Journal of the Neurological Sciences

Editorial Board

2013-06-15

A rare family with Hereditary Spastic Paraplegia Type 35 due to novel FA2H mutations: A case report with literature review

Li Cao, Xiao-Jun Huang, Chan-Juan Chen, Sheng-Di Chen — 2013-04-08

Abstract: Background: Hereditary Spastic Paraplegia Type 35 is a complicated form of HSP characterized by progressive spastic paraparesis, dysarthria, and mild cognitive decline associated with leukodystrophy on brain imaging. Mutations in the fatty acid 2-hydroxylase (FA2H) gene have been associated SPG35.Methods: Sequencing of FA2H gene was conducted in a Chinese non-consanguineous family with two affected siblings manifesting with typical clinical features of SPG 35. 100 healthy individuals were set for control.Result: Triple heterozygous mutations in FA2H gene (c.968C>A; c.976G>A; c.688G>A) were identified in the two affected siblings. All the mutations were not documented previously and were not detected among 100 healthy controls.Conclusion: In this study we identified the first SPG 35 family in Han population. Triple FA2H mutations seem to result in a severe phenotype while more patients are needed to establish the genotype–phenotype correlations.

Season of birth as a risk factor for multiple sclerosis in Brazil

2013-04-18

Abstract: Risk factors for development of multiple sclerosis (MS) are still a matter of debate. Latitude gradient, vitamin D deficiency and season of birth are among the most investigated environmental factors associated with the disease. Several international studies suggest that birth in spring is a substantial risk factor for MS. We investigated the season of birth as a potential risk for MS in different geographical regions of Brazil. We conducted a cross-sectional retrospective study with 2257 clinically definite MS patients enrolled in 13 Brazilian MS clinics in the south, southeast, and northeast regions of Brazil. Demographic and clinical data relating to date of birth and clinical features of the disease were collected and analysed, and subsequently compared with birth date among the general Brazilian population. The distribution of date of birth of MS patients showed an increase in spring and a decrease in autumn, with no difference being observed in the other seasons. In conclusion, season of birth is a probable risk factor for MS in most parts of Brazil. These findings may be related to the role that vitamin D plays in MS pathogenesis.

Study of micronutrients (copper, zinc and vitamin B12) in posterolateral myelopathies

2013-04-05

Abstract: Background: Vitamin B12 deficiency is a well recognized cause of posterolateral myelopathy. In Indian subcontinent, it may coexist with nutritional copper deficiency producing partial response of patients to B12 supplementation. Hence the study was planned to look for association of hypocupremia and B12 deficiency.Methods: Twenty-three patients with posterolateral myelopathy (Romberg sign positive) were enrolled and investigated for levels of vitamin B12, copper and zinc and followed up for six months.Result: In three patients, copper deficiency alone was found to be the cause. In another three, both copper and vitamin B12 were deficient. In all these six patients, ceruloplasmin and 24h urinary copper were found to be low suggesting dietary copper deficiency. Hyperzincemia was found in four of these patients. Magnetic resonance imaging of spine was normal in lone Cu deficient patients but showed T2 hyperintensity of posterior column in lone B12 or combined B12 and copper deficiency.Conclusion: In cases of B12 deficiency myelopathy not responding to supplementation, copper deficiency must be sought at the earliest to avoid and treat persistent neurological disability.

Sweet liking in patients with Parkinson's disease

2013-04-05

Abstract: Pleasant tastes and odors are considered phylogenetically old natural rewards and their hedonic evaluation is regarded as a good indicator of the reward system function. The primary aim of the present study was to compare pleasantness ratings of sucrose solutions (1–30%, w/w) and sweet liking/disliking status in 20 patients with Parkinson's disease (PD) and in 20 age-matched healthy controls. In addition, basic sensory aspects of gustatory (intensity ratings, electrogustometric thresholds) and olfactory function (identification abilities in the Sniffin' Stick test) were assessed in both groups. The number of odors rated as pleasant, unpleasant, and neutral was also compared. As expected, the PD patients showed a significant impairment in olfactory identification abilities. There were no differences between the PD patients and controls in electrogustometric thresholds. Rated intensity of higher sucrose concentrations did not differ between the groups. The PD patients tended to rate water taste as more intense in comparison with the controls. Pleasantness ratings of sucrose solutions, the proportion of subjects rating 30% sucrose as the most pleasant (sweet likers), and the number of odors rated as pleasant did not differ between the study groups. The present results suggest that PD does not lead to any obvious alterations in pleasantness ratings of chemosensory stimuli. The study requires replication in larger samples.

