Early-stage volume losses in the corpus callosum and thalamus predict the progression of brain atrophy in patients with multiple sclerosis.

BACKGROUND: A method that can be used in the early stage of multiple sclerosis (MS) to predict the progression of brain volume loss (BVL) has not been fully established. METHODS: To develop a method of predicting progressive BVL in patients with MS (pwMS), eighty-two consecutive Japanese pwMS-with either relapsing-remitting MS (86%) or secondary progressive MS (14%)-and 41 healthy controls were included in this longitudinal retrospective analysis over an observational period of approximately 3.5 years. Using a hierarchical cluster analysis with multivariate imaging data obtained by FreeSurfer analysis, we classified the pwMS into clusters. RESULTS: At baseline and follow-up, pwMS were cross-sectionally classified into three major clusters (Clusters 1, 2, and 3) in ascending order by disability and BVL. Among the patients included in Cluster 1 at baseline, approximately one-third of patients (12/52) transitioned into Cluster 2 at follow-up. The volumes of the corpus callosum, the thalamus, and the whole brain excluding the ventricles were significantly decreased in the transition group compared with the nontransition group and were found to be the most important predictors of transition. CONCLUSION: Decreased volumes of the corpus callosum and thalamus in the relatively early stage of MS may predict the development of BVL.

Impact of chronic exposure to legacy environmental contaminants on the corpus callosum microstructure: A diffusion MRI study of Inuit adolescents.

Exposure to environmental contaminants is an important public health concern for the Inuit population of northern Québec, who have been exposed to mercury (Hg), polychlorinated biphenyls (PCBs) and lead (Pb). During the last 25 years, the Nunavik Child Development Study (NCDS) birth cohort has reported adverse associations between these exposures and brain function outcomes. In the current study, we aimed to determine whether contaminant exposure is associated with alterations of the corpus callosum (CC), which plays an important role in various cognitive, motor and sensory function processes. Magnetic resonance imaging (MRI) was administered to 89 NCDS participants (mean age ± SD = 18.4 ± 1.2). Diffusion-weighted imaging was assessed to characterize the microstructure of the CC white matter in 7 structurally and functionally distinct regions of interest (ROIs) using a tractography-based segmentation approach. The following metrics were computed: fiber tract density, fractional anisotropy (FA), axial diffusivity (AD) and radial diffusivity (RD). Multiple linear regression models adjusted for sex, age, current alcohol/drug use and fish nutrients (omega-3 fatty acids and selenium) were conducted to assess the association between diffusion-weighted imaging metrics and Hg, PCB 153 and Pb concentrations obtained at birth in the cord blood and postnatally (mean values from blood samples at 11 and 18 years of age). Exposures were not associated with fiber tract density. Nor were significant associations found with cord and postnatal blood Pb concentrations for FA. However, pre- and postnatal Hg and PCB concentrations were significantly associated with higher FA of several regions of the CC, namely anterior midbody, posterior midbody, isthmus, and splenium, with the most pronounced effects observed in the splenium. FA results were mainly associated with lower RD. This study shows that exposure to Hg and PCB 153 alters the posterior microstructure of the CC, providing neuroimaging evidence of how developmental exposure to environmental chemicals can impair brain function and behavior in late adolescence.

Susceptibility of subregions of prefrontal cortex and corpus callosum to damage by high-dose oxytocin-induced labor in male neonatal mice.

Induction and augmentation of labor is one of the most common obstetrical interventions. However, this intervention is not free of risks and could cause adverse events, such as hyperactive uterine contraction, uterine rupture, and amniotic-fluid embolism. Our previous study using a new animal model showed that labor induced with high-dose oxytocin (OXT) in pregnant mice resulted in massive cell death in selective brain regions, specifically in male offspring. The affected brain regions included the prefrontal cortex (PFC), but a detailed study in the PFC subregions has not been performed. In this study, we induced labor in mice using high-dose OXT and investigated neonatal brain damage in detail in the PFC using light and electron microscopy. We found that TUNEL-positive or pyknotic nuclei and Iba-1-positive microglial cells were detected more abundantly in infralimbic (IL) and prelimbic (PL) cortex of the ventromedial PFC (vmPFC) in male pups delivered by OXT-induced labor than in the control male pups. These Iba-1-positive microglial cells were engulfing dying cells. Additionally, we also noticed that in the forceps minor (FMI) of the corpus callosum (CC), the number of TUNEL-positive or pyknotic nuclei and Iba-1-positive microglial cells were largely increased and Iba-1-positive microglial cells phagocytosed massive dying cells in male pups delivered by high-dose OXT-induced labor. In conclusion, IL and PL of the vmPFC and FMI of the CC, were susceptible to brain damage in male neonates after high-dose OXT-induced labor.

