Neuropsychiatric Manifestations of Wilson Disease: Correlation with MRI and Glutamate Excitotoxicity.

This study aims to identify neuropsychiatric manifestations in neurological Wilson disease (NWD), and their correlation with MRI changes and glutamate excitotoxicity. Forty-three consecutive patients with NWD from a tertiary care teaching hospital were evaluated prospectively who fulfilled the inclusion criteria. The neuropsychiatric evaluation was done using Neuropsychiatric Inventory (NPI) battery that assesses 12 domains including delusion, hallucination, agitation/aggression, dysphoria/depression, anxiety, euphoria, apathy, disinhibition, irritability, aberrant motor activity, appetite change, and abnormal nighttime behavior. Cranial MRI was done using a 3 T machine, and locations of signal changes were noted including the total number of MRI lesions. Serum glutamate level was measured by a fluorescence microplate reader. Abnormal NPI in various domains and total NPI scores were correlated with MRI lesions, serum and urinary copper, and glutamate level. The median age of the patients was 16 years. Forty-one (48.8%) patients had cognitive impairment and 37 (86%) had movement disorder. Neurobehavioral abnormality was detected in all-commonest being agitation (90.7%) followed by appetite change (81.4%), elation (74.4%), irritability (69.8%), anxiety (67.4%), depression (65.1%), apathy (44.2%), night time abnormal behavior (32.6%), aberrant motor behavior (20.9%), delusions (16.3%), and hallucination (18.6%). The thalamic lesion was associated with depression, globus pallidus with depression and anxiety, caudate with anxiety and agitation, brainstem with irritability, and frontal cortex with apathy. Serum glutamate level was higher in NWD. NPI sum score correlated with MRI load and glutamate level. Varying severity of neurobehavioral abnormalities are common in the patients with NWD and correlate with the location of MRI lesion and glutamate level.

Systemic Elevation of n-3 Polyunsaturated Fatty Acids (n-3-PUFA) Is Associated with Protection against Visual, Motor, and Emotional Deficits in Mice following Closed-Head Mild Traumatic Brain Injury.

Traumatic brain injury (TBI) causes neuroinflammation and neurodegeneration leading to various pathological complications such as motor and sensory (visual) deficits, cognitive impairment, and depression. N-3 polyunsaturated fatty acid (n-3 PUFA) containing lipids are known to be anti-inflammatory, whereas the sphingolipid, ceramide (Cer), is an inducer of neuroinflammation and degeneration. Using Fat1+-transgenic mice that contain elevated levels of systemic n-3 PUFA, we tested whether they are resistant to mild TBI-mediated sensory-motor and emotional deficits by subjecting Fat1-transgenic mice and their WT littermates to focal cranial air blast (50 psi) or sham blast (0 psi, control). We observed that visual function in WT mice was reduced significantly following TBI but not in Fat1+-blast animals. We also found Fat1+-blast mice were resistant to the decline in motor functions, depression, and fear-producing effects of blast, as well as the reduction in the area of oculomotor nucleus and increase in activated microglia in the optic tract in brain sections seen following blast in WT mice. Lipid and gene expression analyses confirmed an elevated level of the n-3 PUFA eicosapentaenoic acid (EPA) in the plasma and brain, blocking of TBI-mediated increase of Cer in the brain, and decrease in TBI-mediated induction of Cer biosynthetic and inflammatory gene expression in the brain of the Fat1+ mice. Our results demonstrate that suppression of ceramide biosynthesis and inflammatory factors in Fat1+-transgenic mice is associated with significant protection against the visual, motor, and emotional deficits caused by mild TBI. This study suggests that n-3 PUFA (especially, EPA) has a promising therapeutic role in preventing neurodegeneration after TBI.

Movement Disorder in Wilson Disease: Correlation with MRI and Biomarkers of Cell Injury.

