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Distinctive RNA Expression Profiles in Blood Associated With White Matter Hyperintensities in Brain
Abstract
White matter hyperintensities (WMH) are areas of high signal detected by T2 and fluid-attenuated inversion recovery sequences on brain MRI. Although associated with aging, cerebrovascular risk factors, and cognitive impairment, the pathogenesis of WMH remains unclear. Thus, RNA expression was assessed in the blood of individuals with and without extensive WMH to search for evidence of oxidative stress, inflammation, and other abnormalities described in WMH lesions in brain.
Subjects included 20 with extensive WMH (WMH+), 45% of whom had Alzheimer disease, and 18 with minimal WMH (WMH-), 44% of whom had Alzheimer disease. All subjects were clinically evaluated and underwent quantitative MRI. Total RNA from whole blood was processed on human whole genome Affymetrix HU133 Plus 2.0 microarrays. RNA expression was analyzed using an analysis of covariance.
Two hundred forty-one genes were differentially regulated at ± 1.2-fold difference (P < 0.005) in subjects with WMH+ as compared to WMH-, regardless of cognitive status and 50 genes were differentially regulated with ± 1.5-fold difference (P < 0.005). Cluster and principal components analyses showed that the expression profiles for these genes distinguished WMH+ from WMH- subjects. Function analyses suggested that WMH-specific genes were associated with oxidative stress, inflammation, detoxification, and hormone signaling, and included genes associated with oligodendrocyte proliferation, axon repair, long-term potentiation, and neurotransmission.
The unique RNA expression profile in blood associated with WMH is consistent with roles of systemic oxidative stress and inflammation, as well as other potential processes in the pathogenesis or consequences of WMH.
... Recently, a multi-ethnic genome-wide association study identified four novel genetic loci including Chr10q24 (e.g., SH3PXD2A), Chr2p21 (e.g., HAAO), Chr2p16 (e.g., EFEMP1) and Chr1q22 (e.g., PMF1) (Verhaaren et al., 2015). Additionally, together with microarray RNA expression analysis of cerebral white matter lesions tissues, multiple whole blood expression profiles revealed large numbers of up-/down-regulated genes in LA (Simpson et al., 2009;Xu et al., 2010). These evidences support the multifactorial nature of LA and genetic factors seem to play important roles in LA. ...
... In our methylation data, there were limited overlapping genes with those identified in the Genome-Wide Association Studies (GWAS) and RNA expression analysis of LA (Simpson et al., 2009;Xu et al., 2010;Fornage et al., 2011). However, it's plausible that, similar to the enrichment results of differentially methylated genes identified in our study, data from GWAS and RNA expression profile of LA also illustrated the crucial role of immune and inflammation in the development of LA (Simpson et al., 2009;Xu et al., 2010;Fornage et al., 2011). ...
... In our methylation data, there were limited overlapping genes with those identified in the Genome-Wide Association Studies (GWAS) and RNA expression analysis of LA (Simpson et al., 2009;Xu et al., 2010;Fornage et al., 2011). However, it's plausible that, similar to the enrichment results of differentially methylated genes identified in our study, data from GWAS and RNA expression profile of LA also illustrated the crucial role of immune and inflammation in the development of LA (Simpson et al., 2009;Xu et al., 2010;Fornage et al., 2011). In the GWAS of LA from European descent, 6 novel single nucleotide polymorphisms (SNPs) in the Chr17q25 locus including TRIM65, TRIM47 and WBP2, were identified to be risk factors of LA. ...
Leukoaraiosis (LA) is neuroimaging abnormalities of the cerebral white matter in elderly people. However, the molecular mechanisms underlying the cerebral white matter lesions remain unclear. Here, we reported an epigenetic basis and potential pathogenesis for this complex illness. 317 differentially methylated genes were identified to distinguish the mechanism of occurrence and progression of LA. Gene-Ontology pathway analysis highlighted that those genes with epigenetic changes are mostly involved in four major signaling pathways including inflammation and immune response-associated processes (antigen processing and presentation, T cell costimulation and interferon-γ-mediated signaling pathway), synapse assembly, synaptic transmission and cell adhesion. Moreover, immune response seems to be specific to LA occurrence and subsequent disruption of nervous system functions could drive the progression of LA. The significant change of inflammation-associated ZC3H12D in promoter methylation and mRNA expression was implicated in the occurrence of LA, suggesting its potential functions in the molecular mechanism of LA. Our results suggested that inflammation-associated signaling pathways were involved in the pathogenesis of LA and ZC3H12D may contribute to such inflammatory process underlying LA, and further echoed it as a neuroinflammatory disorder in central nervous system (CNS).
... Function analyses suggested that WMHspecific genes were associated with oxidative stress, inflammation, detoxification, and hormone signaling, and included genes associated with oligodendrocyte proliferation, axon repair, long-term potentiation, and neurotransmission . Notably, only 4 of the 241 WMH genes were previously identified in our studies outlined above of ischemic stroke Xu et al, 2010). This does not exclude ischemia as a causal factor in WMH, but it does suggest that there must be differences between acute ischemic stroke and any 'ischemia-related changes' that might be associated with WMH. ...
... We have avoided major protocol changes unless absolutely necessary. Changes in the protocols that have been made included a DNAase step in RNA isolation, and the use of NuGEN reagents so that very small amounts of RNA can be used for each array Stamova et al, 2010;Xu et al, 2010). If one is contemplating a preliminary study followed by a confirmatory one, one must standardize all methods and arrays across those two studies. ...
... Half of the low WMH subjects had AD and half were cognitively normal. This figure is adapted from Xu et al (2010). used P value cutoffs only (Shi et al, 2010;Tusher et al, 2001). ...
Whole genome expression microarrays can be used to study gene expression in blood, which comes in part from leukocytes, immature platelets, and red blood cells. Since these cells are important in the pathogenesis of stroke, RNA provides an index of these cellular responses to stroke. Our studies in rats have shown specific gene expression changes 24 hours after ischemic stroke, hemorrhage, status epilepticus, hypoxia, hypoglycemia, global ischemia, and following brief focal ischemia that simulated transient ischemic attacks in humans. Human studies show gene expression changes following ischemic stroke. These gene profiles predict a second cohort with >90% sensitivity and specificity. Gene profiles for ischemic stroke caused by large-vessel atherosclerosis and cardioembolism have been described that predict a second cohort with >85% sensitivity and specificity. Atherosclerotic genes were associated with clotting, platelets, and monocytes, and cardioembolic genes were associated with inflammation, infection, and neutrophils. These gene profiles predicted the cause of stroke in 58% of cryptogenic patients. These studies will provide diagnostic, prognostic, and therapeutic markers, and will advance our understanding of stroke in humans. New techniques to measure all coding and noncoding RNAs along with alternatively spliced transcripts will markedly advance molecular studies of human stroke.
... Neuropathological and amyloid PET imaging studies show that WMH are not correlated with AD pathology, but associated with cerebral arteriosclerosis, supporting the relationship between WMH and CVD 7 . Our previous study suggested that WMH found in normal aging and in AD patients are associated with distinctive RNA expression profiles in peripheral blood that are not secondary to AD and may be related in part to oxidative stress 8 . ...
... RNA expression in blood of patients with AD has been assessed in several recent independent studies 1-4, 9, 10 . However, none has considered the possible effects of WMH on RNA expression in blood as a confounder for AD gene profiles 8 . The aim of this study was to examine RNA expression in blood of AD patients with and without WMH as compared to controls. ...
... AD diagnosis was made according to the NINCDS and Communication Disorders and Stroke/AD and Related Disorders Association (NINDS-ADRDA) criteria. AD with and without WMH, as well as controls (cognitively normal subjects with and without WMH) were included in the present study 8 . ...
Defining the RNA transcriptome in Alzheimer Disease (AD) will help understand the disease mechanisms and provide biomarkers. Though the AD blood transcriptome has been studied, effects of white matter hyperintensities (WMH) were not considered. This study investigated the AD blood transcriptome and accounted for WMH.
RNA from whole blood was processed on whole-genome microarrays.
A total of 293 probe sets were differentially expressed in AD versus controls, 5 of which were significant for WMH status. The 288 AD-specific probe sets classified subjects with 87.5% sensitivity and 90.5% specificity. They represented 188 genes of which 29 have been reported in prior AD blood and 89 in AD brain studies. Regulated blood genes included MMP9, MME (Neprilysin), TGFβ1, CA4, OCLN, ATM, TGM3, IGFR2, NOV, RNF213, BMX, LRRN1, CAMK2G, INSR, CTSD, SORCS1, SORL1, and TANC2.
RNA expression is altered in AD blood irrespective of WMH status. Some genes are shared with AD brain.
... We previously found changes in RNA expression in cells of whole blood in patients with lacunar small vessel stroke as well as patients with WMH. [20][21][22][23] Furthermore, inflammation and associated oxidative stress may contribute to WMH through effects on the blood-brain barrier and myelin. In this study, we sought to evaluate the relationship of leucocyte gene expression to changes in WMH volumes over time. ...
... Genes associated with WMH volume progression in the present study differed from genes differentially expressed in blood of patients with large volume WMH compared to low volume WMH. 23 Ephrin signalling was common to both studies. Thus, the immune response that may promote WMH progression has differences from the immune response related to different WMH volumes. ...
Cerebral white matter hyperintensities (WMH) are an important contributor to aging brain pathology. Progression in WMH volume is associated with cognitive decline and gait impairment. Understanding the factors associated with WMH progression provides insight into pathogenesis and may identify novel treatment targets to improve cognitive health. We postulated that the immune system interaction with cerebral vessels and tissue may be associated with disease progression and thus evaluated the relationship of blood leukocyte gene expression to progression of cerebral WMH.
A brain MRI was obtained at baseline in 166 patients assessed for a cognitive complaint, and then repeated at regular intervals over a median of 5.9 years (IQR 3.5-8.2 years). WMH volumes were measured by semi-automated segmentation and percent change in WMH per year calculated. A venous blood sample obtained at baseline was used to measure whole-genome expression by RNA sequencing. The relationship between change in WMH volumes over time and baseline leukocyte gene expression was analyzed.
The mean age was 77.8 (SD 7.5) years and 60.2% of participants were female. The median WMH volume was 13.4 mL (SD 17.4 mL). The mean change in WMH volume was 12% per year. Patients were divided in quartiles by percent change in WMH volume, which was: -3.5% per year in quartile 1, 7.4% per year in quartile 2, 11.7% in quartile 3, and 33.6% per year in quartile 4. There were 148 genes associated with changing WMH volumes over time (p < 0.05 r>|0.2|). Genes and pathways identified have roles in endothelial dysfunction, extracellular matrix remodeling, altered remyelination, inflammation, and response to ischemia. ADAM8, CFD, EPHB4, FPR2, Wnt-B-catenin, FAK, and SIGLEC1 were among the identified genes.
Progression of WMH volumes over time is associated with genes involved in endothelial dysfunction, extracellular matrix remodeling, altered remyelination, inflammation, and response to ischemia. Further studies are needed to evaluate the role of peripheral inflammation in relation to rate of WMH progression and the contribution to cognitive decline.
... Gene expression has proved to be an important intermediate phenotype that helps to bridge genetic variations with many phenotypic traits [32][33][34]. Xu et al. [35] examined the association of gene expression in blood with WMH. Twenty participants with extensive WMH and 18 participants with minimum WMH were enrolled in the study. ...
... We found a single gene in the current study overlapping with those reported previously [35,36]. The lack of overlapping might dues to several reasons. ...
Background
White matter hyperintensities (WMH) are an important biomarker of cumulative vascular brain injury and have been associated with cognitive decline and an increased risk of dementia, stroke, depression, and gait impairments. The pathogenesis of white matter lesions however, remains uncertain. The characterization of gene expression profiles associated with WMH might help uncover molecular mechanisms underlying WMH.
Methods
We performed a transcriptome-wide association study of gene expression profiles with WMH in 3248 participants from the Framingham Heart Study using the Affymetrix Human Exon 1.0 ST Array.
Results
We identified 13 genes that were significantly associated with WMH (FDR < 0.05) after adjusting for age, sex and blood cell components. Many of these genes are involved in inflammation-related pathways.
Conclusion
Thirteen genes were significantly associated with WMH. Our study confirms the hypothesis that inflammation might be an important factor contributing to white matter lesions. Future work is needed to explore if these gene products might serve as potential therapeutic targets.