Chromatin remodeler Arid1a regulates subplate neuron identity and wiring of cortical connectivity.

Loss-of-function mutations in chromatin remodeler gene ARID1A are a cause of Coffin-Siris syndrome, a developmental disorder characterized by dysgenesis of corpus callosum. Here, we characterize Arid1a function during cortical development and find unexpectedly selective roles for Arid1a in subplate neurons (SPNs). SPNs, strategically positioned at the interface of cortical gray and white matter, orchestrate multiple developmental processes indispensable for neural circuit wiring. We find that pancortical deletion of Arid1a leads to extensive mistargeting of intracortical axons and agenesis of corpus callosum. Sparse Arid1a deletion, however, does not autonomously misroute callosal axons, implicating noncell-autonomous Arid1a functions in axon guidance. Supporting this possibility, the ascending axons of thalamocortical neurons, which are not autonomously affected by cortical Arid1a deletion, are also disrupted in their pathfinding into cortex and innervation of whisker barrels. Coincident with these miswiring phenotypes, which are reminiscent of subplate ablation, we unbiasedly find a selective loss of SPN gene expression following Arid1a deletion. In addition, multiple characteristics of SPNs crucial to their wiring functions, including subplate organization, subplate axon-thalamocortical axon cofasciculation ("handshake"), and extracellular matrix, are severely disrupted. To empirically test Arid1a sufficiency in subplate, we generate a cortical plate deletion of Arid1a that spares SPNs. In this model, subplate Arid1a expression is sufficient for subplate organization, subplate axon-thalamocortical axon cofasciculation, and subplate extracellular matrix. Consistent with these wiring functions, subplate Arid1a sufficiently enables normal callosum formation, thalamocortical axon targeting, and whisker barrel development. Thus, Arid1a is a multifunctional regulator of subplate-dependent guidance mechanisms essential to cortical circuit wiring.

Diffuse white matter loss in a transgenic rat model of cerebral amyloid angiopathy.

Diffuse white matter (WM) disease is highly prevalent in elderly with cerebral small vessel disease (cSVD). In humans, cSVD such as cerebral amyloid angiopathy (CAA) often coexists with Alzheimer's disease imposing a significant impediment for characterizing their distinct effects on WM. Here we studied the burden of age-related CAA pathology on WM disease in a novel transgenic rat model of CAA type 1 (rTg-DI). A cohort of rTg-DI and wild-type rats was scanned longitudinally using MRI for characterization of morphometry, cerebral microbleeds (CMB) and WM integrity. In rTg-DI rats, a distinct pattern of WM loss was observed at 9 M and 11 M. MRI also revealed manifestation of small CMB in thalamus at 6 M, which preceded WM loss and progressively enlarged until the moribund disease stage. Histology revealed myelin loss in the corpus callosum and thalamic CMB in all rTg-DI rats, the latter of which manifested in close proximity to occluded and calcified microvessels. The quantitation of CAA load in rTg-DI rats revealed that the most extensive microvascular Aß deposition occurred in the thalamus. For the first time using in vivo MRI, we show that CAA type 1 pathology alone is associated with a distinct pattern of WM loss.

Rare case of Marchiafava-Bignami disease due to thiamine deficiency and malnutrition.

Marchiafava-Bignami disease (MBD) is a rare, toxic demyelinating disorder of the central nervous system associated with chronic alcoholism and malnutrition. The clinical presentation is varied and non-specific, including symptoms of acute dementia, impaired consciousness, dysarthria, hemiparesis, pyramidal tract signs, seizure activity, ataxia and signs of interhemispheric disconnection. The differential diagnosis of MBD may include Wernicke's encephalopathy, multiple sclerosis, encephalitis, infectious or paraneoplastic leucoencephalopathy, infarction, Alzheimer's disease, multi-infarct dementia and frontotemporal lobar degeneration (Pick) disease. The diagnosis of MBD is dependent on MRI findings of hyperintensity of the corpus callosum on T2 and fluid-attenuated inversion recovery T2 sequences, with or without extracallosal lesions. The use of MRI in diagnosis has allowed for early initiation of treatment with parenteral thiamine, and improved the prognosis of MBD from frequently fatal to a mortality of less than 8%. Administration of thiamine within 14 days of symptom onset has demonstrated statistically better outcomes over delayed treatment. We present a case report of MBD diagnosed in a 72-year-old woman who presented with ataxia and slurred speech, in an effort to highlight the importance of obtaining MRI in patients presenting with behavioural disturbance and neurological findings, as well as discuss the relationship between thiamine supplementation and demyelinating diseases in the central nervous system.

