Cerebral White Matter Structures Research Articles

Adenosine A2A receptor availability in cerebral gray and white matter of patients with Parkinson's disease

ObjectiveAtrophic changes in cerebral gray matter of patients with PD have been reported extensively. There is evidence suggesting an association between cortical gyrification changes and white matter abnormalities. Adenosine A2A receptors have been shown to be upregulated in cerebral white matter and on reactive astrocytes in preclinical models of neurodegenerative diseases. We, therefore, sought to investigate in vivo changes in A2A receptor availability in cerebral gray and white matter of PD patients and its association with gray matter atrophy. MethodsEighteen patients with PD without dyskinesia and seven healthy controls were enrolled for this study. Brain MRI and dynamic PET scan was acquired with [11C]TMSX radioligand which binds selectively to A2A receptors. FreeSurfer software was used to segment cerebral gray and white matter structures. The resulting masks were used to calculate region specific volumes and to derive distribution volume ratios (DVRs), after co-registration with PET images, for the quantification of specific [11C]TMSX binding. ResultsWe showed an increase in A2A receptor availability in frontal (P < 0.001) and parietal (P < 0.001) white matter and a decrease in occipital (P = 0.02) gray matter of PD patients as compared to healthy controls. A decrease in gray matter volume ratios was observed in frontal (P < 0.01), parietal (P < 0.001), temporal (P < 0.01) and occipital (P < 0.01) ROIs in patients with PD versus healthy controls. ConclusionsOur results suggest a role of A2A receptor-based signaling in the neurodegenerative changes seen in the cerebral gray and white matter of patients with PD.

Investigation of the association between central arterial stiffness and aggregate g-ratio in cognitively unimpaired adults.

Stiffness of the large arteries has been shown to impact cerebral white matter (WM) microstructure in both younger and older adults. However, no study has yet demonstrated an association between arterial stiffness and aggregate g-ratio, a specific magnetic resonance imaging (MRI) measure of axonal myelination that is highly correlated with neuronal signal conduction speed. In a cohort of 38 well-documented cognitively unimpaired adults spanning a wide age range, we investigated the association between central arterial stiffness, measured using pulse wave velocity (PWV), and aggregate g-ratio, measured using our recent advanced quantitative MRI methodology, in several cerebral WM structures. After adjusting for age, sex, smoking status, and systolic blood pressure, our results indicate that higher PWV values, that is, elevated arterial stiffness, were associated with lower aggregate g-ratio values, that is, lower microstructural integrity of WM. Compared to other brain regions, these associations were stronger and highly significant in the splenium of the corpus callosum and the internal capsules, which have been consistently documented as very sensitive to elevated arterial stiffness. Moreover, our detailed analysis indicates that these associations were mainly driven by differences in myelination, measured using myelin volume fraction, rather than axonal density, measured using axonal volume fraction. Our findings suggest that arterial stiffness is associated with myelin degeneration, and encourages further longitudinal studies in larger study cohorts. Controlling arterial stiffness may represent a therapeutic target in maintaining the health of WM tissue in cerebral normative aging.

Physical Frailty and Brain White Matter Abnormalities: The Atherosclerosis Risk in Communities Study.

Physical frailty is associated with increased risk for dementia and other neurologic sequelae. However, the neurobiological changes underlying frailty and frailty risk remain unknown. We examined the association of cerebral white matter structure with current and future frailty. Atherosclerosis Risk in Communities Study Neurocognitive Study participants who underwent 3T brain MRI were included. Frailty status was classified according to the Fried criteria. Cerebral white matter integrity was defined using white matter hyperintensity (WMH) volume and microstructure, measured using diffusion tensor imaging fractional anisotropy (FA) and mean diffusivity (MD). Multivariable linear regression was used to relate baseline frailty to white matter structure; multivariable logistic regression was used to relate baseline white matter to frailty risk among participants nonfrail at baseline. In the cross-sectional analysis (N = 1 754; mean age: 76 years), frailty was associated with greater WMH volume, lower FA, and greater MD. These associations remained consistent after excluding participants with a history of stroke or dementia. Among participants nonfrail at baseline who completed follow-up frailty assessment (N = 1 379; 6.6-year follow-up period), each standard deviation increase in WMH volume was associated with 1.46 higher odds of frailty at follow-up. Composite FA and MD measures were not associated with future frailty; however, secondary analyses found several significant white matter tract-specific associations with frailty risk. The current study demonstrates a robust association of WMH volume with current and future frailty. Although measures of white matter microstructure were altered in frail individuals, these measures were not generally associated with progression from nonfrail to frail status.

