Cerebral circulation - cognition and behavior最新文献

Introduction

Delirium and infection are risk factors for dementia, with infection more strongly linked to vascular than Alzheimer's-type dementia. It is unclear whether regional atrophy and white matter changes (WMC) of vascular origin modify these relationships. To inform future studies, we determined rates of cognitive frailty and frequency of brain scans in consecutive older hospital in-patients using routinely acquired electronic patient records (EPRs) data.

Methods

The Oxford Cognitive Comorbidity and Ageing Research Database (ORCHARD) includes real-world EPR data from consecutive older patients admitted to four general hospitals in Oxfordshire, UK (n=660,000 population). ORCHARD includes detailed data on cognitive frailty (dementia history, delirium diagnosis using the Confusion Assessment Method-CAM and 10-point Abbreviated-Mental-Test Score, AMTS), comorbidities, nutrition, falls risk, frailty, clinical observations, laboratory tests, and routine brain imaging. Long-term dementia outcomes are obtained from electronic records linkage including to regional mental health databases. Atrophy is rated using the Global Cortical Atrophy scale (GCA) and WMC using the Age-Related WMC (ARWMC) scale.

Results

Between 2017 and 2019, there were 51,202 consecutive unplanned admissions (adults >70 years with >1 unplanned admission lasting >1 day). The mean/SD age of patients was 82/7 years. Cognitive frailty was present in 17,466 (34.5%, 95%CI 34.0-34.9%) overall: delirium=7,411 (14.6%), delirium+dementia=4,757 (9.4%), dementia=3,784 (7.5%), AMTS<8=1,514 (3%). In a subset of 1100 consecutive patients, 668 patients had available brain imaging (CT: 96%, MRI: 22%, both: 18%). On the rated CT scans (n=290 for atrophy, n=117 for WMC), global atrophy was mild in 12%, moderate in 71%, and severe in 17%; temporal lobe atrophy was absent in 1%, mild in 49%, moderate in 46%, and severe in 4%; WMC was mild in 58%, moderate in 38%, and severe in 3%.

Discussion

Cognitive frailty, particularly delirium without dementia, was prevalent in older patients with unplanned hospital admission. Over half of older patients had brain imaging available with high rates of moderate/severe atrophy and WMC. These findings suggest that routinely acquired EPR can be combined with available brain imaging to explore (vascular) dementia risk factors such as delirium and infection in hospital “Big Data” studies.

Introduction

Blood-brain barrier (BBB) leakage is hypothesized to be an early step in the pathophysiology of cerebral amyloid angiopathy (CAA), possibly preceding vessel wall breakdown and hemorrhage. This study aims (1) to measure BBB leakage in vivo in the parenchyma and at the level of the leptomeningeal blood vessels in patients with CAA without lobar intracerebral hemorrhage compared to controls and (2) to study the relationship between BBB leakage and neuroimaging markers of CAA severity.

Methods

To date, 13 participants with probable CAA without prior intracerebral hemorrhage (age 67±9 years, 8 females) and 5 non-CAA controls with mild cognitive impairment (CDR 0.5 or 1) and no microbleeds (age 70±7 years, 1 female) have been included into the study. The 3T MRI protocol included pre- and post-contrast T1-weighted (0.9 × 0.9 × 0.9 mm3) and T2-FLAIR scans (0.9 × 0.9 × 0.9 mm3, TE 500 ms), an SWI (0.6 × 0.6 × 1.4 mm3), and a Dynamic Contrast Enhanced (DCE) scan (0.9 × 0.9 × 3.0 mm3). Participants received (0.2mL/kg) a gadolinium-based contrast agent (Dotarem) intravenously during the DCE scan. DCE scans were analyzed with ROCKETSHIP software to quantify the permeability-surface area product (PS), which represents the rate at which contrast agent leaks from the plasma into the parenchyma. Leptomeningeal CSF enhancement is measured by visually inspecting post-contrast versus pre-contrast T2-FLAIR scans.

