Laura Ludovica Gramegna

Low brain iron content in idiopathic restless legs syndrome patients detected by phase imaging

The objective of this study was to use phase imaging to evaluate brain iron content in patients with idiopathic restless legs syndrome (RLS).

Liver transplantation for mitochondrial neurogastrointestinal encephalomyopathy

Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is a fatal, recessive disease caused by mutations in the gene encoding thymidine phosphorylase, leading to reduced enzymatic activity, toxic nucleoside accumulation, and secondary mitochondrial DNA damage. Thymidine phosphorylase replacement has been achieved by allogeneic hematopoietic stem cell transplantation, a procedure hampered by high mortality. Based on high thymidine phosphorylase expression in the liver, a 25‐year‐old severely affected patient underwent liver transplantation. Serum levels of toxic nucleosides rapidly normalized. At 400 days of follow‐up, the patients clinical conditions are stable. We propose liver transplantation as a new therapy for MNGIE. Ann Neurol 2016;80:448–455

Relationship of white and gray matter abnormalities to clinical and genetic features in myotonic dystrophy type 1

Background Myotonic dystrophy type 1 (DM1) represents a multisystemic disorder in which diffuse brain white and gray matter alterations related to clinical and genetic features have been described. We aimed to evaluate in the brain of adult patients with DM1 (i) white and gray matter differences, including cortical-subcortical gray matter volume and cortical thickness and (ii) their correlation with clinical disability, global neuropsychological performance and triplet expansion. Methods We included 24 adult genetically-confirmed DM1 patients (14 males; age: 38.5 ± 11.8 years) and 25 age- and sex-matched healthy controls (14 males; age: 38.5 ± 11.3 years) who underwent an identical brain MR protocol including high-resolution 3D T1-weighted, axial T2 FLAIR and DTI sequences. All patients underwent an extensive clinical and neuropsychological evaluation. Voxel-wise analyses of white matter, performed by using Tract Based Spatial Statistics, and of gray matter, with Voxel-based Morphometry and Cortical Thickness, were carried out in order to test for differences between patients with DM1 and healthy controls (p < 0.05, corrected). The correlation between MRI measures and clinical-genetic features was also assessed. Results Patients with DM1 showed widespread abnormalities of all DTI parameters in the white matter, which were associated with reduced gray matter volume in all brain lobes and thinning in parieto-temporo-occipital cortices, albeit with less extensive cortical alterations when congenital cases were removed from the analyses. White matter alterations correlated with clinical disability, global cognitive performance and triplet expansions. Conclusion In patients with DM1, the combined smaller overall gray matter volume and white matter alterations seem to be the main morpho-structural substrates of CNS involvement in this condition. The correlation of white matter differences with both clinical and genetic findings lends support to this notion.

Accuracy of MR markers for differentiating Progressive Supranuclear Palsy from Parkinson's disease

Background Advanced brain MR techniques are useful tools for differentiating Progressive Supranuclear Palsy from Parkinsons disease, although time-consuming and unlikely to be used all together in routine clinical work. We aimed to compare the diagnostic accuracy of quantitative morphometric, volumetric and DTI metrics for differentiating Progressive Supranuclear Palsy-Richardsons Syndrome from Parkinsons disease. Methods 23 Progressive Supranuclear Palsy-Richardsons Syndrome and 42 Parkinsons disease patients underwent a standardized 1.5T brain MR protocol comprising high-resolution T1W1 and DTI sequences. Brainstem and cerebellar peduncles morphometry, automated volumetric analysis of brain deep gray matter and DTI metric analyses of specific brain structures were carried out. We determined diagnostic accuracy, sensitivity and specificity of MR-markers with respect to the clinical diagnosis by using univariate receiver operating characteristics curve analyses. Age-adjusted multivariate receiver operating characteristics analyses were then conducted including only MR-markers with a sensitivity and specificity exceeding 80%. Results Morphometric markers (midbrain area, pons to midbrain area ratio and MR Parkinsonism Index), DTI parameters (infratentorial structures) and volumetric analysis (thalamus, putamen and pallidus nuclei) presented moderate to high diagnostic accuracy in discriminating Progressive Supranuclear Palsy-Richardsons Syndrome from Parkinsons disease, with midbrain area showing the highest diagnostic accuracy (99%) (mean ± standard deviation: 75.87 ± 16.95 mm2vs 132.45 ± 20.94 mm2, respectively; p < 0.001). Conclusion Although several quantitative brain MR markers provided high diagnostic accuracy in differentiating Progressive Supranuclear Palsy-Richardsons Syndrome from Parkinsons disease, the morphometric assessment of midbrain area is the best single diagnostic marker and should be routinely included in the neuroradiological work-up of parkinsonian patients.