Electronic supplementary material
The online version of this article (10.1186/s13024-017-0209-5) contains supplementary material, which is available to authorized users.
... The lack of identifiable causal triggers in sporadic SVD (compared to genetically associated forms) -along with multiple susceptibility genes identified in GWAS studies and complex relationships between vascular risk factors in aging populations-make it challenging to disentangle specific vascular vulnerability within the GM or/and the WM of the human brain (e.g. vascular regulation in pial, perforant, terminal arteries/capillaries, or other postulated BBB factors) (Paternoster et al., 2009;Tan et al., 2017;Tran et al., 2016;Xu et al., 2010). ...
Small vessel disease (SVD) is a disorder that causes vascular lesions in the entire parenchyma of the human brain. At present, it is not well known how primary and secondary damage interact to give rise to the complex scenario of white matter (WM) and grey matter (GM) lesions. Using novel cross-sectional and longitudinal connectomic approaches, we unveil the bidirectional nature of GM and WM changes, that is, primary cortical neurodegeneration that leads to secondary alterations in vascular border zones, and WM lesions that lead to secondary neurodegeneration in cortical projecting areas. We found this GM-WM interaction to be essential for executive cognitive performance. Moreover, we also observed that the interlocked degeneration of GM and WM over time associates with prototypical expression levels of genes potentially linked to SVD. Among these connectomic-genetic intersections, we found that the Androgen Receptor (AR) protein coding gene, is a particularly central candidate gene that might confer key vulnerability for brain lesion development in SVD. In conclusion, this study advances in the understanding of the bidirectional relationships between GM and WM lesions, primary and secondary vascular neurodegeneration, and sheds light on the biological mechanisms which underlie the genetic signatures of SVD.
... In addition to these approaches, the potential utility of specific genes in blood as candidate biomarkers have been explored (18). Multiple candidate genes have been reported to show differential expression in the blood of ad patients versus healthy controls (19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30). However, findings have been inconsistent across studies. ...
Alzheimer’s disease (ad) adversely affects the health, quality of life and independence of patients. There is a critical need to identify novel blood gene biomarkers for ad risk assessment. We performed a transcriptome-wide association study to identify biomarker candidates for ad risk. We leveraged two sets of gene expression prediction models of blood developed using different reference panels and modelling strategies. By applying the prediction models to a meta-GWAS including 71 880 (proxy) cases and 383 378 (proxy) controls, we identified significant associations of genetically determined expression of 108 genes in blood with ad risk. Of these, 15 genes were differentially expressed between ad patients and controls with concordant directions in measured expression data. With evidence from the analyses based on both genetic instruments and directly measured expression levels, this study identifies 15 genes with strong support as biomarkers in blood for ad risk, which may enhance ad risk assessment and mechanism-focused studies.
... To date, studies on the genetics of LA have focused on susceptible genes and abnormal gene expression [21,22,[26][27][28][29][30][31][56][57][58]. Very few studies have been carried out to identify the epigenetic factors involved in regulating transcription of risk genes associated with LA. ...
White matter lesions known as leukoaraiosis (LA) are cerebral white matter hyperintensities observed in elderly individuals. Currently, no reliable molecular biomarkers are available for monitoring their progression over time. To identify biomarkers for the onset and progression of LA, we analyzed whole blood-based, microRNA expression profiles of leukoaraiosis, validated those exhibiting significant microRNA changes in clinical subjects by means of quantitative real-time polymerase chain reactions and determined the function of miRNA in cell lines by means of microRNA mimic transfection assays. A total of seven microRNAs were found to be significantly down-regulated in leukoaraiosis. Among the microRNAs, hsa-miR-1972 was downregulated during the early onset phase of leukoaraiosis, as confirmed in independent patients, and it was found to target leukoaraiosis-dependent BAIAP3, decreasing its expression in 293T cell lines. Functional enrichment analysis revealed that significantly dysregulated miRNAs-mRNAs changes associated with the onset of leukoaraiosis were involved in neurogenesis, neuronal development, and differentiation. Taken together, the study identified a set of candidate microRNA biomarkers that may usefully monitor the onset and progression of leukoaraiosis. Given the enrichment of leukoaraiosis-associated microRNAs and mRNAs in neuron part and membrane system, BAIAP3 could potentially represent a novel target of hsa-miR-1972 in leukoaraiosis through which microRNAs are involved in the pathogenesis of white matter lesions.
... While Ab and tau levels in cerebrospinal fluid (CSF) are considered to be potential markers for assessing AD risk, lumbar puncture is painful and routine check of CSF is difficult (Lee et al., 2019). On the other hand, several studies (Rahman et al., 2020;Xu et al., 2010) have suggested specific genes in blood can serve as candidate biomarkers for risk assessment. ...
Motivation
Transcriptome-wide association studies (TWAS) have successfully facilitated the discovery of novel genetic risk loci for many complex traits, including late-onset Alzheimer’s disease (AD). However, most existing TWAS methods rely only on gene expression and ignore epigenetic modification (i.e., DNA methylation) and functional regulatory information (i.e., enhancer-promoter interactions), both of which contribute significantly to the genetic basis of AD.
Results
We develop a novel gene-level association testing method that integrates genetically regulated DNA methylation and enhancer-target gene pairs with genome-wide association study (GWAS) summary results. Through simulations, we show that our approach, referred to as the CMO (cross methylome omnibus) test, yielded well controlled type I error rates and achieved much higher statistical power than competing methods under a wide range of scenarios. Furthermore, compared with TWAS, CMO identified an average of 124% more associations when analyzing several brain imaging-related GWAS results. By analyzing to date the largest AD GWAS of 71,880 cases and 383,378 controls, CMO identified six novel loci for AD, which have been ignored by competing methods.
Availability
Software: https://github.com/ChongWuLab/CMO
Supplementary information
Supplementary data are available at Bioinformatics online.
... Defining these effects will inform and improve patient-specific prediction of ICH outcome. Consider the following points: (1) hemostasis is influenced by gonadal hormones, age, and ethnicity, [25][26][27][28][29][30] (2) hematoma volume is a well-known predictor of outcome after ICH, 6,31-33 (3) outcome after ischemic stroke is affected by age, gender, and ethnicity, 34,35 (4) female gonadal hormones are neuroprotective in a variety of preclinical models, [36][37][38][39][40][41][42] and (5) temporal changes of these hormones in humans vary by gender, age, and ethnicity. 19,20,43 All of these established relationships suggest thorough study of interactive effects of gonadal hormones, gender, and ethnicity on ICH outcome is timely and important. ...
... Notwithstanding observations of lipid peroxidation and increased neurotoxic oxidative products of essential fatty acids in the vicinity of amyloid plaques and neurofibrillary tangles (Markesbery and Carney, 1999), peripheral measurement indicated small vessel disease, not AD per se, in this study. The results concur with those of a previous study, in which peripheral expression of genes in oxidative stress pathways was associated with WMH, regardless of the presence of AD (Xu et al., 2010). In that study of 38 patients (n ¼ 17 with AD), accompanying changes in gene expression related to oligodendrocyte proliferation and axon repair were also observed. ...
White matter hyperintensities (WMH), presumed to indicate small vessel subcortical ischemic vascular disease, are found commonly in elderly individuals with and without Alzheimer’s disease (AD). Oxidative stress may instigate or accelerate the development of vascular disease, and oxidative stress markers are elevated in AD. Here we assess independent relationships between three serum lipid peroxidation markers (lipid hydroperoxides [LPH], 8-isoprostane and 4-hydroxynonenal) and the presence of extensive WMH and/or AD. Patients were recruited from memory and stroke prevention clinics into 4 groups: minimal WMH, extensive WMH, AD with minimal WMH, and AD with extensive WMH. Extensive WMH, but not AD, was associated with higher serum concentrations of 8-isoprostane and LPH. Peripheral LPH concentrations mediated the effect of hypertension on deep, but not periventricular, WMH volumes. 4-hydroxynonenal was associated with hyperlipidemia and cerebral microbleeds, but not with extensive WMH or AD. We conclude that lipid peroxidation mediates hypertensive injury to the deep subcortical white matter, and that peripheral blood lipid peroxidation markers indicate subcortical small vessel disease regardless of an AD diagnosis.
... Additionally, we believe that, except for the effect of genetic factors on LA, aberrant gene expression and epigenetic and small RNA regulation may predominantly contribute to increased LA risk or LA pathogenesis. Simpson [31] and Xu et al [32] identified many genes with abnormal mRNA expression in LA by microarray RNA expression analysis in brain tissue and in whole blood, respectively. [33] Our laboratory has performed genome-scale methylation profiling and miRNA expression analysis on LA in whole blood and revealed some specific hyper/hypo-methylated genes and miRNAs associated with LA occurrence and development (unpublished data). ...
Leukoaraiosis (LA) is a frequent neuroimaging finding commonly observed on brain MRIs of elderly people with prevalence ranging from 50% to 100%. Multiple susceptibility genes or genetic risk factors for LA have been identified in subjects of European descent. Here, we report the first replication study on several common and novel genetic variations in the Chinese population. In this study, a total of 244 subjects (201 LA patients and 43 controls) were enrolled according to our new and strict definition for LA. Subsequently, 6 genetic variants at 5 genes, rs3744028 in TRIM65, rs1055129 in TRIM47, rs1135889 in FBF1, rs1052053 in PMF1, and rs1801133 (C677T) and rs1801131(A1298C) in MTHFR, were selected for genotyping using polymerase chain reaction (PCR)-based pyrosequencing and restriction fragment length polymorphism (RFLP) together with capillary electrophoresis (CE) and agarose gel electrophoresis. Finally, Pearson's χ and multivariate logistic regression tests were used to examine the associations between the genotypes and LA. Among these candidate polymorphisms, except for rs1052053 and rs1801131, rs1135889 (P = 0.012) showed significant associations with LA in the dominant model, and the other 3 SNPs, rs3744028 (P = 0.043), rs1055129 (P = 0.038), and rs1801133 (P = 0.027), showed significant associations with LA in the recessive model. However, these differences no longer remained significant after adjusting for age, gender, hypertension, and diabetes mellitus and applying Bonferroni correction or Sidak correction for multiple testing. These results suggest that the above-mentioned genetic variants are not associated with LA risk. In summary, the study did not replicate the susceptibility of rs3744028, rs1055129, and rs1135889 at the Chr17q25 locus for LA nor did it find any other significant results for rs1052053, rs1801133, and rs1801131 in the Chinese population. It strongly indicated the ethnic differences in the genetics of LA. However, the associations of rs3744028 (TRIM65), rs1055129 (TRIM47), rs1135889 (FBF1), and rs1801133 (MTHFR) with LA before Bonferroni correction and Sidak correction for multiple testing are worth highlighting. Thus, we believe that a genome-wide association study and candidate gene association studies are needed to reassess the previous findings and screen novel risk genes for LA in China.
... Previous studies found that the degree of LA was inversely correlated with the patency of collateral flow [4,5], which could provide retrograde blood flow for cerebral reperfusion when the main feeding artery was occluded. Subjects with severe LA also exhibited increased hypercoagulability [6], platelet activation [7], oxidative stress, and inflammation [8], which may facilitate the formation of microemboli contributing to the failure of reperfusion. In addition, cerebrovascular reactivity and dynamic autoregulation function have been suggested to be compromised in severe LA [9,10], which was consistent with the histopathological findings of vascular changes featured with arteriolosclerosis, tortuous arterioles, venous collagenosis, and endothelium dysfunction [11][12][13]. ...
