Vascular Changes In Brain Research Articles

Assess the Serum Lipid Profile in Patient with Acute Ischemic Stroke at Tertiary Care Center in Nepal

Introduction: Ischemic stroke takes place when the blood flow cessation endures for more than a few minutes leading to brain tissue infarction. After ischemic heart disease, ischemic stroke is the second most common cause of death worldwide and one of the top five diseases based on DALYs (disability-adjusted life years) in Nepal. Though dyslipidemia is a major risk factor for coronary heart disease, it has an unclear role in the pathogenesis of ischemic stroke. In a patient with a previous ischemic stroke, statins reduce the risk of ischemic stroke. So, this study analyses the plasma prevalence of total cholesterol (TC), low-density lipoprotein (LDL), High-density lipoprotein (HDL), and triglyceride (TG) in patients with acute non-cardioembolic ischemic stroke and their association with different non-modifiable risk factors (age, gender & family history) and modifiable risk factors (diabetes, hypertension, obesity, smoking & alcohol intake).  Materials and Method: This is a descriptive and analytical cross-sectional hospital-based study carried out from December 5th, 2021 to December 4th, 2022 including 80 patients admitted to Chitwan Medical College, Chitwan, with a diagnosis of acute ischemic stroke. All the patients underwent a detailed history, physical examination, and baseline investigations including fasting lipid profile along with CT- scan/MRI head. The fasting lipid profile was done within the first 24 hours of hospitalization. Data was entered in MS Excel 2013 and converted it into SPSS 26 for statistical analysis.  Result: A total of 80 patients with the diagnosis of acute ischemic stroke were enrolled. Out of them, 37 (46.25%) were female and 43 (53.75%) were male. A total number of 71 (88.75%) patients were from more than or equal to 55 years of age group and 9 (11.25%) patients were from less than 55 years of age group. The mean age ± standard deviation of male and female patients was 66.69 ±9.14 years and 68.54 ±14.96 respectively. Overall, derangement in serum lipid profile (dyslipidemia) was present in 63.75% of the patients. Among the total cases, high TC is found in 18 patients (22.5%), TG in 24 patients (30%), high LDL is found in 16 patients (20%), and low HDL is found in 23 patients (28.75%).  Conclusion: The study highlights hypertriglyceridemia as the leading dyslipidemia in ischemic stroke patients, showing gender and age variations in prevalence. It confirms dyslipidemia's role in brain vascular changes, notably in the Middle Cerebral Artery, and its link to carotid artery stenosis severity. Despite common risk factors, their direct association with dyslipidemia remains statistically insignificant, stressing the need for focused lipid management to mitigate stroke risks.

Vascular cognitive impairment: Advances in clinical research and management.

Vascular cognitive impairment (VCI) encompasses a wide spectrum of cognitive disorders, ranging from mild cognitive impairment to vascular dementia. Its diagnosis relies on thorough clinical evaluations and neuroimaging. VCI predominately arises from vascular risk factors (VRFs) and cerebrovascular disease, either independently or in conjunction with neurodegeneration. Growing evidence underscores the prevalence of VRFs, highlighting their potential for early prediction of cognitive impairment and dementia in later life. The precise mechanisms linking vascular pathologies to cognitive deficits remain elusive. Chronic cerebrovascular pathology is the most common neuropathological feature of VCI, often interacting synergistically with neurodegenerative processes. Current research efforts are focused on developing and validating reliable biomarkers to unravel the etiology of vascular brain changes in VCI. The collaborative integration of these biomarkers into clinical practice, alongside routine incorporation into neuropathological assessments, presents a promising strategy for predicting and stratifying VCI. The cornerstone of VCI prevention remains the control of VRFs, which includes multi-domain lifestyle modifications. Identifying appropriate pharmacological approaches is also of paramount importance. In this review, we synthesize recent advancements in the field of VCI, including its definition, determinants of vascular risk, pathophysiology, neuroimaging and fluid-correlated biomarkers, predictive methodologies, and current intervention strategies. Increasingly evident is the notion that more rigorous research for VCI, which arises from a complex interplay of physiological events, is still needed to pave the way for better clinical outcomes and enhanced quality of life for affected individuals.

Role of Cardiac Biomarkers in Stroke and Cognitive Impairment.

