Pathogenesis Of White Matter Lesions Research Articles

Frontal white matter lesions in Alzheimer\u2019s disease are associated with both small vessel disease and AD-associated cortical pathology

Cerebral white matter lesions (WML) encompass axonal loss and demyelination and are assumed to be associated with small vessel disease (SVD)-related ischaemia. However, our previous study in the parietal lobe white matter revealed that WML in Alzheimer’s disease (AD) are linked with degenerative axonal loss secondary to the deposition of cortical AD pathology. Furthermore, neuroimaging data suggest that pathomechanisms for the development of WML differ between anterior and posterior lobes with AD-associated degenerative mechanism driving posterior white matter disruption, and both AD-associated degenerative and vascular mechanisms contributed to anterior matter disruption. In this pilot study, we used human post-mortem brain tissue to investigate the composition and aetiology of frontal WML from AD and non-demented controls to determine if frontal WML are SVD-associated and to reveal any regional differences in the pathogenesis of WML. Frontal WML tissue sections from 40 human post-mortem brains (AD, n = 19; controls, n = 21) were quantitatively assessed for demyelination, axonal loss, cortical hyperphosphorylated tau (HPτ) and amyloid-beta (Aβ) burden, and arteriolosclerosis as a measure of SVD. Biochemical assessment included Wallerian degeneration-associated protease calpain and the myelin-associated glycoprotein to proteolipid protein ratio as a measure of ante-mortem ischaemia. Arteriolosclerosis severity was found to be associated with and a significant predictor of frontal WML severity in both AD and non-demented controls. Interesting, frontal axonal loss was also associated with HPτ and calpain levels were associated with increasing Aβ burden in the AD group, suggestive of an additional degenerative influence. To conclude, this pilot data suggest that frontal WML in AD may result from both increased arteriolosclerosis and AD-associated degenerative changes. These preliminary findings in combination with previously published data tentatively indicate regional differences in the aetiology of WML in AD, which should be considered in the clinical diagnosis of dementia subtypes: posterior WML maybe associated with degenerative mechanisms secondary to AD pathology, while anterior WML could be associated with both SVD-associated and degenerative mechanisms.

Emerging role of white matter lesions in cerebrovascular disease.

White matter lesions have been implicated in the setting of stroke, dementia, intracerebral haemorrhage, several other cerebrovascular conditions, migraine, various neuroimmunological diseases like multiple sclerosis, disorders of metabolism, mitochondrial diseases and others. While much is understood vis a vis neuroimmunological conditions, our knowledge of the pathophysiology of these lesions, and their role in, and implications to, management of cerebrovascular diseases or stroke, especially in the elderly, are limited. Several clinical assessment tools are available for delineating white matter lesions in clinical practice. However, their incorporation into clinical decision-making and specifically prognosis and management of patients is suboptimal for use in standards of care. This article sought to provide an overview of the current knowledge and recent advances on pathophysiology, as well as clinical and radiological assessment, of white matter lesions with a focus on its development, progression and clinical implications in cerebrovascular diseases. Key indications for clinical practice and recommendations on future areas of research are also discussed. Finally, a conceptual proposal on putative mechanisms underlying pathogenesis of white matter lesions in cerebrovascular disease has been presented. Understanding of pathophysiology of white matter lesions and how they mediate outcomes is important to develop therapeutic strategies.

Integrated analysis of microRNA and mRNA expression profiling identifies BAIAP3 as a novel target of dysregulated hsa-miR-1972 in age-related white matter lesions.

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.

Aortic stiffness and brain integrity in elderly patients with cognitive and functional complaints.