Leukoaraiosis (LA) is associated with structural and functional cerebrovascular impairment, which may compromise the capacity of ischemic tissue to maximize reperfusion after intravenous thrombolysis (IVT). We aimed to determine whether severe LA is correlated with reperfusion inefficiency, which contributes to infarct growth and poor functional outcome. We analyzed data from our consecutive acute ischemic stroke (AIS) patients who had acquired baseline and 24-h follow-up diffusion- and perfusion-weighted imaging. Reperfusion was defined as reduction of ≥70 % of hypoperfusion lesion at 24 h from baseline. Severe LA was defined as Fazekas score 2 or 3 on FLAIR images. We investigated the relationship between severity of LA and reperfusion status. Multivariate statistical analysis was carried out for modeling the independent predictors of reperfusion, infarct growth, and functional outcome. Finally, 79 patients were included, among them 30 (37.97 %) had severe LA. Reperfusion was observed in 41 (51.89 %) patients, the proportion of reperfusion was very similar in patients with and without severe LA (53.33 vs 51.02 %, p = 1.000). Large artery occlusion was the only independent unfavorable predictor for reperfusion (OR = 0.202, 95 % confidence interval, 0.060–0.673; p = 0.014). Multiple linear regression analysis revealed that severe LA was independently associated with infarct growth (standardized coefficients = 0.191, p = 0.040). Severe LA was also an independent predictor of poor outcome (mRS ≥ 3) (OR = 4.004, 95 % confidence interval, 1.267–12.656, p = 0.018) after adjusting for reperfusion and baseline severity of stroke. Severe LA was associated with infarct growth and poor outcome independent of reperfusion status, which may expand the notion that LA contributes the intrinsic vulnerability of brain tissue to acute ischemic insults. The burden of LA may not serve as an imaging indicator of reperfusion inefficiency after IVT for AIS patients.
... More recent studies evaluating the RNA expression profile in brain or blood samples showed that genes specific for WMH were associated with injury responses, oxidative stress, and in-flammation. 37,38 In a large genome-wide association study of WMH burden in community-based cohorts of individuals of European descent, a novel locus on chromosome 17 was associated with WMH. Although information on the specific genes and functional variants underlying the reported associations was lacking, further characterization of this locus will provide additional insight into the mechanisms of WMH and hopefully new targets for preventive therapies. ...
Lacunar infarcts/lacunes, white matter hyperintensities (WMH), and cerebral microbleeds (CMBs) are considered various manifestations of cerebral small vessel disease (SVD). Since the exact mechanisms of these manifestations differ, their associated risk factors differ. High blood pressure is the most consistent risk factor for all of these manifestations. However, a "J curve" phenomenon in terms of blood pressure probably exists for WMH. The association between cholesterol levels and lacunar infarcts/lacunes or WMH was less consistent and sometimes conflicting; a low cholesterol level probably increases the risk of CMBs. Homocysteinemia appears to be associated with WMH. It is noteworthy that the risk factors profile may also differ between different lacunar patterns and CMBs located at different parts of the brain. Thrombolysis, antihypertensives, and statins are used to treat patients with symptomatic lacunar infarction, just as in those with other stroke subtypes. However, it should be remembered that bleeding risks increase in patients with extensive WMH and CMBs after thrombolysis therapy. According to the Secondary Prevention of Small Subcortical Strokes trial results, a blood pressure reduction to <130 mmHg is recommended in patients with symptomatic lacunar infarction. However, an excessive blood pressure decrease may induce cognitive decline in older patients with extensive WMH. Dual antiplatelet therapy (aspirin plus clopidogrel) should be avoided because of the excessive risk of intracerebral hemorrhage. Although no particular antiplatelet is recommended, drugs such as cilostazol or triflusal may have advantages for patients with SVD since they are associated with less frequent bleeding complications than aspirin.
... Structural white matter abnormalities called white matter hyperintensities (WMH) are known to increase with age, correlate negatively with deficits in processing speed, cognitive control, and visual search performance, and are associated with alterations (both increases and decreases) in brain functional activation and connectivity [8][9][10][11][12][13][14][15]. The underlying pathology of WMH is non-specific and includes demyelination, axonal atrophy, and gliosis [16], and WMH have been attributed to ischemic pathology and vascular processes [17] as well as to oxidative stress and inflammation [18]. Previous work suggests that WMH affect cognition through disruption of structural connectivity of distributed cortical networks necessary for specific functions, such as cognitive and attentional control [7,8], potentially independent of the effects of the aging process alone [9]. ...
The mechanisms by which aging and other processes can affect the structure and function of brain networks are important to understanding normal age-related cognitive decline. Advancing age is known to be associated with various disease processes, including clinically asymptomatic vascular and inflammation processes that contribute to white matter structural alteration and potential injury. The effects of these processes on the function of distributed cognitive networks, however, are poorly understood. We hypothesized that the extent of magnetic resonance imaging white matter hyperintensities would be associated with visual attentional control in healthy aging, measured using a functional magnetic resonance imaging search task. We assessed cognitively healthy older adults with search tasks indexing processing speed and attentional control. Expanding upon previous research, older adults demonstrate activation across a frontal-parietal attentional control network. Further, greater white matter hyperintensity volume was associated with increased activation of a frontal network node independent of chronological age. Also consistent with previous research, greater white matter hyperintensity volume was associated with anatomically specific reductions in functional magnetic resonance imaging functional connectivity during search among attentional control regions. White matter hyperintensities may lead to subtle attentional network dysfunction, potentially through impaired frontal-parietal and frontal interhemispheric connectivity, suggesting that clinically silent white matter biomarkers of vascular and inflammatory injury can contribute to differences in search performance and brain function in aging, and likely contribute to advanced age-related impairments in cognitive control.
... 20 We have used a similar approach to show that genes associated with white matter hyperintensities in brain are not associated with those found in ischemic stroke or TIAs. 21 Despite the successes, there remain several hurdles to translate these proof-of-concept studies to practice. For example, for prospective prediction problems with data normalization need to be solved to eliminate batch effects that occur over time. ...
Many attempts have been made at developing biomarkers for stroke. Although successful to some degree,1–3 none have been sufficiently robust to be used in clinical practice. Thus, there is still a great need for more in-depth studies of the biology of human stroke to understand its pathogenesis better. This should make it possible to develop blood tests for stroke and transient ischemic attacks (TIAs) to guide treatment and ultimately improve outcomes.
The traditional approach to develop stroke biomarkers has been to select candidate markers based on known pathobiology. The majority of markers that have been evaluated are proteins that are measured in patients at various times before or after stroke. The rationale for this approach is that brain injury releases molecules into blood that can be measured as evidence of brain injury; or that other cells and organs release molecules that either cause or contribute to a stroke, or are a response to the stroke. These approaches have been handicapped because they require a guess at the most reliable biomarker.
Our group took a different approach to the problem by assessing the immune system after stroke.4,5 The rationale for this approach is shown in Figure 1. The expression of genes in leukocytes is influenced by many factors associated with ischemic stroke. Leukocytes interact with blood clots, platelets, atherosclerotic plaque, and injured brain endothelial cells via adhesion molecules.5 In addition, leukocytes detect circulating cytokines, chemokines, and hormones. Each has the potential to modulate RNA expression in leukocytes.
Figure 1.
Schematic of interactions between circulating leukocytes and factors involved in ischemic stroke, including blood clots, platelets, atherosclerotic plaque, and damaged endothelial cells. Each factor can influence expression of leukocyte RNA. This figure is reproduced from an article by Sharp et al.5
To provide proof-of-principle that …
... Additional research is needed that examines other factors which may modify the relationship of WMH with cognition among overtly healthy older individuals. Plausible factors include genetic factors, vascular risk factors and diseases (such as hypertension and diabetes), inflammation, and oxidative stress (Novak et al. 2006;Wright et al. 2009;Xu et al. 2010;Satizabal et al. 2012;Raz et al. 2012). ...
Both presence of white matter hyperintensities (WMH) and smaller total gray matter volume on brain magnetic resonance imaging (MRI) are common findings in old age, and contribute to impaired cognition. We tested whether total WMH volume and gray matter volume had independent associations with cognition in community-dwelling individuals without dementia or mild cognitive impairment (MCI). We used data from participants of the Rush Memory and Aging Project. Brain MRI was available in 209 subjects without dementia or MCI (mean age 80; education = 15 years; 74 % women). WMH and gray matter were automatically segmented, and the total WMH and gray matter volumes were measured. Both MRI-derived measures were normalized by the intracranial volume. Cognitive data included composite measures of five different cognitive domains, based on 19 individual tests. Linear regression analyses, adjusted for age, sex, and education, were used to examine the relationship of logarithmically-transformed total WMH volume and of total gray matter volume to cognition. Larger total WMH volumes were associated with lower levels of perceptual speed (p < 0.001), but not with episodic memory, semantic memory, working memory, or visuospatial abilities (all p > 0.10). Smaller total gray matter volumes were associated with lower levels of perceptual speed (p = 0.013) and episodic memory (p = 0.001), but not with the other three cognitive domains (all p > 0.14). Larger total WMH volume was correlated with smaller total gray matter volume (p < 0.001). In a model with both MRI-derived measures included, the relation of WMH to perceptual speed remained significant (p < 0.001), while gray matter volumes were no longer related (p = 0.14). This study of older community-dwelling individuals without overt cognitive impairment suggests that the association of larger total WMH volume with lower perceptual speed is independent of total gray matter volume. These results help elucidate the pathological processes leading to lower cognitive function in aging.
... The number of infections reported over a 5-year period increased the odds of developing AD two-fold [14], and vaccination compliance reduced the risk of developing AD [15]. Though infection has not been associated with WMH, evidence of inflammation has been detected in the peripheral blood of patients with WMH compared to controls [16]. In addition, white matter injury in the neonatal brain has been associated with infection [17]. ...
Ischemia, white matter injury, and Alzheimer's disease (AD) pathologies often co-exist in aging brain. How one condition predisposes to, interacts with, or perhaps causes the others remains unclear.
To better understand the link between ischemia, white matter injury, and AD, adult rats were administered lipopolysaccharide (LPS) to serve as an inflammatory stimulus, and 24 h later subjected to 20-min focal cerebral ischemia (IS) followed by 30-min hypoxia (H).
Myelin and axonal damage, as well as amyloid-β (Aβ) and amyloid-β protein precursor (AβPP) deposition were examined by western blot and immunocytochemistry following LPS/IS/H. Findings were compared to the 5XFAD mouse AD brain.
Myelin/axonal injury was observed bilaterally in cortex following LPS/IS/H, along with an increase in IL-1, granzyme B, and LPS. AβPP deposition was present in ischemic striatum in regions of myelin loss. Aβ1-42 and AβPP were deposited in small foci in ischemic cortex that co-localized with myelin aggregates. In the 5XFAD mouse AD model, cortical amyloid plaques also co-localized with myelin aggregates.
LPS/IS/H produce myelin injury and plaque-like aggregates of myelin. AβPP and Aβ co-localize with these myelin aggregates.
... The present data suggested an association between AoAC and cerebral small artery disease. Oxidative stress might be related to cerebral white matter diseases, and experimental studies have shown that endothelial injury and oxidative stress are implicated in the mechanisms of cerebral white matter diseases and aortic calcification [29][30][31] . Therefore, AoAC and cerebral small artery disorders might have common pathogenic processes in stroke patients. ...
Aim: Aortic arch calcification (AoAC) on chest X-rays represents systemic atherosclerosis and it is associated with ischemic cardiovascular diseases. However, the relationship between ischemic stroke and AoAC has yet to be fully elucidated.
Methods: Patients with acute ischemic stroke who were undergoing chest X-ray, blood, and brain magnetic resonance imaging (MRI) examinations were prospectively studied. The extent of AoAC on chest X-ray was divided into four grades (0-3). Clinical characteristics, biochemical findings, white matter lesions on MRI, and AoAC extent were assessed in each stroke subtype, and the factors associated with AoAC were investigated.
Results: A total of 175 patients (age, 70±13 years; 115 men) were enrolled in the study. According to the Trial of Org 10172 in Acute Stroke Treatment classification with minor modification, 33 patients (19%) had small artery occlusion (SAO), 42 (24%) had large artery atherosclerosis, 49 (28%) had cardioembolism, 24 (14%) had stroke with other determined etiologies, and 27 (17%) had stroke with undetermined etiologies. Compared to other stroke subtypes, the extent of AoAC was independently correlated with SAO (all p＜0.05). Age (odds ratio [OR]: 1.14, 95% confidence interval [CI]: 1.08 to 1.19, p＜0.001), hypertension, (OR: 3.44, 95% CI: 1.23 to 9.66, p=0.019), diabetes mellitus (OR: 2.19, 95% CI: 0.99 to 4.85, p=0.054), white matter lesions (OR: 1.54, 95% CI: 1.00 to 2.36, p=0.048), and SAO (OR: 1.38, 95% CI: 1.02 to 1.89, p=0.040) were significantly associated with AoAC.
Conclusions: Age, hypertension, cerebral small artery disease, and possibly diabetes mellitus appear to be closely associated with AoAC in patients with acute ischemic stroke.