This topical review assesses the growing role of cardiac biomarkers beyond cardiovascular health and focuses on their importance in stroke and dementia. The first part describes blood-based cardiac biomarkers in patients with stroke and highlights applications in the setting of early diagnosis, poststroke complications, outcome prediction as well as secondary prevention. Among other applications, natriuretic peptides can be helpful in differentiating stroke subtypes. They are also currently being investigated to guide prolonged ECG monitoring and secondary prevention in patients with stroke. Elevated cardiac troponin after ischemic stroke can provide information about various poststroke complications recently termed the stroke-heart syndrome. The second part focuses on the role of cardiac biomarkers in vascular cognitive impairment and dementia, emphasizing their association with structural brain lesions. These lesions such as silent brain infarcts and white matter hyperintensities often co-occur with cardiac disease and may be important mediators between cardiovascular disease and subsequent cognitive decline. ECG and echocardiogram measurements, in addition to blood-based biomarkers, show consistent associations with vascular brain changes and incident dementia, suggesting a role in indicating risk for cognitive decline. Together, the current evidence suggests that cardiac blood-based, electrophysiological, and imaging biomarkers can be used to better understand the heart and brain connection in the setting of not only stroke but also dementia.

Nailfold capillary measurements correlated to NOTCH3 R544C mutation in preclinical CADASIL patients

BackgroundCerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) is a hereditary disease caused by NOTCH3 mutation. Nailfold capillaroscopy is a non-invasive technique typically used for rheumatic diseases. It has potential in other conditions linked to vascular pathology. However, capillaroscopy in CADASIL has not been explored. This study aims to investigate whether capillaroscopy measurements can correlate with brain vascular changes in preclinical CADASIL patients, specifically those with NOTCH3 mutation. MethodsThis study included 69 participants from the Taiwan Precision Medicine Initiative (TPMI) dataset who visited Taichung Veterans General Hospital from January to December 2022. All individuals underwent genetic studies, brain imaging and nailfold capillaroscopy. The Mann-Whitney U test was used to compare results of brain imaging between carriers and controls. It was also used to compare measurements in nailfold capillaroscopy within each group. Spearman Rank Correlation Analysis was used to explore the relationship between capillary measurements and brain MRI results. ResultsWhite matter hyperintensities (WMH) expression was positively correlated with capillary dimension and negatively correlated with density. Our results presented that R544C carriers exhibited a diffuse increase in WMH (p < 0.001) and a global reduction in gray matter volume but preserved in specific areas. The white matter lesion scores in all brain regions were higher in the mutation carriers than the controls. (p < 0.001). ConclusionThis research highlights the association of nailfold capillaroscopy findings with white matter lesions in preclinical CADASIL patients. Capillaroscopy guides an effective screening strategy in individuals with NOTCH3 mutations.

Integrated Photoacoustic, Ultrasound, and Angiographic Tomography (PAUSAT) for NonInvasive Whole-Brain Imaging of Ischemic Stroke.

Presented here is an experimental ischemic stroke study using our newly developed noninvasive imaging system that integrates three acoustic-based imaging technologies: photoacoustic, ultrasound, and angiographic tomography (PAUSAT). Combining these three modalities helps acquire multi-spectral photoacoustic tomography (PAT) of the brain blood oxygenation, high-frequency ultrasound imaging of the brain tissue, and acoustic angiography of the cerebral blood perfusion. The multi-modal imaging platform allows the study of cerebral perfusion and oxygenation changes in the whole mouse brain after stroke. Two commonly used ischemic stroke models were evaluated: the permanent middle cerebral artery occlusion (pMCAO) model and the photothrombotic (PT) model. PAUSAT was used to image the same mouse brains before and after a stroke and quantitatively analyze both stroke models. This imaging system was able to clearly show the brain vascular changes after ischemic stroke, including significantly reduced blood perfusion and oxygenation in the stroke infarct region (ipsilateral) compared to the uninjured tissue (contralateral). The results were confirmed by both laser speckle contrast imaging and triphenyltetrazolium chloride (TTC) staining. Furthermore, stroke infarct volume in both stroke models was measured and validated by TTC staining as the ground truth. Through this study, we have demonstrated that PAUSAT can be a powerful tool in noninvasive and longitudinal preclinical studies of ischemic stroke.

