Deep Cerebral White Matter Research Articles

The MRI Features of Intracranial Lesions in MOG-IgG Associated Disease

AimTo summarize and analyze the MRI characteristics of patients with Myelin oligodendrocyte glycoprotein-IgG associated disease (MOGAD), and to enhance the accuracy of disease diagnosis and advance scientific research. Materials and methodsA retrospective collection of clinical data from 103 patients with MOGAD was conducted. The distribution and signal characteristics of intracranial lesions on MRI were analyzed. Further subgroup statistical analysis based on age was performed to explore differences in lesion locations among different subgroups. Statistical comparisons were made using the χ2 test or Fisher's exact test, with a significance level of p<0.05 considered statistically significant. ResultsMRI revealed variable lesion morphologies in patients with MOGAD. Lesions were predominantly located in the cerebral deep white matter (47.6%), subcortical white matter (38.8%) and cortex (38.8%) of supratentorial region, as well as in the brainstem (35.9%) of infratentorial region. Notably, there was a significantly higher proportion of juvenile patients with thalamic involvement compared to adult patients (p=0.013). Juvenile patients were more likely to have lesions involving both the thalamus and cerebral cortex (p=0.040), thalamus and deep white matter (p=0.026), or thalamus and brainstem (p=0.014). Conversely, lesions involving both the corpus callosum and subcortical white matter were more frequently observed in adult patients, with statistically significant differences (p=0.046). Post-contrast MRI showed mild enhancement in some lesions, with a half of cases exhibiting leptomeningeal enhancement. One rare case presented extensive thickening and enhancement of the falx cerebri. ConclusionThe distribution of intracranial lesions on MRI exhibits distinct characteristics. The differences in the spatial distribution of intracranial lesions between juvenile and adult patients suggest that MOGAD may represent a heterogeneous disease spectrum that varies with age.

A Case of the Anti-aquaporine-4 Antibody-negative Neuromyelitis Optica Spectrum Disorders Associated with Atopic Disease with High Concentration of Anti-IgE Autoantibody and HyperIgEemia

We report a 70-year-old male patient with the sero-negative neuromyelitis optica spectrum disorders (NMOSD) associated with atopic disease (AD). He was diagnosed with allergic rhinitis at the age of 20. When he was 61 years old, he subacutely developed orthostatic hypotension, bilateral optic neuritis, quadriparesis, urinary retention, and constipation. The laboratory results revealed allergen-specific IgE positivity for cryptomeria japonica and hinoki, hyperIgEemia, and Th (helper T cell) 1 dominance. The serological tests for autoantibodies revealed negative anti-aquaporine 4 antibody, and high concentration of anti-IgE autoantibody (anti-IgE AAb). Cerebrospinal fluid was negative for anti-myelin-oligodendrocyte glycoprotein antibody and glial fibrillary acidic protein antibody. Fluid-attenuated inversion recovery on brain magnetic resonance imaging (MRI) showed high signal intensities in bilateral cerebral deep white matter. T2 weighted image on spine MRI showed longitudinally extensive high signal intensities in the spinal cord, specifically involving C1 vertebral level to conus medullaris. Intravenous methylprednisolone (IVMP) and plasma exchange resulted in partial improvement. Following the onset of NMOSD, he had relapse of NMOSD four times. In each episode, IVMP was to be partially effective with anti-IgE AAb reduction. Anti-IgE AAb may be a reasonable clinical indicator of increased disease activity in the sero-negative NMOSD associated with AD.

Brain Diffusion Changes in Perinatal Asphyxia Cases.

Prolonged perinatal asphyxia (PA) may cause hypoxic-ischemic damage to the brain. The aim of this study was to investigate the brain diffusion changes of patients with PA and examine the relationship with brain damage. This retrospective study included 55 patients diagnosed with PA, separated into mild and severe PA groups. For the evaluation of brain damage in all the study neonates, brain and diffusion MRI scans were performed using a 3T device. The scans were taken between 5 and 10 days postnatal, after completion of hypothermia treatment, in accordance with the standard clinical protocol of our institution. Apparent diffusion coefficient (ADC) values of the lentiform nucleus, thalamus, frontal white matter, and posterior limbs of the internal capsule were measured. Minitab package programs and SPSS version 20.0 software were used for statistical analysis and graphic drawing. Spearman's rank correlation analysis was used. The bilateral lentiform nucleus, thalamus, frontal white matter, and posterior limbs of the internal capsule ADC values were significantly higher in the severe PA group than in the mild PA group. In neonates with severe perinatal asphyxia, brain damage can be evaluated on diffusion-weighted imaging (DWI) of the cerebral deep white matter and basal ganglia. DWI, imaging with conventional brain MRI comes to the fore in clinical importance in PA patients.

