Journal of the Neurological Sciences

Editorial Board

2012-06-15

Advanced glycation end products and neurodegenerative diseases: Mechanisms and perspective

Jinlong Li, Danian Liu, Ling Sun, Yunting Lu, Zhongling Zhang — 2012-03-14

Abstract: The age-related neurodegenerative disorders such as Alzheimer's, Parkinson's, and Huntington's diseases are characterized by the abnormal accumulation or aggregation of proteins. Advanced glycation end products (AGEs) are proteins or lipids that become glycated after exposure to sugars. The formation of AGEs promotes the deposition of proteins due to the protease resistant crosslinking between the peptides and proteins. Several proteins implicated in neurodegenerative diseases such as amyloid β, tau, α-synuclein, and prions are glycated and the extent of glycation is correlated with the pathologies of the patients. These data suggest that AGEs contribute to the development of neurodegenerative diseases. In this review we summarize recent advances on the investigation of the roles of AGEs in neurodegenerative diseases, with special focus on Alzheimer's and Parkinson's diseases. It is clear that AGEs modification triggers the abnormal deposition and accumulation of the modified proteins, which in turn sustain the local oxidative stress and inflammatory response, eventually leading to the pathological and clinical aspects of neurodegenerative diseases. Further characterization of the molecular mechanisms responsible for AGEs mediated neurotoxicity will provide important clues on the development of novel strategies for the prevention and treatment of neurodegenerative diseases.

Palinacousis—Evidence to suggest a post-ictal phenomenon

Wazim Mohamed, Niharika Ahuja, Aashit Shah — 2012-03-14

Abstract: Introduction: Palinacousis is a paroxysmal auditory illusion in which perseveration of an external auditory stimulus occurs after cessation of the stimulus. The subjects recognize the illusory nature of this experience, which is often a fragment of the last sentence they heard. Palinacousis has been reported in only a few documented cases. It has been described as an aura, a component of complex partial seizures, and a post-ictal event. We put forward evidence demonstrating palinacousis as a post-ictal event.Case: A 68-year-old woman presented with an acute sensory aphasia, and an EEG showed frequent epileptiform discharges from the left temporo-parietal region. MRI showed an enhancing mass in the left inferior parietal lobule that was consistent with a metastasis. A CT scan of the thorax later showed an enhancing mass in the left lung that was determined to be an invasive non-small cell carcinoma. Treatment with levetiracetam resulted in loss of epileptiform activity on EEG and resolution of aphasia, but soon afterward, she started complaining of recurrent auditory illusions in her right ear. These consisted of phrases from the ends of sentences she heard. Continuous EEG monitoring during her auditory symptoms showed intermittent left temporal slowing but no epileptiform discharges or electrographic seizures. An FDG-PET scan with the glucose uptake phase during episodes of auditory illusions revealed hypometabolism of bilateral medial temporal cortices and increased uptake in the metastatic tumor.Review of literature: A systematic review identified 14 cases with palinacousis since 1981. Cases prior to that were excluded due to the lack of sufficient data.Discussion: We propose that palinacousis is a “negative” phenomenon, at least in some individuals. It occurs with a loss of function of a region of the brain that normally suppresses auditory perseveration.

Change in frequency of periodic limb movements during sleep with usage of continuous positive airway pressure in obstructive sleep apnea syndrome

2012-04-13

Abstract: Periodic limb movements during sleep (PLMS) sometimes newly appear on the night of continuous positive airway pressure (CPAP) titration in patients with obstructive sleep apnea syndrome (OSAS). To ascertain the incidence and causative factors of this phenomenon, we investigated differences in its prevalence and the factors associated with newly appeared and persistent PLMS on CPAP titration night. We retrospectively analyzed polysomnographic data of 997 consecutive OSAS outpatients who had undergone overnight CPAP titration. On the basis of changes in periodic limb movements index (PLMI) values (cut off level≥15/h) from baseline polysomnography (BPSG) to CPAP titration PSG, patients were assigned to one of four groups: persistent, CPAP-emergent, CPAP-disappeared, and non-PLMS. The rate of patients was 6.7% in the persistent group, 8.0% in the CPAP-emergent group, 4.0% in the CPAP-disappearance group, and 81.2% in the non-PLMS group. Multivariate logistic regression analysis revealed that a higher apnea–hypopnea index (AHI) on BPSG and ≥47years of age appeared to be associated with the CPAP-emergent group. The results suggest that elderly patients with higher AHI at BPSG may present with CPAP-emergent PLMS.