Mycobacterium tuberculosis Cell Wall Antigens Induce the Formation of Immune Complexes and the Development of Vasculitis in an Experimental Murine Model.

Tuberculosis (TB) of the central nervous system (CNS) presents high mortality due to brain damage and inflammation events. The formation and deposition of immune complexes (ICs) in the brain microvasculature during Mycobacterium tuberculosis (Mtb) infection are crucial for its pathobiology. The relevance of ICs to Mtb antigens in the pathogenesis of CNS-TB has been poorly explored. Here, we aimed to establish a murine experimental model of ICs-mediated brain vasculitis induced by cell wall antigens of Mtb. We administered a cell wall extract of the prototype pathogenic Mtb strain H37Rv to male BALB/c mice by subcutaneous and intravenous routes. Serum concentration and deposition of ICs onto blood vessels were determined by polyethylene glycol precipitation, ELISA, and immunofluorescence. Histopathological changes in the brain, lung, spleen, liver, and kidney were evaluated by hematoxylin and eosin staining. Our results evidenced that vasculitis developed in the studied tissues. High serum levels of ICs and vascular deposition were evident in the brain, lung, and kidneys early after the last cell wall antigen administration. Cell wall Mtb antigens induce strong type III hypersensitivity reactions and the development of systemic vasculitis with brain vascular changes and meningitis, supporting a role for ICs in the pathogenesis of TB.

Plasma Biomarkers of Amyloid and Neurodegeneration predictive of Neuropathologic Scales of Cerebrovascular Disease

AbstractBackgroundBlood‐based biomarkers of amyloid and neurodegeneration are increasingly used in clinical trials and entering clinical use. Differentially mapping the plasma markers to post‐mortem neuropathology in a community‐based sample is critical for interpretation.MethodWe identified 64 Mayo Clinic Study of Aging (MCSA) participants with antemortem plasma markers (Aβ42, Aβ40, NfL, T‐tau, Aβ42/40 ratio) measured on the Quanterix Simoa HD‐1 analyzer and with postmortem neuropathologic assessments of Alzheimer’s pathology (Braak tangle stage, Thal phase, neuritic plaque burden) and cerebrovascular pathology (Strozyk scale focused on macrovascular brain changes and Kalaria scale focused on detailed micro‐ and macro‐ vascular brain changes). Weighted linear regression models with adjustment for time between plasma markers and death were conducted with exact permutation tests to evaluate the relationships between antemortem plasma and postmortem neuropathology markers.ResultHigher plasma NfL levels and Aβ42/40 ratio were associated with both cerebrovascular neuropathologic scales (p&lt;0.05) but were not associated with Braak neurofibrillary tangle stage, neuritic plaque score, or Thal stage (p&gt;0.5). Plasma T‐tau was not associated with any pathological assessment. Plasma Aβ42/40 and NfL explained up to 18% of the variability in cerebrovascular neuropathologic scales.ConclusionIn this community sample of participants predominantly without dementia, plasma markers for amyloid (Aβ42/40) and neurodegeneration (NfL) were associated with cerebrovascular neuropathology at autopsy. NfL is a non‐specific marker of brain injury, therefore, its association with cerebrovascular neuropathology was in the expected direction. The association between greater cerebrovascular neuropathology and elevated Aβ42/40 requires further investigation. These findings provide evidence that cerebrovascular disease may significantly influence levels of plasma biomarkers proposed for Alzheimer’s disease. This information will be important to consider for accurate clinical interpretation of the proposed biomarkers.

Early effects of amyloid-β on structural and vascular brain changes in mid-life cognitively unimpaired individuals.

