Laura Guerrini

Single-voxel long TE 1H-MR spectroscopy of the normal brainstem and cerebellum

To evaluate the feasibility of single voxel 1H‐MRS of the CNS structures contained in the posterior cranial fossa and to determine the distribution of the normal metabolite ratios, concentrations, and T2 relaxation times in the midbrain, pons, medulla, dentate nucleus and cerebellar vermis.

Phenotype variability of neural crest derived tumours in six Italian families segregating the same founder SDHD mutation Q109X

Background: Mutations in genes coding for the mitochondrial complex II succinate dehydrogenase (SDH) subunits cause familial neural crest derived (NCD) tumours. Methods: Index cases from six apparently unrelated families affected by NCD tumours were analysed for mutations in the SDHB, SDHC, and SDHD genes. Results: The same nonsense germline heterozygous mutation (Q109X) in exon 4 of the SDHD gene was found in each of the six families. Overall, 43 heterozygotes were identified. These were evaluated for the presence of NCD tumours through radiological examination of the neck, thorax, and abdomen, and measurement of urinary metanephrines and plasma chromogranin A. A novel missense SDHD variant, T112I, which did not segregate with the Q109X mutation and was not associated with phenotypic manifestations, was observed in one of the families. Microsatellite analysis showed a common haplotype in all individuals heterozygous for the Q109X mutation, indicating a founder effect. Overall, 18 heterozygotes were clinically affected by at least one NCD tumour. Every affected patient inherited the germline mutation from the father, confirming SDHD maternal genomic imprinting. Penetrance of the paternally inherited mutation progressively increased from 33% to 83% at 30 and 60 years, respectively. Affected patients showed high clinical variability, ranging from monolateral to bilateral glomus tumours variably associated or not with paragangliomas or phaeochromocytomas. Loss of heterozygosity was observed in tumour cells isolated by laser capture microdissection. Conclusions: This study shows that a single founder SDHD mutation is present in an area of central Italy and that this mutation is associated with widely variable interfamilial and intrafamilial expressivity.

ADC mapping of neurodegeneration in the brainstem and cerebellum of patients with progressive ataxias.

Analysis of the apparent diffusion coefficient (ADC) maps derived from diffusion-weighted MR imaging is emerging as a reproducible, sensitive, and quantitative tool to evaluate brain damage in diseases of the white and gray matter. To explore the potentials of ADC maps analysis in degenerative ataxias, we examined 28 patients and 26 age-matched controls with T1, T2, and diffusion (b values 0-1000 along the three main body axes)-weighted MR images. Twenty-four patients had inherited genetically proven diseases including spinocerebellar ataxia type 1 (SCA1) (n = 9), spinocerebellar ataxia type 2 (SCA2) (n = 8), and Friedreichs ataxia (FA) (n = 7), whereas four patients had sporadic adult onset pure cerebellar ataxia (three idiopathic, one gluten intolerance). Area and linear measurements of the CNS structures contained in the posterior cranial fossa (PCF) preliminary enabled classification of the patients in the three morphological categories reflecting the gross pathology findings, namely olivopontocerebellar atrophy (OPCA) (n = 10: six SCA2 and four SCA1), spinal atrophy (SA) (n = 7: all FA), and cortical cerebellar atrophy (CCA) (n = 4: three idiopathic and one gluten intolerance). Seven patients with SCA1 (n = 5) or SCA2 (n = 2) had morphologic changes reminiscent of OPCA, but their values were still in the lower normal range and were classified as undefined. Mean diffusivity (D) maps of the entire brain were generated and D was measured with regions of interest (ROI) in the medulla, pons, middle cerebellar peduncles, and the peridentate white matter. Moreover, after exclusion of the skull with manual segmentation and of the CSF with application of a threshold value, histograms were obtained for D of the brainstem and cerebellum and for D of the cerebral hemispheres. As compared to controls, a (P < 0.001) increase of D was observed in the medulla, middle cerebellar peduncles, and peridentate white matter in OPCA and undefined patients groups who had also significantly increased values of the 25th and 50th percentiles in the brainstem and cerebellum D histogram. In CCA (P = 0.01), an increase of the 25th and 50th percentile of the D value was observed in the brainstem and cerebellum histograms. The SA group showed (P < 0.001) an increased D in the medulla only. A correlation between clinical severity as assessed with the Inherited Ataxias Clinical Rating Scale (IACRS) and the 50th percentile of the D value in the brainstem and cerebellum histogram (r = 0.69) was observed in patients with SCA1 or SCA2. Diffusion MR imaging reveals variable patterns of increase of D in the brainstem, cerebellum, and cerebral hemispheres in degenerative ataxias that match the known distribution of the neuropathological changes.