To report the phenomenology of movement disorder (MD) in neurological Wilson disease (NWD), and correlate these with MRI, and biomarkers of oxidative stress, excitotoxicity, and inflammation. Eighty-two patients were included, and their phenomenology of MD was categorized. The severity of dystonia was assessed using the Burke-Fahn-Marsden score, and chorea, athetosis, myoclonus, and tremor on a 0-4 scale. The MRI changes were noted. Serum glutamate, cytokines, and oxidative stress markers were measured. Movement disorders were noted in 78/82 (95.1%) patients and included dystonia in 69 (84.1%), chorea in 31 (37.8%), tremor in 24 (29.3%), parkinsonism in 19 (23.2%), athetosis in 13 (15.9%), and myoclonus in 9 (11.0%) patients. Dystonia was more frequently observed in the patients with thalamic (76.8 vs 23.2%), globus pallidus (72.0 vs 28.0%), putamen (69.5 vs 30.5%), caudate (68.3 vs 31.7%) and brainstem (61.0 vs 39.0%) involvement, and tremor with cerebellar involvement (37.5 vs 5.2%). The median age of onset of neurological symptoms was 12 (5-50) years. WD patients had higher levels of malondialdehyde (MDA), glutamate, and cytokines (IL-6, IL-8, IL-10, and TNFα) and lower levels of glutathione and total antioxidant capacity (TAC) compared with the controls. Serum glutamate, IL-6, IL-8, and plasma MDA levels were increased with increasing neurological severity, while glutathione and TAC levels decreased. The severity of dystonia related to the number of MRI lesions. MD is the commonest neurological symptoms in WD. Oxidative stress, glutamate, and cytokine levels are increased in WD and correlate with neurological severity.

Clinical features and blood iron metabolism markers in children with beta-propeller protein associated neurodegeneration.

BACKGROUND: Neurodegeneration with brain iron accumulation constitutes a group of rare progressive movement disorders sharing intellectual disability and neuroimaging findings as common denominators. Beta-propeller protein-associated neurodegeneration (BPAN) represents approximately 7% of the cases, and its first signs are typically epilepsy and developmental delay. We aimed to describe in detail the phenotype of BPAN with a special focus on iron metabolism. MATERIAL AND METHODS: We present a cohort of paediatric patients with pathogenic variants of WD-Repeat Domain 45 gene (WDR45). The diagnosis was established by targeted panel sequencing of genes associated with epileptic encephalopathies (n = 9) or by Sanger sequencing of WDR45 (n = 1). Data on clinical characteristics, molecular-genetic findings and other performed investigations were gathered from all participating centres. Markers of iron metabolism were analysed in 6 patients. RESULTS: Ten children (3 males, 7 females, median age 8.4 years) from five centres (Prague, Berlin, Vogtareuth, Tubingen and Cologne) were enrolled in the study. All patients manifested first symptoms (e.g. epilepsy, developmental delay) between 2 and 31 months (median 16 months). Seven patients were seizure-free (6 on antiepileptic medication, one drug-free) at the time of data collection. Neurological findings were non-specific with deep tendon hyperreflexia (n = 4) and orofacial dystonia (n = 3) being the most common. Soluble transferrin receptor/log ferritin ratio was elevated in 5/6 examined subjects; other parameters of iron metabolism were normal. CONCLUSION: Severity of epilepsy often gradually decreases in BPAN patients. Elevation of soluble transferrin receptor/log ferritin ratio could be another biochemical marker of the disease and should be explored by further studies.

Serum orexin-A levels are associated with disease progression and motor impairment in multiple sclerosis.