PurposeCerebral white matter lesions (WML) and brain atrophy are frequent in older persons and are associated with adverse outcomes. It has been suggested that aortic stiffness plays a role in the pathogenesis of WML and gray matter (GM) loss. There is, however, little evidence on the association between aortic stiffness and brain integrity in older patients. In this study, we investigated whether aortic stiffness is associated with WML and GM volume in older patients with cognitive and functional complaints.Patients and methodsFazekas score was used to analyze WML on brain imaging data of 84 persons; in a subanalysis on 42 MRI scans, the exact volume of white matter hyperintensities (WMH) and GM was determined using a brain-tissue and WMH tool. Aortic stiffness, measured as aortic pulse wave velocity (aPWV) and central pulse pressure (cPP), and blood pressure levels were non-invasively measured by the Mobil-O-Graph.ResultsMean age was 76.6 (±6.8) years. Age was correlated with cPP (Spearman’s ρ =0.296, P=0.008), aPWV (r2=0.785, P<0.001) and WMH volume (r2=0.297, P<0.001). cPP did not differ between categories of Fazekas, whereas aPWV increased with increasing Fazekas score (P for trend <0.001). After additional adjustment for age, levels of aPWV did not differ between categories. Both cPP and aPWV were associated with WMH volumes (lnB 0.025, P=0.055 and lnB 0.405, P<0.001, respectively); after additional adjustment for age, estimates were less consistent. Both cPP and aPWV were negatively associated with GM volumes in multivariate analysis (B=2.805, P=0.094 and B=111.052, P=0.032).ConclusionHigher aortic stiffness was partly associated with increased volume of WMH and decreased volume of GM and slightly influenced by blood pressure. Age also plays a role in this association in older patients.

Whole blood gene expression and white matter Hyperintensities

BackgroundWhite 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.MethodsWe 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.ResultsWe 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.ConclusionThirteen 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.

PARIETAL WHITE MATTER LESIONS IN ALZHEIMER’S DISEASE ARE ASSOCIATED WITH CORTICAL NEURODEGENERATIVE PATHOLOGY AND NOT WITH SMALL-VESSEL DISEASE

Cerebral white matter lesions (WML), as seen histologically, or white matter hyperintensities (WMH) as seen on MRI, are a frequent finding in both demented and non-demented elderly. WML encompass demyelination and axonal loss, and the pathogenesis is assumed to be small vessel disease (SVD)-related ischemia. However, in the posterior region, WML may also occur as the result of degenerative axonal loss secondary to cortical Alzheimer's disease (AD) pathology, i.e., hyperphosphorylated tau (HPτ) and amyloid-beta (Aβ) as a result of Wallerian degeneration. It is not clear whether pathological and molecular signatures in WML seen in AD differ from normal aged, and elucidation of this is paramount for accurate clinical dementia diagnostics. We investigated differences in the composition of parietal WML using post-mortem human brain tissue of AD and aged controls. WML from parietal tissue of 55 post-mortem brains (AD, n = 27; controls, n = 27) were quantitative assessed for severity, axonal loss and demyelination, as well cortical measures of HPτ, Aβ and WM-SVD. Biochemical assessment measured calpain protease (Wallerian degeneration) and myelin proteins MAG (ischemia) and PLP (axonal atrophy). Our findings support the concept of degenerative axonal loss, secondary to cortical AD-pathology, which is a putative mechanism in the pathogenesis of WML in AD. This new understanding of WML/WMH pathogenesis in AD is paramount for the accurate diagnosis of patients with cognitive impairment and future studies are warranted to investigate diagnostic accuracy of WM changes in AD. Our findings support the concept of posterior degenerative axonal loss that is secondary to cortical AD-pathology, which is a putative mechanism in the pathogenesis of WML in AD. This new understanding of WML/WMH pathogenesis in AD is paramount for the accurate diagnosis of patients with cognitive impairment and future studies are warranted to investigate diagnostic accuracy of WM changes in AD.

Cytokine Storm may Play a Role in the Pathogenesis of Human Parechovirus Type 3-Associated Acute Encephalopathy in Neonates: A Case Report

Background: Human parechovirus type 3 (HPeV3) is an important cause of acute encephalitis in the neonatal and early infantile periods. Typical HPeV3-associated acute encephalitis paradoxically shows no cerebrospinal fluid (CSF) pleocytosis despite virus detection in CSF and diffuse deep white matter involvement of the corpus callosum on magnetic resonance images (MRI). Patient: An 8-day-old full-term infant was found to have HPeV3 infection of the central nervous system (CNS), which was confirmed using diffusion-weighted MRI showing poor diffusivity in the bilateral deep white matter and the corpus callosum without CNS pleocytosis, as seen in previously reported cases. Interestingly, this patient had extremely elevated serum ferritin and urinary beta-2-microglobulin levels, which indicated a surge of the cytokines tumor necrotizing factor alpha and interferon gamma. Conclusion: These findings suggest that the cytokine storm can promote the pathogenesis of white matter lesions in HPeV3-associated acute encephalopathy rather than direct infection of the brain.

Multiple Factors Involved in the Pathogenesis of White Matter Lesions.