Cognitive slowing in Parkinson's disease is related to frontostriatal dopaminergic dysfunction

2013-04-04

Abstract: Background: Frontostriatal and cognitive dysfunctions in Parkinson's disease (PD) are hypothesized to be linked predominately to dopaminergic dysfunction within neural networks linking dorsal striatum to dorsolateral prefrontal cortex.Methods: The authors evaluated the relationship between frontostriatal dopaminergic function and cognitive performance, especially cognitive processing speed by performing [18F]fluorodopa PET and computerized tests of automatic and controlled cognitive processing speed (CogniSpeed) in 23 newly diagnosed and unmedicated PD patients and 14 controls.Results: PD patients were slower than the controls in all the CogniSpeed measures studied. The Fdopa uptake in caudate nucleus correlated negatively with slowing on all the tests. Slower performance in relatively automatic processes measured by choice reaction tasks as well as in more controlled processes measured by a calculation task was related to reduced Fdopa uptake in the anterior cingulate gyrus. The reduced dopaminergic function in the thalamus was associated with the slower performance in the subtraction test.Conclusion: Our study indicates that dopaminergic dysfunction within neural networks linking striatum to prefrontal cortex is involved in the slowing of both automatic and controlled cognitive processing in PD patients.

Immune activation in patients with Alzheimer's disease is associated with high serum phenylalanine concentrations

Philipp Wissmann, Simon Geisler, Friedrich Leblhuber, Dietmar Fuchs — 2013-04-08

Abstract: Background: Immune activation and inflammation represent critical factors in the pathogenesis of Alzheimer's disease (AD) and are associated with increased blood concentrations of markers like neopterin and the kynurenine to tryptophan ratio (Kyn/Trp). In chronic inflammatory conditions, also increased serum phenylalanine concentrations and phenylalanine to tyrosine ratios (Phe/Tyr) were reported and could relate to neuropsychiatric symptoms.Objective: To examine serum phenylalanine and tyrosine concentrations in patients with AD and to compare results to neopterin and Kyn/Trp levels.Materials and methods: Serum was collected from 43 patients with AD and concentrations of phenylalanine and tyrosine as well as neopterin, tryptophan and kynurenine were measured and Phe/Tyr and Kyn/Trp were calculated.Results: A subgroup of AD patients presented with increased phenylalanine and Phe/Tyr concentrations, phenylalanine levels correlated with neopterin (rs=0.329), kynurenine (rs=0.352) and Kyn/Trp levels (rs=0.288; all p<0.05). There was no significant relationship between phenylalanine metabolism and cognitive ability test scores mini-mental state examination and clock drawing test.Conclusions: Higher serum phenylalanine concentrations related to immune activation are detectable in a subgroup of AD patients. The impaired conversion of phenylalanine may affect not only the production of tyrosine but also the biosynthesis of the neurotransmitters dopamine, norepinephrine and epinephrine. Further studies are justified in patients with AD to investigate a possible role of phenylalanine biochemistry in the development of neurovegetative and behavioral abnormalities.

Progressive supranuclear palsy phenotype mimicking synucleinopathies

2013-04-15

Abstract: Background: Atypical parkinsonian syndromes are currently divided into two groups based on their pathological appearance: synucleinopathies and tauopathies. Based on recent clinico-pathological studies it is increasingly clear, that some pathological characteristics are shared by both groups.Study objective: To describe two pathologically proven cases of tauopathy manifesting in vivo in two typical synucleinopathy phenotypes: multiple system atrophy and dementia with Lewy bodies.Patients and methods: There were 67-year-old woman with a phenotype of multiple system atrophy and a 70-year-old man with a phenotype of dementia with Lewy bodies. The clinical diagnosis was based on the commonly used clinical diagnostic criteria. A detailed neuropathological examination of the brain was conducted post-mortem in both cases.Results: The overall pathological picture corresponded with a rare combination of two neurodegenerative entities: 4R tauopathy (meeting the diagnostic criteria for typical progressive supranuclear palsy) and neocortical stage of Alzheimer's disease.Conclusion: The interesting feature in both our cases was the presence of dual pathology: diffuse tauopathy and Alzheimer's pathology. We believe, that our two unique cases should serve as an evidence that tauopathies such as CBS and PSP might mimic practically anything from the family of atypical parkinsonian syndromes, particularly when another concomitant neurodegenerative disease is present.

