Cerebral circulation - cognition and behavior最新文献

Introduction

Nutrition, a modifiable risk factor, presents a low-cost prevention strategy to reduce the burden of cognitive impairment and dementia. However, studies examining the effects of dietary patterns on cognition are lacking in multi-ethnic Asian populations. We investigate the association between diet quality, measured with the Alternative Healthy Eating Index (AHEI)-2010, and cognitive impairment in middle-and old-aged adults of different ethnicities (Chinese, Malay, Indian) in Singapore.

Methods

This cross-sectional study (n=3138) was based on data from the Singapore Multi-Ethnic Cohort. Dietary intake collected with a validated semi-quantitative Food Frequency Questionnaire were converted into AHEI-2010 scores, where trans-fat and sodium consumption were not considered and a score range of 0-90 was allowed. Higher AHEI-2010 score indicates better compliance to recommended dietary pattern. Cognition, assessed with the Mini-Mental State Examination (MMSE), was analysed as a continuous or binary outcome (cognitively impaired is defined using education-based cut-offs of <23, 25 or 27 for participants with no education, primary school education and secondary school education and above). Multivariable linear and logistic regression models were used to examine associations between AHEI-2010 and cognition, adjusting for covariates.

Results

Participants have a mean age of 56.6 (SD = 9.3) years, and 41.6% were male. Participants have a mean AHEI-2010 score of 52.4 (SD = 9.8) and 988 (31.5%) participants had cognitive impairment. Ethnic Chinese (mean = 51.3, SD = 9.6) and Indians (mean = 51.3, SD = 9.7) had higher AHEI-2010 score than Malays (mean = 47.6, SD = 9.9). Higher AHEI-2010 scores were significantly associated with higher MMSE score (p trend < 0.001) and lower odds of cognitive impairment (p trend = 0.01). Compared with lowest quartile, participants from highest quartile had 0.44 (95%CI 0.22, 0.67) higher MMSE score and 31% less cognitive impairment odds (OR = 0.69, 95%CI 0.54, 0.88) after adjusting for all the covariates. However, no significant associations were observed for individual dietary components of the AHEI-2010 with MMSE or cognitive impairment.

Discussion

Healthier dietary patterns were associated with better cognitive function in middle- aged and older Singaporeans. These findings could inform better support to promote healthier dietary patterns in Asian populations.

The Global Burden of Disease Study projects an almost tripling of dementia cases worldwide in the next 30 years making it important to recognize and understand modifiable risks and preventatives for cognitive impairment. Recent studies suggest that prevention or treatment of cardiovascular risks may be an important strategy to prevent or slow the progression of cognitive impairment. In 2017, the American Heart Association and American Stroke Association introduced metrics for "optimal brain health". These metrics defined brain health in terms of ideal health behaviors and factors.

Since then and leading up to 2017, a number of clinical trials have been conducted to investigate the potential of modification of cardiovascular risks on prevention of dementia or cognitive impairment and thus, enhancement of brain health. This discussion is a review of findings from clinical trials focusing on interventions, including antihypertensive agents, glycemic control and lipid-lowering therapies, multidomain approaches, and antithrombotic medications. Notably, the results highlight the promise of intensive blood pressure lowering strategies and multidomain approaches, as evidenced by the FINGER trial. The review also discusses the potential of treatment or prevention of cerebral small vessel disease (cSVD) and the application of Mendelian randomization as a strategy to preserve brain structure and function.

Brain health initiatives and programs are gaining traction worldwide. Some are clinically based, others research based, and some are a combination of clinical and research action plans. Achievement of global brain health is a challenging endeavor with prerequisites including but not limited to multidisciplinary and multisectoral approaches, strengthening of neurologic policies at local and regional levels, global advocacy, leadership and collaboration amongst stakeholders, development of technical and guidance documents, and strengthening and interpretation of the relevant evidence. Over 1 billion persons worldwide are impacted by neurologic disorders, and brain health initiatives are needed to curb the human suffering and cost of these disorders. We provide a brief review of select brain health initiatives and programs and offer possible steps to achieve brain health globally.

