脑梗死患者的脑白质病变危险因素分析

目的：探索脑梗死患者中脑白质病变的危险因素。方法：以2012 年1 月至2014 年12 月我院神经内科收治的837 例脑梗死 患者为研究对象,采用Fazekas量表评价核磁共振T2WI脑室旁白质和皮质下白质病变严重程度。分别比较不同程度脑室旁白质 病变、皮质下白质病变患者间各个危险因素的差异,采用Logistic 回归分析脑白质病变的危险因素。结果：年龄、高血压是脑室旁 白质（OR 年龄=1.090,95%CI:0.073-0.099,P＜0.05;OR 高血压=1.699,95%CI:0.242-0.818,P＜0.05）和皮质下白质病变（OR 年龄 =1.074,95%CI:0.059-0.083,P＜0.05;OR高血压=1.353,95%CI:0.017-0.588,P＜0.05）共同的危险因素。收缩压（OR=1.008,95%CI: 0.001-0.015,P＜0.05）是皮质下白质病变的危险因素。结论：在脑梗死患者中,年龄、高血压是脑室旁白质病变、皮质下白质病变共 同的危险因素,收缩压是皮质下白质病变的危险因素。     

Low Pre-Existing Gray Matter Volume in the Medial Temporal Lobe and White Matter Lesions Are Associated with Postoperative Cognitive Dysfunction after Cardiac Surgery

Objectives

Postoperative cognitive dysfunction (POCD) is recognized as a complication in the elderly after cardiac surgery. Imaging of the brain provides evidence of neurodegeneration in elderly patients; however, abnormalities in brain structure and their relation to POCD are uncertain. This pilot study investigated whether loss of gray matter in the bilateral medial temporal lobe (MTL), seen in preoperative MRI, was associated with POCD.

Methods

Data were collected prospectively on 28 elderly patients scheduled for elective cardiac surgery. MRI of the brains of all patients were assessed for prior cerebral infarctions, and carotid and intracranial arterial stenosis. Patients also completed six neuropsychological tests of memory, attention and executive function before and after surgery. POCD was defined as an individual decrease in more than two tests of at least 1 standard deviation from the group baseline mean for that test. The degree of gray matter loss in the MTL of each patient was calculated using voxel-based morphometry with three-dimensional, T1-weighted MRI. This represented the degree of gray matter change as a Z score.

Results

Postoperative cognitive dysfunction was identified in 8 of the 28 patients (29%). Patients with POCD had significantly more white matter lesions on MRI, and greater loss of gray matter in the bilateral MTL (average Z score 2.0±0.9) than patients without POCD. An analysis by stepwise logistic regression identified gray matter loss in the MTL and cerebral infarctions on MRI as independent predictors of POCD.

Conclusions

These preliminary findings suggested that reduced gray matter in the bilateral MTL and white matter lesions existed in brains of elderly cardiac surgery patients who experienced POCD. Additional studies with larger sample sizes are needed to confirm these findings.     

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.     

Vitamin B12 and Progression of White Matter Lesions. A 2-Year Follow-Up Study in First-Ever Lacunar Stroke Patients

In cross-sectional studies periventricular white matter lesions (WML) were related to low plasma levels of vitamin B12. Whether low vitamin B12 levels are also related to progression of WML is still unknown. We studied baseline vitamin B12 levels and its association with progression of WML over 2 years of follow-up in first-ever lacunar stroke patients. In 107 first-ever lacunar stroke patients in whom baseline brain MRI and vitamin B12 status were available, we obtained a follow-up brain MRI after 2 years. We assessed progression of periventricular WML (pWML) and deep WML (dWML) using a visual WML change scale. We studied the relationship between baseline levels of plasma vitamin B12 and progression of WML after 2 years of follow-up by binary logistic regression analyses. Vitamin B12 deficiency was more frequent in patients with progression of pWML compared to those without progression (41.9% and 19.7% respectively, p = 0.02). Corrected for sex and age, progression of pWML was associated with lower baseline levels of vitamin B12 (OR 1.42 per 50 unit decrease, 95% CI 1.00-1.92). Vitamin B12 levels were not associated with progression of dWML. In conclusion progression of pWML after 2 years of follow-up relates to low levels of vitamin B12 at baseline in first-ever lacunar stroke patients. Whether this population could benefit from vitamin B12 supplementation is unknown and requires further investigation.     

