Central White Matter Research Articles

Synthetic MRI demonstrates prolonged regional relaxation times in the brain of preterm born neonates with severe postnatal morbidity

BackgroundTo identify preterm infants at risk for neurodevelopment impairment that might benefit from early neurorehabilitation, early prognostic biomarkers of future outcomes are needed. ObjectiveTo determine whether synthetic MRI is sensitive to age-related changes in regional tissue relaxation times in the brain of preterm born neonates when scanned at term equivalent age (TEA, 37–42 weeks), and to investigate whether severe postnatal morbidity results in prolonged regional tissue relaxation times. Materials and methodsThis retrospective study included 70 very preterm born infants scanned with conventional and synthetic MRI between January 2017 and June 2019 at TEA. Infants with severe postnatal morbidity were allocated to a high-risk group (n = 22). All other neonates were allocated to a low-risk group (n = 48). Linear regression analysis was performed to determine the relationship between relaxation times and postmenstrual age (PMA) at scan. Analysis of covariance was used to evaluate the impact of severe postnatal morbidity in the high-risk group on T1 and T2 relaxation times. Receiver operating characteristic (ROC) curves were plotted and analysed with area under the ROC curve (AUC) to evaluate the accuracy of classifying high-risk patients based on regional relaxation times. ResultsA linear age-related decrease of T1 and T2 relaxation times correlating with PMA at scan (between 37 and 42 weeks) was found in the deep gray matter, the cerebellum, the cortex, and the posterior limb of the internal capsule (PLIC) (p < .005 each), but not in the global, frontal, parietal, or central white matter. Analysis of covariance for both risk groups, adjusted for PMA, revealed significantly prolonged regional tissue relaxation times in neonates with severe postnatal morbidity, which was best illustrated in the central white matter of the centrum semiovale (T1 Δ = 11.5%, T2 Δ = 13.4%, p < .001) and in the PLIC (T1 Δ = 9.2%, T2 Δ = 6.9%, p < .001). The relaxation times in the PLIC and the central white matter predicted high-risk status with excellent accuracy (AUC range 0.82–0.86). ConclusionSynthetic MRI-based relaxometry in the brain of preterm born neonates is sensitive to age-related maturational changes close to TEA. Severe postnatal morbidity correlated with a significant delay in tissue relaxation. Synthetic MRI may provide early prognostic biomarkers for neurodevelopment impairment.

De novo stop-loss variants in CLDN11 cause hypomyelinating leukodystrophy.

Claudin-11, a tight junction protein, is indispensable in the formation of the radial component of myelin. Here, we report de novo stop-loss variants in the gene encoding claudin-11, CLDN11, in three unrelated individuals presenting with an early-onset spastic movement disorder, expressive speech disorder and eye abnormalities including hypermetropia. Brain MRI showed a myelin deficit with a discrepancy between T1-weighted and T2-weighted images and some progress in myelination especially involving the central and peripheral white matter. Exome sequencing identified heterozygous stop-loss variants c.622T>C, p.(*208Glnext*39) in two individuals and c.622T>G, p.(*208Gluext*39) in one individual, all occurring de novo. At the RNA level, the variant c.622T>C did not lead to a loss of expression in fibroblasts, indicating this transcript is not subject to nonsense-mediated decay and most likely translated into an extended protein. Extended claudin-11 is predicted to form an alpha helix not incorporated into the cytoplasmic membrane, possibly perturbing its interaction with intracellular proteins. Our observations suggest that stop-loss variants in CLDN11 expand the genetically heterogeneous spectrum of hypomyelinating leukodystrophies.

The Epidemiology Study in Multiple Sclerosis - Relevance to Natural History

Multiple sclerosis (MS) is a chronic, demyelinating disease of the central nervous system white matter that has been extensively studied using the epidemiological approach, and yet an etiology for the disease remains elusive. This paper presents a review of past publications that have made suggestions toward the design of epidemiological studies in MS. A formal search strategy is described, and a short summary of these papers is provided. A natural history of MS based on previous studies is proposed as a framework for describing future directions in the neuroepidemiology of the disease, and categorization based on the clinical forms of MS is described. Within the context of a proposed natural history, suggestions are made on the use of sub-regionalization in cluster studies across different domains, as well as on the use of specific reference points in a patient's lifetime in the analysis of clusters.