White matter lesions (WMLs), also known as leukoaraiosis (LA) or white matter hyperintensities (WMHs), are characterized mainly by hyperintensities on T2-weighted or fluid-attenuated inversion recovery (FLAIR) images. With the aging of the population and the development of imaging technology, the morbidity and diagnostic rates of WMLs are increasing annually. WMLs are not a benign process. They clinically manifest as cognitive decline and the subsequent development of dementia. Although WMLs are important, their pathogenesis is still unclear. This review elaborates on the advances in the understanding of the pathogenesis of WMLs, focusing on anatomy, cerebral blood flow autoregulation, venous collagenosis, blood brain barrier disruption, and genetic factors. In particular, the attribution of WMLs to chronic ischemia secondary to venous collagenosis and cerebral blood flow autoregulation disruption seems reasonable. With the development of gene technology, the effect of genetic factors on the pathogenesis of WMLs is gaining gradual attention.

MCP-1-mediated activation of microglia promotes white matter lesions and cognitive deficits by chronic cerebral hypoperfusion in mice.

Microglia activation played a vital role in the pathogenesis of white matter lesions (WMLs) by chronic cerebral hypoperfusion. In addition, hypoxia induced up-regulated expression of MCP-1, promotes the activation of microglia. However, the role of MCP-1-mediated microglia activation in chronic cerebral ischemia is still unknown. To explore that, chronic cerebral hypoperfusion model was established by permanent stenosis of bilateral common carotid artery in mice. The activation of microglia and the related signal pathway p38MAPK/PKC in white matter, and working memory of mice were observed. We found that stenosis of common carotid arteries could induce MCP-1-mediated activation of microglia through p38MAPK/PKC pathway and white matter lesions. Taken together, our findings represent a novel mechanism of MCP-1 involved in activation of microglia and provide a novel therapeutical strategy for chronic cerebral hypoperfusion.

4,4'-Diisothiocyanostilbene-2,2'-disulfonic Acid (DIDS) Ameliorates Ischemia-Hypoxia-Induced White Matter Damage in Neonatal Rats through Inhibition of the Voltage-Gated Chloride Channel ClC-2.

Chronic cerebral hypoperfusion is believed to cause white matter lesions (WMLs), leading to cognitive impairment. Previous studies have shown that inflammation and apoptosis of oligodendrocytes (OLs) are involved in the pathogenesis of WMLs, but effective treatments have not been studied. In this study, 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid (DIDS), a chloride (Cl−) channel blocker, was injected into chronic cerebral ischemia-hypoxia rat models at different time points. Our results showed that DIDS significantly reduced the elevated mRNA levels and protein expression of chloride channel 2 (ClC-2) in neonatal rats induced by ischemia-hypoxia. Meanwhile, DIDS application significantly decreased the concentrations of reactive oxygen species (ROS); and the mRNA levels of inducible nitric oxide synthase (iNOS) and tumor necrosis factor-alpha TNF-α in neonatal rats with hypoxic-ischemic damage. Myelin staining was weaker in neonatal rats with hypoxic-ischemic damage compared to normal controls in corpus callosum and other white matter, which was ameliorated by DIDS. Furthermore, the elevated number of caspase-3 and neural/glial antigen 2 (NG-2) double-labeled positive cells was attenuated by DIDS after ischemia anoxic injury. Administration of DIDS soon after injury alleviated damage to OLs much more effectively in white matter. In conclusion, our study suggests that early application of DIDS after ischemia-hypoxia injury may partially protect developing OLs.

A CADASIL-Like Case with a Novel Noncysteine Mutation of the NOTCH3 Gene and Granular Deposits in the Renal Arterioles.

We herein report the finding of a 62-year-old male, who developed dysarthria and dysphagia, with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy- (CADASIL-) like cerebral lesions. He also suffered from slowly progressive renal failure with the findings of granular deposits similar to electron-dense granular osmiophilic material in the renal arterioles. We found a novel heterozygous missense mutation of the NOTCH3 gene, c.4039G>C in exon 24, resulting in a p.Gly1347Arg substitution in its extracellular domain. The noncysteine substitution may underlie the pathogenesis of white matter lesions in the brain and of the chronic renal failure in the present case.

The reduction of regional cerebral blood flow in normal-appearing white matter is associated with the severity of white matter lesions in elderly: a Xeon-CT study.