The association of structural versus load-dependent large artery stiffness mechanisms with cerebrovascular damage and cortical atrophy in humans.

Large central arterial stiffness is a risk factor for cerebrovascular damage and subsequent progression of neurodegenerative diseases, including Alzheimer's disease and dementia. However, arterial stiffness is determined by both the intrinsic components of the arterial wall (structural stiffness) and the load (i.e., arterial blood pressure) exerted upon it by the blood (load-dependent stiffness). This study aimed to determine the degree to which structural and/or load-dependent mechanisms of central arterial stiffness are associated with cerebrovascular damage. Among 128 healthy individuals (aged 63±6, age range: 50-80 years, 42% men), aortic and carotid artery stiffness was measured via carotid-femoral pulse wave velocity and B-mode ultrasonography, respectively. Using participant-specific exponential models, both aortic and carotid artery stiffness were standardized to a reference blood pressure to separate their structural and load-dependent stiffness mechanisms. Magnetic resonance imaging was used to derive total, periventricular, and deep cerebral white matter lesion volume (WMLV) and global cortical thickness. After adjusting for common cardiovascular disease risk factors, a 1 m/s increase in structural aortic stiffness was associated with 15% greater total WMLV (95% confidence interval [CI] = 0.01, 0.27, P = 0.036), 14% greater periventricular WMLV (95%CI = 0.004, 0.25, P = 0.044) and 0.011mm lower cortical thickness (95%CI = -0.022, -1.18, P = 0.028). No association was observed between structural carotid stiffness and WMLVs (total, periventricular, and deep), and neither aortic nor carotid load-dependent stiffness was associated with WMLVs or cortical thickness. Structural, not load-dependent, mechanisms of aortic stiffness are related to cerebrovascular-related white matter damage.

Dominant CST3 variants cause adult onset leukodystrophy without amyloid angiopathy.

Leukodystrophies are rare genetic white matter disorders that have been regarded as mainly occurring in childhood. This perception has been altered in recent years, as a growing number of leukodystrophies have been described as having an onset in adulthood. Still, many adult patients presenting with white matter changes remain without a specific molecular diagnosis. We describe a novel adult onset leukodystrophy in 16 patients from eight families carrying one of four different stop-gain or frameshift dominant variants in the CST3 gene. Clinical and radiological features differ markedly from the previously described Icelandic cerebral amyloid angiopathy found in patients carrying p.Leu68Asn substitution in CST3. The clinical phenotype consists of recurrent episodes of hemiplegic migraine associated with transient unilateral focal deficits and slowly progressing motor symptoms and cognitive decline in mid to older adult ages. In addition, in some cases acute onset clinical deterioration led to a prolonged episode with reduced consciousness and even early death. Radiologically, pathognomonic changes are found at typical predilection sites involving the deep cerebral white matter sparing a periventricular and directly subcortical rim, the middle blade of corpus callosum, posterior limb of the internal capsule, middle cerebellar peduncles, cerebral peduncles and specifically the globus pallidus. Histopathologic characterization in two autopsy cases did not reveal angiopathy, but instead micro- to macrocystic degeneration of the white matter. Astrocytes were activated at early stages and later displayed severe degeneration and loss. In addition, despite the loss of myelin, elevated numbers of partly apoptotic oligodendrocytes were observed. A structural comparison of the variants in CST3 suggests that specific truncations of cystatin C result in an abnormal function, possibly by rendering the protein more prone to aggregation. Future studies are required to confirm the assumed effect on the protein and to determine pathophysiologic downstream events at the cellular level.

Abstract P230: Central Artery Pulsatile Hemodynamics Are Associated With Cerebral Total, Periventricular, And Deep White Matter Lesions: Role Of Reservoir-excess Pressure Components.