Lipid-suppressed and tissue-fraction corrected metabolic distributions in human central brain structures using 2D 1 H magnetic resonance spectroscopic imaging at 7 T.

IntroductionMagnetic resonance spectroscopic imaging (MRSI) has the potential to add a layer of understanding of the neurobiological mechanisms underlying brain diseases, disease progression, and treatment efficacy. Limitations related to metabolite fitting of low signal‐to‐noise ratios data, signal variations due to partial‐volume effects, acquisition and extracranial lipid artifacts, along with clinically relevant aspects such as scan time constraints, are among the challenges associated with in vivo MRSI.MethodsThe aim of this work was to address some of these factors and to develop an acquisition, reconstruction, and postprocessing pipeline to derive lipid‐suppressed metabolite values of central brain structures based on free‐induction decay measurements made using a 7 T MR scanner. Anatomical images were used to perform high‐resolution (1 mm3) partial‐volume correction to account for gray matter, white matter (WM), and cerebral‐spinal fluid signal contributions. Implementation of automatic quality control thresholds and normalization of metabolic maps from 23 subjects to the Montreal Neurological Institute (MNI) standard atlas facilitated the creation of high‐resolution average metabolite maps of several clinically relevant metabolites in central brain regions, while accounting for macromolecular distributions.Partial‐volume correction improved the delineation of deep brain nuclei. We report average metabolite values including glutamate + glutamine (Glx), glycerophosphocholine, choline and phosphocholine (tCho), (phospo)creatine, myo‐inositol and glycine (mI‐Gly), glutathione, N‐acetyl‐aspartyl glutamate(and glutamine), and N‐acetyl‐aspartate in the basal ganglia, central WM (thalamic radiation, corpus callosum) as well as insular cortex and intracalcarine sulcus.ConclusionMNI‐registered average metabolite maps facilitate group‐based analysis, thus offering the possibility to mitigate uncertainty in variable MRSI data.

Prefronto-Striatal Structural Connectivity Mediates Adult Age Differences in Action Selection.

In complex everyday environments, action selection is critical for optimal goal-directed behavior. This refers to the process of choosing a proper action from the range of possible alternatives. The neural mechanisms underlying action selection and how these are affected by normal aging remain to be elucidated. In the present cross-sectional study, we studied processes of effector selection during a multilimb reaction time task in a lifespan sample of healthy human adults (N = 89; 20-75 years; 48 males, 41 females). Participants were instructed to react as quickly and accurately as possible to visually cued stimuli representing single-limb or combined upper and/or lower limb motions. Diffusion MRI was used to study structural connectivity between prefrontal and striatal regions as critical nodes for action selection. Behavioral findings revealed that increasing age was associated with slowing of action selection performance. At the neural level, aging had a negative impact on prefronto-striatal connectivity. Importantly, mediation analyses revealed that the negative association between action selection performance and age was mediated by prefronto-striatal connectivity, specifically the connections between left rostral medial frontal gyrus and left nucleus accumbens as well as right frontal pole and left caudate. These results highlight the potential role of prefronto-striatal white matter decline in poorer action selection performance of older adults.SIGNIFICANCE STATEMENT As a result of enhanced life expectancy, researchers have devoted increasing attention to the study of age-related alterations in cognitive and motor functions. Here we study associations between brain structure and behavior to reveal the impact of central neural white matter changes as a function of normal aging on action selection performance. We demonstrate the critical role of a reduction in prefronto-striatal structural connectivity in accounting for action selection performance deficits in healthy older adults. Preserving this cortico-subcortical pathway may be critical for behavioral flexibility and functional independence in older age.

Diffuse axonal injury predicts neurodegeneration after moderate-severe traumatic brain injury.