Alterations in somatosensory, visual and auditory pathways in amyotrophic lateral sclerosis: an under-recognised facet of ALS.

While amyotrophic lateral sclerosis (ALS) is widely recognised as a multi-network disorder with extensive frontotemporal and cerebellar involvement, sensory dysfunction is relatively under evaluated. Subtle sensory deficits have been sporadically reported, but there is a prevailing notion that sensory pathways may be relatively spared in ALS. In a prospective neuroimaging study we have systematically evaluated cerebral grey and white matter structures involved in the processing, relaying and mediation of sensory information. Twenty two C9orf72 positive ALS patients (C9+ ALS), 138 C9orf72 negative ALS patients (C9- ALS) and 127 healthy controls were included. Widespread cortical alterations were observed in C9+ ALS including both primary and secondary somatosensory regions. In C9- ALS, cortical thickness reductions were observed in the postcentral gyrus. Thalamic nuclei relaying somatosensory information as well as the medial and lateral geniculate nuclei exhibited volume reductions. Diffusivity indices revealed posterior thalamic radiation pathology and a trend of left medial lemniscus degeneration was also observed in C9- ALS (p = 0.054). Our radiology data confirm the degeneration of somatosensory, visual and auditory pathways in ALS, which is more marked in GGGGCC hexanucleotide repeat expansion carriers. In contrast to the overwhelming focus on motor system degeneration and frontotemporal dysfunction in recent research studies, our findings confirm that sensory circuits are also affected in ALS. The involvement of somatosensory, auditory and visual pathways in ALS may have important clinical ramifications which are easily overlooked in the context of unremitting motor decline. Subtle sensory deficits may exacerbate mobility, contribute to fall risk, impair dexterity, and worsen bulbar dysfunction, therefore comprehensive sensory testing should also be performed as part of the clinical assessments in ALS.

White matter microstructure and volume correlates of premenstrual dysphoric disorder.

Background:Premenstrual dysphoric disorder (PMDD) is a mood disorder characterized by psychological and physical symptoms. Differences in white matter have been associated with affective and anxiety disorders, which share some symptoms with PMDD. However, whether white matter structure differs between the brains of individuals with PMDD and healthy controls is not known, nor is its relation to symptom severity.Methods:We performed tract-based spatial statistics and voxel-based morphometry analyses of diffusion tensor imaging metrics and white matter volume, using 2 neuroimaging data sets (n = 67 and n = 131) and a combined whole-brain and region-of-interest approach. We performed correlation analyses to investigate the relationship between regions with different white matter microstructure and volume and PMDD symptom severity.Results:We found greater fractional anisotropy in the left uncinate fasciculus (d = 0.69) in individuals with PMDD compared to controls. Moreover, the volume of the right uncinate fasciculus was higher in individuals with PMDD compared to controls (d = 0.40). As well, the severity of premenstrual depression was positively correlated with fractional anisotropy in the right superior longitudinal fasciculus (r = 0.35).Limitations:It is challenging to interpret group differences in diffusion tensor imaging metrics in terms of their underlying biophysical properties. The small size of the control group in the diffusion tensor imaging study may have prevented effects of interest from being detected.Conclusion:The findings of the present study provide evidence of differential cerebral white matter structure associated with PMDD and its symptoms.

Principal component analysis denoising improves sensitivity of MR diffusion to detect white matter injury in neuroHIV.