White matter lesions (WMLs) in normal elderly are related to chronic ischemia, and progression of WML occurs mostly in moderate to severe disease. However, the mechanism is uncertain. Thus, we enrolled fifty-six normal elderly patients without large artery disease. The severity of WML on MRI was graded as grade 0, I, II and III using the modified Fazekas scale. Cerebral blood flow (CBF) was measured by Xenon-CT. We found that CBF (mL/100 g/min) within periventricular lesions and in the right and left centrum semiovales were 20.33, 21.27 and 21.03, respectively, in group I; 16.33, 15.55 and 15.91, respectively, in group II; and 14.05, 14.46 and 14.23, respectively, in group III. CBF of normal-appearing white matter (NAWM) around periventricular areas and in the right and left centrum semiovales were 20.79, 22.26 and 22.15, respectively, in group 0; 21.12, 22.17 and 22.25, respectively, in group I; 18.02, 19.45 and 19.62, respectively, in group II; and 16.38, 18.18 and 16.74, respectively, in group III. Significant reductions in CBF were observed not only within lesions but also in NAWM surrounding the lesions. In addition, CBF was reduced significantly within lesions compared to NAWM of the same grade. Furthermore, CBF was reduced significantly in NAWM in grades II and III when compared to grades 0 and I. Our finding indicates that ischemia may play a role in the pathogenesis of WML. Additionally, our finding provides an alternative explanation for finding that the progression of WML occurred more commonly in patients with moderate to severe WML.

Microglial activation with reduction in autophagy limits white matter lesions and improves cognitive defects during cerebral hypoperfusion.

Microglial activation plays a vital role in the pathogenesis of white matter lesions (WMLs) during chronic cerebral hypo perfusion. Autophagy has been associated with both microglia survival and cell death. Yet, the role of autophagy during microglial activation in chronic cerebral ischemia is still unknown. We used a chronic cerebral hypoperfusion model by permanent stenosis of bilateral common carotid artery in mice to study microglial activation and autophagy. However, the autophagy inhibitor (3-methyladenine) could attenuate microglial autophagic activation, decrease white matter lesions, and improve working memory during chronic cerebral hypoperfusion in mice. In conclusion, chronic cerebral hypoperfusion that leads to microglial activation and autophagy induction exacerbates white matter lesions and cognitive deficits in mice. Our findings represent a potential novel target for chronic cerebral hypoperfusion therapy.

Catalpol promotes oligodendrocyte survival and oligodendrocyte progenitor differentiation via the Akt signaling pathway in rats with chronic cerebral hypoperfusion

Chronic cerebral hypoperfusion is thought to induce white matter lesions (WMLs), which contribute to cognitive impairment. Although inflammation and oligodendrocyte apoptosis are believed to be involved in the pathogenesis of WMLs, effective therapies have not been identified yet. This study investigated whether catalpol, an iridoid glycoside, can alleviate WMLs by promoting oligodendrocyte survival and oligodendrocyte progenitor differentiation via the Akt signaling pathway in rats with chronic cerebral hypoperfusion. A rat model of chronic cerebral hypoperfusion was created through permanent occlusion of bilateral common carotid arteries. Catalpol (5mg/kg) or saline was intraperitoneally administered daily for 10 days following the operation. On the 30th day after surgery, inflammation, oligodendrocyte apoptosis, and myelin damage in the ischemic white matter were more severe and evident than in the sham control group. Treatment with catalpol significantly suppressed white matter inflammation and attenuated oligodendrocyte apoptosis and myelin damage. The expression of phosphorylated Akt (p-Akt) and the number of mature oligodendrocytes were also markedly increased by catalpol treatment, and these effects were reversed by the PI3K inhibitor LY294002. In conclusion, catalpol attenuates hypoperfusion-induced WMLs by promoting oligodendrocyte survival and oligodendrocyte progenitor differentiation through the Akt signaling pathway. Our results suggest that catalpol may be a candidate for treating cerebrovascular WMLs.

Abstract W P364: Relationships Between Endothelial Function, Biological Markers and Cerebral Small Vessel Diseasein Patients with Chronic Cerebrovascular Disease and Comorbidity