Cognitive Processing Speed in Older Adults: Relationship with White Matter Integrity

Cognitive processing slows with age. We sought to determine the importance of white matter integrity, assessed by diffusion tensor imaging (DTI), at influencing cognitive processing speed among normal older adults, assessed using a novel battery of computerized, non-verbal, choice reaction time tasks. We studied 131 cognitively normal adults aged 55–87 using a cross-sectional design. Each participant underwent our test battery, as well as MRI with DTI. We carried out cross-subject comparisons using tract-based spatial statistics. As expected, reaction time slowed significantly with age. In diffuse areas of frontal and parietal white matter, especially the anterior corpus callosum, fractional anisotropy values correlated negatively with reaction time. The genu and body of the corpus callosum, superior longitudinal fasciculus, and inferior fronto-occipital fasciculus were among the areas most involved. This relationship was not explained by gray or white matter atrophy or by white matter lesion volume. In a statistical mediation analysis, loss of white matter integrity mediated the relationship between age and cognitive processing speed.     

DTI of the Visual Pathway - White Matter Tracts and Cerebral Lesions

DTI is a technique that identifies white matter tracts (WMT) non-invasively in healthy and non-healthy patients using diffusion measurements. Similar to visual pathways (VP), WMT are not visible with classical MRI or intra-operatively with microscope. DTI will help neurosurgeons to prevent destruction of the VP while removing lesions adjacent to this WMT. We have performed DTI on fifty patients before and after surgery between March 2012 to January 2014. To navigate we used a 3DT1-weighted sequence. Additionally, we performed a T2-weighted and DTI-sequences. The parameters used were, FOV: 200 x 200 mm, slice thickness: 2 mm, and acquisition matrix: 96 x 96 yielding nearly isotropic voxels of 2 x 2 x 2 mm. Axial MRI was carried out using a 32 gradient direction and one b0-image. We used Echo-Planar-Imaging (EPI) and ASSET parallel imaging with an acceleration factor of 2 and b-value of 800 s/mm². The scanning time was less than 9 min.The DTI-data obtained were processed using a FDA approved surgical navigation system program which uses a straightforward fiber-tracking approach known as fiber assignment by continuous tracking (FACT). This is based on the propagation of lines between regions of interest (ROI) which is defined by a physician. A maximum angle of 50, FA start value of 0.10 and ADC stop value of 0.20 mm²/s were the parameters used for tractography.There are some limitations to this technique. The limited acquisition time frame enforces trade-offs in the image quality. Another important point not to be neglected is the brain shift during surgery. As for the latter intra-operative MRI might be helpful. Furthermore the risk of false positive or false negative tracts needs to be taken into account which might compromise the final results.     

MRI Markers for Mild Cognitive Impairment: Comparisons between White Matter Integrity and Gray Matter Volume Measurements

The aim of the study was to evaluate the value of assessing white matter integrity using diffusion tensor imaging (DTI) for classification of mild cognitive impairment (MCI) and prediction of cognitive impairments in comparison to brain atrophy measurements using structural MRI. Fifty-one patients with MCI and 66 cognitive normal controls (CN) underwent DTI and T1-weighted structural MRI. DTI measures included fractional anisotropy (FA) and radial diffusivity (DR) from 20 predetermined regions-of-interest (ROIs) in the commissural, limbic and association tracts, which are thought to be involved in Alzheimer''s disease; measures of regional gray matter (GM) volume included 21 ROIs in medial temporal lobe, parietal cortex, and subcortical regions. Significant group differences between MCI and CN were detected by each MRI modality: In particular, reduced FA was found in splenium, left isthmus cingulum and fornix; increased DR was found in splenium, left isthmus cingulum and bilateral uncinate fasciculi; reduced GM volume was found in bilateral hippocampi, left entorhinal cortex, right amygdala and bilateral thalamus; and thinner cortex was found in the left entorhinal cortex. Group classifications based on FA or DR was significant and better than classifications based on GM volume. Using either DR or FA together with GM volume improved classification accuracy. Furthermore, all three measures, FA, DR and GM volume were similarly accurate in predicting cognitive performance in MCI patients. Taken together, the results imply that DTI measures are as accurate as measures of GM volume in detecting brain alterations that are associated with cognitive impairment. Furthermore, a combination of DTI and structural MRI measurements improves classification accuracy.     