The apolipoprotein E (APOE) is the strongest genetic risk factor for late-onset Alzheimer's disease (AD). It has been shown that APOE ε4 allele (ε4) relates to early pathological accumulation of cerebral amyloid-β (Aβ), leading to decade earlier age-of-onset of AD. However vascular and anatomical brain changes in the presence of Aβ and ε4 gene have not yet been fully examined in middle age. We aim to investigate how ε4 and Aβ level influence MR neuroimaging biomarkers such as white-matter hyperintensities and hippocampus volume in mid-life (45-65 year old) cognitively unimpaired (CU) individuals. 149 middle age (44 to 66 years of age) CU adults (age 58.2±5.4, 115 Females, years of education 13.5±2.8) underwent 3T MRI and amyloid PET scans using 18 F-Florbetaben as part of the PISA study. Of this ε4 enriched cohort (N=78 ε4 carriers), 12 were classified as Aβ+ (Centiloid≥20). 5 participants with ε2ε4 genotypes were excluded due to the protective effect of the ε2 allele. Multivariable general linear models were implemented to study the association of ε4 and Aβ with structural neuroimaging markers including white-matter hyperintensity volume (WMHV) and Hippocampus volume (HV). Both volumes were normalised using total intracranial volume, and age, gender and years-of-education were used as independent covariates. There was no age difference between ε4+ and ε4- groups (Kruskal-Wallis test, p-value=0.8), but Aβ+ participants were older compared to Aβ- (p-value=0.005). There was no HV differences between ε4+ and ε4- groups when controlling for Centiloid (p-value=0.55). When comparing HV differences between groups based on joint ε4 and Aβ, Aβ+ε4+ had significantly lower HV compared to Aβ-ε4+ (p-value=0.01) and Aβ-ε4- (p-value=0.021) as shown in Figure 1. For WMHV differences, a trend towards significance exists for Aβ+ε4+ when compared to and Aβ+ε4- and Aβ-ε4- (p-value=0.069) as shown in Figure 2. In this study, we found that early signs of hippocampus degeneration may occur in the middle age in the presence of both high Aβ level and APOE ε4 allele. Future studies will investigate the effective age spread for middle-aged preclinical AD population which will be beneficial for participant recruitment for new clinical trials.

Changes in white matter microstructure and MRI-derived cerebral blood flow after 1-week of exercise training

Exercise is beneficial for brain health, inducing neuroplasticity and vascular plasticity in the hippocampus, which is possibly mediated by brain-derived neurotrophic factor (BDNF) levels. Here we investigated the short-term effects of exercise, to determine if a 1-week intervention is sufficient to induce brain changes. Fifteen healthy young males completed five supervised exercise training sessions over seven days. This was preceded and followed by a multi-modal magnetic resonance imaging (MRI) scan (diffusion-weighted MRI, perfusion-weighted MRI, dual-calibrated functional MRI) acquired 1 week apart, and blood sampling for BDNF. A diffusion tractography analysis showed, after exercise, a significant reduction relative to baseline in restricted fraction—an axon-specific metric—in the corpus callosum, uncinate fasciculus, and parahippocampal cingulum. A voxel-based approach found an increase in fractional anisotropy and reduction in radial diffusivity symmetrically, in voxels predominantly localised in the corpus callosum. A selective increase in hippocampal blood flow was found following exercise, with no change in vascular reactivity. BDNF levels were not altered. Thus, we demonstrate that 1 week of exercise is sufficient to induce microstructural and vascular brain changes on a group level, independent of BDNF, providing new insight into the temporal dynamics of plasticity, necessary to exploit the therapeutic potential of exercise.

Abstract P121: Twenty-two-year Cognitive Decline Was Significantly Associated With Vascular And Neurodegenerative Brain Changes In The Aric Neurocognitive Study

