Spinal Cord Atrophy Predicts Progressive Disease in Relapsing Multiple Sclerosis.

OBJECTIVE: A major challenge in multiple sclerosis (MS) research is the understanding of silent progression and Progressive MS. Using a novel method to accurately capture upper cervical cord area from legacy brain MRI scans we aimed to study the role of spinal cord and brain atrophy for silent progression and conversion to secondary progressive disease (SPMS). METHODS: From a single-center observational study, all RRMS (n = 360) and SPMS (n = 47) patients and 80 matched controls were evaluated. RRMS patient subsets who converted to SPMS (n = 54) or silently progressed (n = 159), respectively, during the 12-year observation period were compared to clinically matched RRMS patients remaining RRMS (n = 54) or stable (n = 147), respectively. From brain MRI, we assessed the value of brain and spinal cord measures to predict silent progression and SPMS conversion. RESULTS: Patients who developed SPMS showed faster cord atrophy rates (-2.19%/yr) at least 4 years before conversion compared to their RRMS matches (-0.88%/yr, p < 0.001). Spinal cord atrophy rates decelerated after conversion (-1.63%/yr, p = 0.010) towards those of SPMS patients from study entry (-1.04%). Each 1% faster spinal cord atrophy rate was associated with 69% (p < 0.0001) and 53% (p < 0.0001) shorter time to silent progression and SPMS conversion, respectively. INTERPRETATION: Silent progression and conversion to secondary progressive disease are predominantly related to cervical cord atrophy. This atrophy is often present from the earliest disease stages and predicts the speed of silent progression and conversion to Progressive MS. Diagnosis of SPMS is rather a late recognition of this neurodegenerative process than a distinct disease phase. ANN NEUROL 2022;91:268-281.

Concussion Disrupts Normal Brain White Matter Microstructural Symmetry.

Injuries and illnesses can alter the normal bilateral symmetry of the brain, and determining the extent of this disruption may be useful in characterizing the pathology. One way of quantifying brain symmetry is in terms of bilateral correlation of diffusion tensor metrics between homologous white matter tracts. With this approach, we hypothesized that the brains of patients with a concussion are more asymmetrical than those of healthy individuals without a history of a concussion. We scanned the brains of 35 normal individuals and 15 emergency department patients with a recent concussion. Fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD) were determined for regions of interest (ROI) defined by a standard white-matter atlas that included 21 bilateral ROIs. For each ROI pair, bilateral correlation coefficients were calculated and compared between the two subject groups. A symmetry index, defined as the ratio between the difference and the sum of bilateral measures, was also calculated for each ROI pair and compared between the groups. We found that in normal subjects, the extent of symmetry varied among regions and individuals, and at least subtle forms of structural lateralization were common across regions. In patients, higher asymmetry was found overall as well as in the corticospinal tract specifically. Results indicate that a concussion can manifest in brain asymmetry that deviates from a normal state. The clinical utility of characterizing post-concussion pathology as abnormal brain asymmetry merits further exploration.

Disrupted White Matter Microstructure of the Cerebellar Peduncles in Scholastic Athletes After Concussion.

Concussion, or mild traumatic brain injury (mTBI), is a major public health concern, linked with persistent post-concussive syndrome, and chronic traumatic encephalopathy. At present, standard clinical imaging fails to reliably detect traumatic axonal injury associated with concussion and post-concussive symptoms. Diffusion tensor imaging (DTI) is an MR imaging technique that is sensitive to changes in white matter microstructure. Prior studies using DTI did not jointly investigate white matter microstructure in athletes, a population at high risk for concussive and subconcussive head traumas, with those in typical emergency room (ER) patients. In this study, we determine DTI scalar metrics in both ER patients and scholastic athletes who suffered concussions and compared them to those in age-matched healthy controls. In the early subacute post-concussion period, athletes demonstrated an elevated rate of regional decreases in axial diffusivity (AD) compared to controls. These regional decreases of AD were especially pronounced in the cerebellar peduncles, and were more frequent in athletes compared to the ER patient sample. The group differences may indicate differences in the mechanisms of the concussive impacts as well as possible compound effects of cumulative subconcussive impacts in athletes. The prevalence of white matter abnormality in cerebellar tracts lends credence to the hypothesis that post-concussive symptoms are caused by shearing of axons within an attention network mediated by the cerebellum, and warrant further study of the correlation between cerebellar DTI findings and clinical, neurocognitive, oculomotor, and vestibular outcomes in mTBI patients.

Absence of the basilar pons in mice lacking a functional Large glycosyltransferase gene suggests a defect in pontine neuron migration.

Several forms of congenital muscular dystrophy result from mutations in glycosyltransferases that modify alpha-dystroglycan. As pontine hypoplasia has been reported in some clinical cases of congenital muscular dystrophy, we have begun to examine whether these glycosyltransferases are required for the normal development of the basilar pons, one of several precerebellar nuclei of the hindbrain. In veils (Large(vls)) mice, which carry a loss-of-function mutation in the Large glycosyltransferase gene, the basilar pons is absent. Instead, ectopic clusters of pontine neurons are found lateral to their normal site, suggesting that these neurons are unable to migrate to their appropriate site. Two other precerebellar nuclei, the lateral reticular nucleus and the inferior olive, are present in Large(vls) mice. In addition, the basilar pons forms normally in dystrophin-deficient mice. These results demonstrate that the Large glycosyltransferase but not dystrophin is required for normal basilar pontine development.