Introduction: Accumulating evidence suggests that increased central, rather than peripheral, blood pressure (BP) may be a better predictor of cardiovascular risk. The shape of the central BP waveform is determined by ventricular-arterial interactions that can be quantified via novel hemodynamic analyses, from which some parameters have been implicated in the development of cardiac, vascular, and renal dysfunction. Comparatively, the potential effect of central pulsatile hemodynamics on brain structure has been understudied. Thus, we sought to determine the association of novel central hemodynamic parameters with cerebral white matter lesions. Methods: Central BP waveforms were measured in 130 healthy adults (age 63±6y; 58% female) via non-invasive carotid tonometry and modeled using reservoir-excess pressure analysis to separate the central BP waveform into a reservoir (Rp TI ) and excess (Ep TI ) pressure component. Systolic (Sk) and diastolic (Dk) rate constants were estimated from the rate of increase and decrease of the Rp TI component, respectively. Total, periventricular, and deep cerebral white matter lesion volumes (WMLV) were estimated from T2 weighted and FLAIR MRI and adjusted for total intracranial volume. Results: Both Sk and Ep TI were correlated with total (Sk: r = -0.19, p = 0.033; Ep TI : r = 0.21, p = 0.016), periventricular (Sk: r = -0.18, p = 0.037; Ep TI : r = 0.23, p = 0.009), and deep (Sk: r = -0.28, p = 0.002; Ep TI : r = 0.20, p = 0.027) WMLV. The association of Sk with total ( B = -0.032; 95% confidence interval [CI] = -0.054, -0.010; p = 0.0056), periventricular ( B = -0.030; 95%CI = -0.051, -0.009; p = 0.0063), and deep ( B = -0.064; 95%CI = -0.101, -0.028; p &lt;0.001) WMLV remained significant in multivariable analyses adjusting for age, sex, BMI, peripheral pulse pressure, carotid-femoral pulse wave velocity, heart rate, and non-HDL cholesterol. Additionally, the association between Ep TI and deep WMLV persisted in multivariable analysis ( B = 0.158; 95%CI = 0.045, 0.271; p = 0.007). Conclusion: Pulsatile components of central artery hemodynamics are associated with cerebral WMLV independent of traditional cardiovascular risk factors. In particular, Sk may represent a novel biomarker of early central BP-related cerebral white matter damage.

Neuroimaging assessment of pediatric cerebral changes associated with SARS-CoV-2 infection during pregnancy.

SARS-CoV-2 infection and perinatal neurologic outcomes are still not fully understood. However, there is recent evidence of white matter disease and impaired neurodevelopment in newborns following maternal SARS-CoV-2 infection. These appear to occur as a consequence of both direct viral effects and a systemic inflammatory response, with glial cell/myelin involvement and regional hypoxia/microvascular dysfunction. We sought to characterize the consequences of maternal and fetal inflammatory states in the central nervous system of newborns following maternal SARS-CoV-2 infection. We conducted a longitudinal prospective cohort study from June 2020 to December 2021, with follow-up of newborns born to mothers exposed or not exposed to SARS-CoV-2 infection during pregnancy. Brain analysis included data from cranial ultrasound scans (CUS) with grayscale, Doppler studies (color and spectral), and ultrasound-based brain elastography (shear-wave mode) in specific regions of interest (ROIs): deep white matter, superficial white matter, corpus callosum, basal ganglia, and cortical gray matter. Brain elastography was used to estimate brain parenchymal stiffness, which is an indirect quantifier of cerebral myelin tissue content. A total of 219 single-pregnancy children were enrolled, including 201 born to mothers exposed to SARS-CoV-2 infection and 18 from unexposed controls. A neuroimaging evaluation was performed at 6 months of adjusted chronological age and revealed 18 grayscale and 21 Doppler abnormalities. Predominant findings were hyperechogenicity of deep brain white matter and basal ganglia (caudate nuclei/thalamus) and a reduction in the resistance and pulsatility indices of intracranial arterial flow. The anterior brain circulation (middle cerebral and pericallosal arteries) displayed a wider range of flow variation than the posterior circulation (basilar artery). Shear-wave US elastography analysis showed a reduction in stiffness values in the SARS-CoV-2 exposed group in all analyzed regions of interest, especially in the deep white matter elasticity coefficients (3.98 ± 0.62) compared to the control group (7.76 ± 0.77); p-value < 0.001. This study further characterizes pediatric structural encephalic changes associated with SARS-CoV-2 infection during pregnancy. The maternal infection has been shown to be related to cerebral deep white matter predominant involvement, with regional hyperechogenicity and reduction of elasticity coefficients, suggesting zonal impairment of myelin content. Morphologic findings may be subtle, and functional studies such as Doppler and elastography may be valuable tools to more accurately identify infants at risk of neurologic damage.