Female cluster headache in the United States of America: What are the gender differences? Results from the United States Cluster Headache Survey

Todd D. Rozen, Royce S. Fishman — 2012-04-09

Abstract: Objective: To present results from the United States Cluster Headache Survey regarding gender differences in cluster headache demographics, clinical characteristics, diagnostic delay, triggers, treatment response and personal burden.Background: Very few studies have looked at the gender differences in cluster headache presentation. The United States Cluster Headache Survey is the largest study of cluster headache sufferers ever completed in the United States and it is also the largest study of female cluster headache patients ever presented.Methods: The total survey consisted of 187 multiple choice questions which dealt with various issues related to cluster headache including: demographics, clinical characteristics, concomitant medical conditions, family history, triggers, smoking history, diagnosis, treatment response and personal burden. A group of questions were specifically targeted to female cluster headache patients. The survey was placed on a website from October to December 2008. For all survey responders the diagnosis of cluster headache needed to be made by a neurologist but there was no validation of the headache diagnosis by the authors.Results: 1134 individuals completed the survey (816 male, 318 female).Key Points that define the differences between female and male cluster headache include:Conclusion: Overall women and men with cluster headache have a similar presentation but there are some distinct differences that have been suggested in smaller studies of female cluster headache that we have now verified, while some of our study conclusions have not been shown previously. One major limitation to the study is a lack of validation of diagnosis. A substantial false positive cluster headache diagnosis rate, especially in females, cannot be excluded by the study methods utilized.

Decreased hippocampal expression of calbindin D28K and cognitive impairment in MELAS

2012-04-09

Abstract: Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) is a maternally inherited mitochondrial syndrome characterized by seizures, migrainous headaches, lactic acidosis, vomiting, and recurrent stroke-like episodes. Patients often suffer from cognitive dysfunction of unclear pathogenesis. In this study, we explored a possible link between cognitive dysfunction and hippocampal expression of calbindin D28KD (CB), a high affinity calcium-binding protein, in four MELAS patients, using post mortem hippocampal tissues. We found significantly reduced CB levels in all patients by immunohistochemistry, Western blot, and quantitative real-time PCR. Reduction in CB expression has been associated with aging and with neurodegenerative disorders, including Alzheimer's disease. We postulate that the reduced CB expression may play a role in the cognitive abnormalities associated with MELAS.

Ischemic stroke as a primary symptom of neurosyphilis among HIV-negative emergency patients

2012-04-06

Abstract: Background: Neurosyphilis is known as “the great imitator” or “the great impostor” because of its wide range of clinical symptoms. A high misdiagnosis rate of ischemic stroke was observed among neurosyphilis patients in clinical practice, which prevents patients from receiving the most appropriate treatment, and often results in more severe neurologic damage.Methods: A total of 149 neurosyphilis patients were retrospectively reviewed. The control group comprised 1570 non-neurosyphilitic ischemic stroke patients. The proportion of patients with ischemic stroke as the primary symptom of the different types of neurosyphilis and the misdiagnosis rate of neurosyphilitic ischemic stroke were analyzed, including the risk factors for cardiovascular disease.Results: Among the 149 neurosyphilis patients, 21 (14.09%) developed ischemic stroke as a primary symptom, including three cases of syphilitic meningitis and 18 cases of meningovascular neurosyphilis. Only four of the neurosyphilis patients had histories of ischemic stroke and recurrence. The other 17 cases were treated for the first time in the emergency department; however, none of the patients were initially suspected of neurosyphilitic ischemic stroke. All of the patients were only diagnosed with neurosyphilis during their follow-up treatment. The misdiagnosis rate of neurosyphilitic ischemic stroke was as high as 80.95% (17/21). Furthermore, except for hypertension, no significant differences in cardiovascular risk factors were observed between the groups (P>0.05).Conclusions: In clinical practice, particularly during emergencies, any ischemic stroke patient should be screened for neurosyphilis.

Neuroprotective effects of adipose-derived stem cells against ischemic neuronal damage in the rabbit spinal cord

2012-04-04

Abstract: Transplantation of adipose-derived stem cells (ASCs) is one of the possible therapeutic tools for ischemic damage. In this study, we observed the effects of ASCs against ischemic damage in the ventral horn of L5–6 levels in the rabbit spinal cord. ASCs were isolated from rabbits, and cell type was confirmed by flow cytometry analysis, labeling with CM-DiI dye and differentiation into adipocytes in adipogenesis differentiation medium. ASCs were administered intrathecally into recipient rabbits (2×105) immediately after reperfusion following a 15-min aortic artery occlusion in the subrenal region. Transplantation of ASCs significantly improved functions of the hindlimb and morphology of the ventral horn of spinal cord although CM-DiI-labeled ASCs were not observed in the spinal cord parenchyma. In addition, transplantation of ASCs significantly increased brain-derived neurotrophic factor (BDNF) levels at 72h after ischemia/reperfusion. These results suggest that transplantation of ASCs prevents motor neurons from spinal ischemic damage and reactive gliosis by increasing neurotrophic factors such as BDNF in the spinal cord.