Background and Purpose: Pathogenesis of white matter lesions is thought to be associated with endothelial dysfunction and inflammation. Ultrasound assessment of brachial artery flow mediated dilation (FMD) as a noninvasive and useful method has been recently used as an index of endothelium-dependent vasodilation. The aim of this study was to investigate the associations between endothelial function which was evaluated by FMD and the severity of white matter lesions in patients with chronic cerebrovascular disease and comorbidity. Additionally, we evaluated association between FMD and the number of circulating progenitor cells. Methods: Patients with cerebrovascular diseases history and other untypical neurological problems were enrolled in this study (n=63; 39 male, 69.8±10.0 years). Patients were classified according to periventricular hyperintensities (PVH) and deep white matter hyperintensities (DWMH) scores by fluid-attenuate inversion recovery image of magnetic resonance images (Fazekas gradings). Endothelial dysfunction was defined as a FMD≤4.5%. The numbers of CD34+/CD133+ cells defined as circulating progenitor cells were evaluated by flow cytometry. Results: The patients with endothelial dysfunction (n=39, 61.9%) were older (72.4±7.6 vs. 65.5±11.8, P=0.007), more frequently male (74.4% vs. 41.7%, P=0.016) and more frequently had hypertension (89.7% vs. 37.5%, P&lt;0.001) than the patients without. FMD was negatively correlated with age, the severity of PVH and the severity of DWMH (R 2 =0.120, p=0.006, R 2 =0.280, p&lt;0.001 and R 2 =0.234, p&lt;0.001, respectively). In addition, FMD was positively correlated with the number of circulating progenitor cell (R 2 =0.078, p=0.034). After multivariate analysis with age, sex, presence of stroke and comorbidities, endothelial dysfunction was independently associated with the severity of PVH (standardized partial regression coefficient [β] 0.703, p=0.002), as well as DWMH (β 0.589, p=0.042). Conclusion: Endothelial dysfunction which was evaluated by FMD might be predictive for the grade of cerebral small vessel disease.

Oxidative stress and other risk factors for white matter lesions in chronic hemodialysis patients

Chronic kidney disease (CKD) is a risk factor for cardiovascular disease and promotes oxidative tress (OS), which has been implicated in the pathogenesis of white matter lesions (WML), a form of small-vessel cerebrovascular disease. The relationship between OS and WML in chronic hemodialysis (HD) patients has not yet been studied. We studied 67 chronic HD patients, aged 40 - 65 years (average 54 years) without known cerebrovascular disease. All patients underwent brain magnetic resonance imaging and subcortical and periventricular WML were evaluated using semiquantitative measures. Patients were classified into two groups depending on the presence or absence of WML (Fazekas classification), and the WML were scored. Carotid ultrasonography was also performed to evaluate the presence of carotid artery plaques and/or stenosis. Markers of protein and lipid oxidation (protein carbonyl and oxLDL antibodies), the glutathione system, enzymatic antioxidants (superoxide dismutase, glutathione peroxidase, glutathione reductase and catalase) and total antioxidant capacity (ORAC) were measured. OS markers were compared to those of a group of 36 healthy subjects. WML were present in 54% of the total population. Patients who had WML were older and had lower predialysis diastolic blood pressure than patients without WML. Other potential cardiovascular risk factors for WML, including obesity, hyperlipidemia, diabetes mellitus, presence of carotid artery plaques or stenosis, and duration and adequacy of HD were not related to the presence of WML. Compared to controls, HD patients had increased OS and decreased antioxidant capacity. However, OS did not differ between patients with WML and those without, and we found no association between OS markers and mean WML scores. After adjusting for several factors, only age and low predialysis diastolic blood pressure independently predicted an increased risk of WML. Our results confirm that chronic HD patients have increased OS, but this is not related to the presence or severity of WML.

遺伝性白質脳症とhereditary diffuse leukoencephalopathy with spheroids（HDLS）の分子病態

Adult-onset leukoencephalopathy involving the white matter of the brain is a heterogeneous disorder that exhibits a wide range of clinical manifestations. Recent advances in molecular genetics enable gene-based diagnosis of some forms of adult-onset leukoencephalopathy. In this review, the classification of adult-onset leukoencephalopathy based on molecular genetic findings is proposed. The autosomal dominant forms of adult-onset leukoencephalopathy include hereditary diffuse leukoencephalopathy with spheroids (HDLS), autosomal dominant adult-onset leukoencephalopathy (ALDL), cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), and Alexander disease. The autosomal recessive forms of adult-onset leukoencephalopathy include cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL), vanishing white matter (VWM) with leukoencephalopathy, Nasu-Hakola disease, and metachromatic leukodystrophy (MDL). X-chromosome-linked disorders include fragile X-associated tremor and ataxia syndrome (FXTAS) and adrenoleukodystrophy (ALD). Identification of the genes responsible for adult-onset leukoencephalopathy provides an important clue for elucidation of molecular pathophysiology underlying white matter disorders. One example is the identification of mutations in colony stimulating factor 1 receptor (CSF-1R) in patients with HDLS. Missense and splice site mutations have been found in the tyrosine kinase domain of CSF-1R. CSF-1R is highly expressed in microglia in the brain. It has been demonstrated that mice depleted of CSF-1R exhibit loss of microglia in the brain. In addition, stimulation of IL-34, a ligand of CSF-1R, induces proliferation and activation of microglia. These findings raise an intriguing possibility that dysfunction of microglia may play a role in the pathogenesis of white matter lesions occurring in patients with HDLS.

