Patrícia Pita Lobo

Substantia nigra neuromelanin-MR imaging differentiates essential tremor from Parkinson's disease.

Essential tremor (ET) is a very common movement disorder that has no diagnostic markers. Differentiation with Parkinsons disease (PD) can be clinically challenging in some cases, with a high rate of misdiagnosis. Magnetic resonance imaging (MRI) studies have been able to identify neuromelanin changes in the substantia nigra (SN) of PD patients, but they have thus far not been investigated in ET. In this study, we aimed to characterize neuromelanin‐MR signal changes in ET and evaluate its diagnostic accuracy in the differential diagnosis with PD.

Time- and frequency-domain parameters of heart rate variability and sympathetic skin response in Parkinson's disease

The autonomic nervous system (ANS) is regularly affected in Parkinson’s disease (PD). Information on autonomic dysfunction can be derived from e.g. altered heart rate variability (HRV) and sympathetic skin response (SSR). Such parameters can be quantified easily and measured repeatedly which might be helpful for evaluating disease progression and therapeutic outcome. In this 2-center study, HRV and SSR of 45 PD patients and 26 controls were recorded. HRV was measured during supine metronomic breathing and analyzed in time- and frequency-domains. SSR was evoked by repetitive auditory stimulation. Various ANS parameters were compared (1) between patients and healthy controls, (2) to clinical scales (Unified Parkinson’s disease rating scale, Mini-Mental State Examination, Becks Depression Inventory), and (3) to disease duration. Root mean square of successive differences (RMSSD) and low frequency/high frequency (LF/HF) ratio differed significantly between PD and controls. Both, HRV and SSR parameters showed low or no association with clinical scores. Time-domain parameters tended to be affected already at early PD stages but did not consistently change with longer disease duration. In contrast, frequency-domain parameters were not altered in early PD phases but tended to be lower (LF, LF/HF ratio), respectively higher (HF) with increasing disease duration. This report confirms previous results of altered ANS parameters in PD. In addition, it suggests that (1) these ANS parameters are not relevantly associated with motor, behavioral, and cognitive changes in PD, (2) time-domain parameters are useful for the assessment of early PD, and (3) frequency-domain parameters are more closely associated with disease duration.

Primary writing tremor and writer's cramp: Two faces of a same coin?

Institute of Experimental Medicine, Christian-Albrechts University, Kiel, Germany; Hertie-Institute for Clinical Brain Research, T€ ubingen, Germany; Department of Neurology, University Hospital Schleswig Holstein, Kiel, Germany; Section of Clinical and Molecular Neurogenetics at the Department of Neurology, University of L€ ubeck, Germany; Department of Psychiatry and Psychotherapy, University Hospital Schleswig Holstein, L€ ubeck, Germany; Department of Neurodegeneration, University of T€ ubingen and German Centre for Neurodegenerative Diseases (DZNE); Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, Maryland, United States of America

Gene expression differences in peripheral blood of Parkinson's disease patients with distinct progression profiles.

The prognosis of neurodegenerative disorders is clinically challenging due to the inexistence of established biomarkers for predicting disease progression. Here, we performed an exploratory cross-sectional, case-control study aimed at determining whether gene expression differences in peripheral blood may be used as a signature of Parkinson’s disease (PD) progression, thereby shedding light into potential molecular mechanisms underlying disease development. We compared transcriptional profiles in the blood from 34 PD patients who developed postural instability within ten years with those of 33 patients who did not develop postural instability within this time frame. Our study identified >200 differentially expressed genes between the two groups. The expression of several of the genes identified was previously found deregulated in animal models of PD and in PD patients. Relevant genes were selected for validation by real-time PCR in a subset of patients. The genes validated were linked to nucleic acid metabolism, mitochondria, immune response and intracellular-transport. Interestingly, we also found deregulation of these genes in a dopaminergic cell model of PD, a simple paradigm that can now be used to further dissect the role of these molecular players on dopaminergic cell loss. Altogether, our study provides preliminary evidence that expression changes in specific groups of genes and pathways, detected in peripheral blood samples, may be correlated with differential PD progression. Our exploratory study suggests that peripheral gene expression profiling may prove valuable for assisting in prediction of PD prognosis, and identifies novel culprits possibly involved in dopaminergic cell death. Given the exploratory nature of our study, further investigations using independent, well-characterized cohorts will be essential in order to validate our candidates as predictors of PD prognosis and to definitively confirm the value of gene expression analysis in aiding patient stratification and therapeutic intervention.