Different Patterns of Punctate White Matter Lesions in Serially Scanned Preterm Infants

Background and Purpose

With the increased use of MRI in preterm infants, punctate white matter lesions (PWML) are more often recognized. The aim of this study was to describe the incidence and characteristics of these lesions as well as short-term outcome in a cohort of serially scanned preterm infants, using both conventional imaging, diffusion (DWI) and susceptibility (SWI) weighted imaging.

Materials and Methods

112 preterm infants with 2 MRIs in the neonatal period, with evidence of punctate white matter lesions, were included. Appearance, lesion load, location, and abnormalities on DWI and SWI were scored and outcome data were collected.

Results

Different patterns of punctate white matter lesions did appear: a linear appearance associated with signal loss on SWI, and a cluster appearance associated with restricted diffusion on DWI on the first MRI. Cluster and mixed lesions on the first scan changed in appearance in over 50% on the second scan, whereas linear lesions generally kept their appearance. Lesions were only visible on the early scan in 33%, and were only seen at term equivalent age in 20%. Nine infants developed cerebral palsy, due to additional overt white matter lesions in six.

Conclusion

Two patterns of punctate white matter lesions were identified: one with loss of signal on SWI in a linear appearance, and the other with DWI lesions with restricted diffusion in a cluster appearance. These different patterns are suggestive of a difference in underlying pathophysiology. To reliably classify PWML in the preterm infant in either pattern, an early MRI with DWI and SWI sequences is required.     

Altered Glutamatergic Metabolism Associated with Punctate White Matter Lesions in Preterm Infants

Preterm infants (∼10% of all births) are at high-risk for long-term neurodevelopmental disabilities, most often resulting from white matter injury sustained during the neonatal period. Glutamate excitotoxicity is hypothesized to be a key mechanism in the pathogenesis of white matter injury; however, there has been no in vivo demonstration of glutamate excitotoxicity in preterm infants. Using magnetic resonance spectroscopy (MRS), we tested the hypothesis that glutamate and glutamine, i.e., markers of glutamatergic metabolism, are altered in association with punctate white matter lesions and “diffuse excessive high signal intensity” (DEHSI), the predominant patterns of preterm white matter injury. We reviewed all clinically-indicated MRS studies conducted on preterm infants at a single institution during a six-year period and determined the absolute concentration of glutamate, glutamine, and four other key metabolites in the parietal white matter in 108 of those infants after two investigators independently evaluated the studies for punctate white matter lesions and DEHSI. Punctate white matter lesions were associated with a 29% increase in glutamine concentration (p = 0.002). In contrast, there were no differences in glutamatergic metabolism in association with DEHSI. Severe DEHSI, however, was associated with increased lactate concentration (p = 0.001), a marker of tissue acidosis. Findings from this study support glutamate excitotoxicity in the pathogenesis of punctate white matter lesions, but not necessarily in DEHSI, and suggest that MRS provides a useful biomarker for determining the pathogenesis of white matter injury in preterm infants during a period when neuroprotective agents may be especially effective.     

Role of Recurrent Hypoxia-Ischemia in Preterm White Matter Injury Severity

Objective

Although the spectrum of white matter injury (WMI) in preterm infants is shifting from cystic necrotic lesions to milder forms, the factors that contribute to this changing spectrum are unclear. We hypothesized that recurrent hypoxia-ischemia (rHI) will exacerbate the spectrum of WMI defined by markers of inflammation and molecules related to the extracellular matrix (hyaluronan (HA) and the PH20 hyaluronidase) that regulate maturation of the oligodendrocyte (OL) lineage after WMI.