Diffusion-weighted imaging is able to capture important information about cerebral white matter (WM) structure. However, diffusion data can suffer from MRI and biological noise that degrades the quality of the images and makes finding important features difficult. We investigated how effectively local and nonlocal denoising increased the sensitivity to detect differences in cerebral WM in neuroHIV. We utilized principal component analysis (PCA) denoising to detect WM differences using fractional anisotropy. Local and nonlocal PCA denoising paradigms were implemented that varied in search area and number of components. We examined different-sized WM tracts that consistently show differences between people living with Human Immunodeficiency Virus (HIV) (PWH) and HIV-negative individuals (corpus callosum, forceps minor, and right uncinate fasciculus), and size-matched tracts not typically associated with HIV-related differences (spinothalamic, right medial lemniscus, and left occipitopontine). We first conducted a full sample comparison of WM differences between groups, and then randomly reduced the sample to the point where we still found differences in WM. Nonlocal PCA denoising allowed us to detect differences after a sample reduction of 35% in the forceps minor, 17% in the right uncinate fasciculus, and 6% in the corpus callosum. PCA denoising had a beneficial effect on detecting significant differences in PWH after sample size reduction. The smaller forceps minor tract and right uncinate fasciculus showed greater sensitivity to PCA denoising than the larger corpus callosum. These results show the importance of identifying the most effective PCA denoising strategy when investigating WM in PWH.

White matter imaging of ethanol-fixed rat brain by phase-contrast X-ray computed tomography.

Phase-contrast X-ray computed tomography imaging (PCI) based on crystal X-ray interferometry can detect minute density differences within biological soft tissues without contrast agents. Ethanol fixation yields increased tissue-background density differences due to the dehydrating and delipidifying effects of ethanol. To obtain high image contrast of cerebral white matter structures in PCI, tissue fixation using ethanol and routinely used formalin have been examined. Ethanol-fixed (EF) (n = 4) and formalin-fixed (FF) (n = 4) rat brains were imaged by crystal X-ray interferometry-based PCI. Tissue staining/microscopy was also performed for histological comparison and myelin density evaluation. Three-dimensional white matter tract images were reconstructed. Superior image contrast was obtained in the images of EF brains (EF images) compared to those of formalin-fixed brains (FF images), particularly for white matter structures. Significant density differences between the white matter structures and hippocampus (P < 0.01)/thalamus (P < 0.001) were observed in the EF, but not FF, images. Ethanol fixation enhanced the image contrast of white matter tracts by approximately sixfold compared to formalin fixation, and close agreement (r2 = 0.97; P < 0.05) between the density values on the CT images and the myelin density values in histological images was observed for the EF brains. Three-dimensional reconstruction of the white matter tracts was possible from the EF images, but not FF images. Ethanol fixation resulted in marked contrast enhancement of cerebral white matter structures in PCI. Thus, high-resolution PCI using ethanol for tissue fixation could be valuable for experimental neurological studies and postmortem neuropathology evaluation.

Strucutural brain imaging at the onset of schizophrenia:What have we learned and what have we missed

Over the past 50 years, the application of structural neuroimaging techniques to schizophrenia research has added relevant information about the pathophysiology of the disorder. Several lines of investigation gave strong evidence that schizophrenia is associated with multiple subtle brain abnormalities that involve both cerebral grey and white matter volumes and structure. The time of onset and longitudinal course of brain morphological abnormalities support the notion that brain pathology of schizophrenia has a neurodevelopmental component and a progressive course, although several confounders of brain changes should be carefully taken into account. Brain anomalies detected before and close to the onset of schizophrenia are likely to be unrelated to confounders of brain changes such as antipsychotic drug treatment, duration of illness or illicit substance abuse, i.e. they related to the pathological process of the disorder per se. Nonetheless, clinically useful diagnostic or prognostic biomarkers have not derived from neuroimaging studies and this is likely related to the neurobiological heterogeneity of the disorder. Thus, there is the compelling need to set new methodological standards for developing innovative hypothesis-driven studies to overcome what we have missed to date in neuroimaging research in schizophrenia.

Sleep deprivation impairs molecular clearance from the human brain.