Introduction: Studies have found that smaller brain volumes, cerebral infarcts, and white matter abnormalities are associated with dementia and mild cognitive impairment. However, these studies have been limited by short follow-up precluding a strong establishment of temporality. Therefore, it is unknown whether brain imaging findings are preceded by long-term changes in cognition. We sought to address this gap by examining brain imaging and two decades of cognitive changes in and a large, representative population-based cohort of older adults of black and white race. Hypothesis: We hypothesized that 22-year declines in global cognitive factor scores (GCFS) would be associated with a pattern of smaller total brain and temporal lobe meta region of interest (likely to be affected by Alzheimer’s disease) volumes, larger white matter hyperintensity volumes, and greater odds of ≥1 lacunar infarct and elevated brain β-amyloid deposition. Methods: ARIC participants with brain imaging data, complete cognitive factor score, and not missing key covariates were included. GCFS were collected at three visits across 22 years (1990-2013), and brain MRI and florbetapir PET imaging were collected in 2011-13; PET in subset of n=327. Mixed effects models with random intercepts and slopes predicted individual change in GCFS. Outcomes of interest were total brain volume (cc), temporal lobe meta region volume, log 2 (white matter hyperintensity volume), ≥1 lacunar infarct, and elevated brain β-amyloid deposition (SUVR &gt;1.2). Multivariable linear and logistic regression was used to relate outcomes to GCFS slopes after adjusting for confounders, including vascular risk factors. As appropriate, models were also adjusted for total intracranial volume. Results: Among 1957 with complete brain MRI imaging, 1830 were included in the study, 60% (n=1096) women and 26% (n=480) black. At the first visit, the mean (SD) baseline age was 55 (5.2) yrs. The mean (SD) observed GCFS at the three visits were 0.16 (0.79), 0.05 (0.75), and -0.78 (0.86). After adjustment, a 1-SD larger decline in GCFS was significantly associated with a smaller brain volume by 1.6% [95%CI: 1.3, 1.8] relative to mean brain volume, a smaller temporal lobe meta region volume by 2.4% [2.1, 2.8] relative to the mean volume, a 15% [11, 19] larger volume of white matter hyperintensities, 1.3-fold [1.2, 1.4] higher odds of having ≥1 lacune, and 1.8-fold [1.4, 2.4] higher odds of elevated brain β-amyloid deposition. Associations remained significant after further adjustment for first or last GCFS. Conclusions: Greater declines in long-term cognitive functioning were significantly associated with smaller brain volumes and dementia-related brain characteristics and were independent of last visit GCFS. This suggests long-term changes in cognition may precede late-life brain morphology and outperform cross-sectional cognitive measures.

Sleep, brain vascular health and ageing.

Sleep maintains the function of the entire body through homeostasis. Chronic sleep deprivation (CSD) is a prime health concern in the modern world. Previous reports have shown that CSD has profound negative effects on brain vasculature at both the cellular and molecular levels, and that this is a major cause of cognitive dysfunction and early vascular ageing. However, correlations among sleep deprivation (SD), brain vascular changes and ageing have barely been looked into. This review attempts to correlate the alterations in the levels of major neurotransmitters (acetylcholine, adrenaline, GABA and glutamate) and signalling molecules (Sirt1, PGC1α, FOXO, P66shc, PARP1) in SD and changes in brain vasculature, cognitive dysfunction and early ageing. It also aims to connect SD-induced loss in the number of dendritic spines and their effects on alterations in synaptic plasticity, cognitive disabilities and early vascular ageing based on data available in scientific literature. To the best of our knowledge, this is the first article providing a pathophysiological basis to link SD to brain vascular ageing.

Body Composition Is Not Related to Structural or Vascular Brain Changes.

Background: It is known that obesity [measured with body mass index (BMI)] relates to brain structure and markers of cerebral small vessel disease (CSVD). However, BMI may not adequately represent body composition. Furthermore, whether those cross-sectional associations hold longitudinally remains uncertain.Methods: Three thousand six hundred and fourty-eight participants underwent baseline (2006–2014) dual-energy X-ray absorptiometry (DXA)-scan to obtain detailed measures of body composition and a magnetic resonance imaging (MRI) scan to assess brain structure. One thousand eight hundred and fourty-four participants underwent a second MRI-scan at follow-up (2010–2017; median follow-up: 5.5 years). To assess cross-sectional and longitudinal associations (measures of change have been calculated) between body composition [BMI, fat mass index (FMI), fat-free mass index (FFMI)], and brain tissue volume (gray matter, white matter, hippocampus), white matter microstructure [fractional anisotropy (FA), mean diffusivity (MD)], and CSVD markers (white matter hyperintensity volume, lacunes, microbleeds) we used multivariable linear and logistic regression models.Results: A higher BMI and FMI were cross-sectionally associated with smaller white matter volumes (difference in Z-score per SD higher BMI: −0.064 [95% CI: −0.094, −0.035]) and FMI: −0.067 [95% CI: −0.099, −0.034], higher FA and MD. A higher FFMI was associated larger gray matter volume (difference: 0.060 [95% CI: 0.018, 0.101]). There was no statistically significant or clinically relevant association between body composition and brain changes.Conclusions: Body composition, distinguishing between fat mass and fat-free mass, does not directly influence changes in brain tissue volume, white matter integrity and markers of CSVD. Cross-sectional associations between body composition and brain tissue volume likely reflect cumulative risk or shared etiology.

Association between white matter hyperintensities, cortical volumes, and late-onset epilepsy.