Methods

We employed a preterm fetal sheep model of in utero moderate hypoxemia and global severe but not complete cerebral ischemia that reproduces the spectrum of human WMI. The response to rHI was compared against corresponding early or later single episodes of HI. An ordinal rating scale of WMI was compared against an unbiased quantitative image analysis protocol that provided continuous histo-pathological outcome measures for astrogliosis and microglial activation. Late oligodendrocyte progenitors (preOLs) were quantified by stereology. Analysis of hyaluronan and the hyaluronidase PH20 defined the progressive response of the extracellular matrix to WMI.

Results

rHI resulted in a more severe spectrum of WMI with a greater burden of necrosis, but an expanded population of preOLs that displayed reduced susceptibility to cell death. WMI from single episodes of HI or rHI was accompanied by elevated HA levels and increased labeling for PH20. Expression of PH20 in fetal ovine WMI was confirmed by RT-PCR and RNA-sequencing.

Conclusions

rHI is associated with an increased risk for more severe WMI with necrosis, but reduced risk for preOL degeneration compared to single episodes of HI. Expansion of the preOL pool may be linked to elevated hyaluronan and PH20.     

PGJ2 Provides Prolonged CNS Stroke Protection by Reducing White Matter Edema

Few clinically effective approaches reduce CNS-white matter injury. After early in-vivo white matter infarct, NFκB-driven pro-inflammatory signals can amplify a relatively small amount of vascular damage, resulting in progressive endothelial dysfunction to create a severe ischemic lesion. This process can be minimized by 15-deoxy-Δ^12,14-prostaglandin J2 (PGJ₂), an analog of the metabolically active PGD₂ metabolite. We evaluated PGJ₂''s effects and mechanisms using rodent anterior ischemic optic neuropathy (rAION); an in vivo white matter ischemia model. PGJ₂ administration systemically administered either acutely or 5 hours post-insult results in significant neuroprotection, with stereologic evaluation showing improved neuronal survival 30 days post-infarct. Quantitative capillary vascular analysis reveals that PGJ₂ improves perfusion at 1 day post-infarct by reducing tissue edema. Our results suggest that PGJ₂ acts by reducing NFκB signaling through preventing p65 nuclear localization and inhibiting inflammatory gene expression. Importantly, PGJ₂ showed no in vivo toxicity structurally as measured by optic nerve (ON) myelin thickness, functionally by ON-compound action potentials, on a cellular basis by oligodendrocyte precursor survival or changes in ON-myelin gene expression. PGJ₂ may be a clinically useful neuroprotective agent for ON and other CNS infarcts involving white matter, with mechanisms of action enabling effective treatment beyond the currently considered maximal time for intervention.     

Plasma tPA-Activity and Progression of Cerebral White Matter Hyperintensities in Lacunar Stroke Patients

Introduction

Tissue plasminogen activator (tPA)-activity and plasminogen activator inhibitor type 1 (PAI-1) antigen are considered to be haemostasis-related markers of endothelial activation and relate to presence of cerebral white matter hyperintensities (WMH) as was earlier shown in a cross-sectional study. We investigated whether tPA-activity and PAI-1 levels are associated with WMH progression in a longitudinal study.

Methods

In 127 first-ever lacunar stroke patients in whom baseline brain MRI and plasma levels of tPA-activity and PAI-1-antigen were available, we obtained a 2-year follow-up MRI. We assessed WMH progression by a visual WMH change scale. We determined the relationship between levels of tPA-activity and PAI-1 and WMH progression, by logistic regression analysis.

Results

Plasma tPA-activity was associated with periventricular WMH progression (OR 2.36, 95% CI 1.01–5.49, with correction for age and sex and baseline presence of WMH), but not with deep or any (periventricular and/or deep) WMH progression. PAI-1 levels were lower in patients with WMH progression, but these results were not significant.