It remains an enigma why human beings spend one-third of their life asleep. Experimental data suggest that sleep is required for clearance of waste products from brain metabolism. This has, however, never been verified in humans. The primary aim of the present study was to examine in vivo whether one night of total sleep deprivation affects molecular clearance from the human brain. Secondarily, we examined whether clearance was affected by subsequent sleep. Multiphase MRI with standardized T1 sequences was performed up to 48 h after intrathecal administration of the contrast agent gadobutrol (0.5 ml of 1 mmol/ml), which served as a tracer molecule. Using FreeSurfer software, we quantified tracer enrichment within 85 brain regions as percentage change from baseline of normalized T1 signals. The cerebral tracer enrichment was compared between two cohorts of individuals; one cohort (n = 7) underwent total sleep deprivation from Day 1 to Day 2 (sleep deprivation group) while an age and gender-matched control group (n = 17; sleep group) was allowed free sleep from Day 1 to Day 2. From Day 2 to 3 all individuals were allowed free sleep. The tracer enriched the brains of the two groups similarly. Sleep deprivation was the sole intervention. One night of sleep deprivation impaired clearance of the tracer substance from most brain regions, including the cerebral cortex, white matter and limbic structures, as demonstrated on the morning of Day 2 after intervention (sleep deprivation/sleep). Moreover, the impaired cerebral clearance in the sleep deprivation group was not compensated by subsequent sleep from Day 2 to 3. The present results provide in vivo evidence that one night of total sleep deprivation impairs molecular clearance from the human brain, and that humans do not catch up on lost sleep.

Developmental abnormalities of the brain exposed to childhood maltreatment detected by diffusion tensor imaging

ABSTRACTObjective: This study aimed to investigate brain developmental alterations in individuals exposed to childhood maltreatment (CM) with dissociative experiences and motor coordination symptoms using diffusion tensor imaging on a 3Tesla (3T) magnetic resonance (MR) system.Methods: Five individuals exposed to CM who manifest behavioral and developmental problems with dissociative experiences and motor coordination symptoms (age range: 14–18 years; all female), as well as seven age- and gender-matched normal control individuals, participated in the study using a 3T MR system. Diffusion characteristics, as indexed by fractional anisotropy (FA), were assessed for cerebral white matter structures. A preliminary whole brain analysis was performed complementary to an anatomically guided region of interest (ROI) analysis.Results: In individuals exposed to CM, scattered decreases in FA were detected in multiple brain regions over the frontoparietal and temporal areas in the whole brain map. ROI analysis subsequently identified significant decreases in FA (p < 0.05) in the right parietal white matter area as well as in the right prefrontal, bilateral premotor, bilateral orbitofrontal, and temporal white matter areas in CM-exposed individuals compared to that in controls.Conclusion: The observed altered diffusion characteristics indicate attendant developmental abnormalities within the white matter structures, which are associated with the observed clinical and behavioral patterns including dissociative experiences and coordination symptoms in individuals exposed to CM. The study provides objective evidence regarding the effects of CM on brain microstructure.

Diffusion Tensor Imaging Evaluation of Neural Network Development in Patients Undergoing Therapeutic Repetitive Transcranial Magnetic Stimulation following Stroke.

We aimed to investigate plastic changes in cerebral white matter structures using diffusion tensor imaging following a 15-day stroke rehabilitation program. We compared the detection of cerebral plasticity between generalized fractional anisotropy (GFA), a novel tool for investigating white matter structures, and fractional anisotropy (FA). Low-frequency repetitive transcranial magnetic stimulation (LF-rTMS) of 2400 pulses applied to the nonlesional hemisphere and 240 min intensive occupation therapy (OT) daily over 15 days. Motor function was evaluated using the Fugl-Meyer assessment (FMA) and Wolf Motor Function Test (WMFT). Patients underwent diffusion tensor magnetic resonance imaging (MRI) on admission and discharge, from which bilateral FA and GFA values in Brodmann area (BA) 4 and BA6 were calculated. Motor function improved following treatment (p < 0.001). Treatment increased GFA values for both the lesioned and nonlesioned BA4 (p < 0.05, p < 0.001, resp.). Changes in GFA value for BA4 of the lesioned hemisphere were significantly inversely correlated with changes in WMFT scores (R2 = 0.363, p < 0.05). Our findings indicate that the GFA may have a potentially more useful ability than FA to detect changes in white matter structures in areas of fiber intersection for any such future investigations.

Cerebral white matter structure is disrupted in Gulf War Veterans with chronic musculoskeletal pain.