Traumatic brain injury is associated with elevated rates of neurodegenerative diseases such as Alzheimer's disease and chronic traumatic encephalopathy. In experimental models, diffuse axonal injury triggers post-traumatic neurodegeneration, with axonal damage leading to Wallerian degeneration and toxic proteinopathies of amyloid and hyperphosphorylated tau. However, in humans the link between diffuse axonal injury and subsequent neurodegeneration has yet to be established. Here we test the hypothesis that the severity and location of diffuse axonal injury predicts the degree of progressive post-traumatic neurodegeneration. We investigated longitudinal changes in 55 patients in the chronic phase after moderate-severe traumatic brain injury and 19 healthy control subjects. Fractional anisotropy was calculated from diffusion tensor imaging as a measure of diffuse axonal injury. Jacobian determinant atrophy rates were calculated from serial volumetric T1 scans as a measure of measure post-traumatic neurodegeneration. We explored a range of potential predictors of longitudinal post-traumatic neurodegeneration and compared the variance in brain atrophy that they explained. Patients showed widespread evidence of diffuse axonal injury, with reductions of fractional anisotropy at baseline and follow-up in large parts of the white matter. No significant changes in fractional anisotropy over time were observed. In contrast, abnormally high rates of brain atrophy were seen in both the grey and white matter. The location and extent of diffuse axonal injury predicted the degree of brain atrophy: fractional anisotropy predicted progressive atrophy in both whole-brain and voxelwise analyses. The strongest relationships were seen in central white matter tracts, including the body of the corpus callosum, which are most commonly affected by diffuse axonal injury. Diffuse axonal injury predicted substantially more variability in white matter atrophy than other putative clinical or imaging measures, including baseline brain volume, age, clinical measures of injury severity and microbleeds (>50% for fractional anisotropy versus <5% for other measures). Grey matter atrophy was not predicted by diffuse axonal injury at baseline. In summary, diffusion MRI measures of diffuse axonal injury are a strong predictor of post-traumatic neurodegeneration. This supports a causal link between axonal injury and the progressive neurodegeneration that is commonly seen after moderate/severe traumatic brain injury but has been of uncertain aetiology. The assessment of diffuse axonal injury with diffusion MRI is likely to improve prognostic accuracy and help identify those at greatest neurodegenerative risk for inclusion in clinical treatment trials.

Genetic disorders with central nervous system white matter abnormalities: An update.

Several genetic disorders have variable degree of central nervous system white matter abnormalities. We retrieved and reviewed 422 genetic conditions with prominent and consistent involvement of white matter from the literature. We herein describe the current definitions, classification systems, clinical spectrum, neuroimaging findings, genomics, and molecular mechanisms of these conditions. Though diagnosis for most of these disorders relies mainly on genomic tests, specifically exome sequencing, we collate several clinical and neuroimaging findings still relevant in diagnosis of clinically recognizable disorders. We also review the current understanding of pathophysiology and therapeutics of these disorders.

Clinical Radiobiology of Fast Neutron Therapy: What Was Learnt?

Neutron therapy was developed from neutron radiobiology experiments, and had identified a higher cell kill per unit dose and an accompanying reduction in oxygen dependency. But experts such as Hal Gray were sceptical about clinical applications, for good reasons. Gray knew that the increase in relative biological effectiveness (RBE) with dose fall-off could produce marked clinical limitations. After many years of research, this treatment did not produce the expected gains in tumour control relative to normal tissue toxicity, as predicted by Gray. More detailed reasons for this are discussed in this paper. Neutrons do not have Bragg peaks and so did not selectively spare many tissues from radiation exposure; the constant neutron RBE tumour prescription values did not represent the probable higher RBE values in late-reacting tissues with low α/β values; the inevitable increase in RBE as dose falls along a beam would also contribute to greater toxicity than in a similar megavoltage photon beam. Some tissues such as the central nervous system white matter had the highest RBEs partly because of the higher percentage hydrogen content in lipid-containing molecules. All the above factors contributed to disappointing clinical results found in a series of randomised controlled studies at many treatment centres, although at the time they were performed, neutron therapy was in a catch-up phase with photon-based treatments. Their findings are summarised along with their technical aspects and fractionation choices. Better understanding of fast neutron experiments and therapy has been gained through relatively simple mathematical models—using the biological effective dose concept and incorporating the RBEmax and RBEmin parameters (the limits of RBE at low and high dose, respectively—as shown in the Appendix). The RBE itself can then vary between these limits according to the dose per fraction used. These approaches provide useful insights into the problems that can occur in proton and ion beam therapy and how they may be optimised. This is because neutron ionisations in living tissues are mainly caused by recoil protons of energy proportional to the neutron energy: these are close to the proton energies that occur close to the Bragg peak region. To some extent, neutron RBE studies contain the highest RBE ranges found within proton and ion beams near Bragg peaks. In retrospect, neutrons were a useful radiobiological tool that has continued to inform the scientific and clinical community about the essential radiobiological principles of all forms of high linear energy transfer therapy. Neutron radiobiology and its implications should be taught on training courses and studied closely by clinicians, physicists, and biologists engaged in particle beam therapies.