... Furthermore, microglial activation and reactive astrocytes are also present in the lesions (Akiguchi et al., 1998;Simpson et al., 2007;Tomimoto et al., 1996) (Figure 6). Markers of endothelial activation, hemostasis, inflammation, and oxidative stress are also upregulated in blood, consistent with more widespread effects in the systemic circulation (Gallacher et al., 2010;Knottnerus et al., 2010;Markus et al., 2005;Rouhl et al., 2012a;Shibata et al., 2004;Xu et al., 2010) (Figure 6). The mechanisms of these responses have not been fully elucidated, but several factors may play a role. ...
Vascular cognitive impairment defines alterations in cognition, ranging from subtle deficits to full-blown dementia, attributable to cerebrovascular causes. Often coexisting with Alzheimer's disease, mixed vascular and neurodegenerative dementia has emerged as the leading cause of age-related cognitive impairment. Central to the disease mechanism is the crucial role that cerebral blood vessels play in brain health, not only for the delivery of oxygen and nutrients, but also for the trophic signaling that inextricably links the well-being of neurons and glia to that of cerebrovascular cells. This review will examine how vascular damage disrupts these vital homeostatic interactions, focusing on the hemispheric white matter, a region at heightened risk for vascular damage, and on the interplay between vascular factors and Alzheimer's disease. Finally, preventative and therapeutic prospects will be examined, highlighting the importance of midlife vascular risk factor control in the prevention of late-life dementia.
... RNAs are known to be released into blood, and their profiles change in brain disorders (Scholer et al., 2010;Sharp et al., 2011b). Many studies showed that mRNA profiles in human blood can serve as a sensitive index to identify various stroke subtypes and disease progression (Jickling et al., 2013;Jickling et al., 2012a;Jickling et al., 2011;Jickling et al., 2010;Jickling et al., 2012b;Liu et al., 2010a;Stamova et al., 2010;Xu et al., 2010). ...
The mammalian genome is replete with various classes of non-coding (nc) RNA genes. Many of them actively transcribe, and their relevance to CNS diseases is just beginning to be understood. CNS is one of the organs in the body that shows very high ncRNAs activity. Recent studies demonstrated that cerebral ischemia rapidly changes the expression profiles of different classes of ncRNAs: including microRNA, long noncoding RNA and piwi-interacting RNA. Several studies further showed that post-ischemic neuronal death and/or plasticity/regeneration can be altered by modulating specific microRNAs. These studies are of interest for therapeutic development as they may contribute to identifying new ncRNA targets that can be modulated to prevent secondary brain damage after stroke.
... To exemplify this, patients exhibiting varying degrees of white matter hyperintensity (WMH), magnetic resonance-responsive brain injury foci of uncertain etiology but associated with aging and vascular risk factors, were analyzed. 77 Cluster analysis of gene expression patterns differentiated patients with minimal from those with extensive WMH (Fig. 5), and functional analysis implicated genes involved in oxidative and inflammatory stress as well as oligodendrocyte proliferation and axon repair. Despite certain hypotheses postulating chronic ischemia as a contributor to the development of WMH however, overlap between WMHimplicated genes and genes identified in the stroke studies was highly limited, suggesting a mechanistic difference between the two pathologies at least by the time of WMH presentation. ...
Stroke is a leading cause of death and disability, and considerable effort is being expended to investigation of its pathological mechanisms, as well as the identification of clinically relevant biomarkers that could assist in diagnosis. RNA-based analysis of gene expression in blood represents a new field of study addressing both paradigms. A number of recent animal and human studies using microarray technology demonstrate rapidly-induced, measurable changes in gene expression in response to ischemic trauma, and distinct expression ?profiles? specific to the injury subtype. The incorporation of newer technologies for a more detailed transcriptome analysis holds great promise for further improving our knowledge of stroke at the molecular level, and potentially enhancing standards of diagnosis.
... CA caudate, PU putamen, GP globus pallidus, TH thalamus, RN red nucleus, SN substantia nigra, FWM frontal white matter Table 2 Associations between regional R2* and CWMHV using partial Pearson correlation analysis models Model 1 adjusted for age, Model 2 adjusted for age and other sociodemographic variables (sex and years of education), Model 3 adjusted for age, sex, years of education, and vascular risk factors (hypertension, diabetes, hyperlipidemia, serum glucose level, systolic and diastolic blood pressure, total cholesterol, total homocysteine, and highsensitivity C-reactive protein) 1988). A recent postmortem microarray RNA expression analysis found that approximately 10.6 % of WMH-related gene was involved in immune regulation (Xu et al. 2010). Biomarkers of inflammation were also observed to be increased in WMH patients (Fornage et al. 2008). ...
Iron accumulation has been implicated in the pathogenesis of demyelinating diseases. Therefore, we hypothesized that abnormal high cerebral iron deposition may be involved in the development of white matter hyperintensities (WMHs). We used R2* relaxometry to assess whether iron levels in different brain regions correlate with the severity of WMHs. This technique has been recently validated in a postmortem study to demonstrate in vivo brain iron accumulation in a quantitative manner. Fifty-two consecutive WMH patients and 30 healthy controls with 3-T magnetic resonance imaging (MRI) were reviewed in this study. We measured WMH volume (as a marker of the severity of WMHs) on MRI, and the transverse relaxation rate R2*, as an estimate of iron content in seven brain regions. We found that R2* in globus pallidus was associated with WMH volume after adjusting for sociodemographic variables (partial correlation coefficient = 0.521, P < 0.001) and in a multivariate analysis adjusted for common vascular risk factors (partial correlation coefficient = 0.572, P = 0.033). Regional R2* in globus pallidus was also significantly higher in WMHs than in controls (P = 0.042). Iron content in globus pallidus, as assessed by R2* relaxometry, is independently linked to the severity of WMHs in our cohort of patients, suggesting that iron deposition in the brain may play a role in the pathogenesis of WMHs. This may provide prognostic information on patients with WMHs and may have implications for therapeutic interventions in WMHs.
... The threshold used to detect baseline WMH 1 from the native FLAIR images might be considered too conservative. However, our method has been used for many years to report clinically relevant associations among risk factors, WMH, and cognition in a number of large-scale aging studies 8,19,37,11,39,40 ; the reliabilities between raters, between scans, and between scanners are high. 26 In addition, the effect of FLAIR intensity on the risk to convert to WMH was continuous and significant at values far below the threshold used to segment the images at baseline. ...
Background and purpose:
WMH, associated with cognitive decline and cardiovascular risk factors, may represent only the extreme end of a more widespread continuous WM injury process that progresses during aging and is poorly understood. We investigated the ability of FLAIR and DTI to characterize the longitudinal course of WMH development.
Materials and methods:
One hundred nineteen participants (mean age, 74.5 ± 7.4), including cognitively healthy elders and subjects diagnosed with Alzheimer disease and mild cognitive impairment, received a comprehensive clinical evaluation and brain MR imaging, including FLAIR and DTI on 2 dates. The risk for each baseline normal-appearing WM voxel to convert into WMH was modeled as a function of baseline FA (model M1) and both baseline FA and standardized FLAIR (M2). Sensitivity, specificity, accuracy, and AUC for predicting conversion to WMH were compared between models.
Results:
Independent of clinical diagnosis, lower baseline FA (P < .001, both models) and higher baseline FLAIR intensity (P < .001, M2) were independently associated with increased risk for conversion from normal WM to WMH. M1 exhibited higher sensitivity but lower specificity, accuracy, and AUC compared with M2.
Conclusions:
These findings provide further evidence that WMH result from a continuous process of WM degeneration with time. Stepwise decreases in WM integrity as measured by both DTI and FLAIR were independently associated with stepwise increases in WMH risk, emphasizing that these modalities may provide complementary information for understanding the time course of aging-associated WM degeneration.
... While such studies are not yet able to replace conventional investigative techniques for determining ischaemic stroke subtype, identification of a expression profiles may give novel insights into stroke pathogenesis, and perhaps identification of suitable biomarkers for monitoring risk reduction treatments. This technique has also been applied to associated phenotypes such as white matter hyperintensity in the brain, currently only detectable by MRI [37]. ...
Stroke is the third commonest cause of death and the major cause of adult neurological disability worldwide. While much is known about conventional risk factors such as hypertension, diabetes and incidence of smoking, these environmental factors only account for a proportion of stroke risk. Up to 50% of stroke risk can be attributed to genetic risk factors, although to date no single risk allele has been convincingly identified as contributing to this risk. Advances in the field of genetics, most notably genome wide association studies (GWAS), have revealed genetic risks in other cardiovascular disease and these techniques are now being applied to ischaemic stroke. This paper covers previous genetic studies in stroke including candidate gene studies, discusses the genome wide association approach, and future techniques such as next generation sequencing and the post-GWAS era. The review also considers the overlap from other cardiovascular diseases and whether findings from these may also be informative in ischaemic stroke.
... Recently, postmortem Medical Research Council Cognitive Function and Ageing Study using RNA microarray and pathway analysis found that 8 major pathways in which multiple genes showed altered RNA transcription (immune regulation, cell cycle, apoptosis, proteolysis, ion transport, cell structure, electron transport, metabolism) and WMC represented areas with a complex molecular phenotype [63]. Xu et al. study revealed that 241 genes specific for WMC expression were associated with inflammation, oxidative stress, detoxification, and hormonal responses, included genes associated with brain repair, long-term potentiation, and axon guidance, and included genes associated with oligodendrocyte proliferation, axon repair, long-term potentiation, and neurotransmission [64]. These neurogenetic findings support the ischemia, blood-brain barrier dysfunction, systemic oxidative stress, and inflammation in the pathogenesis of WMC, as well as other potential processes in the pathogenesis which warrant future research. ...
Age-related white matter changes (WMC) are considered manifestation of arteriolosclerotic small vessel disease and are related to age and vascular risk factors. Most recent studies have shown that WMC are associated with a host of poor outcomes, including cognitive impairment, dementia, urinary incontinence, gait disturbances, depression, and increased risk of stroke and death. Although the clinical relevance of WMC has been extensively studied, to date, only very few clinical trials have evaluated potential symptomatic or preventive treatments for WMC. In this paper, we reviewed the current understanding in the pathophysiology, epidemiology, clinical importance, chemical biomarkers, and treatments of age-related WMC.
... Progression of white matter hyperintensities on MRI which may reflect small vessel disease has been associated with a higher plasma level of intercellular adhesion molecule (ICAM) [46]. A profile of differentially expressed genes has also been reported for WMH in patients with and without Alzheimer's disease [47]. Among 38 subjects with minimal or several WMH, 50 differentially expressed genes (p<0.005, fold change>|1.5|) ...
This review provides a summary of the protein and RNA biomarkers that have been studied for the diagnosis and assessment of ischemic stroke. Many of the biomarkers identified relate to the pathophysiology of ischemic stroke, including ischemia of CNS tissue, acute thrombosis and inflammatory response. These biomarkers are summarized by their intended clinical application in ischemic stroke including diagnosis, prediction of stroke severity and outcome, and stratification of patients for stroke therapy. Among the biomarkers discussed are recent whole genome studies using RNA expression profiles to diagnose ischemic stroke and stroke etiology. Though many candidate blood based biomarkers for ischemic stroke have been identified, none are currently used in clinical practice. With further well designed study and careful validation, the development of blood biomarkers to improve the care of patients with ischemic stroke may be achieved.
Leukoaraiosis (LA) manifests as cerebral white matter hyperintensities on T2-weighted magnetic resonance imaging scans and corresponds to white matter lesions or abnormalities in brain tissue. Clinically, it is generally detected in the early 40s and is highly prevalent globally in individuals aged >60 years. From the imaging perspective, LA can present as several heterogeneous forms, including punctate and patchy lesions in deep or subcortical white matter; lesions with periventricular caps, a pencil-thin lining, and smooth halo; as well as irregular lesions, which are not always benign. Given its potential of having deleterious effects on normal brain function and the resulting increase in public health burden, considerable effort has been focused on investigating the associations between various risk factors and LA risk, and developing its associated clinical interventions. However, study results have been inconsistent, most likely due to potential differences in study designs, neuroimaging methods, and sample sizes as well as the inherent neuroimaging heterogeneity and multi-factorial nature of LA. In this article, we provided an overview of LA and summarized the current knowledge regarding its epidemiology, neuroimaging classification, pathological characteristics, risk factors, and potential intervention strategies.