Chronic musculoskeletal pain (CMP) affects ∼25% of the 700,000 Veterans deployed during the Persian Gulf War (1990-1991). The cause of their pain is unknown, and there are no efficacious treatments. A small body of literature suggests that brain abnormalities exist in Gulf War Veterans (GVs), yet relationships between brain abnormalities and disease symptoms remain largely unexplored. Our purpose was to compare white matter (WM) integrity between GVCMP and matched, healthy Veteran controls (GVCO) and investigate relationships between cerebral WM integrity and symptoms. Thirty GVCMP and 31 controls completed magnetic resonance imaging with diffusion tensor imaging. Tract-based spatial statistics estimated WM fractional anisotropy, mean diffusivity, radial diffusivity, and axial diffusivity over the whole brain (P < 0.05) and were corrected using threshold-free cluster enhancement. GVCMP had greater pain symptoms and mood disturbance and lower quality of life and physical function compared with GVCO (P < 0.05). GVCMP had lower WM integrity across several brain regions implicated in chronic pain (P < 0.05) including the middle and inferior frontal gyrus, corpus callosum, corona radiata, precentral gyrus, external capsule, and posterior thalamic radiation. For GVCMP, WM integrity was associated with pain and mood symptoms in widespread brain areas that were found to be different between groups (P < 0.05). Results indicate widespread WM microstructure disruption across brain regions implicated in pain processing and modulation in chronic pain. The observed relationships between WM microstructure and symptoms encourage the testing of treatments designed to improve the brain health of affected Veterans.

Alterations of cerebral white matter structure in psychosis and their clinical correlations: a systematic review of Diffusion Tensor Imaging studies.

Schizophrenia is a common, severe and chronically disabling mental illness. Most of MRI studies in schizophrenia suggest the involvement of white matter (WM) pathology in multiple cerebral regions in the neurobiology of this condition. White matter fiber tracts connecting numerous cortical regions have been the focus of a number of studies using a magnetic resonance technique called “Diffusion Tensor Imaging” (DTI). A literature search of published DTI studies was conducted using the major database National Centre for Biotechnology information (NCBI) PubMed (MEDLINE). Our review covers 95 published papers. We summarise the main DTI findings involving the different brain regions in patients affected by or at high-risk for psychosis; we discuss clinical implications of these white matter disruptions and the limitations of current studies, listing the potential confounds and suggesting potential future research directions.

The association of cognitive impairment with gray matter atrophy and cortical lesion load in clinically isolated syndrome

BackgroundMultiple sclerosis can impair cognition from the early stages and has been shown to be associated with gray matter damage in addition to white matter pathology. ObjectivesTo investigate the profile of cognitive impairment in clinically isolated syndrome (CIS), and the contribution of cortical inflammation, cortical and deep gray matter atrophy, and white matter lesions to cognitive decline. MethodsThirty patients with clinically isolated syndrome and twenty demographically- matched healthy controls underwent neuropsychologic assessment through the Rao Brief Repeatable Battery, and brain magnetic resonance imaging with double inversion recovery using a 3T scanner. ResultsPatients with clinically isolated syndrome performed significantly worse than healthy controls on tests that evaluated verbal memory, visuospatial learning and memory, and verbal fluency. Significant deep gray matter atrophy was found in the patients but cortical volume was not lower than the controls. Visual memory tests correlated with the volume of the hippocampus, cerebral white matter and deep gray matter structures and with cerebellar cortical atrophy. Cortical or white matter lesion load did not affect cognitive test results. ConclusionIn our patients with CIS, it was shown that cognitive impairment was mainly related to cerebral white matter, cerebellar cortical and deep gray matter atrophy, but not with cortical inflammation, at least in the early stage of disease.

Cerebral white matter structure is associated with DSM-5 schizophrenia symptom dimensions.