A variety of mild stresses upregulate stanniocalcin-1 (STC-1) and induce mitohormesis in neural crest-derived cells

2013-04-08

Abstract: We induced upregulation of stanniocalcin-1 (STC-1) by various mild and long lasting stresses and assayed its influence on mitochondrial membrane potential (MMP) in the neural crest-derived cell line Paju. The obtained data showed that starvation (24–96h), exposure to 10nM TPA, and low concentrations (0.05–1μM) of As2O3 significantly (3–5 times) upregulated Paju cell STC-1 RNA and stabilized the mitochondrial membrane potential (MMP). However, high concentrations of As2O3 (2.5–5.0μM) increased intracellular ROS and free calcium levels and, consequently, suppressed STC-1 and MMP. The results show that cells preconditioned by various mild stresses expressed more STC-1 and their MMP were more resistant to a secondary exposure to As2O3 (2.5–5μM, 96h) demonstrating mitohormesis. We suggest that MMP deviation from control levels, to an extent innocuous to cell viability, is a general signal for STC-1-induction and MMP-protection. Our findings of Paju cell MMP-regulation may be of great importance for inventing new ways to prevent neurodegenerative diseases and unravel the mechanisms behind drug resistance.

Neuronal nuclear antigen (NeuN): A useful marker of neuronal immaturity in sudden unexplained perinatal death

Anna M. Lavezzi, Melissa F. Corna, Luigi Matturri — 2013-04-09

Abstract: Introduction: In the developing brain neuronal differentiation is associated with permanent exit from the mitotic cycle. Neuronal nuclear antigen (NeuN) is a nuclear protein widely expressed in the mature postmitotic neurons.Methods: We applied NeuN immunocytochemistry in 65 cases of perinatal death (16 victims of sudden intrauterine unexplained death syndrome/SIUDS, 19 of sudden infant death syndrome/SIDS and 30 controls) to test the physiological status of the brain neurons. In addition we applied both TUNEL and Caspase 3 immunohistochemical methods in order to highlight a possible relation between decreased NeuN expression and apoptotic outcome. We also attempted to see whether or not NeuN pathological changes can be related to cigarette smoke absorption in pregnancy.Results: NeuN staining was considerably reduced or lost in SIUDS/SIDS compared to controls. However neurons with decreased NeuN-labeling showed no sign of apoptosis. A significant association was found between NeuN depletion and maternal smoking.Conclusion: Altered NeuN expression can be a marker of immature and/or suffering neurons. The exclusive presence of this pattern of expression in SIUDS/SIDS victims, leads us to recommend the NeuN immunohistochemistry as a routine method in neuropathological protocols to convalidate a diagnosis of sudden perinatal death.

Comparison of the 2010 and 2005 versions of the McDonald MRI criteria for dissemination-in-time in Taiwanese patients with classic multiple sclerosis

2013-04-18

Abstract: In 2010, the International Panel on the Diagnosis of Multiple Sclerosis revised the 2005 version of the McDonald criteria. The revisions to MRI dissemination-in-time criteria include adoption of a new criterion by demonstration of simultaneous asymptomatic gadolinium-enhancing and nonenhancing lesions on baseline MRI scans. The purpose of this study was to demonstrate the diagnostic validity of the modified MRI dissemination-in-time criteria. We collected 80 patients with an initial clinical attack suggestive of an acute central nervous system demyelinating disease. The patients were followed for at least two years or until the development of definite multiple sclerosis. The nonconverters were taken as negative cases. Their baseline and follow-up brain MRI studies were retrospectively reviewed by two neuroradiologists. The 2010 version had higher sensitivity (68.2% vs. 45.5%), slightly lower specificity (80.6% vs. 83.3%), and higher accuracy (73.8% vs. 62.5%) than the 2005 version, but the differences were without statistical significance. The new criteria are more sensitive and accurate and specific just as the old criteria. They allow the diagnosis of definite multiple sclerosis in 34.1% patients at first presentation of the clinically isolated syndrome.