Teaching NeuroImages: Infantile-onset Krabbe disease with tigroid appearance of the white matter

An 8-month-old girl presented with a 1-month history of developmental regression, irritability, and opisthotonic posturing. A brain MRI revealed abnormal T2 hyperintensities in the periventricular and deep cerebral white matter and peridentate cerebellar white matter. Reduced galactocerebrosidase activity in leukocytes confirmed the diagnosis of Krabbe disease.

Turning and multitask gait unmask gait disturbance in mild-to-moderate multiple sclerosis: Underlying specific cortical thinning and connecting fibers damage.

Multiple sclerosis (MS) causes gait and cognitive impairments that are partially normalized by compensatory mechanisms. We aimed to identify the gait tasks that unmask gait disturbance and the underlying neural correlates in MS. We included 25 patients with MS (Expanded Disability Status Scale score: median 2.0, interquartile range 1.0-2.5) and 19 healthy controls. Fast-paced gait examinations with inertial measurement units were conducted, including straight or circular walking with or without cognitive/motor tasks, and the timed up and go test (TUG). Receiver operating characteristic curve analysis was performed to distinguish both groups by the gait parameters. The correlation between gait parameters and cortical thickness or fractional anisotropy values was examined by using three-dimensional T1-weighted imaging and diffusion tensor imaging, respectively (corrected p < .05). Total TUG duration (>6.0s, sensitivity 88.0%, specificity 84.2%) and stride velocity during cognitive dual-task circular walking (<1.12 m/s, 84.0%, 84.2%) had the highest discriminative power of the two groups. Deterioration of these gait parameters was correlated with thinner cortical thickness in regional areas, including the left precuneus and left temporoparietal junction, overlapped with parts of the default mode network, ventral attention network, and frontoparietal network. Total TUG duration was negatively correlated with fractional anisotropy values in the deep cerebral white matter areas. Turning and multitask gait may be optimal to unveil partially compensated gait disturbance in patients with mild-to-moderate MS through dynamic balance control and multitask processing, based on the structural damage in functional networks.

Electrochemically induced in vitro focal hypoxia in human neurons.

Focalised hypoxia is widely prevalent in diseases such as stroke, cardiac arrest, and dementia. While in some cases hypoxia improves cellular functions, it mostly induces or exacerbates pathological changes. The lack of methodologies that can simulate focal acute hypoxia, in either animal or cell culture, impedes our understanding of the cellular consequences of hypoxia. To address this gap, an electrochemical localised oxygen scavenging system (eLOS), is reported, providing an innovative platform for spatiotemporal in vitro hypoxia modulation. The electrochemical system is modelled showing O2 flux patterns and localised O2 scavenging and hypoxia regions, as a function of distance from the electrode and surrounding flux barriers, allowing an effective focal hypoxia tool to be designed for in vitro cell culture study. O2 concentration is reduced in an electrochemically defined targeted area from normoxia to hypoxia in about 6 min depending on the O2-flux boundaries. As a result, a cell culture-well was designed, where localised O2 scavenging could be induced. The impact of localised hypoxia was demonstrated on human neural progenitor cells (hNPCs) and it was shown that miniature focal hypoxic insults can be induced, that evoke time-dependent HIF-1α transcription factor accumulation. This transcription is “patterned” across the culture according to the electrochemically induced spatiotemporal hypoxia gradient. A basic lacunar infarct model was also developed through the application of eLOS in a purpose designed microfluidic device. Miniature focal hypoxic insults were induced in cellular processes of fully oxygenated cell bodies, such as the axons of human cortical neurons. The results demonstrate experimentally that localised axonal hypoxic stress can lead to significant increase of neuronal death, despite the neurons remaining at normoxia. This suggests that focal hypoxic insult to axons alone is sufficient to impact surrounding neurons and may provide an in vitro model to study the impact of microinfarcts occurring in the deep cerebral white matter, as well as providing a promising tool for wider understanding of acute hypoxic insults with potential to uncover its pathophysiology in multiple diseases.

Retinal microvasculature and imaging markers of brain frailty in normal aging adults.