Diffusion tensor imaging (DTI) studies have provided evidence of widespread white matter (WM) abnormalities in schizophrenia. Although these abnormalities appear clinically significant, the relationship to specific clinical symptoms is limited and heterogeneous. This study examined the association between WM microstructure and the severity of the five main DSM-5 schizophrenia symptom dimensions. DTI was measured in forty patients with schizophrenia spectrum disorders. Using Tract-Based Spatial Statistics controlling for age, gender and antipsychotic dosage, our analyses revealed significant negative relationships between WM microstructure and two DSM-5 symptom dimensions: Whereas abnormal psychomotor behavior was particularly related to WM of motor tracts, negative symptoms were associated with WM microstructure of the prefrontal and right temporal lobes. However, we found no associations between WM microstructure and delusions, hallucinations or disorganized speech. These data highlight the relevance of characteristic WM disconnectivity patterns as markers for negative symptoms and abnormal psychomotor behavior in schizophrenia and provide evidence for relevant associations between brain structure and aberrant behavior.

White matter structure alterations in HIV-1-infected men with sustained suppression of viraemia on treatment.

Cognitive impairment is highly prevalent in HIV-1-infected (HIV+) patients, despite adequate suppression of viral replication by combination antiretroviral therapy (cART). Cerebral white matter structure alterations are often associated with cognitive impairment and have commonly been reported in the natural course of HIV infection. However, the existence of these alterations in adequately treated HIV+ patients remains unknown, as well as its possible association with cognitive impairment. We used diffusion tensor imaging (DTI) to investigate whether white matter structure alterations exist in HIV+ patients with sustained suppressed viral replication on cART, and if such alterations are related to HIV-associated cognitive deficits. We compared 100 aviraemic HIV+ men on cART with 70 HIV-uninfected, otherwise comparable men. Clinical and neuropsychological assessments were performed. From DTI data, white matter fractional anisotropy and mean diffusion were calculated. Subsequently, tract-based spatial statistics (TBSS) was performed, with and without masking out white matter lesions. HIV+ patients showed diffuse white matter structure alterations as compared with HIV-uninfected controls, observed as widespread decreased fractional anisotropy and an increased mean diffusion. These white matter structure alterations were associated with the number of years spent with a CD4 cell count below 500 cells/μl, but not with HIV-associated cognitive deficits. Cerebral white matter structure alterations are found in middle-aged HIV+ men with sustained suppression of viraemia on cART, and may result from periods with immune deficiency when viral toxicity and host-inflammatory responses were at their peak. These white matter structure alterations were not associated with the observed subtle HIV-associated cognitive deficits. .

Analysis of YFP(J16)-R6/2 reporter mice and postmortem brains reveals early pathology and increased vulnerability of callosal axons in Huntington's disease.

Cumulative evidence indicates that the onset and severity of Huntington's disease (HD) symptoms correlate with connectivity deficits involving specific neuronal populations within cortical and basal ganglia circuits. Brain imaging studies and pathological reports further associated these deficits with alterations in cerebral white matter structure and axonal pathology. However, whether axonopathy represents an early pathogenic event or an epiphenomenon in HD remains unknown, nor is clear the identity of specific neuronal populations affected. To directly evaluate early axonal abnormalities in the context of HD in vivo, we bred transgenic YFP(J16) with R6/2 mice, a widely used HD model. Diffusion tensor imaging and fluorescence microscopy studies revealed a marked degeneration of callosal axons long before the onset of motor symptoms. Accordingly, a significant fraction of YFP-positive cortical neurons in YFP(J16) mice cortex were identified as callosal projection neurons. Callosal axon pathology progressively worsened with age and was influenced by polyglutamine tract length in mutant huntingtin (mhtt). Degenerating axons were dissociated from microscopically visible mhtt aggregates and did not result from loss of cortical neurons. Interestingly, other axonal populations were mildly or not affected, suggesting differential vulnerability to mhtt toxicity. Validating these results, increased vulnerability of callosal axons was documented in the brains of HD patients. Observations here provide a structural basis for the alterations in cerebral white matter structure widely reported in HD patients. Collectively, our data demonstrate a dying-back pattern of degeneration for cortical projection neurons affected in HD, suggesting that axons represent an early and potentially critical target for mhtt toxicity.