Elderly Hypertensive Patients: Silent White Matter Lesions, Blood Pressure Variability, Baroreflex Impairment and Cognitive Deterioration

Introduction: Hypertension may increase the risk for stroke and is frequently associated with subcortical and periventricular white matter lesions (WML). This is considered a prognostic factor for the development of stroke and cognitive impairment, particularly in attention processes. Additionally, in elderly subjects, it is known the implications of alterations in the neural cardiovascular regulation and the cardiovascular risk. Aims: To evaluate, in asymptomatic elderly hypertensives, the association of ambulatory blood pressure values and autonomic activity with neurocognitive impairment and WML. In addition, we also evaluated the role of the autonomic nervous system particularly the vagal component, in the pathogenesis of white matter lesions. Methods: We studied 22 elderly essential hypertensive patients (69±1.1y) and as control group, 16 normotensive elderly subjects (age 67±3.2y) were also enrolled. To each one of them, a cerebral MRI was performed to classify them, by a neuro-radiologist blinded of the subject clinical status, using a 0 to 9 scale where 0 denoted no WML and 9 the most severe lesions. Twenty four hours arterial blood pressure monitoring was performed to each one of the subjects under study. Office blood pressure was measured 3 times and the mean value reported. Beat to beat finger arterial pressure monitoring (Finapres) was performed for a 2h period. During the first hour the patient remained lying supine in a quiet darkened room and during the second hour four manoeuvres: stand-up, cold pressor test, handgrip and quiet activity were randomly performed. Mean blood pressure and pulse interval values, from the two periods, and their respective variabilities, baroreflex sensitivity and power spectral analysis were calculated. Regarding neuropsychological assessment: Minimental test, attention evaluation, RAVLT, visual memory, language and executive function, geriatric depression scale, cognitive deficit rate tests were performed in all subject.....

Cardiac Autonomic Dysfunction Is Associated With White Matter Lesions in Patients With Mild Cognitive Impairment

Cardiac autonomic dysfunction has been associated with cognitive impairment, but the underlying pathogenesis is complex and cerebral white matter lesions (WMLs) might be implicated. Time and frequency heart rate variability (HRV) and visual rating of WMLs were carried out in 42 patients with mild cognitive impairment. After adjustment for relevant demographic and clinical characteristics, including left ventricular mass, reduced HRV indices of parasympathetic (root mean square of successive difference of RR intervals, RMSSD) and sympathetic modulation (low-frequency [LF] power) were associated with increased WML score (RMSSD: B -0.30, 95% CI -0.52 to -0.08, p = .01; LF: B -0.24, 95% CI -0.46 to -0.02, p = .05). In a multiple-adjusted model, RMSSD was the major independent predictor of WMLs (B -0.35, 95% CI -0.57 to -0.13, p = .002). The evidence for an independent association of cardiac autonomic dysfunction with WMLs might suggest its role in the pathogenesis of WMLs.

The relation between white-matter lesions and cognition

To summarize recent findings and developments in the field of the relation between white-matter lesions and cognition. Recent studies have provided further evidence that white-matter lesions exert a detrimental effect on cognitive profile. New magnetic-resonance techniques may help in clarifying the meaning and extent of this effect. Evidence is also increasing about lesion progression occurring over time, at least in patients with severe white-matter lesions, and this progression is one of the factors related to cognitive decline in the elderly. The need to delay or halt the progression of white-matter lesions has led to clarification of the role of some risk factors and to performance of therapeutic trials where white-matter lesions are used as a surrogate marker for the end point of small-vessel disease. In addition to cognitive effects, white-matter lesions have a role in the decline of other functional performances, and this places individuals with higher-grade lesions at increased risk of developing disability. White-matter lesions cannot be considered as mere incidental findings, at least in patients who show severe lesions. The pathogenesis of white-matter lesions must be clarified further and strategies found to delay their progression.