Preliminary Results

Preliminary analysis revealed higher whole-brain PS in participants with CAA compared to non-CAA controls (Figure 1). Figure 2 shows an example of leptomeningeal CSF enhancement on post-contrast T2-FLAIR (2b) versus pre-contrast T2-FLAIR (2a). Ongoing analyses will compare PS-values in the cortex and white matter and in the occipital and frontal lobe. Furthermore, we aim to study the relationship between parenchymal and leptomeningeal contrast leakage with hemorrhagic neuroimaging markers (i.e. cortical microbleeds and cortical superficial siderosis) on SWI.

Discussion

These preliminary results indicate that we can capture BBB leakage in vivo in our cohort, and that parenchymal BBB leakage is higher in patients with CAA compared to controls. Successful completion of this ongoing study will aid our understanding of the role of BBB leakage in the pathophysiology of CAA and the potential added value of BBB imaging as an early disease biomarker in CAA.

Cerebrovascular dysfunction has been implicated as a major early contributor to Alzheimer's Disease (AD) pathology, with endothelial cell (EC) stress resulting in focal ischemia, cerebral blood flow impairments, and blood brain barrier (BBB) permeability. Recent evidence suggests that cardiovascular (CV)/cerebrovascular risk factors, such as hyperhomocysteinemia (Hhcy) contribute to increasing AD pathology and risk, but it remains unknown whether Amyloid beta (Aβ) and homocysteine function through common molecular mechanisms to induce EC dysfunction. Additionally, Aβ is known to mediate degeneration of the brain neuro-signaling pathways. Neurotrophic factors depletion, together with vascular and peripheral amyloid accumulation, may also result in the derangement of the peripheral nervous system, culminating in detrimental effects on other organs, including the heart. However, whether and how AD pathology modulates cardiac function, cardiac amyloidosis and heart innervation is still unknown. Here, we will discuss two important and new mechanistic perspectives on the vascular contributions to cognitive impairment and dementia:

Our new mechanistic data demonstrates that Hhcy specifically potentiates Aβ-mediated activation of the death receptors 4/5 (DR4/5)-mediated extrinsic apoptotic pathway in cerebral ECs. Additionally, we revealed that Hhcy potentiates Aβ-mediated EC barrier permeability, deregulating specific junction proteins expression, localization, and phosphorylation. Moreover, Hhcy and Aβ impair VEGF-A and VEGFR2 signaling and VEGFR2 endosomal trafficking, additively decreasing EC angiogenic capabilities. This work highlights new potential molecular targets against cerebrovascular pathology in comorbid AD/CAA and Hhcy conditions.

We will describe the first report of cardiac remodeling, amyloid deposition, and neuro-signaling dysregulation in the heart of Tg2576 mice, a widely used model of AD and cerebral amyloidosis. Tg2576 mice hearts exhibited an accumulation of amyloid aggregates, including Aβ40, together with a robust reduction in NGF and BDNF protein expression, leading to interstitial fibrosis and severe cardiac nervous system dysfunction. The transgenic mice also showed a significant decrease in cardiac adrenergic and regenerating nerve endings. Our data suggest that AD amyloid pathology can cause deleterious functional effects on the heart, and the peripheral neurotrophic pathway may represent a potential therapeutic target to limit these effects.

Introduction

White matter hyperintensities (WMH) are related to cognitive decline, particularly processing speed and executive functioning (EF). However, all cognitive domains might be affected. WMH can regress and this might have positive consequences for cognition, but the effects of WMH regression on cognition are unknown. This study aims to assess whether changes in global cognition, processing speed and EF are related to progressing and regressing WMH.

Methods

We recruited mild, non-disabling, ischemic stroke patients with sporadic small vessel disease. They underwent MRI and cognitive assessment within 3 months post-stroke and 1 year later. Cognitive assessment included MoCA (global cognition; score 0-30), trail making test (TMT) A (processing speed; seconds) and TMT B (EF; seconds). WMH volumes are reported as % intracranial volume (ICV). WMH volume change (%ICV) is defined as WMH volume difference between baseline and 1 year. We calculated quintiles (Q) of WMH volume change to group volume change. We performed three linear mixed models, with MoCA, TMT-A and B as outcomes, to assess relationships over time with quintile of WMH volume change. Predictors in addition to quintile are age, sex, premorbid intelligence (NART), stroke severity (NIHSS). Extra predictor for TMT-B analysis is the TMT-A time to correct for speed.