Oral contraceptive use and clinical outcomes in patients with multiple sclerosis

2012-03-29

Abstract: Experimental and clinical data suggest a role of sex steroids in the pathogenesis of multiple sclerosis (MS). Scant information is available about the potential effect of oral contraceptive (OC) use on the prognosis of the disease. We aimed to evaluate this. The study population consisted of 132 women with relapsing–remitting MS before receiving disease modifying treatment and a mean disease duration 6.2 (SD 5.1) years. Three groups of patients were distinguished according to their OC behavior: [1] never-users, patients who never used OC [2] past-users, patients who stopped OC use before disease onset, and [3] after-users, those who used these drugs after disease onset. Multiple linear and logistic regression models were used to analyze the association between oral contraceptive use and annualized relapse rates, disability accumulation and severity of the disease. After-user patients had lower Expanded Disability Status Scale (EDSS) and Multiple Sclerosis Severity Score (MSSS) values than never users (p<0.001 and p=0.002, respectively) and past users (p=0.010 and p=0.002, respectively). These patients were also more likely to have a benign disease course (MSSS<2.5) than never and past users together (OR: 4.52, 95%CI: 2.13–9.56, p<0.001). This effect remained significant after adjustment for confounders, including smoking and childbirths (OR: 2.97, 95%CI: 1.24, 6.54, p=0.011 and for MSSS β: −1.04; 95% C.I. −1.78, −0.30, p=0.006). These results suggest that OC use in women with relapsing–remitting MS is possible associated with a milder disabling disease course.

LINGO1 and risk for essential tremor: Results of a meta-analysis of rs9652490 and rs11856808

2012-03-19

Abstract: Background/objectives: Recently, a genome-wide association study revealed a significant statistical association between LINGO1 rs9652490 and rs11856808 polymorphisms and the risk of developing essential tremor (ET) in Icelandic people. Because the results of further association studies were controversial, we conducted a meta-analysis including all the studies published on the risk of ET related with these polymorphisms.Methods: The metaanalysis included 11 association studies between LINGO1 rs9652490 (3972 ET patients, 20,714 controls) and 7 association studies between LINGO1 rs11856808, and risk for ET (2076 ET patients, 18,792 controls), and was carried out by using the software Meta-Disc 1.1.1 (http://www.hrc.es/investigacion/metadisc.html; Unit of Clinical Statistics, Hospital Ramón y Cajal, Madrid, Spain). Heterogeneity between studies in terms of degree of association was tested using the Q-statistic.Results: Global diagnostic odds-ratios (ORs) and 95% confidence intervals (CI) for rs9652490 and rs11856808 of the total series were, respectively, 1.17 (1.00–1.36) (p=0.069) and 1.20 (1.05–1.36) (p=0.016). After excluding data on Icelandic people of the discovery series (that was responsible of a high degree of heterogeneity for rs9652490 polymorphism), the ORs and CI were 1.10 (0.97–1.26) (p=0.063) and 1.12 (0.99–1.27) (p=0.034). Global ORs and 95% CI for rs9652490 and rs11856808 of familial ET patients were, respectively, 1.27 (1.03–1.57) (p=0.014) and 1.21 (1.10–1.44) (p=0.031).Conclusions: The results of the meta-analysis suggest a relationship between LINGO1 rs11856808 polymorphism and the risk for ET and for familial ET, while rs9652490 polymorphism was only related with the risk for familial ET.

Study of the HFE gene common polymorphisms in French patients with sporadic amyotrophic lateral sclerosis

2012-03-16

Abstract: Our objective was to investigate whether the C282Y (p.Cys 282 Tyr) and H63D (p. His 63 Asp) HFE polymorphisms were associated with sporadic amyotrophic lateral sclerosis (SALS) in the French population. We searched for a relation of HFE polymorphisms with the clinical characteristics of the disease.The HFE polymorphisms were studied in 824 patients with SALS and 583 controls. We compared the frequency of the polymorphisms between SALS and controls groups by univariate and multivariate statistics, taking into account gender, site, age-at-onset and survival.We did not observe significant difference in the frequency of H63D polymorphism between SALS and control group. We observed a significant difference for C282Y between patients and controls with a low frequency of the Y allele in patients (3.2%) compared to our control group (5.9%). Disease duration, distribution of gender, site-of-onset, age-at-onset did not differ between groups taking into account genotypes of each polymorphism.Our results in this large cohort of ALS patients indicate that H63D polymorphism is not associated with SALS in the French population. This conclusion does not exclude a weak effect of the HFE gene polymorphisms in certain ALS populations, or an effect of other rare HFE gene variants.