Background

The disruption of the neurovascular unit (NVU), which maintains the integrity of the blood brain barrier (BBB), has been identified as a critical mechanism in the development of cerebrovascular and neurodegenerative disorders. However, the understanding of the pathophysiological mechanisms linking NVU dysfunction to the disorders is incomplete, and reliable blood biomarkers to measure NVU dysfunction are yet to be established. This systematic review and meta-analysis aimed to identify biomarkers associated with BBB dysfunction in large vessel disease, small vessel disease (SVD) and vascular cognitive disorders (VCD).

Methods

A literature search was conducted in PubMed, EMBASE, Scopus and PsychINFO to identify blood biomarkers related to dysfunction of the NVU in disorders with vascular pathologies published until 20 November 2023. Studies that assayed one or more specific markers in human serum or plasma were included. Quality of studies was assessed using the Newcastle-Ottawa Quality Assessment Scale. Effects were pooled and methodological heterogeneity examined using the random effects model.

Results

A total of 112 studies were included in this review. Where study numbers allowed, biomarkers were analysed using random effect meta-analysis for VCD (1 biomarker; 5 studies) and cerebrovascular disorders, including stroke and SVD (9 biomarkers; 29 studies) while all remaining biomarkers (n = 17 biomarkers; 78 studies) were examined through qualitative analysis. Results of the meta-analysis revealed that cerebrospinal fluid/serum albumin quotient (Q-Alb) reliably differentiates VCD patients from healthy controls (MD = 2.77; 95 % CI = 1.97–3.57; p < 0.0001) while commonly measured biomarkers of endothelial dysfunction (VEGF, VCAM-1, ICAM-1, vWF and E-selectin) and neuronal injury (NfL) were significantly elevated in vascular pathologies. A qualitative assessment of non-meta-analysed biomarkers revealed NSE, NfL, vWF, ICAM-1, VCAM-1, lipocalin-2, MMP-2 and MMP-9 levels to be upregulated in VCD, although these findings were not consistently replicated.

Conclusions

This review identifies several promising biomarkers of NVU dysfunction which require further validation. A panel of biomarkers representing multiple pathophysiological pathways may offer greater discriminative power in distinguishing possible disease mechanisms of VCD.

Introduction

Delirium, an acute and fluctuating disturbance of attention, cognition, and consciousness, may occur in the acute phase of stroke. Research on long-term outcomes of stroke patients experiencing delirium is limited. Our previous findings suggested that patients experiencing acute delirium had increased cognitive and psychiatric symptoms in the chronic phase. In the current study, this was further examined in a larger sample, including measures of global cognition, as well as psychiatric symptoms.

Methods

As part of the Nor-COAST study, 373 stroke patients were screened for delirium using the Confusion Assessment

Methods

Patients were included in the study if they had available data from any of the follow-ups at three, 18 or 36 months, totaling 334 (44.6% women, mean (SD) age: 72.1 (12.5) years, 17 (5.1%) diagnosed with delirium). Global cognition was measured using the Montreal Cognitive Assessment (MoCA). Psychiatric symptoms were measured using the Hospital Anxiety and Depression Scale (HADS) and the Neuropsychiatric Inventory-Questionnaire (NPI-Q). Subscales of NPI-Q were used to measure specific psychiatric symptoms. Mixed-model linear regression was applied with MoCA, HADS, and NPI-Q, one at a time, as dependent variables. The independent variables were delirium, time as a categorical covariate, and their interaction. Mixed- model binary logistic regression was used to analyze differences in specific psychiatric symptoms.

Results

At three months, delirium was only significantly associated with a higher NPI-Q score (mean (SD) 2.9 (3.6) vs 1.4 (2.2)). At 18 and 36 months respectively, delirium was associated with a lower MoCA score (mean (SD) 19.7 (6.6) vs 24.3 (5.0), and 20.6 (7.6) vs 24.6 (4.8)), higher HADS anxiety symptoms (5.0 (4.3) vs 3.3 (3.3), and 5.9 (4.1) vs 3.4 (3.6)), higher HADS depression symptoms (7.2 (4.7) vs 3.4 (3.3), and 6.6 (5.1) vs 3.7 (3.7)), and higher NPI-Q score (2.4 (4.4) vs 1.7 (2.3), 2.6 (4.5) vs 1.0 (1.9)). Delirium significantly predicted the psychiatric symptoms hallucinations and agitation.

Discussion

Patients with delirium in the acute phase of stroke may be particularly vulnerable to developing cognitive and psychiatric symptoms in the chronic phase.