Isolated involvement of corpus callosum in metronidazole-induced encephalopathy with concomitant peripheral neuropathy: A case report.

RATIONALE: Metronidazole is widely used for treating infection of anaerobic bacteria and protozoa. Metronidazole is generally well tolerated, although metronidazole-associated peripheral neuropathy (PN) and metronidazole-induced encephalopathy (MIE) have been reported as rare side effects. The most common sites of MIE involve the bilateral dentate nucleus of the cerebellum. Herein, we present a rare case of MIE with isolated corpus callosum involvement, with concomitant metronidazole-associated PN. PATIENT CONCERNS: A middle-aged man with ulcerative colitis was diagnosed with amoebic dysentery because of unhygienic eating. After receiving metronidazole (1.8 g/d, cumulative dose 61.2 g) for >1 month, he started to complain of continuous paresthesia of the limbs, and intermittent speech problems. Magnetic resonance imaging demonstrated an isolated lesion in the splenium of the corpus callosum. DIAGNOSIS: A diagnosis of reversible splenial lesion syndrome and PN was made. Given the patient's medical history, MIE and metronidazole-associated PN were considered. INTERVENTIONS: Metronidazole was stopped. Mecobalamine and vitamin B1 were used for adjuvant treatment. OUTCOMES: At 1.5 months after stopping metronidazole, his symptoms of numbness and hyperesthesia had not improved, although he felt less ill. The isolated lesion disappeared on follow-up magnetic resonance imaging. At 6 months later, the hyperesthesia symptoms remained, and he was unable to resume his previous work. CONCLUSIONS: Physicians should consider MIE in their differentials for reversible splenial lesion syndrome when encountering a patient with a history of metronidazole medication and symptoms of encephalopathy, especially with concomitant PN. Early identification of this metronidazole-related complication and early cessation of the drug are essential for treatment.

Understanding the impact of bilateral brain injury in children with unilateral cerebral palsy.

The presence of bilateral brain injury in patients with unilateral cerebral palsy (CP) may impact neuroplasticity in the ipsilateral hemisphere; however, this pattern of injury is typically under-analyzed due to the lack of methods robust to severe injury. In this study, injury-robust methods have been applied to structural brain magnetic resonance imaging (MRI) data of a cohort of 91 children with unilateral CP (37 with unilateral and 54 with bilateral brain injury, 4-17 years) and 44 typically developing controls (5-17 years), to determine how brain structure is associated with concurrent motor function, and if these associations differ between patients with unilateral or bilateral injury. Regression models were used to associate these measures with two clinical scores of hand function, with patient age, gender, brain injury laterality, and interaction effects included. Significant associations with brain structure and motor function were observed (Pearson's r = .494-.716), implicating several regions of the motor pathway, and demonstrating an accurate prediction of hand function from MRI, regardless of the extent of brain injury. Reduced brain volumes were observed in patients with bilateral injury, including volumes of the thalamus and corpus callosum splenium, compared to those with unilateral injury, and the healthy controls. Increases in cortical thickness in several cortical regions were observed in cohorts with unilateral and bilateral injury compared to controls, potentially suggesting neuroplasticity might be occurring in the inferior frontal gyrus and the precuneus. These findings identify prospective useful target regions for transcranial magnetic stimulation intervention.

Pathogenic variants in NUBPL result in failure to assemble the matrix arm of complex I and cause a complex leukoencephalopathy with thalamic involvement.