Tetanus in adults: Clinical presentation, treatment and predictors of mortality in a tertiary hospital in Ethiopia

Amanuel Amare, Yilma Melkamu, Desalew Mekonnen — 2012-03-16

Abstract: Background: Tetanus remains a major health problem in the developing world. The aim of this study was to evaluate the clinical presentation, risk factors, complications, treatment, outcome and predictors of death in patients with tetanus.Methods: Patients aged ≥13years admitted to Tikur Anbessa Hospital from June 2001 to May 2009 with the diagnosis of tetanus were included in this retrospective study.Results: Data from 68 patients were analyzed; majority (77.9%) were males, the mean age was 33.8years. None of them was vaccinated for tetanus. The types were: generalized (91.2%), cephalic (7.4%), localized (1.5%), severe (72.1%), moderate (19.1%) and mild (8.8%). One or more complication(s) occurred in 75%; dysautonomia (58.8%), pneumonia (44.1%) and hypoxemia (41.2%). Tracheostomy and mechanical ventilation was used in 45.6% and 11.8%, respectively. Case-fatality was 35.3%. Predictors of mortality were age ≥40years, duration of symptoms prior to presentation <4days, severe tetanus, incubation period <7days, period of onset <3days and dysautonomia. The cause of death was early acute respiratory failure due to uncontrolled spasms in 87.5%.Conclusions: Most tetanus patients were young males and there was high case fatality due to acute respiratory failure. Age ≥40years and dysautonomia were independent predictors of mortality. Preventing tetanus by vaccination and treating patients in a well equipped ICU is recommended.

Tunicamycin produces TDP-43 cytoplasmic inclusions in cultured brain organotypic slices

2012-03-29

Abstract: The cellular distribution of TAR DNA binding protein (TDP-43) is disrupted in several neurodegenerative disorders, including frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTLD-U subtype) and amyotrophic lateral sclerosis (ALS). In these conditions, TDP-43 is found in neuronal cytoplasmic inclusions, with loss of the normal nuclear expression. The mechanisms leading to TDP-43 redistribution and its role in disease pathophysiology remain unknown. We describe an in vitro neural tissue model that reproduces TDP-43 relocalization and inclusion formation. Two week-old coronal organotypic mouse brain slice cultures were treated with tunicamycin for 7days. In cortical regions of treated slice cultures, cytoplasmic inclusions of TDP-43 immunoreactivity were observed, with loss of nuclear TDP-43 immunoreactivity. These inclusions were found in both astrocytes and neurons, and were of both skein-like and round morphologies. In contrast, TDP-43 cytoplasmic inclusions were not found in slices treated with staurosporine to induce apoptosis, or with trans-4-carboxy-l-proline (PDC) to induce chronic glutamate excitotoxicity. Furthermore, TDP-43 cytoplasmic inclusions did not co-localize with cleaved caspase-3, suggesting that TDP-43 mislocalization does not generally accompany caspase activation or apoptosis. The induction of TDP-43 cytoplasmic translocation in cerebrocortical slice cultures by tunicamycin provides a platform for further mechanistic investigations of pathological processing of TDP-43.

Residual disability 10years after falling ill in Guillain–Barré syndrome: A prospective follow-up study

Anette Forsberg, Rayomand Press, Lotta Widén Holmqvist — 2012-03-19

Abstract: Objective: To describe residual disability 10years after onset of Guillain–Barré syndrome (GBS) and longitudinal changes from 2weeks after onset until 10years afterwards. The Erasmus GBS Outcome score (EGOS) was applied for predicting prognosis at 2 and 10years.Methods: Twenty-nine patients, mean age at onset 49years, were followed prospectively from 2weeks to 10years after GBS onset. Measures included; GBS disability score, EGOS, Barthel Index, Frenchay Activity Index, Sickness Impact Profile (SIP), Overall Neuropathy Limitations Scale (ONLS), Walk-12, and Fatigue Severity Scale.Results: At 10years, the facial paralysis found in 5 participants at 2years was still present, 11 participants (38%) experienced paresthesia, 6 (21%) had limitations in their arms, and 15 (52%) had limitations in walking. Decreased health-related quality of life on comparison to the general population was seen in the physical dimension of SIP at 10years. The median EGOS at 2weeks was 4.5, which correlated highly only with the Barthel Index at 2years and the ONLS arm scale at 10years.Conclusion: The residual disabilities at 1–2years comprised mainly of reduced walking ability, and are still persistent 10years after GBS onset. For some individuals, facial paralysis caused major disability. The EGOS only partly predicted residual disability at 2 and 10years after onset.

Meta-analysis of association between PITX3 gene polymorphism and Parkinson's disease

2012-03-20

Abstract: Parkinson's disease (PD) is one of the most common neurodegenerative diseases. Several studies had researched the association between the PITX3 gene polymorphism and Parkinson's disease. However, the results were inconsistent. To evaluate whether PITX3 gene polymorphism is involved in the risk of PD we conducted this meta-analysis. All the eligible studies were searched from the databases of Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library, MEDLINE, EMBASE, and Science Citation Index EXPANDED in any languages up to May 2011. Finally ten studies about PITX3 gene including 5172 patients and 7290 controls were identified for meta-analysis. Meta-analysis was carried out to evaluate whether PITX3 gene polymorphism was associated with PD, and subgroup analysis was also performed when necessary. This meta-analysis finds that rs4919621 allele A was significantly associated with PD in the Caucasian population (P=0.04,). Subgroup analysis of early onset PD (EOPD) and late onset PD (LOPD) revealed that the rs2281983 allele C and rs4919621 allele A were significantly associated with the risk of PD (all of the P values were ≤0.0001) in EOPD population. This research indicated that the presence of the rs4919621 allele A significantly increased the risk of PD patients in Caucasian population while rs2281983 allele C and rs4919621 allele A were both risk factors in EOPD.