Results

202 participants had WMH change volumes available (mean age: 66.03 years [SD=11.15), 33% female]. Q1 reflect greatest WMH volume reduction and Q5 greatest volume increase, while Q3 is lowest overall volume change (Figure 1). MoCA score increased over time (Figure 2). Older age (std. B [std. 95%CI]: -0.303 [-0.400, -0.206]), worse NART (-0.463 [-0.557, -0.368]), increasing NIHSS (-0.208 [-0.286, -0.130]) and more WMH increase (Q5; -0.513 [-0.814, -0.211]) predict lower MoCA. Older age (0.257 [0.135, 0.380]), worse NART (0.259 [0.139, 0.378]) and higher NIHSS (0.152 [0.078, 0.226]) predict worse TMT-A time (Figure 3A). Older age (0.224 [0.132, 0.316]), worse NART (0.295 [0.207, 0.383]), worse TMT-A (0.469 [0.384, 0.555]), worsening WMH volume (Q2; 0.382 [0.115, 0.0.649] and Q5; 0.425 [0.150, 0.699]) predict worse TMT-B time (Figure 3B).

Discussion

More WMH progression independently predicts worse global cognition and EF but not processing speed. WMH regression (Q1) was not related to worsening or improving global cognition, processing speed and EF. Cognitive consequences of WMH regression might be comparable to stable WMH (Q3).

Introduction

Mid-life cardiovascular and late-life structural cerebrovascular pathology play a major role in accelerating cognitive decline in normal aging and dementia. Cerebral blood flow (CBF) may be a critical intermediate biomarker of future cognitive decline, however our understanding of normal CBF variability and its relation with mid-life cardiovascular and late-life structural cerebrovascular parameters is limited. The MRC National Survey of Health and Development neuroimaging sub-study ‘Insight 46’ provides a unique opportunity to study the effects of cardiovascular and cerebrovascular health on CBF in a cohort with a fixed chronological age. We explored associations of life-long cardiovascular parameters and WMH volume with ASL MRI CBF in this cognitively healthy population-based sample.

Methods

3D T1-weighted, FLAIR, and pseudo-continuous ASL (labeling duration = 1800ms; post-labelling delay = 1800ms) data (3T) were acquired in 295 participants (Table 1). Clinical data included systolic blood pressure (SBP), diastolic blood pressure (DBP), mean arterial pressure (MAP), pulse pressure (PP), and the Framingham Risk Score (FRS). MRI scans were processed with ExploreASL. Grey matter (GM), white matter (WM) and white matter hyperintensity (WMH) volume were segmented from the T1w and FLAIR images. ASL- derived partial volume-corrected CBF and the spatial coefficient of variation (sCoV) were obtained in whole-brain GM and WM. Linear regression models examined associations between life-long cardiovascular health (ages 43, 53, 60-64, 69, and 69-71 years), ASL metrics (at 69-71 years), and WMH load (at 69-71 years). Models were corrected for sex, and sex interactions were tested if applicable.

Results

While mid-life cardiovascular parameters were associated with late-life sCoV and CBF, the strongest associations were seen at 69-71 years. At this time point, higher SBP and MAP were associated with lower GM CBF in men (1A-B, β=-0.16,-0.28) and relatively stable GM CBF in women (1A-B, β=0.02,-0.02); higher DBP was associated with lower GM CBF (β=-0.18). Higher WMH volume was related to higher GM and WM CBF (2A-B, β=2.04,1.45), and lower GM and WM sCoV (2C-D, β=-0.04,0.05).