Orofacial apraxia in motor neuron disease.

Introduction: Cognitive and behavioral impairments are considered to occur frequently in amyotrophic lateral sclerosis/motor neuron disease (MND). Rarely, apraxia has been reported in MND. Orofacial, or buccofacial, apraxia is characterized by a loss of voluntary control of facial, lingual, pharyngeal and masticatory muscles in the presence of preserved reflexive and automatic functions of the same muscles. Methods: We report a patient with MND who presented with spastic dysarthria and asymmetric orofacial apraxia. She progressed to frontotemporal dementia (FTD). Results: Clinical and neurophysiological examinations were suggestive of bulbar-onset MND-FTD. Tractography showed a reduction of fractional anisotropy in the centrum semiovale, corona radiata, corticomedullary pathway and inferior aspect of the medulla; the changes were more severe on the left side. To our knowledge, this is the first report of an asymmetric presentation of an apraxic syndrome in MND-FTD.

Study of hTERT and Histone 3 Mutations in Medulloblastoma.

Hotspot activating mutations of the telomerase reverse transcriptase (hTERT) promoter region were recently described in several tumor types. These mutations lead to enhanced expression of telomerase, being responsible for telomere maintenance and allowing continuous cell division. Additionally, there are alternative telomere maintenance mechanisms, associated with histone H3 mutations, responsible for disrupting the histone code and affecting the regulation of transcription. Here, we investigated the clinical relevance of these mechanistically related molecules in medulloblastoma. Sixty-nine medulloblastomas, formalin fixed and paraffin embedded, from a cohort of patients aged 1.5-70 years, were used to investigate the hotspot mutations of the hTERT promoter region, i.e. H3F3A and HIST1H3B, using Sanger sequencing. We successfully sequenced hTERT in all 69 medulloblastoma samples and identified a total of 19 mutated cases (27.5%). c.-124:G>A and c.-146:G>A mutations were detected, respectively, in 16 and 3 samples. Similar to previous reports, hTERT mutations were more frequent in older patients (p < 0.0001), being found only in 5 patients <20 years of age. In addition, hTERT-mutated tumors were more frequently recurrent (p = 0.026) and hTERT mutations were significantly enriched in tumors located in the right cerebellar hemisphere (p = 0.039). No mutations were found on the H3F3A or HIST1H3B genes. hTERT promoter mutations are frequent in medulloblastoma and are associated with older patients, prone to recurrence and located in the right cerebellar hemisphere. On the other hand, histone 3 mutations do not seem to be present in medulloblastoma.

Substantia Nigra Neuromelanin as an Imaging Biomarker of Disease Progression in Parkinson’s Disease

BACKGROUND A specific T1-weighted magnetic resonance imaging (MRI) sequence has been shown to detect substantia nigra (SN) neuromelanin (NM) signal changes that accurately discriminate Parkinsons disease (PD) patients from controls, even in early disease stages. However, it is unclear what happens to these SN changes in later disease stages and if they can be a marker of disease progression. OBJECTIVE to investigate the pattern of SN-NM area loss and contrast ratio (CR) intensity changes in late-stage PD (LSPD) compared to earlier disease stages. METHODS A comparative cross-sectional study was performed, analyzing SN-NM MRI signal in LSPD (Schwab and England Activities of Daily Living Scale score <50 or Hoehn Yahr Stage [HY] >3), comparing this group with de novo, 2-5 year PD and controls. SN-NM signal area and CR values for the internal and lateral SN regions were obtained with semi-automated methods. RESULTS 13 LSPD, 12 de novo patients with PD, 10 PD patients with a 2-5 year disease duration, and 10 controls were included. NM signal area was significantly decreased in LSPD compared to de novo PD (P-value = 0.005; sensitivity: 75%; specificity 92% and AUC: 0.86). In the lateral SN region, a decrease in the CR was detected in all PD groups compared to controls; despite not reaching statistical significance, a slight increment was observed comparing LSPD to 2-5 year PD. NM signal area significantly correlated with HY (R = -0.37; P < 0.05) and Movement disorder Society Unified Parkinsons Disease Rating Scale part II (MDS-UPDRS) (R = -0.4; P < 0.05) while a weak correlation was found with MDS-UPDRS part III (R = -0.26; P: 0.1). CONCLUSION SN area evaluated by NM-sensitive MRI may be a promising biomarker of nigral degeneration and disease progression in PD patients.

