) study and invited to a follow-up after one and seven years with cognitive assessments and diagnoses of dementia, mild cognitive impairment (MCI) or normal. After seven years, we measured serum glial fibrillary acidic protein (GFAP), neuron-specific enolase (NSE), Interleukin (IL) 8, 12, 18, and high sensitive C-reactive protein (hsCRP) and brain MRI for assessment of Fazekas and global cortical and medial temporal lobe atrophy (MTA).

Results

Of 227 subjects recruited, 116 completed the seven-year follow-up, 113 with blood biomarkers, and were included in this study. Of these, 77 had complete MRI examinations. Mean age at baseline was 67.9 (SD 11.0) years, 87 (77 %) suffered an ischemic stroke, and 52 (46%) were women. The mean age after seven years was 75.4 (SD 11.1). At one- and seven-years follow-up, 62 (55%) and 45 (40%) had normal cognition, 37 (33%) and 42 (37 %) MCI, while 14 (12 %) and 26 (23%) had dementia, respectively. Cognitively, 35 patients progressed during follow-up. In unadjusted logistic regression, only hsCRP was associated with post-stroke dementia (odds ratio 1.08, 95% confidence interval 1.02 to 1.14, p=0.01). Adjusting for age did not change the result (OR 1.09, 95% confidence interval 1.06-1.19, p<0.001). In univariate ordinal regression, only NSE was associated MTA, but not after age adjustment. None of the biomarkers was associated with deterioration of cognition from one to seven years post-stroke.

Discussion

In this exploratory study, only elevated levels of hsCRP were associated with dementia seven years post-stroke, indicating a role of neuroinflammation in the development of cognitive impairment in long-term follow-up. [Clinicaltrials.gov (NCT00506818)]

Introduction

Identifying novel cerebral small vessel disease (cSVD) biomarkers in blood is critical to advance therapeutic and preventive strategies for Vascular Contributions to Cognitive Impairment and Dementia (VCID). This exploratory analysis aimed to identify novel blood-based markers of cSVD using proteomics in a Hispanic sample. This is critical, as most biomarker discovery has focused on non-Hispanic Whites, despite increased cardiometabolic risk and cognitive impairment among minoritized populations.

Methods

We included 107 dementia-free Mexican American participants from the MarkVICD-1 San Antonio site (73% women, mean age 70 ±7 years, Table 1). Participants provided fasting blood samples and underwent a comprehensive clinical and neuroimaging evaluation. Serum aliquots were shipped to Olink for proteomic profiling with the Explore 3072 panel. Normalized protein levels were related to cSVD markers, including White Matter Hyperintensities (WMH), Peak-with of Skeletonized Mean Diffusivity (PSMD), and Free Water (FW), using linear regression models adjusting for age, age2, sex, and total intracranial volume. P-values were corrected using False Discovery Rate (FDR) to account for multiple testing.

Results

We identified 36, and 128 proteins significantly associated with PSDM, and FW, respectively (Figure 1). The strongest associations were seen for elevated neurogranin with higher PSMD (Beta ±SE, 0.20 ±0.04, FDR=0.005) and FW (0.23 ±0.04, FDR=0.002), and Cartilage Intermediate Layer Protein (CILP) with higher PSMD (0.07 ±0.014, FDR=0.005). Neurogranin is a marker of synaptic dysfunction and CSF levels have shown potential as a predictor of cognitive decline. CILP may antagonize TGFB1 and IGF1 and has been related to mortality in patients with heart failure.

Discussion

Our results uncovered multiple novel blood-based cSVD biomarkers for risk stratification in VCID studies, including neurogranin and CILP. Further studies are needed to confirm these findings in larger samples.

This study assessed whether the effect of vascular risk on cerebral blood flow (CBF) varies by gene dose of apolipoprotein (APOE) ε4 alleles. 144 older adults without dementia from the Alzheimer's Disease Neuroimaging Initiative underwent arterial spin labeling and T1-weighted MRI, APOE genotyping, fluorodeoxyglucose positron emission tomography (FDG-PET), lumbar puncture, and blood pressure (BP) assessment. Vascular risk was assessed using pulse pressure (systolic BP – diastolic BP). CBF was examined in six AD-vulnerable regions: entorhinal cortex, hippocampus, inferior temporal cortex, inferior parietal cortex, rostral middle frontal gyrus, and medial orbitofrontal cortex. Linear regressions tested the interaction between APOE ε4 dose and pulse pressure on CBF in each region, adjusting for age, sex, cognitive classification, antihypertensive medication use, FDG-PET, reference CBF region, and AD biomarker positivity. There was a significant interaction between pulse pressure and APOE ɛ4 dose on CBF in the entorhinal cortex, hippocampus, and inferior parietal cortex, such that higher pulse pressure was associated with lower CBF only among ε4 homozygous participants. These findings demonstrate that the association between pulse pressure and regional CBF differs by APOE ε4 dose, suggesting that targeting modifiable vascular risk factors may be particularly important for those genetically at risk for AD.

Background

There are conflicting results whether serum lipid pattern is related to the amount of white matter hyperintensities (WMHs) on magnetic resonance imaging. Little is known of the associations between lipid concentrations and the subsequent risk of the subcortical small vessel type of dementia (SSVD), in which WMHs are a prominent manifestation. Here, we determined whether lipid levels are associated with the risk of SSVD, Alzheimer's disease (AD), or mixed dementia (combined AD and SSVD).

Methods

This was a longitudinal, prospective study of 329 patients with subjective or objective mild cognitive impairment at baseline. The statistical analyses included Cox proportional hazards regression with adjustments for age, gender, education, body mass index, current smoking, hypertension, diabetes mellitus, and APOE ε4 genotype.

Results

During the follow-up (mean 4.1 years), 80 patients converted to dementia [SSVD, n = 15 (5 %); AD, n = 39 (12 %); and mixed dementia, n = 26 (8 %)]. Serum high-density lipoprotein cholesterol (HDL, per SD increase) was inversely associated with the risk of SSVD, whereas triglycerides (TG), low-density lipoprotein cholesterol (LDL)/HDL ratio, and TG/HDL ratio were positively associated with SSVD risk. Furthermore, the lowest HDL tertile was associated with a sevenfold, and the highest tertile of TG/HDL ratio with a threefold, increase in SSVD risk. There were no associations with the risk of AD or mixed dementia after adjustment for covariates.

Conclusion

In a memory clinic population, low HDL and high TG/HDL ratio were independent risk factors of SSVD, but not of AD or mixed dementia.