BackgroundThe retina and brain share a similar embryologic origin, blood barriers, and microvasculature features. Thus, retinal imaging has been of interest in the aging population to help in the early detection of brain disorders. Imaging evaluation of brain frailty, including brain atrophy and markers of cerebral small vessel disease (CSVD), could reflect brain health in normal aging, but is costly and time-consuming. In this study, we aimed to evaluate the retinal microvasculature and its association with radiological indicators of brain frailty in normal aging adults.MethodsSwept-source optical coherence tomography angiography (SS-OCTA) and 3T-MRI brain scanning were performed on normal aging adults (aged ≥ 50 years). Using a deep learning algorithm, microvascular tortuosity (VT) and fractal dimension parameter (Dbox) were used to evaluate the superficial vascular complex (SVC) and deep vascular complex (DVC) of the retina. MRI markers of brain frailty include brain volumetric measures and CSVD markers that were assessed.ResultsOf the 139 normal aging individuals included, the mean age was 59.43 ± 7.31 years, and 64.0% (n = 89) of the participants were females. After adjustment of age, sex, and vascular risk factors, Dbox in the DVC showed a significant association with the presence of lacunes (β = 0.58, p = 0.007), while VT in the SVC significantly correlated with the score of cerebral deep white matter hyperintensity (β = 0.31, p = 0.027). No correlations were found between brain volumes and retinal microvasculature changes (P > 0.05).ConclusionOur report suggests that imaging of the retinal microvasculature may give clues to brain frailty in the aging population.

Infantile status epilepticus disrupts myelin development

Temporal lobe epilepsy (TLE) is the most prevalent type of epilepsy in adults; it often starts in infancy or early childhood. Although TLE is primarily considered to be a grey matter pathology, a growing body of evidence links this disease with white matter abnormalities. In this study, we explore the impact of TLE onset and progression in the immature brain on white matter integrity and development utilising the rat model of Li-pilocarpine-induced TLE at the 12th postnatal day (P). Diffusion tensor imaging (DTI) and Black-Gold II histology uncovered disruptions in major white matter tracks (corpus callosum, internal and external capsules, and deep cerebral white matter) spreading through the whole brain at P28. These abnormalities were mostly not present any longer at three months after TLE induction, with only limited abnormalities detectable in the external capsule and deep cerebral white matter. Relaxation Along a Fictitious Field in the rotating frame of rank 4 indicated that white matter changes observed at both timepoints, P28 and P72, are consistent with decreased myelin content. The animals affected by TLE-induced white matter abnormalities exhibited increased functional connectivity between the thalamus and medial prefrontal and somatosensory cortex in adulthood. Furthermore, histological analyses of additional animal groups at P15 and P18 showed only mild changes in white matter integrity, suggesting a gradual age-dependent impact of TLE progression. Taken together, TLE progression in the immature brain distorts white matter development with a peak around postnatal day 28, followed by substantial recovery in adulthood. This developmental delay might give rise to cognitive and behavioural comorbidities typical for early-onset TLE.

Elongated Internal Carotid Arteries in Patients with Severe Carotid Artery Stenosis.

This study aimed to investigate the risk factors and asymptomatic cerebrovascular diseases associated with elongated internal carotid arteries (ICAs) and the relationship between ICA elongation and severe carotid artery (CA) stenosis. We evaluated risk factors for stroke and magnetic resonance imaging (MRI) findings in patients with severe CA stenosis compared with people without neurological disorders who underwent brain screening (controls). On magnetic resonance angiography (MRA) images, we measured the longest distance, defined as the ICA distance, from the most distant anterior wall of the cervical ICA at the site of bending or kinking to the line between the origin of the external CA and the anterior protrusion of the ICA near the petrosal bone. We retrospectively compared various asymptomatic findings, including cerebral microbleeds, lacunar infarctions, and deep white matter hyperintensities (WMHs), between participants with an ICA distance ≥ 1.2 cm vs. < 1.2 cm. The prevalence of findings and stroke risk factors were compared using multivariate logistic regression models. We evaluated 53 patients (70.0 ± 8.1 years old, nine female) with severe CA stenosis treated by CA stenting and 400 controls (63.0 ± 9.2 years old, 227 females). Multivariate analyses showed that ICA distance ≥ 1.2 cm was associated with age ≥ 65 years (odds ratio (OR) = 1.8, p < 0.01), severe deep WMHs (OR = 2.0, p = 0.02), and severe CA stenosis (OR = 0.17, p < 0.01). ICA elongation, measured by ICA distance, was positively associated with age and deep WMHs and negatively associated with severe CA stenosis.

