Emil Malucelli

Diffusion tensor MRI changes in cerebellar structures of patients with familial essential tremor

Objective: The aim of our study was to investigate the microstructural integrity of brain regions functionally involved in the tremor loop in patients with familial essential tremor (FET), using diffusion tensor imaging (DTI). Methods: Twenty-five patients with FET, 15 patients with Parkinson disease (PD), and 15 healthy subjects were studied. DTI was performed to measure fractional anisotropy (FA) and mean diffusivity (MD) in various regions of interest: red nucleus, dentate nucleus (DN), cerebellar white matter, middle (MCP) and superior cerebellar peduncle (SCP), and ventrolateral thalamus. Results: In patients with FET, FA values in the DN (median 0.19, range 0.13–0.23) were reduced (p < 0.001) compared with patients with PD (median 0.37, range 0.32–0.58) and healthy controls (median 0.36, range 0.33–0.40). In patients with FET, FA was also reduced (p = 0.003) and MD values increased (p < 0.001) in the SCP compared with patients with PD and healthy controls. Among patients with FET, those with longer disease duration showed FA values in the DN lower than those with shorter disease duration (p = 0.018). Patients with FET could be completely distinguished from both patient with PD and healthy controls using FA values of the DN alone. Conclusion: Neuroimaging evidence of microstructural changes consistent with neurodegeneration was found in the dentate nucleus (DN) and SCP of patients with familial essential tremor. This suggests that neurodegenerative pathology of cerebellar structures may play a role in essential tremor. Further studies are needed to assess the role of fractional anisotropy and mean diffusivity changes in DN and SCP in the differential diagnosis of essential tremor and Parkinson disease, which may present similar clinical signs at the onset of disease.

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).

Abnormal medial thalamic metabolism in patients with idiopathic restless legs syndrome

Pathophysiology of restless legs syndrome is poorly understood. A role of the thalamus, specifically of its medial portion which is a part of the limbic system, was suggested by functional magnetic resonance imaging and positron emission tomography studies. The aim of this study was to evaluate medial thalamus metabolism and structural integrity in patients with idiopathic restless legs syndrome using a multimodal magnetic resonance approach, including proton magnetic resonance spectroscopy, diffusion tensor imaging, voxel-based morphometry and volumetric and shape analysis. Twenty-three patients and 19 healthy controls were studied in a 1.5u2009T system. Single voxel proton magnetic resonance spectra were acquired in the medial region of the thalamus. In diffusion tensor examination, mean diffusivity and fractional anisotropy were determined at the level of medial thalamus using regions of interest delineated to outline the same parenchyma studied by spectroscopy. Voxel-based morphometry was performed focusing the analysis on the thalamus. Thalamic volumes were obtained using FMRIBs Integrated Registration and Segmentation Tool software, and shape analysis was performed using the FMRIB Software Library tools. Proton magnetic resonance spectroscopy study disclosed a significantly reduced N-acetylaspartate:creatine ratio and N-acetylaspartate concentrations in the medial thalamus of patients with restless legs syndrome compared with healthy controls (Pu2009<u20090.01 for both variable). Lower N-acetylaspartate concentrations were significantly associated with a family history of restless legs syndrome (βu2009=u2009-0.49; Pu2009=u20090.018). On the contrary, diffusion tensor imaging, voxel-based morphometry and volumetric and shape analysis of the thalami did not show differences between the two groups. Proton magnetic resonance spectroscopic findings in patients with restless legs syndrome indicate an involvement of medial thalamic nuclei of a functional nature; however, the other structural techniques of the same region did not show any changes. These findings support the hypothesis that dysfunction of the limbic system plays a role in the pathophysiology of idiopathic restless legs syndrome.

Magnetic resonance diagnostic markers in clinically sporadic prion disease: a combined brain magnetic resonance imaging and spectroscopy study