Brain metal accumulation in Wilson's disease

2013-04-17

Abstract: Introduction: Brain metal accumulation is suggested in the pathogenesis of numerous neurodegenerative disorders. In Wilson's disease (WD), only copper has been examined. The aim of the present study was to evaluate the copper, iron, manganese, and zinc concentrations in autopsy tissue samples from the brains of WD patients.Methods: The study material consisted of 17 brains (12 WD patients, 5 controls) obtained at autopsy. Samples were taken from four different regions of each brain: frontal cortex, putamen, pons, and nucleus dentatus. The copper, manganese, and zinc content were determined using inductively coupled plasma mass spectrometry, and iron was assessed using flame atomic absorption spectroscopy. The results were analyzed according to select clinical variables.Results: Copper content was increased homogenously in all investigated structures of the WD brains compared to controls (41.0±18.6μg/g vs.5.4±1.8μg/g; P<0.01). The mean concentrations of iron, manganese, and zinc were similar in WD and controls, but the iron level in the nucleus dentatus was higher in WD compared to controls (56.8±14.1μg/g vs. 32.6±6.0μg/g; P<0.05). Gender, age, and type and duration of WD treatment did not impact brain metals storage, but some correlations between the duration of the disease and copper and iron accumulation were observed.Conclusions: During the course of WD, copper accumulates equally in different parts of the brain. Zinc and manganese do not seem to be involved in WD pathology, but increased levels of iron were found in the nucleus dentatus. Thus, additional studies of brain iron accumulation in WD are needed.

Obstructive hydrocephalus due to CNS toxocariasis

2013-04-08

Abstract: A 46-year-old man developed intermittent headache, diplopia, and visual obscuration for two months. Funduscopic examination showed optic disk swelling in both eyes. Brain MRI exhibited hydrocephalus and leptomeningeal enhancement at the prepontine cistern, left cerebellopontine angle cistern and bilateral cerebral hemisphere, and hemosiderin deposition along the cerebellar folia. CSF analysis revealed an elevated opening pressure with xanthochromic appearance and small amount of red blood cells. Antibody titer against Toxocariasis using ELISA was elevated both in blood and CSF. Obstructive hydrocephalus and hemosiderin deposition in this case may result from the active inflammatory process due to CNS toxocariasis within the subarachnoid space.

Malignant meningitis presenting as pseudotumor cerebri

R.M. Ahmed, G.M. Halmagyi — 2013-04-11

Abstract: Malignant leptomeningitis can present as the clinical syndrome of pseudotumor cerebri due to infiltration of arachnoid villi in the superior sagittal sinus. We show that malignant pachymeningitis can also present with pseudotumor cerebri, likely due to cerebral venous hypertension from transverse sinus compression. We present 3 cases of pseudotumor cerebri due to pachymeningeal or leptomeningeal metastases and discuss the mechanism of intracranial hypertension in such cases, its diagnosis and treatment.

Insights into thermoregulation: A clinico-radiological description of Shapiro syndrome

2013-04-10

Abstract: Shapiro syndrome is a rare entity, comprising a triad of recurrent hypothermia, hyperhidrosis and congenital agenesis of the corpus callosum. Fewer than 50 cases have been described, almost invariably in patients presenting in childhood or early adulthood. We present a case of an 80year old woman presenting with recurrent bouts of shivering, sweating and profound malaise, who sought medical attention because the frequency and severity of attacks worsened in her later years. MRI Brain demonstrated agenesis of the corpus callosum; a rigorous work-up excluded other causes for her symptomatology.The intricate interplay of neuronal networks involved in thermoregulation remains to be fully elucidated and as such, little is known about the pathophysiological mechanisms underlying the clinical manifestations of Shapiro syndrome. We present novel data from FDG-PET imaging of our patient, demonstrating hypermetabolism in a number of brainstem and cerebellar regions during the symptomatic phase. These findings imply that aberrant thermoregulation in Shapiro syndrome involves a number of structures remote from the callosal region. We also present neuropsychometric findings in our patient, of which there have been no reports to date. We postulate that the ageing brain may be more susceptible to the paroxysmal neurochemical fluxes implicated in the syndrome.