To identify the association between brain vascular changes and cortical volumes on MRI and late-onset epilepsy. In 1993-1995, 1,920 participants (median age 62.7, 59.9% female) in the community-based Atherosclerosis Risk in Communities (ARIC) Study underwent MRI, and white matter hyperintensities were measured. In addition, in 2011-2013, 1,964 ARIC participants (median age 72.4, 61.1% female) underwent MRI, and cortical volumes and white matter hyperintensities were measured. We identified cases of late-onset epilepsy (starting at age 60 or later) from ARIC hospitalization records and Medicare claims data. Using the 1993-1995 MRI, we evaluated the association between white matter hyperintensities and subsequent epilepsy using survival analysis. We used the 2011-2013 MRI to conduct cross-sectional logistic regression to examine the association of cortical volumes and white matter hyperintensities with late-onset epilepsy. All models were adjusted for demographics, hypertension, diabetes, smoking, and APOE ε4 allele status. Ninety-seven ARIC participants developed epilepsy after having an MRI in 1993-1995 (incidence 3.34 per 1,000 person-years). The degree of white matter hyperintensities measured at ages 49-72 years was associated with the risk of late-onset epilepsy (hazard ratio 1.27 per age-adjusted SD, 95% confidence interval [CI] 1.06-1.54). Lower cortical volume scores were associated cross-sectionally with higher odds of late-onset epilepsy (odds ratio 1.87, 95% CI 1.16-3.02) per age-adjusted SD. This study demonstrates associations between earlier-life white matter hyperintensities on MRI and later-life incident epilepsy, and between cortical volumes measured later in life and late-onset epilepsy. These findings may help illuminate the causes of late-onset epilepsy.

Brain vascular changes in adults with congenital heart disease: A systematic review.

Less information is available on brain integrity in adults with congenital heart disease than on brain changes in newborns and children with heart defects. Nevertheless, the number of adults with congenital heart disease is increasing rapidly and it has been shown that adults with congenital heart disease develop dementia almost twice as frequently as adults in the general population.In the context of a rapidly growing congenital heart disease population, neuroradiological-oriented investigations of biomarkers distinctive for vascular damage, brain aging, and possible cognitive impairment is a crucial challenge. We provide an overview of the existing literature on neuroimaging studies in adults with congenital heart disease and discuss methodology issues to further investigate this subject. Overall, we aim to raise awareness of the importance of brain health studies in adults with congenital heart disease given the likely increasing impact on social and healthcare systems.

Associations of Echocardiography Markers and Vascular Brain Lesions: The ARIC Study.

BackgroundAssociations between subtle changes in cardiac and cerebral structure and function are not well understood, with some studies suggesting that subclinical cardiac changes may be associated with markers of vascular brain insult.Methods and ResultsData from the ARIC (Atherosclerosis Risk in Communities) Study (5th ARIC visit; 2011‐2013; N=1974) were used to explore relationships between abnormalities of cardiac structure/function and subclinical brain disease and to test specific associations between those cardiac and vascular brain changes that share a common mechanism. In adjusted models white matter hyperintensities were 0.66 cm3 greater (95% confidence interval [CI] 0.08‐1.25) for every 1‐mm increase in left ventricular LV wall thickness and 0.64 cm3 greater (95% CI 0.19‐1.08) for every 10 g/m2 increase in LV mass index, both markers of LV structure. Odds of brain infarction also increased with greater LV wall thickness (odds ratio 1.11, 95% CI 1.01‐1.23 per 1 mm) and larger LV mass (odds ratio 1.08, 95% CI 1.00‐1.17 per 10 g/m2). Higher ejection fraction (per 5%), a marker of systolic function, was significantly associated with decreased odds of overall infarct (odds ratio 0.85, 95% CI0.77‐0.95), but not with cortical infarction (odds ratio 0.92, 95% CI0.78‐1.08).ConclusionsAmong elderly participants in a large cohort study, subclinical markers of LV structure and LV systolic dysfunction were associated with increased odds of brain infarction and more white matter hyperintensities, independent of other vascular risk factors. This suggests end‐organ dysfunction occurs in the heart and brain in parallel, with further studies needed to determine causality.