OBJECTIVE: Diencephalon is frequently affected in multiple sclerosis (MS), and lesions of this region are associated with increased disability. Orexin-A and melatonin, two foremost mediators of diencephalon, modulate cognitive and motor functions through several pathways including the brain-derived neurotrophic factor (BDNF)-cAMP response element-binding protein (CREB) signaling pathway. In this pilot study, our aim was to investigate the prognostic value of these factors in progression of cognitive and physical disability. METHODS: Levels of BDNF, melatonin, CREB, and orexin-A were determined by ELISA in sera of 25 relapsing remitting MS (RRMS) patients, 15 secondary progressive MS (SPMS) patients, and 20 healthy controls. Cognitive and motor functions were assessed by a neuropsychological test battery, timed 25-ft walk (T25-FW) and 9-hole peg (9-HP) tests. RESULTS: MS patients had significantly lower serum levels of orexin-A and BDNF than healthy controls, and SPMS patients had significantly lower levels of melatonin and orexin-A than RRMS patients. Serum orexin-A levels were negatively correlated with 9-HP, T25-FW test scores, and progression index in RRMS patients. BDNF, CREB, and melatonin levels did not show any significant correlation with clinical features including EDSS and cognitive/motor performance of the patients. CONCLUSION: Our results suggest that orexin-A levels are decreased in parallel to disease progression and motor system deterioration in the earlier stages of the disease. Thus, orexin-A might be used as a potential biomarker of physical disability.

Assessing the Relationship between Vitamin D Status and Impairments in Cognitive and Physical Performance in Older Adults Using a Dual Task Physical Performance Test.

BACKGROUND: Vitamin D deficiency has been associated with an increased risk of falls in older adults. Several studies have demonstrated an association between vitamin D deficiency and gait and cognitive impairments, which are two risk factors for falls in the elderly. There is lack of research about the role of vitamin D in cognitive function in the context of mobility. OBJECTIVE: The purpose of this study was to evaluate the association between vitamin D status with the age-related changes in mobility through higher order cognitive function using a dual task physical performance test. DESIGN: Cross-sectional. SETTING: Community-dwelling older adult population located in Miami, Fl. PARTICIPANTS: Healthy participants over the age of 55 (n=97) who participated in the parent interventional study. MEASUREMENTS: Participants completed assessments that included serum levels of vitamin D, surveys, and dual task physical performance tests. Spearman's correlations, independent t-tests, repeated measures ANOVAs and multiple logistic regressions were used to examine the relationship between vitamin D insufficiency (25-hydroxyvitamin D <30 ng/ml) and sufficiency (≥30 ng/ml) and dual task physical performance variables. The significance level was set at α=0.05. RESULTS: There were no significant associations between vitamin D insufficiency and gait velocity during either task. Using Spearman correlations, slower single (P=0.011) and dual task counting rates (P=0.006) were significantly associated with vitamin D insufficiency. Independent t-tests showed dual and single task counting rates were significantly lower in the vitamin D insufficient group compared to the sufficient group (P=0.018 and P=0.028, respectively). The results for the ANOVAs indicated that velocities and counting rates were not significantly different by vitamin D status (Wilk's Lambda =0.999; F (1, 95) =.11, P=.740) (Wilk's Lambda =.999, F(1,95)=.13, P=.718). Vitamin D status was not significantly associated with dual task physical performance (defined as the difference in dual and single task) in gait velocity (OR=1.00, 95% CI: 0.98; 1.02, P=0.772) and counting rate (OR=1.684, 95% CI: 0.15; 19.57, P=0.677), when controlling for confounders. CONCLUSIONS: Since counting backward is a mental tracking task, which is a component of executive function, our results suggest a relationship between vitamin D insufficiency and executive dysfunction. Executive dysfunction has been previously associated with fall risks in the elderly, and it could be a possible mediator between vitamin D and falls. Our data suggest that cognition may play a significant role in vitamin D's influence on falls, while motor function may play a lesser role.

The significance of uric acid in the diagnosis and treatment of Parkinson disease: An updated systemic review.