Disorders of the white matter are genetically very heterogeneous including several genes involved in mitochondrial bioenergetics. Diagnosis of the underlying cause is aided by pattern recognition on neuroimaging and by next-generation sequencing. Recently, genetic changes in the complex I assembly factor NUBPL have been characterized by a consistent recognizable pattern of leukoencephalopathy affecting deep white matter including the corpus callosum and cerebellum. Here, we report twin boys with biallelic variants in NUBPL, an unreported c.351 G > A; p.(Met117Ile) and a previously reported pathological variant c. 693 + 1 G > A. Brain magnetic resonance imaging showed abnormal T2 hyperintense signal involving the periventricular white matter, external capsule, corpus callosum, and, prominently, the bilateral thalami. The neuroimaging pattern evolved over 18 months with marked diffuse white matter signal abnormality, volume loss, and new areas of signal abnormality in the cerebellar folia and vermis. Magnetic resonance spectroscopy showed elevated lactate. Functional studies in cultured fibroblasts confirmed pathogenicity of the genetic variants. Complex I activity of the respiratory chain was deficient spectrophotometrically and on blue native gel with in-gel activity staining. There was absent assembly and loss of proteins of the matrix arm of complex I when traced with an antibody to NDUFS2, and incomplete assembly of the membrane arm when traced with an NDUFB6 antibody. There was decreased NUBPL protein on Western blot in patient fibroblasts compared to controls. Compromised NUBPL activity impairs assembly of the matrix arm of complex I and produces a severe, rapidly-progressive leukoencephalopathy with thalamic involvement on MRI, further expanding the neuroimaging phenotype.

Brain structure in children with congenital visual disorders and visual impairment.

AIM: To examine if congenital visual impairment is associated with differences in brain anatomy in children. METHOD: Ten children (8-12y) with congenital disorders of the peripheral visual system with severe visual impairment (SVI; >0.8 logMAR) or mild-to-moderate visual impairment (MVI; 0.6-0.8 logMAR) were compared to 21 typically sighted comparison (TSC) children. Thalamus volume, grey matter density, white matter microstructure, and integrity of visual tracts were investigated in SVI, MVI, and TSC groups with anatomical and diffusion-weighted magnetic resonance imaging. RESULTS: Compared to the TSC group, the SVI group had lower white matter integrity in tracts of the visual system (optic radiations: SVI 0.35±0.015, TSC 0.39±0.007 [p=0.022]; posterior corpus callosum: SVI 0.37±0.019; TSC 0.42±0.009 [p=0.033]) and lower left thalamus volume (SVI 4.37±0.087; TSC 4.99±0.339 [p=0.015]). Neuroanatomical differences were greater in the SVI group, while no consistent differences between the MVI and TSC group were observed. INTERPRETATION: Posterior tracts of the visual system are compromised in children with congenital visual impairment versus those who are typically sighted. The severity of visual input appears to have affected neuroanatomical development as significant reductions were only found in the SVI group. WHAT THIS PAPER ADDS: Severe visual impairment in mid-childhood is associated with reduced integrity of visual pathways and reduced thalamus volume.

The effect of age of first exposure to competitive fighting on cognitive and other neuropsychiatric symptoms and brain volume.

It has long been established that fighting sports such as boxing and mixed martial arts can lead to head injury. Prior work from this group on the Professional Fighters Brain Health Study found that exposure to repetitive head impacts is associated with lower brain volumes and decreased processing speed in fighters. Current and previously licensed professional fighters were recruited, divided into active and retired cohorts, and matched with a control group that had no prior experience in sports with likely head trauma. This study examined the relationship between age of first exposure (AFE) to fighting sports and brain structure (MRI regional volume), cognitive performance (CNS Vital Signs, iComet C3), and clinical neuropsychiatric symptoms (PHQ-9, Barratt Impulsiveness Scale). Brain MRI data showed significant correlations between earlier AFE and smaller bilateral hippocampal and posterior corpus callosum volumes for both retired and active fighters. Earlier AFE in active fighters was correlated with decreased processing speed and decreased psychomotor speed. Retired fighters showed a correlation between earlier AFE and higher measures of depression and impulsivity. Overall, the results help to inform clinicians, governing bodies, parents, and athletes of the risks associated with beginning to compete in fighting sports at a young age.

Cytotoxic Lesions of the Corpus Callosum Caused by Thermogenic Dietary Supplements.

Consumption of over-the-counter dietary supplements to reduce body weight is common among the population. Thermogenics are herbal combinations that claim to produce a fat-burning process through an increase in the cellular metabolic rate and greater cellular energy consumption, having a high risk for patients developing toxic leukoencephalopathy. We present a series of 6 patients with acute neurologic symptoms and MR imaging showing restricted diffusion and decreased apparent diffusion coefficient values (mean value, 400 mm2/s × 10-6) in the entire corpus callosum compatible with a cytotoxic lesion of the corpus callosum. Although patients responded favorably to the product discontinuation with rapid recovery of neurologic symptoms, there was a more prolonged resolution on imaging alterations. Because of the widespread availability and unregulated nature of thermogenic dietary supplements, physicians must be aware of the clinical and radiologic characteristics of these potential complications of their use.