The intra vitam diagnosis of prion disease is challenging and a definite diagnosis still requires neuropathological examination in non-familial cases. Magnetic resonance imaging has gained increasing importance in the diagnosis of prion disease. The aim of this study was to compare the usefulness of different magnetic resonance imaging sequences and proton magnetic resonance spectroscopy in the differential diagnosis of patients with rapidly progressive neurological signs compatible with the clinical diagnosis of sporadic prion disease. Twenty-nine consecutive patients with an initial diagnosis of possible or probable sporadic prion disease, on the basis of clinical and electroencephalography features, were recruited. The magnetic resonance protocol included axial fluid-attenuated inversion recovery-T2- and diffusion-weighted images, and proton magnetic resonance spectroscopy of the thalamus, striatum, cerebellum and occipital cortex. Based on the clinical follow-up, genetic studies and neuropathology, the final diagnosis was of prion disease in 14 patients out of 29. The percentage of correctly diagnosed cases was 86% for diffusion-weighted imaging (hyperintensity in the striatum/cerebral cortex), 86% for thalamic N-acetyl-aspartate to creatine ratio (cutoff ≤1.21), 90% for thalamic N-acetyl-aspartate to myo-inositol (mI) ratio (cutoff ≤1.05) and 86% for cerebral spinal fluid 14-3-3 protein. All the prion disease patients had N-acetyl-aspartate to creatine ratios ≤1.21 (100% sensitivity and 100% negative predictive value) and all the non-prion patients had N-acetyl-aspartate to myo-inositol ratios >1.05 (100% specificity and 100% positive predictive value). Univariate logistic regression analysis showed that the combination of thalamic N-acetyl-aspartate to creatine ratio and diffusion-weighted imaging correctly classified 93% of the patients. The combination of thalamic proton magnetic resonance spectroscopy (10 min acquisition duration) and brain diffusion-weighted imaging (2 min acquisition duration) may increase the diagnostic accuracy of the magnetic resonance scan. Both sequences should be routinely included in the clinical work-up of patients with suspected prion disease.

Brain diffusion-weighted imaging in Friedreich's ataxia.

Friedreich ataxia (FRDA) is the commonest form of autosomal recessive ataxia. This study aimed to define the extent of the brain damage in FRDA patients and to identify in vivo markers of neurodegeneration, using diffusion‐weighted imaging (DWI).

Defective mitochondrial adenosine triphosphate production in skeletal muscle from patients with dominant optic atrophy due to OPA1 mutations.

OBJECTIVEnTo assess whether impaired energy metabolism in skeletal muscle is a hallmark feature of patients with dominant optic atrophy due to several different mutations in the OPA1 gene.nnnDESIGNnWe used phosphorus 31 magnetic resonance spectroscopy to assess calf muscle oxidative metabolism in subjects with molecularly defined dominant optic atrophy carrying different mutations in the OPA1 gene. In a subset of patients, we also evaluated serum lactate levels after exercise and muscle biopsy results for histology and mitochondrial DNA analysis.nnnSETTINGnUniversity neuromuscular and neurogenetics and magnetic resonance imaging units.nnnPATIENTSnEighteen patients with dominant optic atrophy were enrolled from 8 unrelated families, 7 of which carried an OPA1 mutation predicted to induce haploinsufficiency and 1 with a missense mutation in exon 27. Fifteen patients had documented optic atrophy.nnnMAIN OUTCOME MEASURESnPresence of skeletal muscle mitochondrial oxidative phosphorylation dysfunction as assessed by phosphorus 31 magnetic resonance spectroscopy, serum lactate levels, and histological and mitochondrial DNA analysis.nnnRESULTSnPhosphorus 31 magnetic resonance spectroscopy showed reduced phosphorylation potential in the calf muscle at rest in patients with an OPA1 mutation (-24% from normal mean; P = .003) as well as a reduced maximum rate of mitochondrial adenosine triphosphate synthesis (-36%; P < .001; ranging from -28% to -49% in association with different mutations). In 4 of 10 patients (40%), the serum lactate level after exercise was elevated. Only 2 of 5 muscle biopsies, from the 2 patients with a missense mutation, showed slight myopathic changes. Low levels of mitochondrial DNA multiple deletions were found in all muscle biopsies.nnnCONCLUSIONSnDefective oxidative phosphorylation in skeletal muscle is a subclinical feature of patients with OPA1-related dominant optic atrophy, indicating a systemic expression of the OPA1 defect, similar to that previously reported for Leber hereditary optic neuropathy due to complex I dysfunction. This defect of oxidative phosphorylation does not appear to depend on the low amounts of mitochondrial DNA multiple deletions detected in muscle biopsies.