BACKGROUND: Parkinson disease (PD) is a neurodegenerative disease characterized by chronic and progressive loss of dopaminergic neurons in substansia nigra pars compacta. Oxidative stress is proposed to play a critical role in the pathogenesis of PD. Uric acid (UA), as an important physiological antioxidant, is identified a molecular predictor associated with a decreased risk and a slower disease progression for PD and potential neuroprotectant of PD by increasing epidemiological and clinical evidences. Within this review, we will present a comprehensive overview of the data linking UA to PD in recent years. METHODS: We searched PubMed, EMBASE, Web of Science databases for relevant studies. Any observational or experimental studies that evaluated UA and PD were our goal of searching the electric databases. RESULTS: Twelve studies that evaluated UA and PD were identified in this review. We reviewed the roles of UA in the pathogenesis of PD, the association of UA with morbidity, severity/progression, nonmotor symptoms, motor complications of PD, with an attempt to provide new ideas for diagnosis and treatment in PD. CONCLUSION: Our findings supported that lots of clinical and epidemiological data observed lower UA levels in PD patients. Manipulation of UA or its precursors' concentration could be effective to treat or prevent PD. However, it is still suspectable that higher UA levels are better enough to PD patients. Furthermore, for the complex nature of PD and its heterogeneous genetic and environmental influences, it is inadequate for just manipulating UA in treating the disease.

A simple blood test expedites the diagnosis of glucose transporter type 1 deficiency syndrome.

Glucose transporter type 1 (GLUT1) deficiency syndrome (GLUT1-DS) leads to a wide range of neurological symptoms. Ketogenic diets are very efficient to control epilepsy and movement disorders. We tested a novel simple and rapid blood test in 30 patients with GLUT1-DS with predominant movement disorders, 18 patients with movement disorders attributed to other genetic defects, and 346 healthy controls. We detected significantly reduced GLUT1 expression only on red blood cells from patients with GLUT1-DS (23 patients; 78%), including patients with inconclusive genetic analysis. This test opens perspectives for the screening of GLUT1-DS in children and adults with cognitive impairment, movement disorder, or epilepsy. Ann Neurol 2017;82:133-138.

Laboratory diagnosis of creatine deficiency syndromes: a technical standard and guideline of the American College of Medical Genetics and Genomics.

Disclaimer: These ACMG Standards and Guidelines are intended as an educational resource for clinical laboratory geneticists to help them provide quality clinical laboratory genetic services. Adherence to these standards and guidelines is voluntary and does not necessarily assure a successful medical outcome. These Standards and Guidelines should not be considered inclusive of all proper procedures and tests or exclusive of others that are reasonably directed to obtaining the same results. In determining the propriety of any specific procedure or test, clinical laboratory geneticists should apply their professional judgment to the specific circumstances presented by the patient or specimen. Clinical laboratory geneticists are encouraged to document in the patient's record the rationale for the use of a particular procedure or test, whether or not it is in conformance with these Standards and Guidelines. They also are advised to take notice of the date any particular guideline was adopted, and to consider other relevant medical and scientific information that becomes available after that date. It also would be prudent to consider whether intellectual property interests may restrict the performance of certain tests and other procedures.Cerebral creatine deficiency syndromes are neurometabolic conditions characterized by intellectual disability, seizures, speech delay, and behavioral abnormalities. Several laboratory methods are available for preliminary and confirmatory diagnosis of these conditions, including measurement of creatine and related metabolites in biofluids using liquid chromatography-tandem mass spectrometry or gas chromatography-mass spectrometry, enzyme activity assays in cultured cells, and DNA sequence analysis. These guidelines are intended to standardize these procedures to help optimize the diagnosis of creatine deficiency syndromes. While biochemical methods are emphasized, considerations for confirmatory molecular testing are also discussed, along with variables that influence test results and interpretation.Genet Med 19 2, 256-263.

Baseline CSF/Serum-Ratio of Apolipoprotein E and Rate of Differential Decline in Alzheimer's Disease.