Recovery after copper-deficiency myeloneuropathy in Wilson's disease.

Wilson’s disease (WD) treatment focuses on removing excess copper from the body and preventing reaccumulation, but there are reports of neuropathy and myeloneuropathy (MN) linked to copper deficiency (CD) induced by excessive depletion [1]. Here we report on a WD patient with MN associated with longstanding CD. The patient is a 36-year-old male diagnosed with WD at 20 years old, having displayed generalized dystonia, bradykinesia and freezing of gait. Clinical stability was achieved with zinc sulphate 150 mg/ day and trientine 500 mg/day. In 2006, he developed low urinary copper (24 h urine copper = 128 lg/24 h, recommended 200–500 lg/24 h; serum copper 6.35 lg/dL) [6], which worsened in the following years. In 2008 he was switched to D-penicillamine 600 mg/day due to drug availability problems. Soon after, he developed a nephrotic syndrome with focal segmental glomerular sclerosis which resolved with corticosteroid therapy and switching back to trientine. In February 2011, he developed subjective numbness of both hands and feet and over the following months worsening of gait with frequent falls. In July 2011 neurological examination revealed de novo algic hypoesthesia of the limbs in a ‘‘glove and stocking’’ pattern, postural and vibratory hypoesthesia of the lower limbs and gait ataxia. Analytical studies revealed low serum and urine copper (serum copper 13.3 lg/dL, urine copper 40.5 lg/24 h), low ceruloplasmin (3.0 mg/dL), normal zinc levels (14.7 lmol/ L) and anemia (Hb 8.2 g/dL). Electromyography with conduction velocities revealed a mixed sensory-motor peripheral neuropathy and spinal MRI showed signs of posterior dorsal cord myelopathy (Fig. 1). Other causes of MN were excluded: both vitamin E and B12 levels were normal, and serological tests for HIV, syphilis and autoantibodies were negative. Therefore, a causal relationship between CD and MN was considered as probable. Trientine (500 mg/day) and zinc sulfate (330 mg/day) were substituted for zinc acetate 100 mg daily, which was progressively reduced and stopped in January 2012, due to persistent CD. Copper deficiency resolved by March 2012 (24 h urinary copper = 97 lg/24 h, recommended B100 lg/24 h for zinc monotherapy) [6]. Parallel improvement of sensorial ataxia allowed recovery of walking capacity without assistance. Spinal MRI showed mild regression of myelopathy signs (Fig. 1). Conduction velocities studies disclosed slight improvement in amplitude of sensory action potentials and conduction velocities (Table 1). At this point, zinc acetate 150 mg/day was reintroduced, and his condition remains stable 1 year after treatment. T. Teodoro (&) D. Neutel P. Lobo I. Conceição M. M. Rosa L. Albuquerque J. J. Ferreira Department of Neurology, Hospital de Santa Maria (CHLN, EPE), Lisbon, Portugal e-mail: tiagoteodoro@gmail.com

Wearing-off phenomena and levodopa-induced dyskinesias in posttraumatic hemiparkinsonism