Brain Structural Signature of RFC1-Related Disorder.

The cerebellar ataxia, neuropathy, and vestibular areflexia syndrome was initially described in the early 1990s as a late-onset slowly progressive condition. Its underlying genetic cause was recently mapped to the RFC1 gene, and additional reports have expanded on the phenotypic manifestations related to RFC1, although little is known about the pattern and extent of structural brain abnormalities in this condition. The aim is to characterize the structural signature of brain damage in RFC1-related disorder, correlating the findings with clinical symptoms and normal brain RFC1 expression. We recruited 22 individuals with molecular confirmation of RFC1 expansions and submitted them to high-resolution 3T magnetic resonance imaging scans. We performed multimodal analyses to assess separately cerebral and cerebellar abnormalities within gray and white matter (WM). The results were compared with a group of 22 age- and sex-matched controls. The mean age and disease duration of patients were 62.8 and 10.9 years, respectively. Ataxia, sensory neuronopathy, and vestibular areflexia were the most frequent manifestations, but parkinsonism and pyramidal signs were also noticed. We found that RFC1-related disorder is characterized by widespread and relatively symmetric cerebellar and basal ganglia atrophy. There is brainstem volumetric reduction along all its segments. Cerebral WM is also involved-mostly the corpus callosum and deep tracts, but cerebral cortical damage is rather restricted. This study adds new relevant insights into the pathophysiological mechanisms of RFC1-related disorder. It should no longer be considered a purely cerebellar and sensory pathway disorder. Basal ganglia and deep cerebral WM are additional targets of damage. © 2021 International Parkinson and Movement Disorder Society.

Diving-related disorders in commercial breath-hold divers (Ama) of Japan.

Decompression illness (DCI) is well known in compressed-air diving but has been considered anecdotal in breath-hold divers. Nonetheless, reported cases and field studies of the Japanese Ama, commercial or professional breath-hold divers, support DCI as a clinical entity. Clinical characteristics of DCI in Ama divers mainly suggest neurological involvement, especially stroke-like cerebral events with sparing of the spinal cord. Female Ama divers achieving deep depths have rarely experienced a panic-like neurosis from anxiety disorders. Neuroradiological studies of Ama divers have shown symptomatic and/or asymptomatic ischaemic lesions situated in the basal ganglia, brainstem, and deep and superficial cerebral white matter, suggesting arterial insufficiency. The underlying mechanism(s) of brain damage in breath-hold diving remain to be elucidated; one of the plausible mechanisms is arterialization of venous nitrogen bubbles passing through right to left shunts in the heart or lungs. Although the treatment for DCI in Ama divers has not been specifically established, oxygen breathing should be given as soon as possible for injured divers. The strategy for prevention of diving-related disorders includes reducing extreme diving schedules, prolonging surface intervals and avoiding long periods of repetitive diving. This review discusses the clinical manifestations of diving-related disorders in Ama divers and the controversial mechanisms.

Current state of cerebral microangiopathy in hypertension

Hypertension is the main cause and the most important risk factor for both acute cerebrovascular accident and chronic progressive cerebrovascular insufficiency that is accompanied by severe neurological and mental disorders even to the extent of developing dementia. They are based on hypertension-induced pathology of the intracerebral arteries and cerebral microvasculature - cerebral microangiopathy that leads to small deep (lacunar) infarcts (SDIs) and diffuse cerebral white matter diseases. This review highlights the morphology, pathogenesis, clinical and neuroimaging diagnosis of hypertensive SDIs, and their differential diagnosis with atherosclerotic SDIs in the historical aspect. It is emphasized that the lacunar state of the brain in hypertension is a predictor of massive cerebral hemorrhages. Special attention is paid to current studies of the morphology and pathogenesis of diffuse changes in white matter and to the role of blood-brain barrier impermeability in the development of progressive leukoencephalopathy.

Women with Fragile X-associated Tremor/Ataxia Syndrome.