Association between Left Atrial Deformation and Brain Involvement in Patients with Anderson-Fabry Disease at Diagnosis.

Background: Anderson-Fabry disease (AFD) can induce both central nervous system white matter lesions (WMLs) and cardiac abnormalities including left atrial (LA) dysfunction. We sought to evaluate the possible interrelations of LA structure and function impairment with the presence of WMLs in AFD patients. Methods 22 AFD patients and 22 controls, matched for age and sex, underwent an echo-Doppler exam including quantification of peak atrial longitudinal strain (PALS). AFD patients underwent also a 3-T brain magnetic resonance imaging with a visual quantification of WMLs by Fazekas’ score (FS) on 3D FLAIR images. Results AFD patients had significantly higher left ventricular (LV) mass index (LVMi) and relative wall thickness, and lower PALS compared to controls. Among AFD patients, 9 showed a FS = 0, and 13 a FS > 1. AFD patients with FS ≥ 1 showed lower PALS (29.4 ± 6.7 vs. 37.2 ± 3.9%, p = 0.003) than those with FS = 0, without difference in LA volume index and LVMi. In AFD patients, FS was inversely related to PALS (r = −0.49, p < 0.0001), even after adjusting for LVMi (r = −0.43, p < 0.05). Conclusions In the absence of significant alterations in LA size, AFD patients had lower PALS compared to controls. The inverse association between PALS and presence of WMLs indicates a possible parallel early involvement of heart and brain.

MRI in CLN2 disease patients: Subtle features that support an early diagnosis.

Neuronal ceroid lipofuscinosis type 2 (CLN2) disease is a rare, paediatric-onset, neurodegenerative disorder characterised in its early stages by language delay, seizures and loss of motor function. It is rapidly progressive and ultimately results in the premature death of patients. We aim to highlight common magnetic resonance imaging (MRI) features seen in early CLN2 disease and increase disease awareness among clinicians in order to facilitate early diagnosis and treatment of patients with disease-modifying enzyme replacement therapy. We obtained MRI scans from 12 Turkish children with CLN2 disease, at symptom onset or time of diagnosis, and at various times during disease progression. Patient details including age at onset of symptoms, age at diagnosis and clinical presentation were collected. MRIs were analysed to identify common features present in patients with CLN2 disease. The median diagnostic delay in this cohort was 2 years, highlighting the need for increased disease awareness among clinicians. Key MRI features suggestive of CLN2 disease that were identified included cerebellar atrophy in 11 patients, linear hyperintensity of central white matter in 10 patients, cerebral atrophy in 8 patients and thinning of the corpus callosum in 6 patients. Thalamic hypointensity was seen in 1 patient and may also indicate CLN2 disease. It is important to consider the presenting symptoms alongside clinical test results in order to support early diagnosis of CLN2 disease. Clinical suspicion of CLN2 disease accompanied by the detection of any of the above-mentioned features on MRI should encourage healthcare professionals to test for CLN2 disease.

Multimodal MRI Longitudinal Assessment of White and Gray Matter in Different SPG Types of Hereditary Spastic Paraparesis.