Hemoglobin A1C is independently associated with severity and prognosis of brainstem infarctions

2012-03-19

Abstract: Objective: To assess the association of Hemoglobin A1C (HbA1c) with acute brainstem infarctions (BSIs) and to determine whether HbA1c is an independent risk factor in BSIs patients.Methods: 96 only BSIs patients were categorized into four groups according to HbA1c as <6%, ≥6% but <7%, ≥7% but <8%, or≥8%, respectively. The association of the four HbA1c groups with diffusion-weighted imaging (DWI) infarct volumes (DIV), National Institutes of Health Stroke Scale (NIHSS), and follow-up modified Rankin Scale (FmRS) scores were analyzed. Patients also were categorized into two groups according to HbA1c<6% or ≥6%. Logistic regression analyses were performed to determine independent risk factors.Results: There was a significant correlation between HbA1c and DIV (Spearman ρ=0.339, P=0.001), NIHSS scores (ρ=0.292, P=0.004) and FmRS scores (ρ=0.315, P=0.002). The incidence of pons infarction was highest in BSIs and patients with HbA1c≥6% showed significantly more frequent isolated pontine infarction. Logistic regression analyses showed that only HbA1c was independently associated with larger DIV (P=0.025) and FmRS scores (P=0.026).Conclusions: These results suggest that elevated HbA1c level may be a potential serologic marker in the evaluation of the severity and prognosis of acute BSIs. There is an urgent need to study control of diabetes mellitus (DM) before and after BSIs.

The role of autonomic testing in the differentiation of Parkinson's disease from multiple system atrophy

2012-03-15

Abstract: Differentiation of idiopathic Parkinson's disease (PD) from multiple system atrophy (MSA) can be difficult. Methods devised to help distinguish the two disorders include standardized autonomic testing and cardiac imaging with iodine-123 meta-iodobenzylguanidine myocardial scintigraphy. MSA patients had more severe adrenergic and overall autonomic dysfunction when compared to control and PD patients. Area of anhidrosis on thermoregulatory sweat test was greater in MSA (67.4±12.42, p<0.001) versus PD patients (area of anhidrosis, 1.7±2.96). Postganglionic cardiac sympathetic innervation (iodine-123 meta-iodobenzylguanidine) expressed as heart to mediastinal ratio was significantly lower in Parkinson's disease patients (1.4±0.40, p=0.025) compared to controls (2.0±0.29), but not in multiple system atrophy (2.0±0.76). These findings indicate that autonomic dysfunction is generalized and predominantly preganglionic in multiple system atrophy, and postganglionic in Parkinson's disease. In our hands the thermoregulatory sweat test provides the best distinction between MSA and PD. However further confirmatory studies using larger patient numbers are required. Currently a combination of clinical judgment and autonomic testing is recommended to help differentiate MSA and PD.

Affective symptoms and cognitive functions in Parkinson's disease

Michele Poletti, Anna De Rosa, Ubaldo Bonuccelli — 2012-04-16

Abstract: Patients with Parkinson's disease (PD) typically present with motor symptoms, but several non-motor symptoms, such as cognitive impairment, autonomic dysfunction and neuropsychiatric symptoms, are usually also present, when adequately looked for. The objective of this paper is to provide an up-to-date, comprehensive review of the influence of affective disorders, mainly depression and apathy, on cognitive functioning of PD patients. Reviewed empirical findings suggest that, although depression and apathy have differential neurobiological bases in PD, both are associated to an increased risk of cognitive impairment, especially of executive functions, in this clinical population. The potential influence of other affective disorders, as anxiety and alexithymia, on cognitive functioning of PD patients is actually almost unknown and needs further empirical investigation. The clinical implication of these findings is that the best assessment and management of PD patients should include both neuropsychological and neuropsychiatric evaluations and the presence of non-motor symptoms as cognitive disturbances and affective features should be investigated with patients and caregivers.

Variable results after rituximab in neuromyelitis optica

J.W. Lindsey, K.M. Meulmester, S.A. Brod, F. Nelson, J.S. Wolinsky — 2012-03-14

Abstract: Our objective was to assess the efficacy of rituximab (RTX) in neuromyelitis optica (NMO). We conducted a retrospective review of cases personally treated by the authors. We identified nine subjects meeting criteria for either NMO or recurrent longitudinally extensive transverse myelitis (LETM) who were treated with RTX and documented their clinical course. Six of the nine subjects continued to have relapses after RTX treatment. RTX was the first immunosuppressive treatment used after diagnosis in five subjects, and four of these continued to have relapses. We conclude that outcomes after RTX treatment of NMO are inconsistent. The observed variability may reflect differences in disease activity between individuals, differences in disease activity over time, or differences in the underlying immunopathogenesis of NMO. More effective treatments are needed.