Diffusion Imaging of Cerebral Diaschisis in Neonatal Arterial Ischemic Stroke.

BACKGROUND: Neonatal arterial ischemic stroke is a leading cause of cerebral palsy and lifelong disability. Diffusion-weighted imaging has revolutionized diagnosis and facilitated outcome prognostication in acute neonatal arterial ischemic stroke. Diaschisis refers to changes in brain areas functionally connected but structurally remote from primary injury. We hypothesized that acute diffusion-weighted imaging can quantify cerebral diaschisis and is associated with outcome from neonatal arterial ischemic stroke. METHODS: Subjects were identified from a prospective, population-based research cohort (Alberta Perinatal Stroke Project). Inclusion criteria were unilateral middle cerebral artery neonatal arterial ischemic stroke, diffusion-weighted magnetic resonance imaging within 10 days of birth, and more than 12-months follow-up (pediatric stroke outcome measure). Diaschisis was characterized and quantified using a validated software method (ImageJ). Volumetric analysis assessed atrophy of affected structures. Diaschisis scores were corrected for infarct size and compared with outcomes (Mann-Whitney). RESULTS: From 20 eligible neonatal arterial ischemic strokes, two were excluded for poor image quality. Of 18 remaining (61% male, median age 3.2 days), 16 (89%) demonstrated diaschisis. Thalamus (88%) was the most common location in addition to corpus callosum (50%). Age at imaging was not associated with diaschisis. Affected structures demonstrated atrophy on imaging. Long-term outcomes available in 81% (median age 7.5 years) were not associated with diaschisis scores. CONCLUSIONS: Cerebral diaschisis occurs in neonatal arterial ischemic stroke and can be quantified with diffusion-weighted imaging. Occurrence is common and should not be mistaken for additional infarction. Determining clinical significance will require larger samples with well-characterized long-term outcomes.

Therapeutic effect of oligomeric proanthocyanidin in cuprizone-induced demyelination.

NEW FINDINGS: What is the central question of this study? Oligomeric proanthocyanidin has the capacity to alleviate abnormalities in neurological functioning. However, whether oligomeric proanthocyanidin can reduce the progression of demyelination or promote remyelination in demyelinating diseases remains unknown. What is the main finding and its importance? Oligomeric proanthocyanidin can improve cuprizone-induced demyelination by inhibiting immune cell infiltration, reversing overactivated microglia, decreasing the inflammatory cytokines secreted by inflammatory cells and decreasing the production of myelin oligodendrocyte glycoprotein35-55 -specific antibody in the brain. ABSTRACT: Demyelinating diseases of the CNS, including multiple sclerosis, neuromyelitis optica and acute disseminated encephalomylitis, are characterized by recurrent primary demyelination-remyelination and progressive neurodegeneration. In the present study, we investigated the therapeutic effect of oligomeric proanthocyanidin (OPC), the most effective component of grape seed extract, in cuprizone-fed C57BL/6 mice, a classic demyelination-remyelination model. Our results showed that OPC attenuated abnormal behaviour, reduced demyelination and increased expression of myelin basic protein and expression of O4+ oligodendrocytes in the corpus callosum. Oligomeric proanthocyanidin also reduced the numbers of B and T cells, activated microglia in the corpus callosum and inhibited secretion of inflammatory factors. Furthermore, concentrations of myelin oligodendrocyte glycoprotein-specific antibodies were significantly reduced in serum and brain homogenates after OPC treatment. Together, these results demonstrate a potent therapeutic effect for OPC in cuprizone-mediated demyelination and clearly highlight multiple effects of this natural product in attenuating myelin-specific autoantibodies and the inflammatory microenvironment in the brain.

Pathological cut-offs of global and regional brain volume loss in multiple sclerosis.