Posttraumatic parkinsonism (PTP) secondary to a strategically located lesion is extremely rare. PTP patients may improve with levodopa, as in Parkinson’s disease (PD). However, whereas L-dopa–induced motor complications are frequent in PD, they have not yet been reported in PTP cases. On the other hand, the occurrence of motor complications secondary to a static and nondegenerative lesion in the substantia nigra (SN) is well documented in animal models. A 74-year-old man suffered a head trauma at age 37 after a car crash, that resulted in coma and a mild residual left hemiparesis. One month after recovering consciousness, he noticed rest and action tremor of his left hand and slowness of left limbs. He responded well to L-dopa treatment, but 10 years later, he reported a shorter duration of effect for each L-dopa dose and involuntary movements of left hemiface and upper limb. We first saw him 38 years after onset when he was autonomous for the activities of daily living, and had no symptoms in the right side of his body, postural instability, or non-motor symptoms. However, formal neuropsychological evaluation was not performed to exclude mild cognitive or mood dysfunction. He was taking 750 mg of L-dopa (250 mg 33) with wearing-off 1 hour before each L-dopa dose. In the practically defined off state, we observed a moderate left hemiparkinsonism (scoring 29 in the Movement Disorders Society (MDS)–Unified Parkinson’s Disease Rating Scale, Testing of Motor function [UPDRS part III]), and a dystonic posturing of left foot was present during gait (Video 1, Segment 1). MDS-UPDRS motor score improved 62% after an acute L-dopa challenge test. When the patient was in the on state, rest and action tremor remitted, and bradykinesia, rigidity, and gait markedly improved. There was a left hemifacial dystonia, and chorea and dystonia of left upper limb, whereas left foot dystonia was unchanged (Video 1, Segment 2). However, during the bicycle ride a significant reduction of dystonia and bradykinesia of the left lower limb was verified (Video 1, Segment 3). There was no change in his right side. Brain computed tomography (CT) and magnetic resonance imaging (MRI) showed a chronic lesion involving the right SN without striatal involvement (Fig. 1A and B). [123I]FP-CIT ([I]-2betacarbometoxy-3beta-(4-iodophenyl)-N-(3-fluoropropyl) nortropane) single-photon emission computed tomography (SPECT; DaTscan) showed complete loss of radiotracer binding in the right striatum body and normal uptake in left striatum (Fig. 1C). Even though some patients with PTP benefit from L-dopa, the emergence of motor complications is exceptional in cases of traumatic SN-isolated lesions treated with L-dopa. Nevertheless, Ruzicka et al. reported the occurrence of motor complications after surgery to a colloid cyst that led to a brain hemorrhage in the SN and its boundaries. Our patient is unique, as he presents with a hemiparkinsonism responsive to L-dopa shortly after a traumatic brain lesion of the SN. Under L-dopa treatment, he developed wearing-off and choreodystonic peak-dose dyskinesias 10 years after treatment onset, restricted to the symptomatic parkinsonian hemibody, contralateral to the side of striatal denervation observed in the DaTscan (Fig. 1C), which strongly supports the fact that the symptoms are secondary to this symptomatic lesion. Additionally, we are dealing Additional Supporting Information may be found in the online version of this article.

Myeloradiculopathy associated to Schistosoma mansoni.

Neuroschistosomiasis caused by Schistosoma mansoni (Sm) is a rare and severe condition potentially leading to permanent neurological deficit. An 18-year-old Brazilian female was admitted due to a severe conus medullaris and cauda equina syndrome. MRI of thoracic/lumbar spine showed an expanded conus medullaris with patchy gadolinium-enhancement, needle electromyography revealed acute bilateral radiculopathy (L5-S1-S2), cerebrospinal fluid (CSF) showed lymphocytosis and increased proteins and lesion’ surgical biopsy documented a lymphocyte infiltrate. Immunodiagnosis with cercariae hullen reaction using Sm cercariae in CSF and serum and immunoelectrodiffusion for circulating antigens detection using anti-Sm antibodies were positive. No schistosoma parasites were found. The patient was treated with praziquantel and corticotherapy for 6 months. At 1 month, partial clinical improvement was noticed, and MRI showed a normal size conus medullaris. At 6 months, there was complete clinical recovery. This case shows that a severe neurological deficit by Sm may have a clinical full recovery after treatment.