Serum hepatocyte growth factor is associated with small vessel disease in Alzheimer's dementia

Background: While hepatocyte growth factor (HGF) is known to exert cell growth, migration and morphogenic effects in various organs, recent studies suggest that HGF may also play a role in synaptic maintenance and cerebrovascular integrity. Although increased levels of HGF have been reported in brain and cerebrospinal fluid (CSF) samples of patients with Alzheimer's disease (AD), it is unclear whether peripheral HGF may be associated with cerebrovascular disease (CeVD) and dementia. In this study, we examined the association of baseline serum HGF with neuroimaging markers of CeVD in a cohort of pre-dementia (cognitive impaired no dementia, CIND) and AD patients. Methods: Serum samples from aged, Non-cognitively impaired (NCI) controls, CIND and AD subjects were measured for HGF levels. CeVD (cortical infarcts, microinfarcts, lacunes, white matter hyperintensities (WMH) and microbleeds) were assessed by magnetic resonance imaging (MRI). Results: After controlling for covariates, higher levels of HGF were associated with both CIND and AD. Among the different CeVD MRI markers in CIND and AD, only small vessel disease, but not large vessel disease markers were associated with higher HGF levels. Conclusion: Serum HGF may be a useful peripheral biomarker for small vessel disease in subjects with cognitive impairment and AD

Serum IL-8 is a marker of white-matter hyperintensities in patients with Alzheimer's disease

Introduction Neuroinflammation and cerebrovascular disease (CeVD) have been implicated in cognitive impairment and Alzheimer's disease (AD). The present study aimed to examine serum inflammatory markers in preclinical stages of dementia and in AD, as well as to investigate their associations with concomitant CeVD. Methods We performed a cross-sectional case–control study including 96 AD, 140 cognitively impaired no dementia (CIND), and 79 noncognitively impaired participants. All subjects underwent neuropsychological and neuroimaging assessments, as well as collection of blood samples for measurements of serum samples interleukin (IL)-6, IL-8, and tumor necrosis factor α levels. Subjects were classified as CIND or dementia based on clinical criteria. Significant CeVD, including white-matter hyperintensities (WMHs), lacunes, and cortical infarcts, was assessed by magnetic resonance imaging. Results After controlling for covariates, higher concentrations of IL-8, but not the other measured cytokines, were associated with both CIND and AD only in the presence of significant CeVD (CIND with CeVD: odds ratios [ORs] 4.53; 95% confidence interval [CI] 1.5–13.4 and AD with CeVD: OR 7.26; 95% CI 1.2–43.3). Subsequent multivariate analyses showed that among the types of CeVD assessed, only WMH was associated with higher IL-8 levels in CIND and AD (WMH: OR 2.81; 95% CI 1.4–5.6). Discussion Serum IL-8 may have clinical utility as a biomarker for WMH in AD. Longitudinal follow-up studies would help validate these findings

Synthesising practice guidelines for the development of community-based exercise programmes after stroke

This is a freely-available open access publication. Please cite the published version which is available via the DOI link in this record.Multiple guidelines are often available to inform practice in complex interventions. Guidance implementation may be facilitated if it is tailored to particular clinical issues and contexts. It should also aim to specify all elements of interventions that may mediate and modify effectiveness, including both their content and delivery. We conducted a focused synthesis of recommendations from stroke practice guidelines to produce a structured and comprehensive account to facilitate the development of community-based exercise programmes after stroke.National Institute for Health Research (NIHR) Collaboration for Leadership in Applied Health Research and Care (CLAHRC) for the South West Peninsul

Excess cardiovascular risk in diabetic women: a case for intensive treatment.

