Frontal and thalamic changes of GABA concentration indicate dysfunction of thalamofrontal networks in juvenile myoclonic epilepsy.

OBJECTIVE: Juvenile myoclonic epilepsy (JME) has been considered to be a frontal variant of thalamocortical network dysfunction in epilepsy. Changes of γ-aminobutyric acid (GABA)ergic neurotransmission may play a key role in this dysfunction. Magnetic resonance spectroscopy (MRS) is the only noninvasive method to measure GABA concentrations in different brain regions. We measured GABA and other metabolite concentrations in the thalamus and frontal lobe of patients with JME. METHODS: A specific protocol was used for determining GABA concentrations in the thalamus, frontal lobe, and motor cortex contralateral to the handedness in 15 patients with JME and 15 age-matched controls. In addition, we measured concentrations of glutamate and glutamine, N-acetyl-aspartate (NAA), myoinositol, creatine, and choline using MRS with short echo time. JME-related concentration changes were analyzed comparing patients to controls, also considering potential effects of antiepileptic drugs. RESULTS: In patients with JME, GABA and NAA were reduced in the thalamus (p = 0.03 and p = 0.02), whereas frontal GABA and glutamine were elevated (p = 0.046 and p = 0.03). MRS revealed reduced NAA in the thalamic gray matter contralateral to the handedness (p = 0.04 each). These changes were found consistently in patients treated with new antiepileptic drugs and with valproate, although the extent of metabolic changes differed between these treatments. SIGNIFICANCE: Decreased thalamic and increased frontal GABA suggest a dysfunction of GABAergic neurotransmission in these brain regions of patients with JME. The NAA decrease in the gray matter of the thalamus may hint to a damage of GABAergic neurons, whereas frontal increase of GABA and its precursor glutamine may reflect increased density in GABAergic neurons due to subtle cortical disorganization in the thalamofrontal network.

MRI-Derived Dural Sac and Lumbar Vertebrae 3D Volumetry Has Potential for Detection of Marfan Syndrome.

PURPOSE: To assess the feasibility and diagnostic accuracy of MRI-derived 3D volumetry of lower lumbar vertebrae and dural sac segments using shape-based machine learning for the detection of Marfan syndrome (MFS) compared with dural sac diameter ratios (the current clinical standard). MATERIALS AND METHODS: The final study sample was 144 patients being evaluated for MFS from 01/2012 to 12/2016, of whom 81 were non-MFS patients (46 [67%] female, 36 ± 16 years) and 63 were MFS patients (36 [57%] female, 35 ± 11 years) according to the 2010 Revised Ghent Nosology. All patients underwent 1.5T MRI with isotropic 1 × 1 × 1 mm3 3D T2-weighted acquisition of the lumbosacral spine. Segmentation and quantification of vertebral bodies L3-L5 and dural sac segments L3-S1 were performed using a shape-based machine learning algorithm. For comparison with the current clinical standard, anteroposterior diameters of vertebral bodies and dural sac were measured. Ratios between dural sac volume/diameter at the respective level and vertebral body volume/diameter were calculated. RESULTS: Three-dimensional volumetry revealed larger dural sac volumes (p < 0.001) and volume ratios (p < 0.001) at L3-S1 levels in MFS patients compared with non-MFS patients. For the detection of MFS, 3D volumetry achieved higher AUCs at L3-S1 levels (0.743, 0.752, 0.808, and 0.824) compared with dural sac diameter ratios (0.673, 0.707, 0.791, and 0.848); a significant difference was observed only for L3 (p < 0.001). CONCLUSION: MRI-derived 3D volumetry of the lumbosacral dural sac and vertebral bodies is a feasible method for quantifying dural ectasia using shape-based machine learning. Non-inferior diagnostic accuracy was observed compared with dural sac diameter ratio (the current clinical standard for MFS detection).

Resolving the spatial architecture of myeloma and its microenvironment at the single-cell level.

In multiple myeloma spatial differences in the subclonal architecture, molecular signatures and composition of the microenvironment remain poorly characterized. To address this shortcoming, we perform multi-region sequencing on paired random bone marrow and focal lesion samples from 17 newly diagnosed patients. Using single-cell RNA- and ATAC-seq we find a median of 6 tumor subclones per patient and unique subclones in focal lesions. Genetically identical subclones display different levels of spatial transcriptional plasticity, including nearly identical profiles and pronounced heterogeneity at different sites, which can include differential expression of immunotherapy targets, such as CD20 and CD38. Macrophages are significantly depleted in the microenvironment of focal lesions. We observe proportional changes in the T-cell repertoire but no site-specific expansion of T-cell clones in intramedullary lesions. In conclusion, our results demonstrate the relevance of considering spatial heterogeneity in multiple myeloma with potential implications for models of cell-cell interactions and disease progression.