BACKGROUND/OBJECTIVE: Apolipoprotein E (ApoE) has an active part in the pathogenesis of Alzheimer's disease (AD). Cerebrospinal fluid (CSF) and plasma level alterations have been reported in AD patients. In search of a biomarker potentially predictive of cognitive, functional, or motor decline, we analyzed the CSF to serum ratios of ApoE levels (CSF/serum ApoE) in AD patients in this regard. METHODS: Subjects with newly diagnosed AD were followed within a longitudinal observational study (rpAD study). Annual neuropsychological testing and physical examination were performed. Multiple regression analyses were used to determine possible associations of the ApoE CSF/serum concentration ratios and velocity of decline on a variety of cognitive, functional and motor scales (MMSE, iADL, bADL, GDS, UPDRSIII) adjusted for relevant co-variables. RESULTS: CSF/serum ratios of ApoE levels were associated with progression on the UPDRSIII (change of UPDRSIII slope [pt/yr] per unit of ApoE CSF/serum = -0.06, p <  0.01) and instrumental ADL scale (change of iADL slope [pt/yr] per unit of ApoE CSF/serum = 0.01, p = 0.01) ("the lower the ratio, the faster the deterioration" and vice versa). Secondarily, higher age at onset was associated with faster UPDRSIII progression, antidepressant use with faster iADL decline, and better baseline function with more rapid decline on either MMSE, iADL, or GDS scale. CONCLUSION: Here, CSF/serum ApoE at time of AD diagnosis was shown to be inversely associated with medium-term functional and motor progression. Whether this ratio qualifies for the use as a predictive biomarker must be validated in larger cohort studies over the long term.

Biosynthesis of homoarginine (hArg) and asymmetric dimethylarginine (ADMA) from acutely and chronically administered free L-arginine in humans.

Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of nitric oxide (NO) synthesis, whereas L-arginine (Arg) and L-homoarginine (hArg) serve as substrates for NO synthesis. ADMA and other methylated arginines are generally believed to exclusively derive from guanidine (N (G))-methylated arginine residues in proteins by protein arginine methyltransferases (PRMTs) that use S-adenosylmethionine (SAM) as the methyl donor. L-Lysine is known for decades as a precursor for hArg, but only recent studies indicate that arginine:glycine amidinotransferase (AGAT) is responsible for the synthesis of hArg. AGAT catalyzes the formation of guanidinoacetate (GAA) that is methylated to creatine by guanidinoacetate methyltransferase (GAMT) which also uses SAM. The aim of the present study was to learn more about the mechanisms of ADMA and hArg formation in humans. Especially, we hypothesized that ADMA is produced by N (G)-methylation of free Arg in addition to the known PRMTs-involving mechanism. In knockout mouse models of AGAT- and GAMT-deficiency, we investigated the contribution of these enzymes to hArg synthesis. Arg infusion (0.5 g/kg, 30 min) in children (n = 11) and ingestion of high-fat protein meals by overweight men (n = 10) were used to study acute effects on ADMA and hArg synthesis. Daily Arg ingestion (10 g) or placebo for 3 or 6 months by patients suffering from peripheral arterial occlusive disease (PAOD, n = 20) or coronary artery disease (CAD, n = 30) was used to study chronic effects of Arg on ADMA synthesis. Mass spectrometric methods were used to measure all biochemical parameters in plasma and urine samples. In mice, AGAT but not GAMT was found to contribute to plasma hArg, while ADMA synthesis was independent of AGAT and GAMT. Arg infusion acutely increased plasma Arg, hArg and ADMA concentrations, but decreased the plasma hArg/ADMA ratio. High-fat protein meals acutely increased plasma Arg, hArg, ADMA concentrations, as well as the plasma hArg/ADMA ratio. In the PAOD and CAD studies, plasma Arg concentration increased in the verum compared to the placebo groups. Plasma ADMA concentration increased only in the PAOD patients who received Arg. Our study suggests that in humans a minor fraction of free Arg is rapidly metabolized to ADMA and hArg. In mice, GAMT and N (G)-methyltransferases contribute to ADMA and hArg synthesis from Arg, whereas AGAT is involved in the synthesis of hArg but not of ADMA. The underlying biochemical mechanisms remain still elusive.