Diabetes is a common and rapidly growing disease that affects more than 380 million people worldwide and is an established risk factor for cardiovascular disease with differential effects on women compared to men. While the general population of women, particularly young women, has more favourable cardiovascular risk profiles than men, this protective effect has been shown to be lost or even reversed in diabetic women. Several studies have demonstrated a significant diabetes-associated excess risk of cardiovascular disease in women. Sex-specific differences in risk factors associated with diabetes and their management may be responsible for the relative excess cardiovascular risk in women with diabetes. Diabetic women need intensive treatment in order to optimize management of cardiovascular risk factors. Further studies are needed to elucidate the mechanisms underlying the excess cardiovascular risk in diabetic women in order to tailor prevention and treatment strategies

Association of plasma GFAP with elevated brain amyloid is dependent on severity of white matter lesions in an Asian cognitively impaired cohort

INTRODUCTION: While elevated blood glial fibrillary acidic protein (GFAP) has been associated with brain amyloid pathology, whether this association occurs in populations with high cerebral small vessel disease (CSVD) concomitance remains unclear. METHODS: Using a Singapore-based cohort of cognitively impaired subjects, we assessed associations between plasma GFAP and neuroimaging measures of brain amyloid and CSVD, including white matter hyperintensities (WMH). We also examined the diagnostic performance of plasma GFAP in detecting brain amyloid beta positivity (Aβ+). RESULTS: When stratified by WMH status, elevated brain amyloid was associated with higher plasma GFAP only in the WMH– group (β = 0.383; P < 0.001). The diagnostic performance of plasma GFAP in identifying Aβ+ was significantly higher in the WMH– group (area under the curve [AUC] = 0.896) than in the WMH+ group (AUC = 0.712, P = 0.008). DISCUSSION: The biomarker utility of plasma GFAP in detecting brain amyloid pathology is dependent on the severity of concomitant WMH. Highlight: Glial fibrillary acidic protein (GFAP)’s association with brain amyloid is unclear in populations with high cerebral small vessel disease (CSVD). Plasma GFAP was measured in a cohort with CSVD and brain amyloid. Plasma GFAP was better in detecting amyloid in patients with low CSVD versus high CSVD. Biomarker utility of GFAP in detecting brain amyloid depends on the severity of CSVD

Mixed-location cerebral microbleeds as a biomarker of neurodegeneration in a memory clinic population

Cerebral microbleeds (CMBs) in the lobar and deep locations are associated with two distinct pathologies: cerebral amyloid angiopathy and hypertensive arteriopathy. However, the role of mixed-location CMBs in neurodegeneration remains unexplored. We investigated the associations between strictly lobar, strictly deep and mixed-location CMBs with markers of neurodegeneration. This study recruited 477 patients from a memory clinic who underwent 3T MRI scans. CMBs were categorized into strictly lobar, strictly deep and mixed-location. Cortical thickness, white matter volume and subcortical structural volumes were quantified using Free-Surfer. Linear regression models were performed to assess the association between CMBs and cerebral atrophy, and the mean difference (β) and 95% confidence intervals (CIs) were reported. In the regression analyses, mixed-location CMBs were associated with smaller cortical thickness of limbic region [β=-0.01; 95% CI=-0.02,-0.00, p=0.007) as well as with smaller accumbens volume [β=-0.01; 95% CI=-0.02,-0.00, p=0.004) and presubiculum region of hippocampus [β=-0.01; 95% CI=-0.02,-0.00, p=0.002). Strictly lobar CMBs were associated with smaller total white matter volume [β=-0.03; 95% CI=-0.04,-0.01, p<0.001] and with region specific white mat

Interethnic differences in neuroimaging markers and cognition in Asians, a population-based study

We examined interethnic differences in the prevalence of neuroimaging markers of cerebrovascular and neurodegenerative disease in 3 major Asian ethnicities (Chinese, Malays, and Indians), as well as their role in cognitive impairment. 3T MRI brain scans were acquired from 792 subjects (mean age: 70.0 ± 6.5years, 52.1% women) in the multi-ethnic Epidemiology of Dementia In Singapore study. Markers of cerebrovascular disease and neurodegeneration were identified. Cognitive performance was evaluated using Mini Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA), and a neuropsychological assessment. Compared to Chinese, Malays had a higher burden of intracranial stenosis (OR: 2.28. 95%CI: 1.23-4.20) and cortical atrophy (β: -0.60. 95%CI: -0.78, -0.41), while Indians had a higher burden of subcortical atrophy (β: -0.23. 95%CI: -0.40, -0.06). Moreover, Malay and Indian ethnicities were likely to be cognitively impaired (OR for Malays: 3.79. 95%CI: 2.29-6.26; OR for Indians: 2.87. 95%CI: 1.74-4.74) and showed worse performance in global cognition (β for Malays: -0.51. 95%CI: -0.66, -0.37; and Indians: -0.32. 95%CI: -0.47, -0.17). A higher burden of cerebrovascular and neurodegenerative markers were found in Malays and Indians when compared to Chinese. Further research is required to fully elucidate the factors and pathways that contribute to these observed differences