Cognitive decline has emerged as one of the greatest health threats of old age. Meanwhile, aging is the primary risk factor for Alzheimer's disease (AD) and other prevalent neurodegenerative disorders. Developing therapeutic interventions for such conditions demands a greater understanding of the processes underlying normal and pathological brain aging. Despite playing an important role in the pathogenesis and incidence of disease, brain aging has not been well understood at a molecular level. Recent advances in the biology of aging in model organisms, together with molecular- and systems-level studies of the brain, are beginning to shed light on these mechanisms and their potential roles in cognitive decline. This chapter seeks to integrate the knowledge about the neurological mechanisms of age-related cognitive changes that underlie aging.
Background and Purpose
Left ventricular (LV) mass index is a marker of subclinical LV remodeling that relates to white matter damage in aging, but molecular pathways underlying this association are unknown. This study assessed if LV mass index related to cerebrospinal fluid (CSF) biomarkers of microglial activation (sTREM2 [soluble triggering receptor expressed on myeloid cells 2]), axonal injury (NFL [neurofilament light]), neurodegeneration (total-tau), and amyloid-β, and whether these biomarkers partially accounted for associations between increased LV mass index and white matter damage. We hypothesized higher LV mass index would relate to greater CSF biomarker levels, and these pathologies would partially mediate associations with cerebral white matter microstructure.
Methods
Vanderbilt Memory and Aging Project participants who underwent cardiac magnetic resonance, lumbar puncture, and diffusion tensor imaging (n=142, 72±6 years, 37% mild cognitive impairment [MCI], 32% APOE -ε4 positive, LV mass index 51.4±8.1 g/m ² , NFL 1070±588 pg/mL) were included. Linear regressions and voxel-wise analyses related LV mass index to each biomarker and diffusion tensor imaging metrics, respectively. Follow-up models assessed interactions with MCI and APOE -ε 4 . In models where LV mass index significantly related to a biomarker and white matter microstructure, we assessed if the biomarker mediated white matter associations.
Results
Among all participants, LV mass index was unrelated to CSF biomarkers ( P >0.33). LV mass index interacted with MCI ( P =0.01), such that higher LV mass index related to increased NFL among MCI participants. Associations were also present among APOE -ε4 carriers ( P =0.02). NFL partially mediated up to 13% of the effect of increased LV mass index on white matter damage.
Conclusions
Subclinical cardiovascular remodeling, measured as an increase in LV mass index, is associated with neuroaxonal degeneration among individuals with MCI and APOE -ɛ4. Neuroaxonal degeneration partially reflects associations between higher LV mass index and white matter damage. Findings highlight neuroaxonal degeneration, rather than amyloidosis or microglia, may be more relevant in pathways between structural cardiovascular remodeling and white matter damage.
OMICs-based technologies prove the opportunity to assess multiple nucleic acids, proteins, lipids, and metabolites associated with stroke. They could prove useful in understanding the pathophysiology of ischemic stroke (IS) and intracerebral hemorrhage (ICH) as well as potentially providing novel biomarkers for diagnosis, prognosis, treatment selection, cause of IS and ICH, and discovery of novel subgroups. In this chapter we review OMICs-based approaches in stroke including epigenomics, transcriptomics, proteomics, metabolomics, and lipidomics. Epigenetics is DNA methylation, histone modifications, transcription factors, microRNAs, and long intervening noncoding RNAs. Transcriptomics refers to the entire transcriptome of ∼20,000 genes which are alternatively spliced into ∼250,000 alternatively spliced, unique mRNA transcripts. RNAseq, arrays, and other technologies are used to study the transcriptome. Proteomics refers to all of the proteins found within a cell or biofluid (like serum or plasma), with >250,000 proteins from their mRNA transcripts. Mass spectrometry, antibody arrays, and other approaches are used to study the proteome. Metabolomics refers to the study of all metabolites in a cell or biological fluid, and similarly lipidomics is the study of all lipids in a cell or fluid. Nuclear magnetic resonance spectroscopy and mass spectrometry are used to study the metabolome and lipidome. To date, there are emerging studies providing proof of principle that OMICs approaches might eventually be used to diagnose and differentiate IS or ICH, identify the causes of IS and ICH, predict the cause of cryptogenic stroke, differentiate transient ischemic attacks (TIAs) from TIA mimics, predict patients likely to develop stroke, predict prognosis of IS and ICH, identify patients at greatest risk for hemorrhagic transformation, and potentially stratify patients for different types of treatments. While no OMICs-based test is currently used in practice, ongoing studies over the next decade will likely identify precision markers to aid clinicians in the diagnosis, treatment decisions, and risk classification of patients with stroke.
Loss of white matter (WM) integrity contributes to subcortical vascular mild cognitive impairment (svMCI). Diffusion tensor imaging (DTI) has revealed damage beyond the area of WM hyperintensity (WMH) including in normal-appearing WM (NAWM); however, the functional significance of this observation is unclear. To answer this question, in this study we investigated the relationship between microstructural changes in the WMH penumbra (WMH-P) and cognitive function in patients with svMCI by regional tract-based analysis. A total of 111 patients with svMCI and 72 patients with subcortical ischemic vascular disease (SIVD) without cognitive impairment (controls) underwent DTI and neuropsychological assessment. WMH burden was determined before computing mean values of fractional anisotropy (FA) and mean diffusivity (MD) within WMHs and WMH-Ps. Pearson’s partial correlations were used to assess the relationship between measurements showing significant intergroup differences and composite Z -scores representing global cognitive function. Multiple linear regression analysis was carried out to determine the best model for predicting composite Z -scores. We found that WMH burden in the genu, body, and splenium of the corpus callosum (GCC, BCC, and SCC respectively); bilateral anterior, superior, and posterior corona radiata; left sagittal stratum was significantly higher in the svMCI group than in the control group ( p < 0.05). The WMH burden of the GCC, BCC, SCC, and bilateral anterior corona radiata was negatively correlated with composite Z -scores. Among diffusion parameters showing significant differences across the 10 WM regions, mean FA values of WMH and WMH-P of the BCC were correlated with composite Z -scores in svMCI patients. The results of the multiple linear regression analysis showed that the FA of WMH-P of the BCC and WMH burden of the SCC and GCC were independent predictors of composite Z -score, with the FA of WMH-P of the BCC making the largest contribution. These findings indicate that disruption of the CC microstructure—especially the WMH-P of the BCC—may contribute to the cognitive deficits associated with SIVD.
Mitogen-activated protein (MAP) kinases are a central component in signaling networks in a multitude of mammalian cell types. This review covers recent advances on specific functions of p38 MAP kinases in cells of the central nervous system. Unique and specific functions of the four mammalian p38 kinases are found in all major cell types in the brain. Mechanisms of p38 activation and downstream phosphorylation substrates in these different contexts are outlined and how they contribute to functions of p38 in physiological and under disease conditions. Results in different model organisms demonstrated that p38 kinases are involved in cognitive functions, including functions related to anxiety, addiction behavior, neurotoxicity, neurodegeneration, and decision making. Finally, the role of p38 kinases in psychiatric and neurological conditions and the current progress on therapeutic inhibitors targeting p38 kinases are covered and implicate p38 kinases in a multitude of CNS-related physiological and disease states.
Neurodegenerative processes alter neuronal and glial physiology and cause cognitive and mnemonic impairments. Aim of this PhD thesis is to investigate the involvement of the cholinergic system and the role of mTOR pathway in the mechanisms of memory encoding in the hippocampus and to study the pathophysiological processes at the base of the cognitive impairments in different experimental models of neurodegeneration: in particular normal brain aging, neuroinfiammation and chronic cerebral hypoperfusion. These mechanisms are studied focusing on the morpho-functional alterations in the neuron-astrocytemicroglia triad.
Acute brain injury as a result of stroke and traumatic brain injury are leading causes of disability and mortality. Methods to improve patient diagnosis and prognosis for these common conditions are needed. Molecular biomarkers are one method that has been evaluated to diagnose acute brain injury, determine its cause, and predict outcomes and response to therapy. Markers that have been identified include a variety of proteins, nucleic acids, and lipids that relate to the pathophysiology of acute brain injury. Inflammation plays an important role in acute brain injury and several molecules involved in inflammation have been identified as biomarkers. However, biomarkers for acute brain injury is a developing field that requires additional study is to identify markers for use in clinical practice. These studies will include evaluating a larger number of candidate markers using proteomic, genomic, metabolomic, and lipidomic approaches. Additionally, novel markers such as microRNA and the use of panels that integrate multiple markers may also prove to be valuable tools in acute brain injury. In this chapter, we provide a summary of identified inflammatory biomarkers in acute brain injury, and how these biomarkers could add to patient care.
Introduction: Lacunar infarcts, white matter lesions (WMLs), deep intracerebral hemorrhages (ICHs), and microbleeds are now considered various manifestations of age- and vascular risk factor-related cerebral small vessel disease (SVD). As a whole, these lesions are associated with a plethora of disabilities commonly seen in elderly persons. These may include cognitive impairment, dementia, depression, motor and gait disturbances, urinary symptoms, functional impairment, and stroke. More importantly, presence of these lesions increases mortality [1, 2]. Given the close association of WMLs with vascular risk factors, morbidity and mortality associated with these lesions are likely preventable. This chapter reviews the risk factors for the presence and progression of each of these manifestations. Knowledge of such risk factors generates hypotheses regarding possible targets for prevention. Lacunar infarcts: Background: Understanding the pathogenesis of lacunar infarcts provides an important link to potential risk factors. The term “lacune” originated in the neuropathologic literature to describe a small cavity that remained in the brain tissue after the necrotic parenchyma of a small deep infarction had cleared [3, 4]. Dechambre was credited for using the term in 1838, and Durand-Fardel provided a treatise on the topic in 1843 [3]. According to Durand-Fardel, an associated term, “état criblé” (i.e., tissue riddled with holes or a sieve-like state) referred to dilated perivascular spaces and “atrophie interstitielle du cerveau” to rarefaction of the nervous system, viewed as being tantamount to leukoaraiosis [4]. Pierre Marie has been recognized for finding lacunes in 45 of 50 brains at necropsy and linked the healed area to obliteration or rupture of a perforating artery or its branches due to local arteriosclerosis [3].
Objective:
To assess differences in the gene expression profile of peripheral blood cells between patients with early recurrent thrombosis versus patients without recurrent events after withdrawal of anticoagulant therapy for a first episode of unprovoked deep vein thrombosis (uDVT), in order to identify novel predictors of recurrence.
Methods:
In the discovery population (N=32), a microarray RNA assay followed by RT-PCR confirmation were performed. In the validation population (N=44) a multiple RT-PCR-based strategy was applied to assess genes differentially expressed in the discovery population.
Results:
The sex-adjusted Linear Model for Microarray Data analysis showed 102 genes differentially expressed (p<0.01) in the discovery population. Nineteen of them underwent further confirmation in the validation population. The gene encoding for Acyl-CoA Synthetase Family Member 2 (ACSF2) was underexpressed in recurrent DVT patients in both, the discovery (p=0.007) and validation populations (p=0.004). In the receiver operator characteristic (ROC) analysis, the areas under the curve of ACSF2 expression were 0.77 and 0.80, respectively.
Conclusions:
For the first time an association between ACSF2 expression and the risk of recurrent DVT is suggested. Should this association be confirmed in larger prospective studies, ACSF2 could become useful for the selection of patients requiring extended anticoagulant therapy. This article is protected by copyright. All rights reserved.
Leukoaraiosis (LA), also called white matter lesions (WMLs) and white matter hyperintensities (WMHs), is a frequent neuroimaging finding commonly seen on magnetic resonance imaging brain scans of elderly people with prevalence ranging from 50% to 100%. Although it remains asymptomatic, LA is not considered to be benign, and it is showed to be related to a host of poor clinical outcomes and increases the risk of disability, dementia, depression, stroke, and the overall morbidity and mortality. Pathologically, LA is characterized by loss of myelin and axons, patchy demyelination, and denudation of ependyma in regions of WMH. Age and hypertension are the most importantly established risk factors for LA. However, the precise pathogenic mechanisms remain unclear. Together with the previous findings, our recent genetic results strongly supported that LA is associated with immune response and neuroinflammation. Therefore, we confidently hypothesized that LA was not only a common neuroimaging phenomenon in the elderly but also an emerging neuroinflammatory disorder in the central nervous system. This article focusing on neuroimaging classification, genetics basis, and putative molecular mechanism introduced the basic knowledge and current status of LA and put forward some of our research ideas and results from our molecular genetics research, which may pave the way for deciphering the putative pathogenic mechanism, risk factor, epigenetic index, and its application in diagnostic agents or drug target for prevention and treatment. Thus, it could provide clinicians and researchers with a specific and modern overview of LA to enable the understanding of recent progress and future directions in this illness.