Prognostic value of brain proton MR spectroscopy and diffusion tensor imaging in newborns with hypoxic-ischemic encephalopathy treated by brain cooling

IntroductionMRI, proton magnetic resonance spectroscopy (1H-MRS), and diffusion tensor imaging (DTI) have been shown to be of great prognostic value in term newborns with moderate–severe hypoxic-ischemic encephalopathy (HIE). Currently, no data are available on 1H-MRS and DTI performed in the subacute phase after hypothermic treatment. The aim of the present study was to assess their prognostic value in newborns affected by moderate–severe HIE and treated with selective brain cooling (BC).MethodsTwenty infants treated with BC underwent conventional MRI and 1H-MRS at a mean (SD) age of 8.3 (2.8) days; 15 also underwent DTI. Peak area ratios of metabolites and DTI variables, namely mean diffusivity (MD), axial and radial diffusivity, and fractional anisotropy (FA), were calculated. Clinical outcome was monitored until 2xa0years of age.ResultsAdverse outcome was observed in 6/20 newborns. Both 1H-MRS and DTI variables showed higher prognostic accuracy than conventional MRI. N-acetylaspartate/creatine at a basal ganglia localisation showed 100xa0% PPV and 93xa0% NPV for outcome. MD showed significantly decreased values in many regions of white and gray matter, axial diffusivity showed the best predictive value (PPV and NPV) in the genu of corpus callosum (100 and 91xa0%, respectively), and radial diffusivity was significantly decreased in fronto white matter (FWM) and fronto parietal (FP) WM. The decrement of FA showed the best AUC (0.94) in the FPWM.ConclusionSelective BC in HIE neonates does not affect the early and accurate prognostic value of 1H-MRS and DTI, which outperform conventional MRI.

Combined brain voxel‐based morphometry and diffusion tensor imaging study in idiopathic Restless Legs Syndrome patients

Background and purpose:u2002 The aim of this study was to evaluate the presence of abnormalities in the brain of patients with restless legs syndrome (RLS) using voxel‐based morphometry and diffusion tensor imaging (DTI).

Clinical and neuroimaging evidence of interictal cerebellar dysfunction in FHM2

We used multimodal magnetic resonance (MR) techniques [brain diffusion-weighted magnetic resonance imaging, diffusion-weighted imaging (DWI), proton MR spectroscopy (MRS), 1H-MRS; and skeletal muscle phosphorous MRS, 31P-MRS] to investigate interictal brain microstructural changes and tissue energy metabolism in four women with genetically determined familial hemiplegic migraine type 2 (FHM2), belonging to two unrelated families, compared with 10 healthy women. Brain DWI revealed a significant increase of the apparent diffusion coefficient median values in the vermis and cerebellar hemispheres of FHM2 patients, preceding in two subjects the onset of interictal cerebellar deficits. 31P-MRS revealed defective energy metabolism in skeletal muscle of FHM2 patients, while brain 1H-MRS showed a mild pathological increase in lactate in the lateral ventricles of one patient and a mild reduction of cortical N-acetyl-aspartate to creatine ratio in another one. Our MRS results showed that a multisystem energy metabolism defect in FHM2 is associated with microstructural cerebellar changes detected by DWI, even before the onset of cerebellar symptoms.

Secondary post-geniculate involvement in Leber's hereditary optic neuropathy.

Leber’s hereditary optic neuropathy (LHON) is characterized by retinal ganglion cell (RGC) degeneration with the preferential involvement of those forming the papillomacular bundle. The optic nerve is considered the main pathological target for LHON. Our aim was to investigate the possible involvement of the post-geniculate visual pathway in LHON patients. We used diffusion-weighted imaging for in vivo evaluation. Mean diffusivity maps from 22 LHON visually impaired, 11 unaffected LHON mutation carriers and 22 healthy subjects were generated and compared at level of optic radiation (OR). Prefrontal and cerebellar white matter were also analyzed as internal controls. Furthermore, we studied the optic nerve and the lateral geniculate nucleus (LGN) in post-mortem specimens obtained from a severe case of LHON compared to an age-matched control. Mean diffusivity values of affected patients were higher than unaffected mutation carriers (P<0.05) and healthy subjects (P<0.01) in OR and not in the other brain regions. Increased OR diffusivity was associated with both disease duration (Bu200a=u200a0.002; P<0.05) and lack of recovery of visual acuity (Bu200a=u200a0.060; P<0.01). Post-mortem investigation detected atrophy (41.9% decrease of neuron soma size in the magnocellular layers and 44.7% decrease in the parvocellular layers) and, to a lesser extent, degeneration (28.5% decrease of neuron density in the magnocellular layers and 28.7% decrease in the parvocellular layers) in the LHON LGN associated with extremely severe axonal loss (99%) in the optic nerve. The post-geniculate involvement in LHON patients is a downstream post-synaptic secondary phenomenon, reflecting de-afferentation rather than a primary neurodegeneration due to mitochondrial dysfunction of LGN neurons.