Hereditary spastic paraplegias (HSP) are a group of genetically and clinically heterogeneous neurologic disorders. Hereby we describe a relatively large group of patients (pts) affected by HSP studied at baseline (31 pts) and at follow-up (mean period 28.9 ± 8.4 months; 23 pts) with multimodal advanced MRI: high-resolution T1 images for voxel-based morphometry (VBM) analysis, magnetic resonance spectroscopy (MRS), and diffusion tensor imaging (DTI). An age-matched healthy control (HC) group underwent the same neuroimaging protocol in a time schedule matched with the HSP patients. At baseline, VBM showed gray matter (GM) reduction in HSP in the right pre-frontal cortex and bilaterally in the thalami. MRS at baseline depicted in HSP patients compared to the HC group reduction of NAA/Cr ratio in the right pre-frontal region, increase of Cho/Cr ratio in the right pre-central regions, and increase of mI/Cr ratio on the left pre-central area. At cross-sectional follow-up analysis and longitudinal evaluation, no VBM and MRS statistically significant results were obtained. Tract-based spatial statistics (TBSS) analysis showed widespread DTI brain white matter (WM) alterations in patients compared to HC at baseline, which are characterized by reduction of fractional anisotropy (FA) and increase of mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity, as confirmed on cross-analysis of the follow-up dataset. A longitudinal analysis with TBSS in HSP patients did not show significant variations, while upon applying region-based analysis we found increased FA and decreased MD and AD in specific brain WM fiber complex during follow-up. The changes were not correlated with the clinical presentation (pure vs complicated HSP), motor function, and motility indexes or history of specific treatments (botulinum toxin). In conclusion, the cross-sectional analysis of the multiparametric MRI data in our HSP patients confirmed the non-prominent involvement of the cortex in the primary motor regions but rather of other more associative areas. On the contrary, DTI demonstrated a widespread involvement of the brain WM, including the primary motor regions, which was confirmed at follow-up. The longitudinal analysis revealed an apparent inversion of tendency when considering the expected evolution of a neurodegenerative process: we detected an increase of FA and a decrease of MD and AD. These time-related modifications may suggest a repair attempt by the residual central WM fibers, which requires confirmation with a larger group of patients and with a longer time interval.

Central residues of the amphipathic β-hairpin loop control the properties of Clostridium perfringens epsilon-toxin channel

Clostridium perfringens epsilon toxin (ETX) is a heptameric pore-forming toxin of the aerolysin toxin family. ETX is the most potent toxin of this toxin family and the third most potent bacterial toxin with high cytotoxic and lethal activities in animals. In addition, ETX shows a demyelinating activity in nervous tissue leading to devastating multifocal central nervous system white matter disease in ruminant animals. Pore formation in target cell membrane is most likely the initial critical step in ETX biological activity. Eight single to quadruple ETX mutants were generated by replacement of polar residues (serine, threonine, glutamine) in middle positions of the β-strands forming the β-barrel and facing the channel lumen with charged glutamic residues. Channel activity and ion selectivity were monitored in artificial lipid monolayer membranes and cytotoxicity was investigated in MDCK cells by the viability MTT test and propidium iodide entry. All the mutants formed channels with similar conductance in artificial lipid membranes and increasing cation selectivity for increasing number of mutations. Here, we show that residues in the central position of each β-strand of the amphipathic β-hairpin loop that forms the transmembrane pore, control the size and ion selectivity of the channel. While the highest cationic ETX mutants were not cytotoxic, no strict correlation was observed between ion selectivity and cytotoxicity.

BMX-HGG: Phase II trial of newly diagnosed high-grade glioma treated with concurrent radiation therapy, temozolomide, and BMX-001.

TPS2577 Background: Patients diagnosed with malignant high-grade gliomas (WHO grade III-IV) experience significant morbidity and mortality associated with these cancers. While the mainstay of therapy for patients with newly diagnosed high-grade glioma is surgery followed by concurrent chemotherapy and radiation therapy (RT), the outcomes remain very poor. BMX-001 (MnTnBuOE-2-PyP5+) is a metalloporphyrin with differential action in response to radiation therapy and chemotherapy-induced oxidative stress. Early preclinical studies demonstrated BMX-001’s ability to act as a radioprotectant to healthy tissue such as a central nervous white matter and as a radiosensitizer to cancer cells, in particular, human glioblastoma xenografts. We evaluated the safety of BMX-001 in combination with concurrent RT and temozolomide (TMZ) in a phase I study of newly diagnosed high-grade glioma patients, and we found that BMX-001 is safe and well-tolerated in this population. The maximum tolerated dose of BMX-001 during concurrent RT and TMZ was determined to be 28 mg delivered subcutaneously (SC) followed by 16 biweekly SC doses at 14 mg (Peters et al., Neuro-Oncology 2018). Methods: For this multi-site, open-label, phase II study (NCT02655601), we will randomize approximately 160 patients 1:1 to concurrent RT and TMZ with BMX-001 versus concurrent RT and TMZ alone. Key eligibility criteria include newly diagnosed histologically confirmed high-grade glioma (WHO III-IV), 18 ≥ years, and Karnofsky performance status ≥ 70%. The primary endpoint is overall survival. Secondary endpoints include cognitive performance as assessed by standardized cognitive testing, bone marrow protection, safety and tolerability, progression-free survival, overall tumor response rate, and plasma pharmacokinetics. Exploratory endpoints are health-related quality of life (as assessed by Functional Assessment of Cancer Therapy–Brain, Functional Assessment of Cancer Therapy-Cognition, and Functional Assessment of Chronic Illness Therapy-Fatigue), qualitative hair loss, and white matter integrity (as measured by MRI diffusion tensor/susceptibility imaging). Since November 2018, this phase II study has enrolled 64 of 160 high-grade glioma patients at six sites with future sites planned to be implemented. Clinical trial information: NCT02655601 .