Isoform-specific immunolocalization of 14-3-3 proteins in atherosclerotic lesions of human carotid and main cerebral arteries

2012-03-14

Abstract: 14-3-3 proteins are now recognized to have a wide range of potential functions and pathological relevance, such as regulating the intercellular signal processes of differentiation, the development and growth of cells, or preventing or mediating cell apoptosis and survival by controlling the localization of potential signaling molecules. We investigated the immunolocalization of 14-3-3 proteins in atherosclerotic lesions of human cerebral and carotid arteries using 14-3-3 isoform-specific antibodies to distinguish 7 isoforms, and confirmed the cell type localization using double immunofluorolabeling. 14-3-3 common (COM)-like immunoreactivity (IR) was intense, mainly in the foam cells and multinucleated giant cells of the carotid artery. The beta, gamma, epsilon, tau, eta, and zeta (6/7) isoform-specific antibodies showed similar results to those with anti-14-3-3 COM antibody. However, among these isoform-specific antibodies, the anti-eta isoform antibody most intensely immunolabeled multinucleated giant cells and foam cells, and the anti-zeta isoform antibody most intensely immunolabeled infiltrating vascular smooth muscle cells (VSMCs), in carotid plaques. Zeta IR was also observed in one part of the mural thrombus and in the nuclei of foam cells. Gamma isoform-like IR was relatively limited in cell components, but extracellular lesions were partly positive for this isoform. In the main cerebral arteries, the anti-epsilon isoform antibody most intensely immunolabeled infiltrating VSMCs in the intima of thickened fibrous cap plaques. Endothelial cells were also positive for the epsilon isoform. These findings may provide a basis for understanding the isoform-specific role associated with atherosclerotic lesions of the cerebral and carotid arteries.

Anxiety, depression and autonomic nervous system dysfunction in hypertension

2012-03-19

Abstract: Objectives: This study examined the relationship between autonomic nervous system dysfunction, anxiety and depression in untreated hypertension.Patients and methods: 86 newly diagnosed hypertensive patients and 98 healthy volunteers were included in the study. The psychological parameters were assessed with Spielberger State-Trait Anxiety Inventory and Beck Depression Inventory by a skilled psychologist. Autonomic parameters were examined during tilt table examination (10min lying position, 10min passive tilt). Heart rate variability (HRV) was calculated by autoregressive methods. Baroreflex sensitivity (BRS) was calculated by non-invasive sequence method from the recorded beat to beat blood pressure values and RR intervals.Results: Significantly higher state (42.6±9.3 vs. 39.6±10.7 p=0.05) and trait (40.1±8.9 vs. 35.1±8.6, p<0.0001) anxiety scores were found in the hypertension group. There was no statistically significant difference in the depression level. LF-RRI (Low Frequency-RR interval) of HRV in passive tilt (377.3±430.6 vs. 494.1±547, p=0.049) and mean BRS slope (11.4±5.5 vs. 13.2±6.4, p=0.07) in lying position were lower in hypertensives. Trait anxiety score correlates significantly with sympatho/vagal balance (LF/HF-RRI) in passive tilt position (Spearman R=−0.286, p=0.01).Conclusions: Anxiety could play a more important role than depression in the development of hypertension. Altered autonomic control of the heart could be one of the pathophysiological links between hypertension and psychological factors.

Serum GFAP levels in optic neuropathies

2012-03-14

Abstract: Background: Complement mediated autoimmunity against aquaporin-4 results in astrocytic damage in neuromyelitis optica (NMO). There is evidence for increased CSF glial fibrillary acidic protein (GFAP) and S100B levels in acute NMO. Here we tested whether the CSF finding also holds true for the diagnostic value of serum GFAP and S100B levels in NMO.Methods: A multicentre study included 322 patients from London (n=160), Nijmegen (n=95), Pecs (n=44), and Lyon (n=24). Patients were classified into the following diagnostic categories: neurological control patients (n=45), MS optic neuritis (MSON, n=38), isolated optic neuritis (ION, n=11), relapsing isolated optic neuritis (RION, n=48), chronic relapsing isolated optic neuropathy (CRION, n=18), unclassified optic neuritis (UCON, n=39), NMO (n=77) and relapsing remitting multiple sclerosis (RRMS, n=47). Serum GFAP and S100B levels were quantified using ELISA.Results: Median serum GFAP but not S100B levels were significantly higher (p<0.0001, general linear model) in patients with NMO (4.83pg/mL) if compared to MSON (1.5pg/mL, p=0.0001), UCON (1.92pg/mL, p<0.01), ION (0.0ng/mL, p<0.05), RION (1.3pg/mL, p<0.0001) and CRION (2.2pg/mL, p=0.01). Serum GFAP levels in the control cohort (3.6pg/mL) were not significantly different to NMO. There was no relationship between serum GFAP levels and any other clinical or demographic parameter. Serum S100B concentrations correlated with the number of relapses in MSON (R=0.83, p=0.005).Conclusion: In contrast to the CSF, neither serum GFAP nor S100B levels were of major diagnostic value for the laboratory supported differential diagnosis between optic neuritis in the context of NMO and other optic neuropathies.