Stroke and Systemic Lupus Erythematosus: A Review

Systemic lupus erythematosus (SLE) is a chronic inflammatory autoimmune disease that involves collagen tissue throughout the body. Several previous studies have shown that the risk of ischaemic and haemorrhagic stroke is significantly higher in SLE when compared to the general population, particularly in young individuals, representing one of the principal causes of death in these patients. Though the precise pathophysiology behind this increased risk is still poorly understood, several mechanisms are suggested to play a role. The high burden of cerebral small vessel disease features noted on brain neuroimaging studies, as well as the accelerated process of atherosclerosis identified in these patients, are likely to be responsible for at least some of the ischaemic strokes occurring in the SLE population. Repeated episodes of arterial and venous thrombosis secondary to antiphospholipid syndrome are likewise important. Less is known regarding the exact pathophysiological relationship between SLE and the high incidence of haemorrhagic stroke, though thrombocytopenia and a greater susceptibility to form typical and atypical brain aneurysms, which may then rupture, are thought to be the main mechanisms responsible for the occurrence of intracerebral and subarachnoid haemorrhage, respectively. Both inflammatory and noninflammatory events, all involving the immune system, are responsible for several pathological changes affecting cerebral vessels of every calibre in SLE, as confirmed by histopathology. In this context, endothelial activation and dysfunction play a critical role. This review will briefly analyse the most important factors responsible for the higher ischaemic and haemorrhagic stroke risk in the SLE population, with a particular focus on brain vascular changes.

BASELINE CARDIOVASCULAR RISK AND AMYLOID BURDEN SYNERGISTICALLY PREDICT LONGITUDINAL COGNITIVE DECLINE IN CLINICALLY NORMAL ELDERLY: FINDINGS FROM THE HARVARD AGING BRAIN STUDY

Neuropathological studies indicate that vascular brain changes commonly co-occur with Alzheimer's disease (AD) pathology in late-onset dementia and are likely contributors to cognitive decline. Given the overlap of cardiovascular and cerebrovascular risk factors, we examined whether well-validated cardiovascular (CV) risk scores would predict cognitive decline alone or synergistically with amyloid burden in clinically normal elderly. 205 clinically normal older adults (mean age = 72.5; range = 65 - 89) in the Harvard Aging Brain Study underwent baseline β-amyloid imaging with Pittsburgh compound-B (PiB)-PET and annual neuropsychological testing for up to 6 years (mean follow-up of 3.77+/-1.2y). QRISK2 2016 and Framingham Heart Study cardiovascular (FHS-CVD) risk scores were calculated from baseline demographic, blood pressure, and cholesterol data. We used linear mixed models (controlled for age, sex, and education) to assess CV risk, amyloid burden, and their interaction as predictors of longitudinal cognitive decline as measured by the Preclinical Alzheimer Cognitive Composite (PACC). Amyloid burden and CV risk each predicted longitudinal cognitive decline (p < 0.0001). We observed a strong synergistic effect of CV risk and amyloid burden on prediction of cognitive decline (Figure 1; p < 0.0001). Follow-up analyses revealed CV risk predicted cognitive decline in both high and low amyloid groups (amyloid positive: p < 0.0001; amyloid negative: p = 0.0191), whereas, amyloid burden predicted decline only among individuals with moderate to high CV risk (low CV risk: p > 0.05; moderate CV risk: p < 0.0005; high CV risk: p< 0.0001). Individuals with high amyloid burden and high CV risk showed the steepest cognitive decline (Figure 1). Results using QRISK2 or FHS-CVD were highly similar. Well-validated measures of baseline CV risk were strong predictors of longitudinal cognitive decline in clinically normal elderly, both alone and synergistically with baseline amyloid burden. The co-occurrence of high amyloid burden with moderate to high levels of CV risk was an especially potent predictor of cognitive decline. These results highlight the potential utility of CV risk scores in AD clinical research, especially in understanding and stratifying risk for cognitive decline in the preclinical phase of AD. Cardiovascular Risk Interacts with Amyloid Burden to Predict Longitudinal Cognitive Decline. Illustration of rates of longitudinal cognitive decline (assessed by declines in the PACC) at varying levels of CV Risk (FHS-CVD) and amyloid burden (PiB PET). All scales have been converted to z-scores. Red axis tick corresponds to a PiB FLR SUVR of 1.2, a previously published, data-driven cutoff to separate high and low- Aβ groups in the Harvard Aging Brain Study. PACC = Preclinical Alzheimer Cognitive Composite; FHS-CVD = Framingham Heart Study cardiovascular disease risk score; PiB PET = Pittsburgh Compound-B PET; FLR = composite cortical region of interest from frontal, lateral, and parietal regions; SUVR = Standardized Uptake Value Ratio.