Foetal onset of EIF2B related disorder in two siblings: cerebellar hypoplasia with absent Bergmann glia and severe hypomyelination

Bi-allelic pathogenic variants in genes of the EIF2B family are responsible for Childhood Ataxia with Central nervous system Hypomyelination/Vanishing White Matter disease, a progressive neurodegenerative disorder of the central white matter. Only seven molecularly proven cases with antenatal onset have been reported so far. We report for the first time the neuropathological findings obtained from two foetuses harbouring deleterious variants in the EIF2B5 gene who presented in utero growth retardation and microcephaly with simplified gyral pattern that led to a medical termination of the pregnancy at 27 and 32 weeks of gestation. Neuropathological examination confirmed microcephaly with delayed gyration, periventricular pseudo-cysts and severe cerebellar hypoplasia. Histologically, the cerebellar cortex was immature, the dentate nuclei were fragmented and myelin stains revealed almost no myelination of the infratentorial structures. Bergmann glia was virtually absent associated to a drastic decreased number of mature astrocytes in the cerebellar white matter, multiple nestin-positive immature astrocytes as well as increased numbers of PDGRFα-positive oligodendrocyte precursors. Whole exome sequencing performed in the two foetuses and their parents allowed the identification of two EIF2B5 compound heterozygous variants in the two foetuses: c.468C > G p.Ile156Met and c.1165G > A p.Val389Met, the parents being heterozygous carriers. These variants are absent in the genome Aggregation Database (gnomAD r2.0.2). Contrary to the variant Ile156Met already described in a patient with CACH syndrome, the variant p.Val389Met is novel and predicted to be deleterious using several softwares. Neuropathological findings further expand the phenotypic spectrum of the disease that very likely occurs during early gestation and may manifest from the second half of pregnancy by a severe impairment of cerebral and cerebellar development.