Discussion

These sex-dependent associations encourage further investigation into the potential mediatory role of CBF between mid-life cardiovascular and late-life structural decline of cerebrovascular health, leading to cognitivexxxxx

Objectives

Cardiovascular conditions like hypercholesterolemia and hypertension increase the risk for Alzheimer's Disease (AD). Thus, certain AD risk profiles may benefit from optimized multi- medication therapies including for example cholesterol-lowering and antihypertensive drugs. We previously showed that the drugs most frequently prescribed in older patients in Sweden are compounds from cardiovascular drug classes such as antithrombotic agents, lipid modifying agents, ACE inhibitors, selective calcium channel blockers and are used in combination. In this study we aim to investigate the effects of two multiple-drug regimens in the APPNL-G-F knock-in (APP KI) mouse model of AD and explore whether this could affect the disease progression at early stages.

Methods

APP KI mice were fed for 2 months with a control or multi-medication diet (including anti- hypertensive, lipid lowering and psychotropic drugs, in two different combinations) based on the most used medications by older adults in Sweden. In addition to the multi-medication regimens, mice were also tested for specific monotherapies from the compounds used in combination. Animals were assessed for locomotion, cognition, and anxiety-like behavior. Brain tissues were collected for molecular biology experiments, while blood was analyzed by GC/LC-MS to measure serum metabolomics.

Results

We found that multi-medication therapies in AD mice differentially affected essential functions such as locomotion, and distinct types of memory. APP KI male mice treated with combination#1 exhibited a rescue of cognitive deficits compared to controls, which we didn´t observe in females. These findings positively correlate with the significant reduction of cortical Aβ plaques observed in treated APP KI males. Conversely, combination#2 didn´t exert a positive effect on cognitive abilities. Monotherapy treatments induced different effects on functional and cognitive outcomes depending on sex, partially explaining the results observed in polypharmacy groups.

Discussion

We show that multi-medication therapies comprising cardiovascular drugs like statins and β-blockers or ACE inhibitors may impact the progression of AD pathophysiology depending on sex and multiple-drug combination, suggesting some synergic effects deriving from the multi- medication rather than the administration of single compounds. The outcomes from this study can provide knowledge for designing more individualized therapies in aging and AD, taking sex and gender into special consideration.

Introduction

Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and leukoencephalopathy (CADASIL) is the most frequent genetic cerebrovascular disease. The clinical aspects of the disease in relation to the various types of lesions on Magnetic Resonance Imaging (MRI) vary widely within families but also between multiple cohorts reported worldwide. Many limitations prevent the comparison of imaging data obtained using different scanners and sequences, in different patients cohorts. We aimed to develop and validate a practical tool to inventory quickly the most important MRI features in CADASIL for comparing imaging data across different populations.

Methods

The Inventory Tool (CADA-MRIT) was designed by consensus after repeated expert meetings. It consisted of eleven imaging items for evaluating periventricular, deep, and superficial white matter hyperintensity (WMH), lacunes, cerebral microbleeds (CMB), centrum semiovale and basal ganglia dilated perivascular spaces (PVS), superficial and deep atrophy, large infarcts, and macrobleeds. The reliability, clinical relevance and time-effectiveness of the CADA-MRIT were assessed using data from three independent cohorts of patients.

Results

Imaging data from 671 CADASIL patients (440 from France, 119 from Germany and 112 from Taiwan) were analyzed. Their mean age was 53.4 ± 12.2 years, 54.5% were women, 56.2% had stroke, and 31.1% had migraine with aura. Any lacune was present in at least 70% of individuals, while CMB were present in 83% of patients from the Asian cohort and in only 35% European patients. The CADA-MRIT scores obtained for WMH, CMB and PVS were comparable regardless of the scanner or sequence used (weighted κ > 0.60). Intrarater and interrater agreements were good to very good (weighted κ > 0.60). Global WMH and atrophy scores strongly correlated with the exact volumetric quantification of WMH or brain parenchymal fraction (Pearson r > 0.60). Different imaging scores were significantly associated with the main clinical manifestations of the disease. The time for evaluating one patient was around 2-3 minutes.

Discussion

The CADA-MRIT is an easy-to-use instrument for analyzing and comparing the most frequent MRI lesions of CADASIL across different populations. This tool is reliable. It can be used with different imaging sequences or scanners.