Combining functional and structural brain magnetic resonance imaging in Huntington disease.

Objective: To concurrently investigate with magnetic resonance (MR) the brain activation and regional brain atrophy in patients with Huntington disease (HD). Methods: Nine symptomatic HD patients and 11 healthy subjects underwent an MR study including functional MR acquisition during finger tapping of the right hand and high-resolution T1-weighted images. Functional and structural data were analyzed using Statistical Parametric Mapping 2 software. Results: As compared with control subjects, HD patients showed decreased activation in the left caudate nucleus and medial frontal and anterior cingulate gyri and increased activation in the right supplementary motor area and supramarginal gyrus and left intraparietal sulcus. The pattern of atrophy included thinning of the gray matter (GM) in the insula, inferior frontal gyrus, caudate, lentiform nucleus, and thalamus, bilaterally, in the left middle frontal, middle occipital, and middle temporal gyri, and of periventricular, subinsular, right temporal lobe, and left internal capsule white matter. Only the decreased activation in the caudate nucleus correlated topographically with the caudate GM loss. Conclusion: The cortical areas of functional changes do not correspond to those of GM atrophy in patients with HD and are likely to reflect decreased output of the motor basal ganglia-thalamo-cortical circuit and compensatory recruitment of accessory motor pathways.

Impact of cerebrospinal fluid contamination on brain metabolites evaluation with 1H-MR spectroscopy: A single voxel study of the cerebellar vermis in patients with degenerative ataxias

To investigate the impact of cerebrospinal fluid (CSF) contamination on metabolite evaluation in the superior cerebellar vermis with single‐voxel 1H‐MRS in normal subjects and patients with degenerative ataxias.

Multiparametric MRI in a patient with adult-onset leukoencephalopathy with vanishing white matter

This is a multiparametric MR study of the first reported patient with adult-onset genetically confirmed vanishing white matter (VWM) disease. It shows that, despite the presence of a severe and diffuse damage of the brain WM, brain gray matter, and cervical cord tissue, the cortical adaptive capacities were relatively preserved. Interpatient variability of brain plasticity may contribute to the known phenotypic variation of patients with VWM disease.

Proton MR spectroscopy of cerebellitis

Single voxel proton MR spectroscopy ((1)H-MRS) of the vermis was obtained in two patients with cerebellitis. In the acute phase (1)H-MRS revealed low N-acetyl-aspartate (NAA)/creatine (Cr) and NAA/choline (Cho) and normal Cho/Cr ratios. Decrease of the concentration of NAA was confirmed by quantitative analysis in one patient. The NAA/Cr and NAA/Cho ratios and NAA concentration were increased in (1)H-MRS examinations obtained 10 and 24 months after the acute episode. (1)H-MRS demonstrates reversible metabolite changes in cerebellitis.