101 Amyotrophic Lateral Sclerosis (ALS) - Not Just a Motor Disease? Isolated Bitter and Sweet Taste Loss in ALS

Specific taste quality deficits in ALS has not heretofore been described. Case Study: A 71 year old right handed female presented with a two year course of progressive reduction in strength in her hands, arms and legs with difficulty tying shoe laces, opening jars, writing and walking. She described nocturnal muscle spasms involving all extremities. Gradually, over eight months prior to presentation, all food began to taste bad and horribly bitter. Associated with no appetite and a seven pounds weight loss. Abnormalities in Neurological examination: Cranial Nerve (CN) examination: CN IX and X: Gag absent bilaterally. Motor examination: Bulk: atrophy in thenar and hypothenar eminences and intrinsics in both upper extremities. Percussion induced fasciculation and myotonia in both shoulders and arms. Fasciculation of tongue with percussion myotonia of tongue. Strength: Intrinsic 4/5 in both upper extremities, 3/5 in abductor policis brevis bilaterally, 3/5 right gastrocnemius soleus, 4/5 bilateral anterior tibialis. Drift testing: left abductor digiti minimi sign. Gait: Heel and toe walking unstable with circumduction of left leg. Tandem gait unstable. Cerebellar: Holmes rebound phenomena positive in the left upper extremity. Deep tendon reflexes: 1+ left brachioradialis. 1+ left triceps. 3+ right ankle jerks. 0 left ankle jerk. Positive jaw jerk. Chemosensory Testing: Normosmia to: Alcohol Sniff Test (46), Pocket Smell Test (3/3) and Retronasal Smell Index (9). Taste Quadrant Testing: ageusia in the palate to sodium chloride and citric acid. Ageusia throughout the palate, tongue and whole mouth to sucrose and quinine hydrochloride. Fungiform papillae count: left 18, right 20 (normal). Lip biopsy (normal). MRI: T2 flair in bilateral corticospinal tracts, left greater than right in the spinal cord and the brain. EMG: fibrillation, positive waves with fasciculation in all four extremities. Voluntary contraction with polyphasic unstable motor unit action potentials. While Lang found no taste loss in ALS (Lang, 2011), Pelletier found reduction in intensity of taste to all modalities in different sectors of the tongue, but paradoxically demonstrated normogeusia in whole mouth taste perception (Pelletier, 2013). Pathological specimens of those with ALS revealed degeneration in the nucleus parabrachialis medialis and tractus trigeminothalamicus dorsalis (Oyanagi, 2015), suggesting that taste deficit may be due to central white matter abnormalities. Sweet taste is localized in the most posterior and rostral aspect of the right insular cortex, immediately adjacent to bitter (Prinster, 2017), suggesting a neighborhood effect phenomena. Weight loss in ALS may be due to sensory distortion and secondary impairment of appetite. It would be worthwhile to investigate those with ALS for evidence of otherwise overlooked gustatory deficits, correction of which may improve appetite and nutritional state.

Microbiome-derived carnitine mimics as previously unknown mediators of gut-brain axis communication.

Alterations to the gut microbiome are associated with various neurological diseases, yet evidence of causality and identity of microbiome-derived compounds that mediate gut-brain axis interaction remain elusive. Here, we identify two previously unknown bacterial metabolites 3-methyl-4-(trimethylammonio)butanoate and 4-(trimethylammonio)pentanoate, structural analogs of carnitine that are present in both gut and brain of specific pathogen-free mice but absent in germ-free mice. We demonstrate that these compounds are produced by anaerobic commensal bacteria from the family Lachnospiraceae (Clostridiales) family, colocalize with carnitine in brain white matter, and inhibit carnitine-mediated fatty acid oxidation in a murine cell culture model of central nervous system white matter. This is the first description of direct molecular inter-kingdom exchange between gut prokaryotes and mammalian brain cells, leading to inhibition of brain cell function.

The Effect of Multiple Sclerosis on Nerve Fiber Layer of the Retina

Abstract Background Multiple Sclerosis is a chronic idiopathic inflammatory demyelinating disease involving Central Nervous System white matter with relapsing-remitting nature. Optic neuritis is a common initial manifestation. Multiple Sclerosis is characterized by dual pathological process of inflammation and neurodegeneration. It causes prominent retinal neural ganglion cell layer loss in addition to related axonal loss which can be identified by thinning of RNFL seen in OCT. Patients and Methods This case control study was carried out at Ain Shams University Hospitals in MS clinic of neurology department and Ophthalmology outpatient clinics. with a total of 100 eyes, from 50 subjects, Group A (10 patients, 20 eyes): normal persons with normal eyes as a Control group and 40 patients (80 eyes) having multiple sclerosis who satisfied the inclusion and exclusion criteria subdivided into 2 groups,(group B) 20 patients having previous attack of Optic Neuritis &amp; (group C) 20 patients not having previous Optic Neuritis. Informed consents were obtained from all subjects and ethics approval were obtained from Ain Shams University Hospitals Ethical Commitee: A complete ophthalmic history and ophthalmological examination were done for each subject. Visual acuity assessment using Auto Refractometer, refraction, uncorrected visual acuity (UCVA) and best corrected visual acuity (BCVA) assessment using Snellen chart and also calculated in Logarithm of Minimum Angle of Resolution (LogMAR).Pupil reaction. Color vision assessment. Anterior segment detailed Slit Lamp examination. Posterior segment examination (ONH examination) using Slit lamp biomicroscopy, Volk +90 Diopter lens. Intraocular tension measured by Goldmann applanation tonometry. OCT to evaluate RNF layer thickness and c/d ratio. Results Our study results demonstrated that: VA &amp; BCVA were statistically significant lower in MS group than the control group (P = 0.011, 0.006 respectively). Total, superior, inferior and temporal RNFL thickness were statistically significant lower in MS group than the control group(P = 0.003, 0.004, 0.028, 0.018 respectively), while there was no statistically significant difference between the two studied groups regarding nasal RNFL thickness. Total, all the four quadrants superior, inferior, temporal and nasal RNFL thickness were statistically significant lower in MS group with previous attack of ON compared with the MS group not having previous ON (P = 0.000, 0.000, 0.004, 0.004, 0.024 respectively). Conclusion This study also suggests a great role of ocular imaging techniques such as OCT as an effective noninvasive, high-resolution, non contact tool in mapping of subclinical retinal changes (GCIP layer) in MS patients. It may also serve as a diagnostic adjunct for monitoring disease activity and responses to neuroprotective drugs.