Stroke and poststroke depression are common and have a profound and ongoing impact on an individual's quality of life. However, reliable biological correlates of poststroke depression and functional outcome have not been well established in humans.
Our aim is to identify biological factors, molecular and imaging, associated with poststroke depression and recovery that may be used to guide more targeted interventions.
In a longitudinal cohort study of 200 stroke survivors, the START - STroke imAging pRevention and Treatment cohort, we will examine the relationship between gene expression, regulator proteins, depression, and functional outcome. Stroke survivors will be investigated at baseline, 24 h, three-days, three-months, and 12 months poststroke for blood-based biological associates and at days 3-7, three-months, and 12 months for depression and functional outcomes. A sub-group (n = 100), the PrePARE: Prediction and Prevention to Achieve optimal Recovery Endpoints after stroke cohort, will also be investigated for functional and structural changes in putative depression-related brain networks and for additional cognition and activity participation outcomes. Stroke severity, diet, and lifestyle factors that may influence depression will be monitored. The impact of depression on stroke outcomes and participation in previous life activities will be quantified.
Clinical significance lies in the identification of biological factors associated with functional outcome to guide prevention and inform personalized and targeted treatments. Evidence of associations between depression, gene expression and regulator proteins, functional and structural brain changes, lifestyle and functional outcome will provide new insights for mechanism-based models of poststroke depression.
Ischemic stroke is a leading cause of adult disability and mortality. With over 15 million strokes occurring every year in the world, methods to better identify patients at risk for stroke are needed, as are methods to improve patient diagnosis and prognosis when stroke occurs. Use of blood-based biomarkers is one method that has been evaluated to predict risk of stroke, diagnose stroke and its causes, predict stroke severity and outcome, and guide prevention therapy. Markers that have been identified include a variety of proteins, nucleic acids and lipids that relate to stroke pathophysiology. The role of blood biomarkers in ischemic stroke is still being defined, and further study is needed to develop blood biomarkers for clinical stroke use. In this review, the authors provide a summary of biomarkers that have been divided by their potential clinical application.
Increasing evidence suggests that cortical astrocytic function is disrupted in mood disorders and suicide. The fine neuroanatomy of astrocytes, however, remains to be investigated in these psychiatric conditions. In this study, we performed a detailed morphometric analysis of 3D-reconstructed gray and white matter astrocytes in Golgi-impregnated anterior cingulate cortex (ACC) samples from depressed suicides and matched controls. Postmortem ACC samples (BA24) from 10 well-characterized depressed suicides and 10 matched sudden-death controls were obtained from the Quebec Suicide Brain Bank. Golgi-impregnated protoplasmic astrocytes (gray matter, layer VI) and fibrous astrocytes (adjacent white matter) were reconstructed, and their morphometric features were analyzed using the Neurolucida software. For each cell, the soma size as well as the number, length, and branching of processes were determined. The densities of thorny protrusions found along the processes of both astrocytic subtypes were also determined. Protoplasmic astrocytes showed no significant difference between groups for any of the quantified parameters. However, fibrous astrocytes had significantly larger cell bodies, as well as longer, more ramified processes in depressed suicides, with values for these parameters being about twice as high as those measured in controls. These results provide the first evidence of altered cortical astrocytic morphology in mood disorders. The presence of hypertrophic astrocytes in BA24 white matter is consistent with reports suggesting white matter alterations in depression, and provides further support to the neuroinflammatory theory of depression.
To cross-sectionally compare the regional white matter fractional anisotropy (FA) of cognitively normal (CN) older individuals and patients with mild cognitive impairment (MCI) and Alzheimer disease (AD), separately focusing on the normal-appearing white matter (NAWM) and white matter hyperintensities (WMH), and to test the independent effects of presumed degenerative and vascular process on FA differences.
Forty-seven patients with AD, 73 patients with MCI, and 95 CN subjects received diffusion tensor imaging and vascular risk evaluation. To properly control normal regional variability of FA, we divided cerebral white matter into 4 strata as measured from a series of young healthy individuals (H1 = highest; H2 = intermediate high; H3 = intermediate low; H4 = lowest anisotropy stratum).
For overall cerebral white matter, patients with AD had significantly lower FA than CN individuals or patients with MCI in the regions with higher baseline anisotropy (H1, H2, and H3), corresponding to long corticocortical association fibers, but not in H4, which mostly includes heterogeneously oriented fibers. Vascular risk showed significant independent effects on FA in all strata except H1, which corresponds to the genu and splenium of the corpus callosum. Similar results were found within NAWM. FA in WMH was significantly lower than NAWM across all strata but was not associated with diagnosis or vascular risk.
Both vascular and Alzheimer disease degenerative process contribute to microstructural injury of cerebral white matter across the spectrum of cognitive ability and have different region-specific injury patterns.
Cerebral white matter of asymptomatic people frequently exhibits circumscribed areas of hyperintensity on magnetic resonance (MR) images and hypodensity on computed tomography scans. However, behavioral implications of this phenomenon remain unclear. In this meta-analysis, the authors examine cumulative evidence regarding the cognitive sequelae of white matter abnormalities in adults without dementia. The influence of potential moderator variables, such as neuroimaging technique, location of the lesions, rating scale, and demographic characteristics of the sample on the association between the burden of white matter hyperintensities and cognitive performance was also examined. Results indicate that white matter abnormalities observed on MR images are associated with attenuated performance on tasks of processing speed, immediate and delayed memory, executive functions, and indices of global cognitive functioning. There was no significant link between the white matter hyperintensities and psychometric indices of intelligence or fine motor performance.
Microtubule-associated proteins such as MAP1B have long been suspected to play an important role in neuronal differentiation, but proof has been lacking. Previous MAP1B gene targeting studies yielded contradictory and inconclusive results and did not reveal MAP1B function. In contrast to two earlier efforts, we now describe generation of a complete MAP1B null allele. Mice heterozygous for this MAP1B deletion were not affected. Homozygous mutants were viable but displayed a striking developmental defect in the brain, the selective absence of the corpus callosum, and the concomitant formation of myelinated fiber bundles consisting of misguided cortical axons. In addition, peripheral nerves of MAP1B-deficient mice had a reduced number of large myelinated axons. The myelin sheaths of the remaining axons were of reduced thickness, resulting in a decrease of nerve conduction velocity in the adult sciatic nerve. On the other hand, the anticipated involvement of MAP1B in retinal development and gamma-aminobutyric acid C receptor clustering was not substantiated. Our results demonstrate an essential role of MAP1B in development and function of the nervous system and resolve a previous controversy over its importance.
Re-myelination in the adult CNS has been demonstrated in different experimental models of demyelinating diseases. However, there is no clear evidence that re-myelination is effective in multiple sclerosis (MS), the most diffuse demyelinating disease. Moreover, chronic disabilities in MS are believed to be due to remyelination failure and consequent neuron damage and degeneration. Due to the presence of numerous oligodendrocyte precursors inside demyelination plaques, reasons for remyelination failure are unknown. In this paper, we reviewed data from embryonic development and in vitro studies supporting the primary role of thyroid hormone in oligodendrocyte maturation. We also reviewed personal data on the possibility of promoting myelination in chronic experimental allergic encephalomyelitis (EAE), a widely used experimental model of MS, by recruiting progenitors and channeling them into oligodendroglial lineage through the administration of thyroid hormone.
Microarray techniques hold great promise for identifying risk factors for schizophrenia (SZ) but have not yet generated widely reproducible results due to methodological differences between studies and the high risk of type I inferential errors. Here we established a protocol for conservative analysis and interpretation of gene expression data from the dorsolateral prefrontal cortex of SZ patients using statistical and bioinformatic methods that limit false positives. We also compared brain gene expression profiles with those from peripheral blood cells of a separate sample of SZ patients to identify disease-associated genes that generalize across tissues and populations and further substantiate the use of gene expression profiling of blood for detecting valid SZ biomarkers. Implementing this systematic approach, we: (i) discovered 177 putative SZ risk genes in brain, 28 of which map to linked chromosomal loci; (ii) delineated six biological processes and 12 molecular functions that may be particularly disrupted in the illness; (iii) identified 123 putative SZ biomarkers in blood, 6 of which (BTG1, GSK3A, HLA-DRB1, HNRPA3, SELENBP1, and SFRS1) had corresponding differential expression in brain; (iv) verified the differential expression of the strongest candidate SZ biomarker (SELENBP1) in blood; and (v) demonstrated neuronal and glial expression of SELENBP1 protein in brain. The continued application of this approach in other brain regions and populations should facilitate the discovery of highly reliable and reproducible candidate risk genes and biomarkers for SZ. The identification of valid peripheral biomarkers for SZ may ultimately facilitate early identification, intervention, and prevention efforts as well.
Ischemic brain and peripheral white blood cells release cytokines, chemokines and other molecules that activate the peripheral white blood cells after stroke. To assess gene expression in these peripheral white blood cells, whole blood was examined using oligonucleotide microarrays in 15 patients at 2.4+/-0.5, 5 and 24 h after onset of ischemic stroke and compared with control blood samples. The 2.4-h blood samples were drawn before patients were treated either with tissue-type plasminogen activator (tPA) alone or with tPA plus Eptifibatide (the Combination approach to Lysis utilizing Eptifibatide And Recombinant tPA trial). Most genes induced in whole blood at 2 to 3 h were also induced at 5 and 24 h. Separate studies showed that the genes induced at 2 to 24 h after stroke were expressed mainly by polymorphonuclear leukocytes and to a lesser degree by monocytes. These genes included: matrix metalloproteinase 9; S100 calcium-binding proteins P, A12 and A9; coagulation factor V; arginase I; carbonic anhydrase IV; lymphocyte antigen 96 (cluster of differentiation (CD)96); monocarboxylic acid transporter (6); ets-2 (erythroblastosis virus E26 oncogene homolog 2); homeobox gene Hox 1.11; cytoskeleton-associated protein 4; N-formylpeptide receptor; ribonuclease-2; N-acetylneuraminate pyruvate lyase; BCL6; glycogen phosphorylase. The fold change of these genes varied from 1.6 to 6.8 and these 18 genes correctly classified 10/15 patients at 2.4 h, 13/15 patients at 5 h and 15/15 patients at 24 h after stroke. These data provide insights into the inflammatory responses after stroke in humans, and should be helpful in diagnosis, understanding etiology and pathogenesis, and guiding acute treatment and development of new treatments for stroke.
To assess the association of Medial Temporal lobe Atrophy (MTA) and White Matter Hyperintensities (WMHs) with gray matter perfusion in Mild Cognitive Impairment (MCI).
56 MCI patients (age = 69.3 +/- 7.0, 32 females) underwent brain MR scan and (99m)Tc ECD SPECT. We evaluated MTA according to Scheltens' fivepoint scale on T1 MR images, and assessed WMHs using the rating scale for age-related white matter changes on T2-weighted and FLAIR MR images. We divided MCI into age-matched subgroups with high and low MTA and high and low WMHs load. We processed SPECT images with SPM2 following an optimized protocol and performed a voxel-based statistical analysis comparing high vs. low MTA and high vs. low WMHs, setting p-value at 0.001 uncorrected, thresholding cluster extent at 100 voxels, using proportional scaling and entering age and WMHs or MTA respectively as nuisance covariates.
MCI with high compared with low MTA showed hypoperfusion in the left hippocampus and in the left parahippocampal gyrus. MCI with high compared with low WMHs showed a hypoperfusion area in the left insular region and superior temporal gyrus.
MTA in MCI is associated with hippocampal gray matter hypoperfusion while WMHs is associated with gray matter hypoperfusion in areas of the insula and temporal neocortex. These results confirm that MTA is associated with local functional changes and suggest that WMHs may be associated with remote brain cortical dysfunction.