Heat shock protein 72 inhibits c-Jun N-terminal kinase 3 signaling pathway via Akt1 during cerebral ischemia

2012-03-05

Abstract: Although recent researches show that Heat Shock Protein 72 (HSP72) plays an important role in neuronal survival, little knowledge is known about the precise mechanisms during cerebral ischemia/reperfusion (I/R). Our present study investigated the neuroprotective mechanisms of HSP72 against ischemic brain injury induced by cerebral I/R. Mild heat shock pretreatment was employed to induce the overexpression of HSP72 by immersing rats into the water bath at 42°C for 20min before cerebral I/R. HSP72 antisense oligodeoxynucleotides (ODNs) were used to inhibit HSP72 expression by intracerebroventricular infusion once per day for 3days before cerebral I/R animal model was induced by four-vessel occlusion for 15min transient ischemia and then reperfused for various time in Sprague–Dawley rats. Immunoprecipitation and immunoblotting were used to detect the expression of the related proteins. HE-staining and TUNEL-staining were carried out to examine the neuronal death of hippocampal CA1 region. Results showed that mild heat shock could increase the phosphorylation of protein kinase B (Akt), inhibit the assembly of MLK3–MKK7–JNK3 signaling module, diminish the phosphorylation of JNK3 and c-Jun, and decrease the activation of caspase-3. Furthermore, mild heat shock could significantly protect neurons against cerebral I/R. Whereas, all of the aforementioned effects of mild heat shock were reversed by HSP72 antisense ODNs. In summary, our results imply that Akt1 activation is involved in the neuroprotection of HSP72 against ischemic brain injury via suppressing JNK3 signaling pathway and provide a new experimental foundation for stroke therapy.

Operative and nonoperative linguistic outcomes in brain injury patients

2012-03-14

Abstract: Objective and background: Linguistic function is one of vulnerable aspects of traumatic brain injury (TBI) which may have destructive effects on patients' communicative activities and daily life, years following trauma. This paper attempts to answer the controversy whether surgery affects increase and decrease of linguistic impairment or not.Materials and methods: Two hundred forty-one TBI patients aged 18–65 with abnormal CT findings and at least 20 minute post-trauma amnesia (PTA), who were conscious at discharge, participated in this study. Based on operative intervention, the samples were divided into two groups: operative and nonoperative. Cognitive and aphasic deficits were inspected formally and pragmatic disorder was informally appraised at discharge.Results: The groups had no significant differences in aphasia incidence and language pragmatic impairment, though they were significantly distinctive in aphasia subcategories and cognitive deficit after trauma. Fluent aphasia was more common in both groups alike. In aphasia subcategories, however, transcortical sensory aphasia (TSA) in operative and anomia in nonoperative group were the most prevalent. Several variables appeared strikingly related to higher aphasia in operative groups as follows: moderate to severe injury, 18–35 and over 50years of age, more than 1week PTA, intracranial surgery of multiple lesions in left or bilateral hemisphere fronto-temporal cortex plus post-trauma cognitive and pragmatic impairments, and diffuse axonal injuries.Discussion: Almost certainly, meaningful drop of cognitive function post surgery roots back in significant loss of initial consciousness level. Related factors to postoperative aphasia suggest taking policies through surgery intervention. Discerning the indispensable contributions of neurosurgeons, neurolinguists, and neuroscientists, results inspire more clinical future studies.

GSTM1 null genotype as risk factor for late-onset Alzheimer's disease in Italian patients

2012-03-01

Abstract: Alzheimer's disease (AD) is the most common form of dementia in the elderly. The causes of AD are very complex but there is general agreement about the existence of a link between Alzheimer's disease and oxidative stress. The Glutathione S-transferases (GSTs) act to detoxify products of oxidation that cause damage to macromolecules. Particular attention has been focused on GST genes because polymorphisms are important determinants of disease risk.To evaluate if GSTA1, GSTM1, GSTP1, and GSTT1 genes are associated with LOAD we screened a case–control population (n=311).Differences in genotype distributions between AD patients and controls were found only for the GSTM1 null genotype (P<0.001). In addition, a logistic regression analysis also conferred a positive association between the GSTM1 null genotype and LOAD after adjustment for age and gender (OR=2.09; 95%CI=1.31–3.35).The GSTM1 enzyme detoxifies substances such as exogenous and endogenous metabolites and plays a regulatory role in cellular signaling. Previous studies have highlighted that GSTM1 has a role in neurodegenerative disorders, but no data have associated the GSTM1 gene with AD risk. Our outcome suggests that the GSTM1 null genotype is a risk factor for AD in Italian patients.