Fragile X-associated tremor and ataxia syndrome (FXTAS) is a late-onset neurodegenerative disorder linked to the FMR1 premutation. FXTAS in women is far less common than in men, and this study represents the largest sample reported to date. A total of 53 female premutation carriers with FXTAS (meanage, 66.83 years; FXTAS stages 2-5) and 55 age-matched and demographic background-matched control participants (meanage, 61.94 years) underwent a comprehensive molecular, physiological, neuropsychological, and psychiatric assessment. The large sample of female premutation carriers showed a wide range of variability of clinical signs and symptom progression. The imaging results showed a middle cerebellar peduncles sign in only 6 patients; another symptom included high-signal intensity in the splenium of the corpus callosum, and diffuse cerebral deep white matter changes (e.g., in the pons) are more common. The rate of psychiatric disorders, especially depression, is higher than in the general population. There is a clear impairment in executive functioning and fine motor skills in connection with a higher FXTAS stage. The manifestation of FXTAS symptoms in female carriers can be diverse with a milder phenotype and a lower penetrance than those observed in male premutation carriers. The middle cerebellar peduncles sign is present in only a small percentage of the sample, and we propose that the imaging criteria for FXTAS in women need to be expanded.

Association of enlarged perivascular spaces and anticoagulant-related intracranial hemorrhage.

ObjectiveTo investigate whether enlarged perivascular spaces (PVS) within the basal ganglia or deep cerebral white matter are risk factors for intracranial hemorrhage in patients taking oral anticoagulants (OACs), independent of established clinical and radiologic risk factors, we conducted a post hoc analysis of Clinical Relevance of Microbleeds in Stroke (CROMIS-2) (atrial fibrillation [AF]), a prospective inception cohort study.MethodsPatients with atrial fibrillation and recent TIA or ischemic stroke underwent standardized MRI prior to starting OAC. We rated basal ganglia PVS (BGPVS) and centrum semiovale PVS (CSOPVS), cerebral microbleeds (CMBs), white matter hyperintensities, and lacunes. We dichotomized the PVS rating using a threshold of >10 PVS in the relevant region of either cerebral hemisphere. The primary outcome was symptomatic intracranial hemorrhage (sICH). We identified risk factors for sICH using Cox regression.ResultsA total of 1,386 participants with available clinical and imaging variables were followed up for a mean of 2.34 years; 14 sICH occurred (11 intracerebral). In univariable analysis, diabetes, CMB presence, lacune presence, and >10 BGPVS, but not CSOPVS, were associated with sICH. In a multivariable model incorporating all variables with significant associations in univariable analysis, >10 BGPVS (hazard ratio [HR] 8.96, 95% [CI] 2.41–33.4, p = 0.001) and diabetes (HR 3.91, 95% CI 1.34–11.4) remained significant risk factors for sICH.ConclusionEnlarged BGPVS might be a novel risk factor for OAC-related ICH. The strength of this association and potential use in predicting ICH in clinical practice should be investigated in larger cohorts.

Effects of Collateral Status on Infarct Distribution Following Endovascular Therapy in Large Vessel Occlusion Stroke.

We aim to examine effects of collateral status and post-thrombectomy reperfusion on final infarct distribution and early functional outcome in patients with anterior circulation large vessel occlusion ischemic stroke. Patients with large vessel occlusion who underwent endovascular intervention were included in this study. All patients had baseline computed tomography angiography and follow-up magnetic resonance imaging. Collateral status was graded according to the criteria proposed by Miteff et al and reperfusion was assessed using the modified Thrombolysis in Cerebral Infarction (mTICI) system. We applied a multivariate voxel-wise general linear model to correlate the distribution of final infarction with collateral status and degree of reperfusion. Early favorable outcome was defined as a discharge modified Rankin Scale score ≤2. Of the 283 patients included, 129 (46%) had good, 97 (34%) had moderate, and 57 (20%) had poor collateral status. Successful reperfusion (mTICI 2b/3) was achieved in 206 (73%) patients. Poor collateral status was associated with infarction of middle cerebral artery border zones, whereas worse reperfusion (mTICI scores 0-2a) was associated with infarction of middle cerebral artery territory deep white matter tracts and the posterior limb of the internal capsule. In multivariate regression models, both mTICI (P<0.001) and collateral status (P<0.001) were among independent predictors of final infarct volumes. However, mTICI (P<0.001), but not collateral status (P=0.058), predicted favorable outcome at discharge. In this cohort of patients with large vessel occlusion stroke, both the collateral status and endovascular reperfusion were strongly associated with middle cerebral artery territory final infarct volumes. Our findings suggesting that baseline collateral status predominantly affected middle cerebral artery border zones infarction, whereas higher mTICI preserved deep white matter and internal capsule from infarction; may explain why reperfusion success-but not collateral status-was among the independent predictors of favorable outcome at discharge. Infarction of the lentiform nuclei was observed regardless of collateral status or reperfusion success.