Quantitative analysis of cerebellar morphology in monotreme, metatherian and eutherian mammals

To superficial inspection, the mammalian cerebellum appears to be a stereotypical structure that varies little in morphology across mammals. In the present study, the volumes of components of the corpus cerebelli, foliation of the cerebellar cortex and the volumes of the pontine and deep cerebellar nuclei have been measured and compared in three species of monotreme, 90 species of marsupial and 57 species of eutherian mammal. In all three mammalian groups, the volume of the corpus cerebelli scales isometrically with brain volume, and pontine nuclear volume also scales isometrically with cerebellar volume. The ratio of hemisphere to vermal cerebellar cortex is comparable in all mammals at small cerebellar volume, but elaboration of cerebellar hemispheres is largely confined to large cerebella of eutherian mammals. At small cerebellar volumes, diprotodontid metatherians have proportionally large cerebellar hemispheres compared to non-diprotodontid metatherians, and metatherian cerebella in general have a high volume of central white matter for a given cerebellar cortex volume compared to eutherians. The degree of foliation of the cerebellum scales similarly in therian mammals, but is relatively low in the monotremes for the volume of their corpus cerebelli. Among metatherians, cerebellar foliation is stronger among diprotodontid as compared to non-diprotodontids. Although the cerebellum has a similar structure in all mammals, there are subtle differences in structure between different mammal groups with possible functional implications.

Diffusion Weighted and Diffusion Tensor MRI in Pediatric Neuroimaging Including Connectomics: Principles and Applications

Diffusion weighted MRI (DWI) including diffusion tensor imaging (DTI) are unique imaging techniques that render qualitative and quantitative information of the central nervous system white matter (WM) ultrastructure. It uses the Brownian movement of water molecules to probe tissue microstructure. It is a noninvasive method, with superb sensitivity to the differential mobility of water molecules within various components of the brain without the necessity to inject contrast agents. By sampling the 3 dimensional shape, direction and magnitude of the water diffusion, DWI/DTI generates unique tissue contrasts that can be used to study the axonal WM organization of the central nervous system. Its application allows to study the normal and anomalous brain development including connectivity, as well as a multitude of WM diseases. This article discusses/summarizes the principles of DWI/DTI and its applications in pediatric neuroscience research.

Transmission Electron Microscopy and Morphometry of the CNS White Matter.

Transmission electron microscopy of central nervous system white matter has provided unparalleled access to the ultrastructural features of axons, their myelin sheaths, and the major cells of white matter; namely, oligodendrocytes, oligodendrocyte precursors, astrocytes, and microglia. In particular, it has been invaluable in elucidating pathological changes in axons and myelin following experimentally induced injury or genetic alteration, in animal models. While also of value in the examination of human white matter, the tissue is rarely fixed adequately for the types of detailed analyses that can be performed on well-preserved samples from animal models, perfusion fixed at the time of death. In this chapter we describe methods for obtaining, processing, and visualizing white matter samples using transmission electron microscopy of perfusion fixed tissue and for unbiased morphometry of white matter, with particular emphasis on axon and myelin pathology. Several advanced electron microscopy techniques are now available, but this method remains the most expedient and accessible for routine ultrastructural examination and morphometry.