Brain magnetic resonance metabolic and microstructural changes in adult-onset autosomal dominant leukodystrophy.

INTRODUCTION adult-onset autosomal dominant leukodystrophy (ADLD) is a rare inherited disorder due to a duplication of lamin-B1 (LMNB1) gene. The aim of this study was to investigate brain metabolic and microstructural alterations by using advanced MR techniques. METHODS we performed brain MR scans including single-voxel proton-MR Spectroscopy ((1)H-MRS) of the lateral ventricles and parietal white matter and diffusion tensor imaging (DTI) in 4 subjects with LMNB1 gene duplication, 6 non-mutated relatives and 7 unrelated healthy controls. Cervical and thoracic spinal cord MR was performed in three symptomatic subjects with LMNB1 mutation. All participants underwent clinical and neuropsychological evaluation. RESULTS all subjects with LMNB1 gene duplication presented pathological accumulation of lactate in lateral ventricles CSF and no alterations of brain white matter absolute metabolites concentrations or metabolites/Cr ratios. We found increased white matter intra- and extracellular water transverse relaxation times. Tract-based spatial statistics analysis detected a significantly reduced fractional anisotropy in the genu of the corpus callosum in mutated cases compared to unrelated healthy controls and non-mutated relatives. Moreover, we detected different degrees of the typical white matter signal intensity alterations and brain and spinal atrophy at conventional MRI in symptomatic subjects with LMNB1 mutation. A mild impairment of executive functions was found in subjects with LMNB1 gene mutation. CONCLUSION in subjects with LMNB1 gene duplication, we found a pathological increase in CSF lactate, likely due to active demyelination along with glial activation, and microstructural changes in the genu of the corpus callosum possibly underpinning the mild neuropsychological deficits.

Combined Cerebellar Proton MR Spectroscopy and DWI Study of Patients with Friedreich’s Ataxia

Friedreich’s ataxia (FRDA) is the commonest autosomal recessive ataxia, caused by GAA triplet expansion in the frataxin gene. Neuropathological studies in FRDA demonstrate that besides the primary neurodegeneration of the dorsal root ganglia, there is a progressive atrophy of the cerebellar dentate nucleus. Diffusion-weighted imaging (DWI) detected microstructural alterations in the cerebellum of FRDA patients. To investigate the biochemical basis of these alterations, we used both DWI and proton MR spectroscopy (1H-MRS) to study the same cerebellar volume of interest (VOI) including the dentate nucleus. DWI and 1H-MRS study of the left cerebellar hemisphere was performed in 28 genetically proven FRDA patients and 35 healthy controls. In FRDA mean diffusivity (MD) values were calculated for the same 1H-MRS VOI. Clinical severity was evaluated using the International Cooperative Ataxia Rating Scale (ICARS). FRDA patients showed a significant reduction of N-acetyl-aspartate (NAA), a neuroaxonal marker, and choline (Cho), a membrane marker, both expressed relatively to creatine (Cr), and increased MD values. In FRDA patients NAA/Cr negatively correlated with MD values (r = −0.396, p = 0.037) and with ICARS score (r = −0.669, p < 0.001). Age-normalized NAA/Cr loss correlated with the GAA expansion (r = −0.492, p = 0.008). The reduced cerebellar NAA/Cr in FRDA suggests that neuroaxonal loss is related to the microstructural changes determining higher MD values. The correlation between NAA/Cr and the severity of disability suggests that this biochemical in vivo MR parameter might be a useful biomarker to evaluate therapeutic interventions.

Magnetic resonance imaging and spectroscopy in the evaluation of neuromuscular disorders and fatigue

Magnetic resonance imaging represents a validated diagnostic tool in the investigation of neuromuscular disorders. Magnetic resonance imaging can detect key skeletal muscle abnormalities such as size, shape and signal intensity changes reflecting fatty infiltration, muscle atrophy or muscle edema. In vivo phosphorus magnetic resonance spectroscopy is able to provide objective measurements of muscle energy metabolism and cytosolic pH at rest, during exercise, and during recovery from exercise. Its primary role is the investigating of metabolic myopathies, and it has been used to detect the underlying biochemical mechanisms responsible for the development of fatigue. In this mini-review, we report the main contribution provided by conventional and advanced magnetic resonance imaging and phosphorus magnetic resonance spectroscopy in the exploration of fatigue in normal muscle and in neuromuscular disorders.