Conclusion

We found a relationship between plasma tPA-activity and progression of periventricular WMH. More research is needed to determine whether there is a (direct) role of tPA in the development and progression of WMH.     

Cerebral White Matter Lesions and Affective Episodes Correlate in Male Individuals with Bipolar Disorder

Background

Cerebral white matter lesions (WML) have been found in normal aging, vascular disease and several neuropsychiatric conditions. Correlations of WML with clinical parameters in BD have been described, but not with the number of affective episodes, illness duration, age of onset and Body Mass Index in a well characterized group of euthymic bipolar adults. Herein, we aimed to evaluate the associations between bipolar course of illness parameters and WML measured with volumetric analysis.

Methods

In a cross-sectional study 100 euthymic individuals with BD as well as 54 healthy controls (HC) were enrolled to undergo brain magnetic resonance imaging using 3T including a FLAIR sequence for volumetric assessment of WML-load using FSL-software. Additionally, clinical characteristics and psychometric measures including Structured Clinical Interview according to DSM-IV, Hamilton-Depression, Young Mania Rating Scale and Beck’s Depression Inventory were evaluated.

Results

Individuals with BD had significantly more (F = 3.968, p < .05) WML (Mdn = 3710mm3; IQR = 2961mm3) than HC (Mdn = 2185mm3; IQR = 1665mm3). BD men (Mdn = 4095mm3; IQR = 3295mm3) and BD women (Mdn = 3032mm3; IQR = 2816mm3) did not significantly differ as to the WML-load or the number and type of risk factors for WML. However, in men only, the number of manic/hypomanic episodes (r = 0.72; p < .001) as well as depressive episodes (r = 0.51; p < .001) correlated positively with WML-load.

Conclusions

WML-load strongly correlated with the number of manic episodes in male BD patients, suggesting that men might be more vulnerable to mania in the context of cerebral white matter changes.     

Abnormal Organization of White Matter Network in Patients with No Dementia after Ischemic Stroke

Structural changes after ischemic stroke could affect information communication extensively in the brain network. It is likely that the defects in the white matter (WM) network play a key role in information interchange. In this study, we used graph theoretical analysis to examine potential organization alteration in the WM network architecture derived from diffusion tensor images from subjects with no dementia and experienced stroke in the past 5.4–14.8 months (N = 47, Mini-Mental Screening Examination, MMSE range 18–30), compared with a normal control group with 44 age and gender-matched healthy volunteers (MMSE range 26–30). Region-wise connectivity was derived from fiber connection density of 90 different cortical and subcortical parcellations across the whole brain. Both normal controls and patients with chronic stroke exhibited efficient small-world properties in their WM structural networks. Compared with normal controls, topological efficiency was basically unaltered in the patients with chronic stroke, as reflected by unchanged local and global clustering coefficient, characteristic path length, and regional efficiency. No significant difference in hub distribution was found between normal control and patient groups. Patients with chronic stroke, however, were found to have reduced betweenness centrality and predominantly located in the orbitofrontal cortex, whereas increased betweenness centrality and vulnerability were observed in parietal-occipital cortex. The National Institutes of Health Stroke Scale (NIHSS) score of patient is correlated with the betweenness centrality of right pallidum and local clustering coefficient of left superior occipital gyrus. Our findings suggest that patients with chronic stroke still exhibit efficient small-world organization and unaltered topological efficiency, with altered topology at orbitofrontal cortex and parietal-occipital cortex in the overall structural network. Findings from this study could help in understanding the mechanism of cognitive impairment and functional compensation occurred in patients with chronic stroke.     

Association between Perivascular Spaces and Progression of White Matter Hyperintensities in Lacunar Stroke Patients

Objectives

Perivascular spaces are associated with MRI markers of cerebral small vessel disease, including white matter hyperintensities. Although perivascular spaces are considered to be an early MRI marker of cerebral small vessel disease, it is unknown whether they are associated with further progression of MRI markers, especially white matter hyperintensities. We determined the association between perivascular spaces and progression of white matter hyperintensities after 2-year follow-up in lacunar stroke patients.