The Immune System in Stroke

Stroke represents an unresolved challenge for both developed and developing countries and has a huge socio-economic impact. Although considerable effort has been made to limit stroke incidence and improve outcome, strategies aimed at protecting injured neurons in the brain have all failed. This failure is likely to be due to both the incompleteness of modelling the disease and its causes in experimental research, and also the lack of understanding of how systemic mechanisms lead to an acute cerebrovascular event or contribute to outcome. Inflammation has been implicated in all forms of brain injury and it is now clear that immune mechanisms profoundly influence (and are responsible for the development of) risk and causation of stroke, and the outcome following the onset of cerebral ischemia. Until very recently, systemic inflammatory mechanisms, with respect to common comorbidities in stroke, have largely been ignored in experimental studies. The main aim is therefore to understand interactions between the immune system and brain injury in order to develop novel therapeutic approaches. Recent data from clinical and experimental research clearly show that systemic inflammatory diseases -such as atherosclerosis, obesity, diabetes or infection - similar to stress and advanced age, are associated with dysregulated immune responses which can profoundly contribute to cerebrovascular inflammation and injury in the central nervous system. In this review, we summarize recent advances in the field of inflammation and stroke, focusing on the challenges of translation between pre-clinical and clinical studies, and potential anti-inflammatory/immunomodulatory therapeutic approaches

Additive effect of cerebral atrophy on cognition in dementia-free elderly with cerebrovascular disease

Objective: To explore the additive effect of neurodegenerative diseases, measured by atrophy, on neurocognitive function in Asian dementia-free elderly with cerebrovascular disease (CeVD). Methods: The present study employed a cross-sectional design and was conducted between 2010 and 2015 among community-dwelling elderly participants recruited into the study. Eligible participants were evaluated with an extensive neuropsychological battery and neuroimaging. The weighted CeVD burden scale comprising markers of both small- and large-vessel diseases was applied, with a score of ≥2, indicating significant CeVD burden. Cortical atrophy (CA) and medial temporal atrophy (MTA) were graded using the global cortical atrophy scale and Schelten's scale, respectively. Global and domain-specific (attention, executive function, language, visuomotor speed, visuoconstruction, visual memory, and verbal memory) neurocognitive performance was measured using a locally validated neuropsychological battery (Vascular Dementia Battery, VDB). Results: A total of 819 dementia-free participants were included in the analysis. Among none-mild CeVD subjects, there was no significant difference in the global cognitive performance across atrophy groups (no atrophy, CA, and CA+MTA). However, in moderate-severe CeVD subjects, CA+MTA showed significantly worse global cognitive performance compared with those with CA alone (mean difference=-0.35, 95% CI -0.60 to -0.11, p=0.002) and those without atrophy (mean difference=-0.46, 95% CI -0.74 to -0.19, p<0.001, p<0.001). In domain-specific cognitive performance, subjects with CA+MTA performed worse than other groups in visual memory (p=0.005), executive function (p=0.001) and visuomotor speed (p<0.001) in moderate-severe CeVD but not in none-mild CeVD. Conclusions and relevance: Atrophy and moderate-severe CeVD burden showed an additive effect on global and domain-specific cognitive performance. This study highlights the importance of investigating the mechanisms of clinico-pathological interactions between neurodegenerative processes and vascular damage, particularly in the pre-dementia stage