Homocysteine and Real-Space Navigation Performance among Non-Demented Older Adults.

High plasma homocysteine (Hcy) level is related to higher risk of Alzheimer's disease (AD) and lower cognitive performance in older adults. To assess the association between plasma Hcy level and real-space navigation performance and the role of vascular risk and protective factors, APOE status, and white matter lesions (WML) on this association. Ninety-two non-demented older adults (29 with amnestic mild cognitive impairment, 46 with subjective cognitive decline, and 17 cognitively normal older adults) underwent spatial navigation testing of egocentric, allocentric, and mixed navigation in a real-space analogue of the Morris water maze, neuropsychological examination, blood collection, and MRI brain scan with evaluation of WML. In the regression analyses controlling for age, gender, education, and depressive symptoms, higher plasma Hcy level was related to worse mixed and egocentric (β= 0.31; p = 0.003 and β= 0.23; p = 0.017) but not allocentric (p > 0.05) navigation performance. Additional controlling for vascular risk and protective factors, WML, and APOE status did not modify the results. High total cholesterol and low vitamin B12 and folate levels increased the adverse effect of Hcy on egocentric and mixed navigation. WML did not explain the association between plasma Hcy level and navigation performance. Elevated plasma Hcy level may affect real-space navigation performance above and beyond vascular brain changes. This association may be magnified in the presence of high total cholesterol and low folate or vitamin B12 levels. Attention to the level of plasma Hcy may be a viable intervention strategy to prevent decline in spatial navigation in non-demented older adults.

Clinicopathological correlation of psychosis and brain vascular changes in Alzheimer's disease.

Psychosis is common in Alzheimer’s disease (AD). However, studies on neuropathology in vascular etiology contributing to psychosis in AD is lacking to date. The aim of this study was to investigate neuropathological vascular related changes in Alzheimer’s disease with psychosis. Data of patients with AD from the National Alzheimer’s Coordinating Center between 2005 to September 2013 was accessed and reviewed. Presence of psychosis was determined based on Neuropsychiatric Inventory Questionnaire taken from the last visit within one year prior to death, and patients were divided into psychosis positive and negative group. Comparison of clinical details and neuropathological vascular changes between the groups was performed using Wilcoxon rank sum test and Chi-square/ Fisher’s exact test. Significant variables were further included in a multivariate logistic model. Overall, 145 patients was included. Of these, 50 patients were psychosis positive. Presence of one or more cortical microinfarcts and moderate to severe arteriosclerosis was found to be positively associated with psychosis. Our results suggest vascular changes correlate with psychosis in Alzheimer’s disease.

Presence of brain pathology in deceased subjects with and without chronic obstructive pulmonary disease.

Patients with chronic obstructive pulmonary disease (COPD) have extrapulmonary co-morbidities, such as cardiovascular disease, musculoskeletal wasting and neuropsychological conditions. To date, it remains unknown whether and to what extent COPD is associated with a higher prevalence of brain pathology. Therefore, the aim of this retrospective study was to compare the prevalence of neuropathological brain changes between deceased donors with and without COPD. Brain autopsy reports of age-matched donors with (n = 89) and without COPD (n = 89) from the Netherlands Brain Bank were assessed for demographics, cause of death, co-morbidities and brain pathology. The prevalence of degenerative brain changes was comparable for donors with and without COPD (50.6% vs. 61.8%, p > 0.05). Neoplastic brain changes were reported in a minority of the donors (5.6% vs. 10.1%, p > 0.05). After correction for cerebrovascular accident or cardiac cause of death and Charlson co-morbidity index score, the prevalence of vascular brain changes was higher among control versus COPD donors (27.0% vs. 11.2%, adjusted p = 0.013, odds ratio = 2.98). Brain autopsy reports of donors with and without COPD did not reveal differences in the presence of degenerative or neoplastic brain changes. Vascular brain changes were described more often in controls. Prospective studies including spirometry and structural and functional brain imaging should corroborate our findings.