Methods

In 118 lacunar stroke patients we obtained brain MRI and 24-hour ambulatory blood pressure measurements at baseline, and a follow-up brain MRI 2 years later. We visually graded perivascular spaces and white matter hyperintensities at baseline. Progression of white matter hyperintensities was assessed using a visual white matter hyperintensity change scale. Associations with white matter hyperintensity progression were tested with binary logistic regression analysis.

Results

Extensive basal ganglia perivascular spaces were associated with progression of white matter hyperintensities (OR 4.29; 95% CI: 1.28–14.32; p<0.05), after adjustment for age, gender, 24-hour blood pressure and vascular risk factors. This association lost significance after additional adjustment for baseline white matter hyperintensities. Centrum semiovale perivascular spaces were not associated with progression of white matter hyperintensities.

Conclusions

Our study shows that extensive basal ganglia perivascular spaces are associated with progression of white matter hyperintensities in cerebral small vessel disease. However, this association was not independent of baseline white matter hyperintensities. Therefore, presence of white matter hyperintensities at baseline remains an important determinant of further progression of white matter hyperintensities in cerebral small vessel disease.     

Cognitive Impairment in Myotonic Dystrophy Type 1 Is Associated with White Matter Damage

Objective

To investigate grey (GM) and white matter (WM) abnormalities and their effects on cognitive and behavioral deficits in a large, phenotypically and genotypically well-characterized cohort of classic adult (aDM1, age at onset ≥20 years) or juvenile (jDM1, age at onset <20 years) patients with myotonic dystrophy type 1 (DM1).

Methods

A case-control study including 51 DM1 patients (17 jDM1 and 34 aDM1) and 34 controls was conducted at an academic medical center. Clinical, cognitive and structural MRI evaluations were obtained. Quantitative assessments of regional GM volumes, WM hyperintensities (WMHs), and microstructural WM tract damage were performed. The association between structural brain damage and clinical and cognitive findings was assessed.

Results

DM1 patients showed a high prevalence of WMHs, severe regional GM atrophy including the key nodes of the sensorimotor and main cognitive brain networks, and WM microstructural damage of the interhemispheric, corticospinal, limbic and associative pathways. WM tract damage extends well beyond the focal WMHs. While aDM1 patients had severe patterns of GM atrophy and WM tract damage, in jDM1 patients WM abnormalities exceeded GM involvement. In DM1, WMHs and microstructural damage, but not GM atrophy, correlated with cognitive deficits.

Conclusions

WM damage, through a disconnection between GM structures, is likely to be the major contributor to cognitive impairment in DM1. Our MRI findings in aDM1 and jDM1 patients support the hypothesis of a degenerative (premature aging) origin of the GM abnormalities and of developmental changes as the principal substrates of microstructural WM alterations in DM1.     

Associations between White Matter Microstructure and Cognitive Performance in Old and Very Old Age

Increasing age is associated with deficits in a wide range of cognitive domains as well as with structural brain changes. Recent studies using diffusion tensor imaging (DTI) have shown that microstructural integrity of white matter is associated with cognitive performance in elderly persons, especially on tests that rely on perceptual speed. We used structural equation modeling to investigate associations between white matter microstructure and cognitive functions in a population-based sample of elderly persons (age ≥ 60 years), free of dementia, stroke, and neurological disorders (n = 253). Participants underwent a magnetic resonance imaging scan, from which mean fractional anisotropy (FA) and mean diffusivity (MD) of seven white matter tracts were quantified. Cognitive functioning was analyzed according to performance in five task domains (perceptual speed, episodic memory, semantic memory, letter fluency, and category fluency). After controlling for age, FA and MD were exclusively related to perceptual speed. When further stratifying the sample into two age groups, the associations were reliable in the old-old (≥78 years) only. This relationship between white matter microstructure and perceptual speed remained significant after excluding persons in a preclinical dementia phase. The observed pattern of results suggests that microstructural white matter integrity may be especially important to perceptual speed among very old adults.