Regional Brain Morphometric Characteristics of Nonsyndromic Cleft Lip and Palate

Nonsyndromic cleft lip and palate (NSCLP) encompasses a group of orofacial abnormalities. Emerging evidence has revealed the presence of structural brain abnormalities in affected individuals. Previous studies have performed structure-based volumetric analysis of the brain assessing gross lobular subdivisions of the cerebral cortex and white matter which may have only vague relationships to the functional subregions implicated in behavioral and cognitive deficits observed in NSCLP patients. High-resolution magnetic resonance imaging structural data were acquired to provide a detailed characterization of the brain with respect to both regional cortical volume and thickness in 26 children with NSCLP and 26 age- and demographically matched typically developing children. Children with NSCLP exhibited abnormally large cerebral cortex grey matter volumes with decreased volumes of subcortical grey matter and cerebral white matter structures. Hemisphere-specific patterns of cortical volume and thickness abnormalities were identified. This study is the first to examine cortical thickness abnormalities in NSCLP. Overall, these findings suggest that the brains of children with NSCLP are less mature than those of their age-matched peers. Gender-specific comparisons reveal that NSCLP females were more immature compared to their typically developing peers compared to NSCLP males.

Autoradiographic evidence for the transmeningeal diffusion of muscimol into the neocortex in rats

Electrophysiological and behavioral studies have demonstrated that muscimol administered through the cranial meninges can prevent focal neocortical seizures. It was proposed that transmeningeal muscimol delivery can be used for the treatment of intractable focal neocortical epilepsy. However, it has not been proved that muscimol administered via the transmeningeal route can penetrate into the neocortex. The purpose of the present study was to solve this problem by using combined autoradiography–histology methods. Four rats were implanted with epidural cups over the parietal cortices. A 50μL mixture of [3H] muscimol and unlabeled muscimol with a final concentration of 1.0mM was delivered through each cup on the dura mater. After a 1-hour exposure, the muscimol solution was removed and replaced with formalin to trap the transmeningeally diffused molecules. Then the whole brain was fixed transcardially, sectioned, with the sections subjected to autoradiography and thionine counterstaining. Results showed that (1) [3H] muscimol diffused through the meninges into the cortical tissue underlying the epidural cup in all rats. (2) [3H] muscimol-related autoradiography grains were distributed in all six neocortical layers. (3) [3H] muscimol-related autoradiography grains were localized to the cortical area underneath the epidural delivery site and were absent in the cerebral cortical white matter and other brain structures. This study provided evidence that muscimol can be delivered via the transmeningeal route into the neocortical tissue in a spatially controlled manner. The finding further supports the rationale of using transmeningeal muscimol for the treatment of intractable focal neocortical epilepsy.

Impact of apolipoprotein E ε4 and HIV on cognition and brain atrophy: antagonistic pleiotropy and premature brain aging.

The apolipoprotein E (APOE) ε4 allele may accelerate the progression of HIV disease, and increase the risk for developing HIV-associated neurocognitive disorder (HAND). Whether APOEε4 allele(s) and age may influence brain atrophy in HIV patients is unknown and was evaluated. Automated morphometry on magnetic resonance images, using FreeSurfer analyses, neuropsychological testing and APOE genotyping were performed in 139 subjects [70 seronegative controls (SN); 69 clinically-stable HIV subjects]. Compared to SN, HIV subjects had smaller volumes throughout the brain regardless of their HAND status. Compared to APOEε4- subjects, SN controls with APOEε4 had better memory and larger global brain volumes (cerebral white matter and cortex) while HIV subjects with the APOEε4 allele(s) had poorer cognition (verbal fluency, learning, executive function and memory) and smaller cerebral and cerebellar white matter and subcortical structures. Further stratification of age showed that younger (<50 years) APOEε4+SN subjects had larger putamen and cerebral white matter, while younger APOEε4+HIV subjects had poorer performance on verbal fluency and smaller brain volumes [3-way (HIV-status×APOEε4×Age) interaction-p-values=0.005 to 0.03]. These findings suggest that APOEε4 allele(s) may show antagonistic pleiotropy on cognition and brain atrophy in SN controls, but may lead to premature aging with neurodegeneration in younger HIV patients prior to the development of HAND. Potential mechanisms for such interactions may include stronger neuro-inflammation or greater amyloid deposition in younger HIV subjects with APOEε4 allele(s). Early screening for the APOEε4 allele and brain atrophy with morphometry may guide neuroprotective intervention of cognitively normal HIV subjects prior to the development of HAND. Longitudinal follow-up studies and larger sample sizes are needed to validate these cross-sectional results.