The effect of diffusion gradient direction number on corticospinal tractography in the human brain: an along-tract analysis

ObjectivesWe evaluated diffusion imaging measures of the corticospinal tract obtained with a probabilistic tractography algorithm applied to data of two acquisition protocols based on different numbers of diffusion gradient directions (NDGDs).Materials and methodsThe corticospinal tracts (CST) of 18 healthy subjects were delineated using 22 and 66-NDGD data. An along-tract analysis of diffusion metrics was performed to detect possible local differences due to NDGD.ResultsFA values at 22-NDGD showed an increase along the central portion of the CST. The mean of partial volume fraction of the orientation of the second fiber (f2) was higher at 66-NDGD bilaterally, because for 66-NDGD data the algorithm more readily detects dominant fiber directions beyond the first, thus the increase in FA at 22-NDGD is due to a substantially reduced detection of crossing fiber volume. However, the good spatial correlation between the tracts drawn at 22 and 66 NDGD shows that the extent of the tract can be successfully defined even at lower NDGD.ConclusionsGiven the spatial tract localization obtained even at 22-NDGD, local analysis of CST can be performed using a NDGD compatible with clinical protocols. The probabilistic approach was particularly powerful in evaluating crossing fibers when present.

Brain functional connectivity in sleep-related hypermotor epilepsy

Objectives To evaluate functional connectivity (FC) in patients with sleep-related hypermotor epilepsy (SHE) compared to healthy controls. Methods Resting state fMRI was performed in 13 patients with a clinical diagnosis of SHE (age = 38.3 ± 11.8 years, 6 M) and 13 matched healthy controls (age = 38.5 ± 10.8 years, 6 M). Data were first analysed using probabilistic independent component analysis (ICA), then a graph theoretical approach was applied to assess topological and organizational properties at the whole brain level. We evaluated node degree (ND), betweenness centrality (BC), clustering coefficient (CC), local efficiency (LE) and global efficiency (GE). The differences between the two groups were evaluated non-parametrically. Results At the group level, we distinguished 16 RSNs (Resting State Networks). Patients showed a significantly higher FC in sensorimotor and thalamic regions (p < 0.05 corrected). Compared to controls, SHE patients showed no significant differences in network global efficiency, while ND and BC were higher in regions of the limbic system and lower in the occipital cortex, while CC and LE were higher in regions of basal ganglia and lower in limbic areas (p < 0.05 uncorrected). Discussion and conclusions The higher FC of the sensorimotor cortex and thalamus might be in agreement with the hypothesis of a peculiar excitability of the motor cortex during thalamic K-complexes. This sensorimotor-thalamic hyperconnection might be regarded as a consequence of an alteration of the arousal regulatory system in SHE. An altered topology has been found in structures like basal ganglia and limbic system, hypothesized to be involved in the pathophysiology of the disease as suggested by the dystonic-dyskinetic features and primitive behaviours observed during the seizures.

Cerebral Mitochondrial Microangiopathy Leads to Leukoencephalopathy in Mitochondrial Neurogastrointestinal Encephalopathy

BACKGROUND AND PURPOSE: Mitochondrial neurogastrointestinal encephalopathy is a rare disorder due to recessive mutations in the thymidine phosphorylase gene, encoding thymidine phosphorylase protein required for mitochondrial DNA replication. Clinical manifestations include gastrointestinal dysmotility and diffuse asymptomatic leukoencephalopathy. This study aimed to elucidate the mechanisms underlying brain leukoencephalopathy in patients with mitochondrial neurogastrointestinal encephalopathy by correlating multimodal neuroradiologic features to postmortem pathology. MATERIALS AND METHODS: Seven patients underwent brain MR imaging, including single-voxel proton MR spectroscopy and diffusion imaging. Absolute concentrations of metabolites calculated by acquiring unsuppressed water spectra at multiple TEs, along with diffusion metrics based on the tensor model, were compared with those of healthy controls using unpaired t tests in multiple white matters regions. Brain postmortem histologic, immunohistochemical, and molecular analyses were performed in 1 patient. RESULTS: All patients showed bilateral and nearly symmetric cerebral white matter hyperintensities on T2-weighted images, extending to the cerebellar white matter and brain stem in 4. White matter, N-acetylaspartate, creatine, and choline concentrations were significantly reduced compared with those in controls, with a prominent increase in the radial water diffusivity component. At postmortem examination, severe fibrosis of brain vessel smooth muscle was evident, along with mitochondrial DNA replication depletion in brain and vascular smooth-muscle and endothelial cells, without neuronal loss, myelin damage, or gliosis. Prominent periependymal cytochrome C oxidase deficiency was also observed. CONCLUSIONS: Vascular functional and histologic alterations account for leukoencephalopathy in mitochondrial neurogastrointestinal encephalopathy. Thymidine toxicity and mitochondrial DNA replication depletion may induce microangiopathy and blood-brain-barrier dysfunction, leading to increased water content in the white matter. Periependymal cytochrome C oxidase deficiency could explain prominent periventricular impairment.