Revisiting cerebral thromboangiitis obliterans

2012-04-13

Abstract: We describe a 56-year-old patient with progressive cognitive decline in the context of heavy tobacco use and migraine, and imaging evidence of an occlusive terminal cerebral vasculopathy. The results of brain biopsy recapitulated the pathological features described by Lindenberg and Spatz in their classic 1939 treatise on cerebral thromboangiitis obliterans, or cerebral Buerger's disease. Although the condition is associated with heavy smoking, the identification of a hypercoagulable state in our patient suggests a multifactorial pathogenesis. The diagnosis of cerebral thromboangiitis obliterans in life is facilitated by modern neuroimaging and should prompt immediate cessation of smoking and a search for an underlying prothrombotic tendency.

Myasthenia gravis appearing 18years after resection of benign thymoma with subsequent limbic encephalitis

2012-04-09

Abstract: Thymoma is associated with multiple autoimmune disorders, most commonly myasthenia gravis (MG). However, symptomatic MG may first present following thymectomy. We report an unusual patient with paraneoplastic limbic encephalitis diagnosed a few months after total thymectomy for asymptomatic thymoma, followed 18years later by the onset of symptomatic MG without evidence of tumor recurrence.

Pure upbeat nystagmus in association with bilateral internuclear ophthalmoplegia

2012-03-27

Abstract: A 66-year-old man developed primary position upbeat nystagmus and bilateral internuclear ophthalmoplegia (INO). Video-oculography showed primary position upbeat nystagmus with exponentially decreasing slow phases, which disappeared in darkness. Brain MRI disclosed enhancing lesions involving bilateral dorsomedial pons extending from the middle to upper portion. Upbeat nystagmus in association with bilateral INO may be attributed by the damage of the cell groups of the paramedian tracts (PMT), the projections from the interstitial nucleus of Cajal (INC) to PMT, or the connections between INC and the nucleus of Roller.

N-Methyl d-aspartate receptor antibody encephalitis associated with myelitis

Catherine Pennington, Shona Livingstone, Celestine Santosh, Saif Razvi — 2012-03-29

Abstract: Encephalitis associated with antibodies to the N-methyl d-aspartate receptor (NMDA-R) was first described in young women with ovarian teratoma []. It has subsequently been described in men, children and in those without an underlying tumour [2]. Characteristic clinical features include neuropsychiatric symptoms, seizures, movement disorders, hypoventilation and autonomic instability. Spinal cord disease in association with other typical clinical features has been described in only one patient previously [3,7].We report a patient presenting with myelitis, with typical features of NMDA-R associated encephalitis manifesting 3months later.

Dysfunction of default-mode network in encephalopathy with a reversible corpus callosum lesion

Shingo Mitaki, Keiichi Onoda, Masaki Ishihara, Yoko Nabika, Shuhei Yamaguchi — 2012-03-14

Abstract: Increasing attention has been paid recently to the study of spontaneous brain activity; moreover, particular attention has been paid to the concept of a default-mode network of brain function. Although the functional significance of the default-mode network remains a matter of debate, it has been suggested to be a candidate for the network subserving basic functions related to consciousness. We report the case of a 29-year-old man with encephalopathy and a reversible lesion of the entire corpus callosum. Despite resolution of corpus callosum lesion on magnetic resonance imaging (MRI) within 1week, the patient persistently presented disturbance of consciousness. Resting-state functional MRI revealed that the posterior cingulate cortex/precuneus was functionally disconnected from other brain regions within the default-mode network. Our case report suggests that assessment of the functional connectivity in the resting-state default-mode network could be a useful marker of consciousness disturbance even in the presence of a reversible brain lesion.

Diminution of hemoglobin-derived hemorphin: An underlying risk factor for cognitive deficit in diabetes

Chang Zheng Song, Qing Wei Wang, Chang Cheng Song — 2012-04-05

Over recent years several studies of this journal have reported that diabetes could boost the risk of cognitive impairment . Cognitive defect represents an independent complication alongside atherosclerotic cardiovascular disease, nephropathy, neuropathy and retinopathy in diabetic patients. Although cognitive decline is considered to be associated with chronic episodes of cardiovascular events, insulin resistance, hyperglycemia or hypoglycemia, yet the mechanism connecting diabetes to impaired cognitive function remains unknown. We address that hemoglobin-derived neuropeptide may illuminate the direct link between diabetes and occurrence of cognitive decline.

Response letter to the manuscript “Diminution of hemoglobin-derived hemorphin: An underlying risk factor for cognitive deficit in diabetes” for Journal of the Neurological Sciences

Marina Petrova, Semen Prokopenko, Elena Pronina, Elena Mozheyko — 2012-04-05

We read with great interest the article written by Song et al. “Diminution of hemoglobin-derived hemorphin: an underlying risk factor for cognitive deficit in diabetes” . The authors mention that hemoglobin-derived hemorphin may clarify the link between diabetes and cognitive impairments.

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2012-06-15