Introduction

The long-term evolution of recent small subcortical infarcts (SSIs) remains insufficiently characterized. Previous studies have indicated haemosiderin deposits (HD) in SSIs during their subacute and chronic stages. Our study aims to provide a comprehensive description of the morphology and evolution of HD in SSI and explore associated factors.

Methods

We enrolled 140 patients with SSI from the Mild Stroke Study 3 (MSS3). Using susceptibility-weighted imaging (SWI), we categorized HD in SSI into five types: none, spots, smudge, rim, and lines/dots around the infarct. The evolution types were classified as single type or mixed type. Over a one-year follow-up period, we examined the evolution of per-infarct associations with HD type and identified influencing factors.

Results

Out of the 119 enrolled SSI patients (mean age: 64.3±11.4 years, 80 men [67.2%]), we analyzed 141 small subcortical infarcts, excluding 5 due to motion artifacts or lack of MR scanning at the six-month and one-year follow-ups. During the one-year follow-up, we observed HD in 101 infarcts, with the percentage of HD increasing from 55.0% at baseline to 100% at the one-year follow-up. The predominant initial HD type was smudge, and the main evolution types were retaining smudge of the single type (32.8%) and smudge with rim in the mixed type (23.3%). Logistic regression analysis revealed that infarct volume (OR=1.55, 95% CI 1.13-2.14; P=0.007) and location (basilar ganglia: OR=5.13, 95% CI 1.26-20.83; P=0.022; centrum semiovale: OR=4.125, 95% CI 1.07-15.86, P=0.039) were independent predictors of HD on SWI.

Discussion

The presence of HD in SSI detected through SWI may be associated with the volume and location of infarct the infarct. The classification of HD and its evolution hold clinical significance in differentiating an infarct from a primary hemorrhage during the subacute and chronic periods.

Introduction

Cerebral small vessel disease (SVD) is a major cause of cognitive impairment and stroke. Neuroinflammation and blood-brain barrier (BBB) leakage may play a role in pathogenesis, but no definitive causal link has been established. In a rodent SVD model, minocycline treatment reduced brain lesions, neuroinflammation and BBB permeability. We tested whether these processes can be altered in SVD.

Methods

MINERVA was a phase II, double-blind, randomised controlled trial in moderate-to-severe symptomatic SVD. Participants with lacunar stroke and confluent white matter hyperintensities underwent simultaneous dynamic contrast-enhanced MRI to measure BBB permeability and 11C- PK11195 positron emission tomography (PET) to quantify microglial signal (figure 1). They were randomised to either minocycline 100mg bd or placebo for three months, after which PET-MRI was repeated. The co-primary outcomes were volumes of ‘hotspots’ of increased BBB permeability and 11C-PK11195 binding in the normal appearing white matter above the 95th percentile of healthy control reference values. A sample size of 44 allowed detection of a 20% reduction in these metrics (power = 80%, α=0.05).

Results

44 patients were recruited from September 2019 - June 2022 at 23.1±24.7 months after lacunar stroke. Mean age was 69.9±10.8 years and 28/44 (63.6%) were male. 86.4% had a history of hypertension, 75.0% of hypercholesterolaemia and 18.2% were diabetic. Participants had mean white matter lesion volume of 31.3±26.0cc and median 2 (IQR 1–3) lacunes. The BBB permeability ‘hotspot’ tissue was 4.08±3.69% in the treatment group at baseline and 6.19±5.09% at follow-up; ‘hotspot’ tissue was 8.49±8.45% in the placebo group at baseline and 13.04±9.24% at follow-up (relative risk of treatment 0.97, 95% CI 0.91–1.03). The 11C-PK11195 ‘hotspot’ tissue was 10.71±4.04% in the treatment group at baseline and 9.97±5.50% at follow-up; ‘hotspot’ tissue was 10.11±4.67% in the placebo group at baseline and 7.79±5.67% at follow-up (RR 1.01, 95% CI 0.98–1.04; figure 2).

Discussion

Minocycline does not alter BBB permeability or microglial activity (measured using DCE-MRI and 11C-PK11195 respectively) in SVD patients. Secondary outcomes include changes in a panel of serum inflammatory biomarkers, and one-year progression of MRI white matter damage and cognitive performance.

International Clinical Trials Registry Platform reference: ISRCTN15483452 (http://isrctn.com/ISRCTN15483452)

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.