There are no biomarkers that differentiate cardioembolic from large-vessel atherosclerotic stroke, although the treatments differ for each and approximately 30% of strokes and transient ischemic attacks have undetermined etiologies using current clinical criteria. We aimed to define gene expression profiles in blood that differentiate cardioembolic from large-vessel atherosclerotic stroke. Peripheral blood samples were obtained from healthy controls and acute ischemic stroke patients (<3, 5, and 24 h). RNA was purified, labeled, and applied to Affymetrix Human U133 Plus 2.0 Arrays. Expression profiles in the blood of cardioembolic stroke patients are distinctive from those of large-vessel atherosclerotic stroke patients. Seventy-seven genes differ at least 1.5-fold between them, and a minimum number of 23 genes differentiate the two types of stroke with at least 95.2% specificity and 95.2% sensitivity for each. Genes regulated in large-vessel atherosclerotic stroke are expressed in platelets and monocytes and modulate hemostasis. Genes regulated in cardioembolic stroke are expressed in neutrophils and modulate immune responses to infectious stimuli. This new method can be used to predict whether a stroke of unknown etiology was because of cardioembolism or large-vessel atherosclerosis that would lead to different therapy. These results have wide ranging implications for similar disorders.
Inflammatory biomarkers, including lipoprotein-associated phospholipase A2 (Lp-PLA2), myeloperoxidase (MPO), and high-sensitivity C-reactive protein (hsCRP) are associated with ischemic stroke risk. White matter hyperintensities (WMH) seen on brain MRI scans are associated with vascular risk factors and an increased risk of incident stroke, but their relation to inflammatory biomarkers is unclear.
The Northern Manhattan Study includes a stroke-free community-based sample of Hispanic, black, and white participants with quantitative measurement of WMH volume (WMHV) and inflammatory biomarkers. We measured the association between Lp-PLA2, MPO, and hsCRP levels, and log-transformed WMHV after adjusting for sociodemographic and vascular risk factors.
The hsCRP (median, 2.42 mg/L; IQR, 1.04, 5.19), Lp-PLA2 (median, 220.97 ng/mL; IQR, 185.77, 268.05), and MPO (median, 15.14 ng/mL; IQR, 12.32, 19.69) levels were available in 527 The Northern Manhattan Study participants with WMHV data but no subclinical infarcts. Those with hsCRP in the upper quartile (Q4 >4.92 mg/L or >3 mg/L), Lp-PLA2 in Q4 (>or=264.9 ng/mL), or MPO levels in Q3 (15.04-19.39 ng/mL) or Q4 (>19.39 ng/mL) each had greater WMHV, adjusting for sociodemographic and vascular risk factors. Adjusting for all biomarkers simultaneously, WMHV was 1.3-fold greater for Lp-PLA2 levels in Q4 compared to Q1 (beta=0.28; P=0.008) and 1.25-fold greater for MPO levels above the median compared to below (beta=0.22; P=0.02), but hsCRP was not associated with WMHV.
Relative elevations of the inflammatory markers Lp-PLA2 and MPO were associated with a greater burden of WMH independent of hsCRP.
New myelinating oligodendrocytes are continuously generated in the white matter of the uninjured adult CNS by oligodendrocyte precursor cells (OPCs) and neural stem cells (NSCs). Currently, little is known about the function of these new cells or the physiological processes that regulate their generation and differentiation. Importantly, new oligodendrocytes are able to contribute to the endogenous repair of white matter damage. Thus, a major biological and biomedical interest in the regulatory mechanisms governing their generation in the adult brain has arisen. Here I discuss work that demonstrates that hormonal changes during pregnancy promote increased OPC proliferation and oligodendrocyte production in the maternal CNS. We found that the maternal increase in oligodendrocyte production is associated with a significantly enhanced ability to regenerate white matter damage. Prolactin (PRL) signaling is both necessary and sufficient for the pregnancy-induced increase in OPC proliferation, and most strikingly, PRL treatments mimic the regenerative effects of pregnancy and promote white matter repair and remyelination in virgin females. I consider the implications of this work for our understanding of maternal adaptations to pregnancy and for the treatment of Multiple Sclerosis.
Arterial stiffening and thickening and endothelial dysfunction may be associated with cognitive decline or white matter hyperintensities (WMH) independently of blood pressure level. We aimed to investigate, using an integrative approach, the relative contributions of structural and functional vascular factors to the degree of cognitive impairment (primary outcome) and the severity of WMH (secondary outcome) in elderly hypertensive patients with subjective memory complaints, a group prone to dementia.
A prospective, dedicated, cross-sectional population of 198 elderly hypertensive patients (mean age 69.3+/-6.2 years) with subjective memory complaints underwent a full set of cognitive function assessments, brain MRI with semiquantification of WMH, carotid ultrasonography, carotid-femoral pulse wave velocity, brachial endothelial function, and plasma von Willebrand Factor measurements.
After adjustment for the usual cardiovascular risk factors, increased arterial stiffness (as assessed by pulse wave velocity) was significantly and independently associated with memory impairment in men. The severity of WMH was independently associated with increased carotid intima media thickness and stiffness (as assessed by augmentation index) as well as with increased age and plasma levels of von Willebrand Factor, a biomarker of endothelial dysfunction.
Our data suggest that vascular abnormalities, independently of blood pressure levels, may play a role in the setting of subjective memory complaints as well as of WMH in elderly hypertensive patients. Arterial thickness and stiffness as well as endothelial function should be assessed simultaneously and may represent additional targets for the prevention of subjective memory complaints and WMH.
Magnetic resonance imaging (MRI) findings of large white matter hyperintensities (LWMH), decreased brain volume and silent cerebral infarcts (SCI) are subclinical indices of brain ischemia and aging. Although the pathophysiology of these findings remains uncertain, extracellular matrix (ECM) remodeling, a process regulated by matrix metalloproteinases (MMPs) and their inhibitors (TIMPs), may be implicated. We evaluated the cross-sectional relations of circulating MMP-9 and TIMP-1 to these MRI indices in 583 stroke and dementia-free, Framingham Offspring participants (mean age 57 years, 58% women). Using multivariable regression MMP-9 (detectable versus non-detectable) and TIMP-1 (modeled as sex-specific quartiles) were related to LWMH (>1S.D. above age-specific mean; yes/no), SCI (yes/no) and total brain volume (ratio of parenchymal to intracranial volume, TCBVr). Mean TCBVr was 0.78 (S.D. 0.03), 13% of subjects had LWMH and 12% had SCI. Detectable MMP-9 was associated with higher prevalence of LWMH (OR 2.09, 95%confidence interval (CI) 1.00-4.37), but not with TCBVr. TIMP-1 was associated with a high prevalence of LWMH (OR for Q4 versus Q1-3: 1.83, 95%CI 1.06-3.18) and with lower mean TCBVr (Q4 associated with 0.17 S.D. units lower value relative to Q1-3; p=0.04). Neither biomarker was associated with SCI. Our findings are preliminary but if confirmed in further studies, suggest a pathophysiological role for the MMP/TIMP pathway in processes of brain ischemia and aging.
White matter lesions (WML) in brain aging are linked to dementia and depression. Ischemia contributes to their pathogenesis but other mechanisms may contribute. We used RNA microarray analysis with functional pathway grouping as an unbiased approach to investigate evidence for additional pathogenetic mechanisms.
WML were identified by MRI and pathology in brains donated to the Medical Research Council Cognitive Function and Ageing Study Cognitive Function and Aging Study. RNA was extracted to compare WML with nonlesional white matter samples from cases with lesions (WM[L]), and from cases with no lesions (WM[C]) using RNA microarray and pathway analysis. Functional pathways were validated for selected genes by quantitative real-time polymerase chain reaction and immunocytochemistry.
We identified 8 major pathways in which multiple genes showed altered RNA transcription (immune regulation, cell cycle, apoptosis, proteolysis, ion transport, cell structure, electron transport, metabolism) among 502 genes that were differentially expressed in WML compared to WM[C]. In WM[L], 409 genes were altered involving the same pathways. Genes selected to validate this microarray data all showed the expected changes in RNA levels and immunohistochemical expression of protein.
WML represent areas with a complex molecular phenotype. From this and previous evidence, WML may arise through tissue ischemia but may also reflect the contribution of additional factors like blood-brain barrier dysfunction. Differential expression of genes in WM[L] compared to WM[C] indicate a "field effect" in the seemingly normal surrounding white matter.
In a prospective magnetic resonance imaging (MRI) study we evaluted the prevalence and severity of white matter changes in 29 patients with Alzheimer's Disease (AD) and 24 age-matched healthy elderly, all without cerebrovascular risk factors.
The AD patients were divided into two groups according to age at onset of symptoms, one with presenile onset AD (n = 13) and one with senile onset AD (n = 16), who were matched for dementia severity. Signal hyperintensities were rated using a semiquantative scoring method, separately in the periventricular region (PVH) and in the lobar white matter (WMH), as well as in the basal ganglia (BGH) and in the infratentorial region (ITFH). Cortical atrophy as a parameter of grey matter involvement was rated on a 0 (absent) to 3 (severe) scale.
We found PVH, WMH and BGH scores to be significantly higher in senile onset AD patients than in age-matched controls. By means of multiple linear logistic regression we found that PVH, WMH and BGH scores were significantly dependent on the diagnosis of senile onset AD, while the PVH score also showed a significant age dependency. Cortical atrophy did not differ significantly between presenile onset AD and senile onset AD patients.
These results indicate that presenile onset AD and senile onset AD patients differ with respect to white matter involvement, but not with respect to grey matter involvement on MRI. Since cerebrovascular risk factors were excluded these findings may indicate that senile onset AD patients, display more small vessel involvement (arteriolosclerosis) than presenile onset AD patients, suggesting additional (microvascular) factors for the dementia syndrome in senile onset AD. Our data lend support to the growing body of evidence that AD is heterogeneous, consisting of at least two types. Based on our findings two forms can be distinguished: (i) a ‘pure’ form of the disease, usually with early disease onset, and no more white matter changes than normal for age; (ii) a ‘mixed’ form, usually with disease onset later in life, and showing more white matter changes on MRI than normal for age.
Clinical criteria for the diagnosis of Alzheimer's disease include insidious onset and progressive impairment of memory and other cognitive functions. There are no motor, sensory, or coordination deficits early in the disease. The diagnosis cannot be determined by laboratory tests. These tests are important primarily in identifying other possible causes of dementia that must be excluded before the diagnosis of Alzheimer's disease may be made with confidence. Neuropsychological tests provide confirmatory evidence of the diagnosis of dementia and help to assess the course and response to therapy. The criteria proposed are intended to serve as a guide for the diagnosis of probable, possible, and definite Alzheimer's disease; these criteria will be revised as more definitive information become available.
To rate magnetic resonance image signal hyperintensities in clearly defined white and deep gray matter areas in patients with early Alzheimer's disease and controls.
Prospective series. The National Institute for Neurological Disorders and Stroke--The Alzheimer's Disease and Related Disorders Association criteria for probable Alzheimer's disease. Blinded assessment.
University hospital, dementia study group.
Thirty-four patients with Alzheimer's disease. Thirty-eight age-matched healthy community volunteers.
Frequency of hyperintensities in axial magnetic resonance images (1.5-T system) seen both in the proton density and T2-weighted scans examined in vascular centrencephalon, centrum semiovale, watershed, periventricular, and subcortical white matter. Periventricular hyperintensities classification include caps, thin lining, and smooth and irregular halo. Hyperintensities in other areas include small and large focal, focal confluent, and diffusely confluent. The hyperintensities were counted and rated using a five-point scale and the Fazekas method.
No difference in the ratings, frequency, or extent of the hyperintensities between patients with early Alzheimer's disease and controls. Majority of patients and controls had two or fewer hyperintensities and they were mostly small foci, caps, and thin linings. The hyperintensities are associated with arterial hypertension, diabetes, cardiac disorder, and age in different combinations, but not with Alzheimer's disease.
Tiny hyperintensities on magnetic resonance images are frequent both in patients with early Alzheimer's disease and in healthy controls; most of the lesions are not related to brain ischemia. When age and vascular risk factors were taken into account, no difference between patients with early Alzheimer's disease and control subjects could be detected.
Our aim was to identify potential risk factors for and clinical manifestations of white matter findings on cranial MRI in elderly people.
Medicare eligibility lists were used to obtain a representative sample of 5888 community-dwelling people aged 65 years or older. Correlates of white matter findings were sought among 3301 participants who underwent MRI scanning and denied a history of stroke or transient ischemic attack. Participants underwent extensive standardized evaluations at baseline and on follow-up, including standard questionnaires, physical examination, multiple blood tests, electrocardiogram, pulmonary function tests, carotid sonography, and M-mode echocardiography. Neuroradiologists graded white matter findings from 0 (none) to 9 (maximal) without clinical information.