BACKGROUND: Volumetric MRI surrogate markers of disease progression are lacking. OBJECTIVE: To establish cut-off values of brain volume loss able to discriminate between healthy controls and MS patients. METHODS: In total, 386 patients after first demyelinating event suggestive of MS (CIS), 964 relapsing-remitting MS (RRMS) patients, 63 secondary-progressive MS (SPMS) patients and 58 healthy controls were included in this longitudinal study. A total of 11,438 MRI scans performed on the same MRI scanner with the same protocol were analysed. Annualised percentage changes of whole brain, grey matter, thalamus and corpus callosum volumes were estimated. We investigated cut-offs able to discriminate between healthy controls and MS patients. RESULTS: At a predefined specificity of 90%, the annualised percentage change cut-off of corpus callosum volume (-0.57%) was able to distinguish between healthy controls and patients with the highest sensitivity (51% in CIS, 48% in RRMS and 42% in SPMS patients). Lower sensitivities (22%-49%) were found for cut-offs of whole brain, grey matter and thalamic volume loss. Among CIS and RRMS patients, cut-offs were associated with greater accumulation of disability. CONCLUSION: We identified cut-offs of annualised global and regional brain volume loss rates able to discriminate between healthy controls and MS patients.

Gray matter atrophy in multiple sclerosis despite clinical and lesion stability during natalizumab treatment.

BACKGROUND: Brain volume loss is an important surrogate marker for assessing disability in MS; however, contribution of gray and white matter to the whole brain volume loss needs further examination in the context of specific MS treatment. OBJECTIVES: To examine whole and segmented gray, white, thalamic, and corpus callosum volume loss in stable patients receiving natalizumab for 2-5 years. METHODS: This was a retrospective study of 20 patients undergoing treatment with natalizumab for 24-68 months. Whole brain volume loss was determined with SIENA. Gray and white matter segmentation was done using FAST. Thalamic and corpus callosum volumes were determined using Freesurfer. T1 relaxation values of chronic hypointense lesions (black holes) were determined using a quantitative, in-house developed method to assess lesion evolution. RESULTS: Over a mean of 36.6 months, median percent brain volume change (PBVC) was -2.0% (IQR 0.99-2.99). There was decline in gray (p = 0.001) but not white matter (p = 0.6), and thalamic (p = 0.01) but not corpus callosum volume (p = 0.09). Gray matter loss correlated with PBVC (Spearman's r = 0.64, p = 0.003) but not white matter (Spearman's r = 0.42, p = 0.07). Age significantly influenced whole brain volume loss (p = 0.010, multivariate regression), but disease duration and baseline T2 lesion volume did not. There was no change in T1 relaxation values of lesions or T2 lesion volume over time. All patients remained clinically stable. CONCLUSIONS: These results demonstrate that brain volume loss in MS is primarily driven by gray matter changes and may be independent of clinically effective treatment.

Combined therapy involving electroacupuncture and treadmill exercise attenuates demyelination in the corpus callosum by stimulating oligodendrogenesis in a rat model of neonatal hypoxia-ischemia.

We investigated whether electroacupuncture (EA) and treadmill (TM) exercise improve behaviors related to motor and memory dysfunction in a cerebral palsy-like rat model via activation of oligodendrogenesis. A neonatal hypoxia-ischemia model was created using Sprague-Dawley rats (P7), and these underwent EA stimulation and treadmill training from 3 to 5weeks after hypoxia-ischemia induction. EA treatment was delivered via electrical stimulation (2Hz, 1mA) at two acupoints, Baihui (GV20) and Zusanli (ST36). Behavioral tests showed that EA alleviated motor dysfunction caused by hypoxia-ischemia on a rotarod test, and TM exercise alleviated motor and memory dysfunction seen on cylinder and passive avoidance tests. Combined therapy with EA and TM exercise showed synergistic effects on the cylinder, rotarod, and catwalk tests. TM exercise significantly restored corpus callosum thickness, and combined therapy with EA and TM restored myelin basic protein (MBP) levels in this region. While EA stimulation only increased activation of cAMP-response element binging protein (CREB) in oligodendrocytes of the corpus callosum, TM exercise increased newly generated oligodendrocyte progenitor cells or oligodendrocytes via activation of CREB. Synergistic effects on oligodendrogenesis were also observed by the combined therapy. Furthermore, the combined therapy induced mature brain-derived neurotrophic factor (BDNF) expression in the cerebral cortex. These results demonstrate that combined therapy with EA and TM exercise may restore myelin components following neonatal hypoxia-ischemia via upregulation of oligodendrogenesis involving CREB/BDNF signaling, which subsequently improves motor and memory function. Therefore, combined therapy with EA and TM exercise offers another treatment option for functional recovery from injuries caused by neonatal hypoxia-ischemia, such as cerebral palsy.