Atypical progressive supranuclear palsy presenting as primary lateral sclerosis

Andrew King, Olimpia Curran, Safa Al-Sarraj — 2013-04-08

In a recent issue of the Journal of the Neurological Sciences, Nagao and colleagues described a case of progressive supranuclear palsy (PSP) presenting as primary lateral sclerosis but lacking parkinsonism, gaze palsy, aphasia or dementia . The case displayed a 4 repeat (4R) tauopathy with pathological findings totally in keeping with PSP, but an atypical distribution of pathology. This included prominent tau pathology in the motor cortex but minimal tau pathology in the brain stem nuclei and basal ganglia. We recently diagnosed a similar atypical case of PSP presenting again as primary lateral sclerosis, but with some notable differences and additional features. The 76year old woman presented with progressive asymmetrical spastic paraparesis. This was later associated with dysarthria and dysphagia but there was never any evidence of cognitive decline, gaze palsy or parkinsonian features. The EMG analysis and nerve conduction studies had been normal. A clinical diagnosis of primary lateral sclerosis type of motor neurone disease was made. She died approximately 9years after first presentation. The macroscopic examination of the left half of the brain (505g) revealed only mild cerebral atrophy, with no obvious abnormality to the motor cortex. The most notable feature was the preservation of pigmentation in the substantia nigra and locus coeruleus similar to the case described by Nagao and colleagues. Histologically there were some striking similarities between the published case and our case. There was extensive tau (AT8 antibody), 4-repeat tau (4R Tau) and p62 positivity in the motor cortex but negativity for 3-repeat tau (3R tau), phosphorylated TDP-43 (p-TDP-43) and fused in sarcoma protein (FUS). The tau (and 4R tau) positivity was predominantly in the form of tufted astrocytes, some thorny astrocytes, some coiled bodies, threads and tangle-like inclusions but no astrocytic plaques. Positivity for p62 and tau (and 4R tau) was also detected in the frontal and the temporal neocortex and white matter. Also unlike Nagao et al.'s case there was moderate immunopositivity for tau in the basal ganglia, internal capsule, midbrain, pons and medulla (including corticospinal tracts) with negativity for p-TDP-43 and FUS. We also had the opportunity to examine the C1 level of the cord. Again there was glial and neuronal positivity for tau. Interestingly, there was tau neuronal positivity in the anterior horn neurones, but without appreciable neuronal loss. The white matter including the lateral corticospinal tracts showed mild–moderate tau immunopositivity in the form of glial inclusions and threads. Therefore our case did reveal marked similarities with that described by Nagao et al. The term PSP with primary lateral sclerosois (PSP–PLS) or atypical PSP with corticospinal tract degeneration has been employed to refer to cases showing not only pyramidal signs but also parkinsonism . Our case differed from this definition and was similar to Nagao et al.'s case because of the lack of parkinsonian features. There were some important differences, however, between Nagao et al.'s case and our own in that there was significant brain stem and basal ganglia (as well as spinal cord) tau pathology in our case. From a practical aspect it would be very difficult to predict the diagnosis at the original macroscopic examination in these two cases because of the well pigmented nigra and locus coeruleus. Whilst an error in the final diagnosis would be unlikely for an experienced neuropathologist, our case illustrates the usefulness of routinely employing a relatively nonspecific but sensitive marker such as p62. In the absence of the expected TDP-43 pathology, the p62 by highlighting the glial pathology, can still point towards the alternative diagnosis of a tauopathy such as PSP and thereby allowing quick resolution of the diagnostic problem.

Progressive supranuclear palsy presenting as primary lateral sclerosis

2013-04-08

We would like to thank Dr. King and his colleagues for their interest in our previously reported atypical progressive supranuclear palsy (PSP) case . They also reported a similar autopsy case of PSP showing an atypical clinical presentation. Their case presented as primary lateral sclerosis (PLS) but lacked gaze palsy, parkinsonism, or dementia. As noted by the authors, the clinical presentation was consistent with that of our atypical PSP case. The pathological features in our case were: (i) evident corticospinal tract degeneration with minimal neuronal loss in the motor cortex, basal ganglia, and substantia nigra, (ii) tau pathology prominent in the posterior portion of the frontal convexity, i.e., the motor cortex, and (iii) relatively mild tau accumulation in the basal ganglia and brain stem nuclei. The topographical distribution of neuronal and glial tau pathology in Dr. King's case was also very similar to that in our PSP case.

Briana N. Perry, Jack W. Tsao — 2013-04-05

As the product of the Attention and Performance Series XXIII workshop, it is not surprising that Decision Making, Affect, and Learning is such a thorough compilation of research. Through informative summaries of past findings, in-depth descriptions of recent advancements, and compelling suggestions for future directions, editors Mauricio Delgado, Elizabeth Phelps, and Trevor Robbins masterfully discuss the psychological and neurological processes behind decision making.

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2013-06-15