Many potential risk factors were related to the white matter grade, but in the multivariate model the factors significantly (all P < .01) and independently associated with increased grade were greater age, clinically silent stroke on MRI, higher systolic blood pressure, lower forced expiratory volume in 1 second (FEV1), and income less than $50,000 per year. If excluded, FEV1 was replaced in the model by female sex, history of smoking, and history of physician-diagnosed hypertension at the baseline examination. Many clinical features were correlated with the white matter grade, especially those indicating impaired cognitive and lower extremity function.
White matter findings were significantly associated with age, silent stroke, hypertension, FEV1, and income. The white matter findings may not be considered benign because they are associated with impaired cognitive and lower extremity function.
White matter lesions on brain CT or MRI are a frequent finding in patients with Alzheimer's disease. However, little is known about the prognostic significance of these changes in cognitively impaired individuals who are at risk for subsequent development of dementia. This study aims at investigating the potential impact of white matter lucencies (WML) on brain CT on the course of mild cognitive impairment.
Twenty-seven patients (mean age 72, SD 4.03) with mild cognitive impairment (MCI) and no signs of cerebrovascular disease were prospectively examined. At their initial presentation, all patients underwent a structured interview for the diagnosis of dementia (SIDAM) and a brain CT. Linear measures of atrophy and visual ratings of white matter changes were performed. At follow-up (mean interval 29 months), these patients were re-examined with the SIDAM. Eight patients had developed dementia and met clinical criteria for Alzheimer's disease (crossover group).
Evaluation of the initial CT scans revealed significantly more frequent and extended white matter abnormalities and a higher degree of temporal lobe atrophy in the crossover group as compared to the cognitively stable group. In the crossover group, high WML severity initially was associated with a lesser degree of temporal lobe atrophy and higher global cognitive performance.
We conclude that WML play a role in the dementia process and that they might accelerate cognitive decline in individuals with mild cognitive impairment. WML should be included in prospective studies of MCI as potential predictor variables.
Using microarray technology, we investigated whether the gene expression profile in white blood cells could be used as a fingerprint of different disease states. Adult rats were subjected to ischemic strokes, hemorrhagic strokes, sham surgeries, kainate-induced seizures, hypoxia, or insulin-induced hypoglycemia, and compared with controls. The white blood cell RNA expression patterns were assessed 24 hours later using oligonucleotide microarrays. Results showed that many genes were upregulated or downregulated at least twofold in white blood cells after each experimental condition. Blood genomic response patterns were different for each condition. These results demonstrate the potential of blood gene expression profiling for diagnostic, mechanistic, and therapeutic assessment of a wide variety of disease states.
The authors investigated the interaction between medial temporal lobe (MTL) atrophy and white matter hyperintensities (WMH) in Alzheimer disease (AD). They measured the MTL and WMH on MRI in 58 AD patients and 28 controls. MTL atrophy was associated with an increased risk of AD (OR = 6.2), but there was no significant association between WMH and AD. Moreover, there was an interaction between MTL and WMH (p = 0.045). These results suggest that vascular and Alzheimer-type pathology act in synergy in the clinical syndrome of AD.
Numerous anatomical and brain imaging studies find substantial differences in brain structure between men and women across the span of human aging. The ability to extend the results of many of these studies to the general population is limited, however, due to the generally small sample size and restrictive health criteria of these studies. Moreover, little attention has been paid to the possible impact of brain infarction on age-related differences in regional brain volumes. Given the current lack of normative data on gender and aging related differences in regional brain morphology, particularly with regard to the impact of brain infarctions, we chose to quantify brain MRIs from more than 2200 male and female participants of the Framingham Heart Study who ranged in age from 34 to 97 years. We believe that MRI analysis of the Framingham Heart Study more closely represents the general population enabling more accurate estimates of regional brain changes that occur as the consequence of normal aging.
The availability of an accessible tissue whose gene expression profile is similar to more inaccessible CNS tissues has the potential to advance research in neuropsychiatric disorders. We conducted secondary data analysis of transcriptional profiling of 79 human tissues for 33,698 genes using the Affymetrix U133A microarray augmented with a custom microarray (Affymetrix GNF1H), which were produced by the Genomics Institute of the Novartis Research Foundation (http://symatlas.gnf.org). Our analyses suggested that: (a) on a transcriptome level, whole blood shares significant gene expression similarities with multiple CNS tissues; (b) the median non-parametric correlation between transcripts present in both whole blood and CNS was around 0.5; (c) this correlation of 0.5 was intermediate relative to all tissues in the Novartis data set--less than for the maximum achievable value of 0.85, less than a set of immune tissues (0.64), comparable to a heterogeneous set of somatic tissues (0.57) but greater than muscle (0.48) and peripheral nervous system tissues (0.36); (d) about half of a set of candidate genes relevant to schizophrenia were expressed in both whole blood and prefrontal cortex; and (e) the expression levels of many classes of biologically relevant processes were not significantly different between whole blood and prefrontal cortex. These analyses suggest that gene expression in whole blood is neither perfectly correlated and useful nor perfectly uncorrelated and useless with gene expression in multiple brain tissues. This suggests that the cautious and thoughtful use of peripheral gene expression may be a useful surrogate for gene expression in the CNS when it has been determined that the relevant gene is expressed in both.
"Incidental" MRI white matter (WM) lesions, comprising periventricular lesions (PVLs) and deep subcortical lesions (DSCLs), are common in the aging brain. Direct evidence of ischemia associated with incidental WM lesions (WMLs) has been lacking, and their pathogenesis is unresolved.
A population-based, postmortem cohort (n=456) of donated brains was examined by MRI and pathology. In a subsample of the whole cohort, magnetic resonance images were used to sample and compare WMLs and nonlesional WM for molecular markers of hypoxic injury.
PVL severity was associated with loss of ventricular ependyma (P=0.004). For DSCLs, there was arteriolar sclerosis compared with normal WM (vessel wall thickness and perivascular enlargement; both P<0.001). Capillary endothelial activation (ratio of intercellular adhesion molecule to basement membrane collagen IV; P<0.001) and microglial activation (CD68 expression; P=0.002) were elevated in WMLs. Immunoreactivity for hypoxia-inducible factors (HIFs) HIF1alpha and HIF2alpha was elevated in DSCLs (P=0.003 and P=0.005). Other hypoxia-regulated proteins were also increased in WMLs: matrix metalloproteinase-7 (PVLs P<0.001; DSCLs P=0.009) and the number of neuroglobin-positive cells (WMLs P=0.02) reaching statistical significance. The severity of congophilic amyloid angiopathy was associated with increased HIF1alpha expression in DSCLs (P=0.04).
The data support a hypoxic environment within MRI WMLs. Persistent HIF expression may result from failure of normal adaptive mechanisms. WM ischemia appears to be a common feature of the aging brain.
Global gene expression analysis using cDNA microarrays has proven to be a sensitive method to gain insight into molecular pathways mediating multiple sclerosis (MS) activity and to develop and refine the molecular taxonomy of the disease. This method was applied as a tool to investigate molecular heterogeneity of MS related gene transcripts in the aim of distinguishing between transcripts that trigger disease activity and account for direct genotype-phenotype correlation, and those whose expression is altered as a downstream effect of other genes. This review summarizes the current state of gene expression microarray applications for the study of MS, and specifically emphasizes the results of gene expression studies using peripheral blood mononuclear cells (PBMC) that were shown to be useful for better understanding of disease related pathways, monitoring of therapeutic responses to various drugs and prediction of clinical outcome. In the long run it is expected that the information provided by cDNA microarrays experiments will allow the determination of key molecular players involved in MS pathogenesis, and lead to better management of the disease using targeted treatments that will prevent its progression.
To analyze the extent and spatial distribution of white matter hyperintensities (WMH) in brain regions from cognitively normal older individuals (CN) and patients with mild cognitive impairment (MCI) and Alzheimer disease (AD).
We studied 26 mild AD, 28 MCI, and 33 CN. MRI analysis included quantification of WMH volume, nonlinear mapping onto a common anatomic image, and spatial localization of each WMH voxel to create an anatomically precise frequency distribution map. Areas of greatest frequency of WMH from the WMH composite map were used to identify 10 anatomic regions involving periventricular areas and the corpus callosum (CC) for group comparisons.
Total WMH volumes were associated with age, extent of concurrent vascular risk factors, and diagnosis. After correcting for age, total WMH volumes remained significantly associated with diagnosis and extent of vascular risk. Regional WMH analyses revealed significant differences in WMH across regions that also differed significantly according to diagnosis. In post-hoc analyses, significant differences were seen between CN and AD in posterior periventricular regions and the splenium of the CC. MCI subjects had intermediate values at all regions. Repeated measures analysis including vascular risk factors in the model found a significant relationship between periventricular WMH and vascular risk that differed by region, but regional differences according to diagnosis remained significant and there was no interaction between diagnosis and vascular risk.
Differences in white matter hyperintensities (WMH) associated with increasing cognitive impairment appear related to both extent and spatial location. Multiple regression analysis of regional WMH, vascular risk factors, and diagnosis suggest that these spatial differences may result from the additive effects of vascular and degenerative injury. Posterior periventricular and corpus callosum extension of WMH associated with mild cognitive impairment and Alzheimer disease indicate involvement of strategic white matter bundles that may contribute to the cognitive deficits seen with these syndromes.
We studied the natural course of white matter hyperintensities (WMH) and lacunes, the main MRI representatives of small vessel disease, over time and evaluated possible predictors for their development.
Baseline and repeat MRI (3-year follow-up) were collected within the multicenter, multinational Leukoaraiosis and Disability study (n=396). Baseline WMH were scored on MRI by the Fazekas scale and the Scheltens scale. WMH progression was assessed using the modified Rotterdam Progression scale (absence/presence of progression in 9 brain regions). Baseline and new lacunes were counted per region. WMH and lacunes at baseline and vascular risk factors were evaluated as predictors of WMH progression and new lacunes.
WMH progressed (mean+/-SD=1.9+/-1.8) mostly in the subcortical white matter, where WMH was also most prevalent at baseline. The majority of new lacunes, which were found in 19% of the subjects (maximum=9), also appeared in the subcortical white matter, mainly of the frontal lobes, whereas most baseline lacunes were located in the basal ganglia. Baseline WMH and lacunes predicted both WMH progression and new lacunes. Furthermore, previous stroke, diabetes, and blood glucose were risk factors for WMH progression. Male sex, hypertension, systolic blood pressure, previous stroke, body mass index, high-density lipoprotein, and triglyceride levels were risk factors for new lacunes.
WMH and lacunes progressed over time, predominantly in the subcortical white matter. Progression was observed especially in subjects with considerable WMH and lacunes at baseline. Moreover, the presence of vascular risk factors at baseline predicted WMH progression and new lacunes over a 3-year period.
To clarify the role of inflammation in the pathogenesis of small vessel disease of the brain, we investigated the association between common variation in the C-reactive protein (CRP) and interleukin (IL)-6 genes, plasma CRP and IL6 levels, and presence of MRI-defined white matter lesions (WML) and brain infarcts (BI) in elderly participants of the Cardiovascular Health Study.
Tag single nucleotide polymorphisms (SNPs) in the CRP and IL6 genes were selected from the SeattleSNPs database. In cross-sectional analyses, logistic regression models adjusting for known cardiovascular disease risk factors were constructed to assess the associations of plasma CRP and IL6 levels and common CRP and IL6 gene haplotypes with presence of WML or BI in Blacks (n=532) and Whites (n=2905).
Plasma IL6 and CRP levels were associated with presence of WML and BI in both races. In Whites, common haplotypes of the IL6 gene were significantly associated with WML and BI. The common haplotype tagged by the -174G/C promoter polymorphism was associated with an increased risk of WML (OR=1.14; 95% CI: [1.02; 1.28]). The common haplotype tagged by the -572G/C promoter polymorphism was associated with an increased risk of BI (OR=1.57; 95% CI: [1.15; 2.14]). Significant associations were lacking for WML or BI with IL6 gene variation in Blacks, or with CRP gene variation in either race.
This study provides evidence of a genetic basis underlying the relationship between plasma biomarkers of inflammation and small vessel disease of the brain. Further studies to elucidate the specific role of IL6 in disease pathogenesis are warranted.
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