HYPOACTIVE-HYPOALERT BEHAVIOR (“PSYCHIC AKINESIA”) IN INTRACRANIAL HYPOTENSION SYNDROME

Hypoactive-hypoalert behavior (HHB), also termed “psychic akinesia,” is characterized by loss of psychic autoactivation, apathy, and stereotyped activity that are reversed by external stimulation.1 Lesions in the brainstem, basal ganglia, or frontal lobes can underlie HHB.1 We report three patients presenting with HHB due to spontaneous intracranial hypotension (SIH) syndrome. Two men aged 49 and 57 years and a woman aged 60 years were referred by relatives because of a 2-, 5-, and 2-year history of a chronic state of decreased behavioral initiative, persistent somnolence, impaired attention, and stereotyped motor activity. The patients would lie inactive for whole days if left unstimulated, but would perform adequately whenever incited to. They were scarcely concerned about their ensuing family and job problems and did not complain of mood depression, but came to our observation only because urged to by the alarmed relatives. Neurologic examination showed diffuse deep tendon hyperreflexia variously combined with limitation of vertical and vergence eye movements, lateral gaze-evoked nystagmus, and right extensor plantar response. All patients displayed simple motor perseverations such as buttoning or unbuttoning the shirt, rubbing the face, blowing the nose, hand wringing, washing, rubbing or beating the legs or the trunk, or clearing the throat. They denied orthostatic headache. They fell asleep when left undisturbed but could be easily aroused by external stimulations. Neuropsychological tests showed normal findings …

SDH mutations in patients affected by paraganglioma syndromes: a personal experience.

Abstract:  Mutations in genes encoding mitochondrial succinate dehydrogenase (SDH) are frequently involved in the development of neural crest‐derived (NCD) tumors, such as pheochromocytomas (PHEOs) or paragangliomas (PGLs). In this study we report the results of sequencing analysis in leukocyte DNA of patients affected by PHEO/PGL who turned out to be SDH mutation carriers. A nonsense germline heterozygous mutation (Q109X) was found in the exon 4 of the SDHD gene in the index cases of six unrelated families affected by PHEO/PGL. Haplotype analysis showed the presence of a founder effect. Affected patients showed high clinical variability, ranging from monolateral to bilateral glomus tumors, variably associated or not with PGLs or PHEOs. A novel missense SDHD variant, T112I, was also found in one of our families. A new missense G106D mutation, involving a highly conserved amino acid, was found in two sisters affected by bilateral glomus tumors. A P81L mutation associated with abdominal and head and neck PGL was detected in three families. A G12S variant of the SDHD gene was found in one patient affected by a PHEO. The finding of this variant in 3 of 100 control subjects suggests that it is a polymorphism and not a mutation. A novel IVS2‐1G>T variant was found at intron 2 of SDHD gene in one patient affected by a glomus tumor. All the tumors associated with SDHD mutations were benign. Conversely, the only mutation we found in SDHB gene (IVS3 + 1G>A) was associated with a malignant PHEO.

Pontine hyperperfusion in sporadic hyperekplexia

Objective: To explore with neuroimaging techniques the anatomical and functional correlates of sporadic hyperekplexia. Methods: Two elderly women with sporadic hyperekplexia underwent neurophysiological assessment, MRI of the brain and proton magnetic resonance spectroscopy (1H-MRS) of the brainstem and frontal lobes. Regional cerebral blood flow was investigated with single photon emission tomography (SPECT) during evoked startles and at rest. Results: Both patients showed excessively large and non-habituating startle responses. In both patients, MRI showed impingement of the brainstem by the vertebrobasilar artery, lack of frontal or brainstem abnormalities on 1H-MRS and hyperperfusion in the dorsal pons and cingulate cortex, and superior frontal gyrus at SPECT during evoked startles. Conclusions: In our patients with hyperekplexia, the vertebrobasilar arteries were found to impinge on the brainstem. Neurophysiological findings and neurofunctional imaging of evoked startles indicated a pontine origin of the movement disorder modulated by activation in cortical, especially frontal, areas. The neurofunctional correlates of evoked startles in human sporadic hyperekplexia are similar to those observed for the startle circuit in animals.