Altered IL-2, IL-6 and IL-8 serum levels in schizophrenia patients with tardive dyskinesia.

Immune deregulation has been postulated to be one of the mechanisms underlying the pathogenesis of tardive dyskinesia (TD). We hypothesized that interleukins would have a link with TD in schizophrenia patients. In this study, the serum IL-2, IL-6 and IL-8 levels were examined by enzyme-linked immunosorbent assay (ELISA) in schizophrenia patients with TD (n=48) and without TD (n=45), and healthy controls (n=44). The psychopathological symptoms of schizophrenia were assessed by the Positive and Negative Syndrome Scale (PANSS). The severity of TD was evaluated using Abnormal Involuntary Movement Scale (AIMS). The results showed that serum IL-2, IL-6 and IL-8 levels were significantly different among schizophrenia patients with TD and without TD and normal controls. Moreover, IL-2 level was significantly correlated with PANSS positive subscale and general subscale in patients with TD and without TD. In addition, IL-2 level was positively correlated with AIMS score in TD patients. The results supported that immune disturbance is related to the schizophrenia patients, especially to the patients with TD and ILs might play an important role in the pathophysiology of schizophrenia patients with TD.

Mn-superoxide dismutase activity is associated with orofacial involuntary movements in schizophrenia patients with tardive dyskinesia.

BACKGROUND: Oxidative stress-induced damage may be involved in tardive dyskinesia (TD) development. Superoxide dismutase (SOD), the key antioxidant enzyme, was found abnormal in TD. OBJECTIVE: We examined the role of oxidative stress in relation to TD and TD subtypes in schizophrenia using manganese SOD (MnSOD) as the biomarker. METHODS: We recruited 152 male chronic patients with (n = 76) and without TD (n = 76) meeting Diagnostic and Statistical Manual of Mental Disorders-IV criteria for schizophrenia and 75 male control subjects. We examined the MnSOD activity for all subjects. Positive and Negative Syndrome Scale and the Abnormal Involuntary Movement Scale (AIMS) were assessed in the patients. RESULTS: Manganese SOD activity was lower in patients with TD than non-TD (p < 0.05). In the patients with TD, orofacial and total scores of AIMS were positively associated with MnSOD levels (both p < 0.05). Multiple regression analysis further confirmed that MnSOD was an independent contributor to both the orofacial and the total scores of AIMS (both p < 0.05). CONCLUSIONS: Oxidative stress reflected by compromised oxidative defense may play a role in the development and severity of TD. There may be an etiologic relationship between increased SOD level and dyskinetic movements associated with TD. In particular, MnSOD activity may have a specific role in orofacial TD.

Movement disorders due to bilirubin toxicity.

Advances in the care of neonatal hyperbilirubinemia have led to a decreased incidence of kernicterus. However, neonatal exposure to high levels of bilirubin continues to cause severe motor symptoms and cerebral palsy (CP). Exposure to moderate levels of unconjugated bilirubin may also cause damage to the developing central nervous system, specifically the basal ganglia and cerebellum. Brain lesions identified using magnetic resonance imaging following extreme hyperbilirubinemia have been linked to dyskinetic CP. Newer imaging techniques, such as diffusion tensor imaging or single-photon emission computed tomography, allow quantification of more subtle white matter injury following presumed exposure to unbound bilirubin, and may explain more subtle movement disorders. New categories of bilirubin-induced neurologic dysfunction, characterized by subtle bilirubin encephalopathy following moderate hyperbilirubinemia, have been implicated in long-term motor function. Further research is needed to identify subtle impairments resulting from moderate-severe neonatal hyperbilirubinemia, to understand the influence of perinatal risk factors on bilirubin toxicity, and to develop neuroprotective treatment strategies to prevent movement disorders due to bilirubin toxicity.