Early pridopidine treatment improves behavioral and transcriptional deficits in YAC128 Huntington disease mice.

Pridopidine is currently under clinical development for Huntington disease (HD), with on-going studies to better characterize its therapeutic benefit and mode of action. Pridopidine was administered either prior to the appearance of disease phenotypes or in advanced stages of disease in the YAC128 mouse model of HD. In the early treatment cohort, animals received 0, 10, or 30 mg/kg pridopidine for a period of 10.5 months. In the late treatment cohort, animals were treated for 8 weeks with 0 mg/kg or an escalating dose of pridopidine (10 to 30 mg/kg over 3 weeks). Early treatment improved motor coordination and reduced anxiety- and depressive-like phenotypes in YAC128 mice, but it did not rescue striatal and corpus callosum atrophy. Late treatment, conversely, only improved depressive-like symptoms. RNA-seq analysis revealed that early pridopidine treatment reversed striatal transcriptional deficits, upregulating disease-specific genes that are known to be downregulated during HD, a finding that is experimentally confirmed herein. This suggests that pridopidine exerts beneficial effects at the transcriptional level. Taken together, our findings support continued clinical development of pridopidine for HD, particularly in the early stages of disease, and provide valuable insight into the potential therapeutic mode of action of pridopidine.

Diverging volumetric trajectories following pediatric traumatic brain injury.

Traumatic brain injury (TBI) is a significant public health concern, and can be especially disruptive in children, derailing on-going neuronal maturation in periods critical for cognitive development. There is considerable heterogeneity in post-injury outcomes, only partially explained by injury severity. Understanding the time course of recovery, and what factors may delay or promote recovery, will aid clinicians in decision-making and provide avenues for future mechanism-based therapeutics. We examined regional changes in brain volume in a pediatric/adolescent moderate-severe TBI (msTBI) cohort, assessed at two time points. Children were first assessed 2-5 months post-injury, and again 12 months later. We used tensor-based morphometry (TBM) to localize longitudinal volume expansion and reduction. We studied 21 msTBI patients (5 F, 8-18 years old) and 26 well-matched healthy control children, also assessed twice over the same interval. In a prior paper, we identified a subgroup of msTBI patients, based on interhemispheric transfer time (IHTT), with significant structural disruption of the white matter (WM) at 2-5 months post injury. We investigated how this subgroup (TBI-slow, N = 11) differed in longitudinal regional volume changes from msTBI patients (TBI-normal, N = 10) with normal WM structure and function. The TBI-slow group had longitudinal decreases in brain volume in several WM clusters, including the corpus callosum and hypothalamus, while the TBI-normal group showed increased volume in WM areas. Our results show prolonged atrophy of the WM over the first 18 months post-injury in the TBI-slow group. The TBI-normal group shows a different pattern that could indicate a return to a healthy trajectory.

Cocaine dependence does not contribute substantially to white matter abnormalities in HIV infection.

This study investigated the association of HIV infection and cocaine dependence with cerebral white matter integrity using diffusion tensor imaging (DTI). One hundred thirty-five participants stratified by HIV and cocaine status (26 HIV+/COC+, 37 HIV+/COC-, 37 HIV-/COC+, and 35 HIV-/COC-) completed a comprehensive substance abuse assessment, neuropsychological testing, and MRI with DTI. Among HIV+ participants, all were receiving HIV care and 46% had an AIDS diagnosis. All COC+ participants were current users and met criteria for cocaine use disorder. We used tract-based spatial statistics (TBSS) to assess the relation of HIV and cocaine to fractional anisotropy (FA) and mean diffusivity (MD). In whole-brain analyses, HIV+ participants had significantly reduced FA and increased MD compared to HIV- participants. The relation of HIV and FA was widespread throughout the brain, whereas the HIV-related MD effects were restricted to the corpus callosum and thalamus. There were no significant cocaine or HIV-by-cocaine effects. These DTI metrics correlated significantly with duration of HIV disease, nadir CD4+ cell count, and AIDS diagnosis, as well as some measures of neuropsychological functioning. These results suggest that HIV is related to white matter integrity throughout the brain, and that HIV-related effects are more pronounced with increasing duration of infection and greater immune compromise. We found no evidence for independent effects of cocaine dependence on white matter integrity, and cocaine dependence did not appear to exacerbate the effects of HIV.