Extracellular signal regulated kinases 1/2 signal pathway and responses of astrocytes after diffuse brain injury*

Abstract BACKGROUND The treatment of diffuse brain injury during an acute period is focused on relieving degrees of secondary brain injury. Generation and development of pathological changes of secondary brain injury depend on signal conduction, so down-regulating over response of astrocyte through interfering a key link of signal conduction pathway may bring a new thinking for the treatment of diffuse brain injury. OBJECTIVE To observe the effect of over activity of extracellular signal regulated kinases 1/2 (ERK1/2) signal pathway on the response of astrocyte during an acute period of diffuse brain injury. DESIGN Completely randomized grouping and controlled animal study. SETTINGS Department of Neurosurgery, the Third Affiliated Hospital, Nanchang University; Department of Neurosurgery, Union Hospital Affiliated to Tongji Medical College, Huazhong University of Science and Technology. MATERIALS A total of 158 healthy male SD rats, of 11 weeks old, weighing 320 – 370 g, were provided by Experimental Animal Faulty, Tongji Medical College, Huazhong University of Science and Technology. Rabbit-anti-phosphorylated ERK1/2 (pERK1/2) polyclonal antibody was provided by RD rabbit-anti-glial fibrillary acidic protein (GFAP) polyclonal antibody, SP immunohistochemical kit and horseradish peroxidase (HRP)-labeled goat-anti-rabbit IgG by Santa Cruz Company; specific inhibitor U0126 of ERK1/2 signal pathway by Alexis Company. METHODS The experiment was carried out in the Laboratory of Neurosurgery, Union Hospital Affiliated to Tongji Medical College, Huazhong University of Science and Technology from September 2004 to March 2006. (1) Detection of pERK1/2 expression; A total of 110 rats were randomly divided into sham operation group (n = 5), model group (n = 35), high-dosage U0126 group (n = 35) and low-dosage U0126 group (n = 35). Rats in the sham operation group were only treated with incision of epicranium and fixation of backup plate, but not hit. Rats in the model group were used to establish diffuse brain injury models based on Marmarou free falling body without drug intervention. Rats in the high- and low-dosage U0126 groups were injected into caudal vein with 0.1 and 0.05 mg/kg U0126, respectively, and then, rats were hit to establish injured models. Every 5 rats were collected from model, high- and low-dosage U0126 groups at 5, 30 minutes, 3, 12, 24, 72 hours and 7 days after diffuse brain injury to detect pERK1/2 expression in cortex of parietal lobe based on Western blot technique. (2) Distribution of pERK1/2 and positive GFAP cells in brain tissue; Another 48 rats were randomly divided into sham operation group (n = 3), model group (n = 5), high-dosage U0126 group (n = 15) and low-dosage U0126 group (n = 15). The intervention and administration were dealt as the same as those mentioned above. Every 3 rats were collected from model, high- and low-dosage U0126 groups at 30 minutes, 3, 12, 24 and 72 hours after model establishment to observe the distribution of pERK1/2 and positive GFAP cells in brain tissue which was cut from coronal section at Bregma – 4.8 mm layer with immunohistochemical staining. MAIN OUTCOME MEASURES pERK1/2 expression in cortex of parietal lobe and distribution of pFRK1/2 and positive GFAP cells in brain tissues. RESULTS (1) pERK1/2 expression: After diffuse brain injury, pERK1/2 expression in cortex of parietal lobe was rapidly increased in the model group, reached at peak at 5 minutes and then decreased gradually. But the expression was still in a high level until the 72nd hour and fallen to the basic level on the 7th day. pERK1/2 level was lower in high- and low-dosage U0126 groups than that in model group at various time points (P CONCLUSION Diffuse brain injury strongly induces the activity of ERK1/2 signal pathway and response of astrocyte; in addition, U0126 can inhibit response of glial cells during an acute period, and the effect manifests dosage dependence.