Is pineal melatonin released in the third ventricle in humans? A study in movement disorders.

In order to determine sources and metabolism of melatonin in human cerebrospinal fluid (CSF), melatonin and 6-sulfatoxymelatonin (aMT6S) concentrations were measured in CSF sampled during neurosurgery in both lateral and third ventricles in patients displaying movement disorder (Parkinson's disease, essential tremor, dystonia or dyskinesia) and compared with their plasma levels. Previous determinations in nocturnal urine had showed that the patients displayed melatonin excretion in the normal range, compared with healthy controls matched according to age. A significant difference in melatonin concentration was observed between lateral and third ventricles, with the highest levels in the third ventricle (8.75±2.75pg/mL vs. 3.20±0.33pg/mL, P=0.01). CSF aMT6s levels were similar in both ventricles and of low magnitude, less than 5pg/mL. They were not correlated with melatonin levels or influenced by the area of sampling. Melatonin levels were significantly higher in third ventricle than in the plasma, whereas there was no difference between plasma and lateral ventricle levels. These findings show that melatonin may enter directly the CSF through the pineal recess in humans. The physiological meaning of these data remains to be elucidated.

Altered BDNF is correlated to cognition impairment in schizophrenia patients with tardive dyskinesia.

BACKGROUND: Long-term antipsychotic treatment for schizophrenia is often associated with the emergence of tardive dyskinesia (TD), which is linked to greater cognitive impairment. Brain-derived neurotrophic factor (BDNF) plays a critical role in cognitive function, and schizophrenia patients with TD have lower BDNF levels than those without TD. OBJECTIVE: This study examines the BDNF levels, the cognitive function, and the association of BDNF with cognitive function in schizophrenia patients with or without TD. METHODS: We recruited 83 male chronic patients with (n=35) and without TD (n=48) meeting DSM-IV criteria for schizophrenia and 52 male control subjects. We examined the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) and BDNF levels for all subjects. Positive and Negative Symptom Scale (PANSS) and the Abnormal Involuntary Movement Scale (AIMS) were assessed in patients. RESULTS: BDNF levels were lower in patients with than those without TD (p<0.05). RBANS total score (p<0.01) and subscales of immediate memory, visuospatial/constructional performance, and attention were lower in patients with than those without TD (all p<0.05). BDNF levels were positively associated with immediate memory in patients without TD, but negatively in TD patients (both p<0.05). Multiple regression analysis confirmed that in either TD or non-TD group, BDNF was an independent contributor to immediate memory (both p<0.05). CONCLUSIONS: BDNF may be involved in the pathophysiology of TD. While the associations between BDNF and cognition in both TD and non-TD patients suggest a close relationship between BDNF and cognition, the different directions may implicate distinct mechanisms between TD and non-TD patients.

Increased proinflammatory cytokines in sera of patients with multifocal motor neuropathy.

BACKGROUND: Multifocal motor neuropathy (MMN) is characterized by clinical improvement with intravenous immunoglobulin and the frequent detection of anti-ganglioside antibodies. However, the immunological background of the neuronal damage in MMN is still unclear. OBJECTIVE: The aim of this study is to investigate abnormalities in the cytokine and chemokine profiles of MMN patients. METHODS: Sera from 16 patients with MMN, 16 patients with sporadic amyotrophic lateral sclerosis (ALS), and 15 patients with other non-inflammatory neurological diseases (ONDs) were analyzed for 27 cytokines and chemokines using a multiplex bead array. We also checked whether the altered cytokine/chemokine profile in the MMN group differed significantly in the presence or absence of abnormal electrophysiological findings. RESULTS: Serum IL-1Ra, IL-2, G-CSF, TNF-α, and TNFR1 levels were significantly higher in the MMN group than in the ONDs group. Of these, G-CSF and TNF-α also showed significant increases compared to the ALS group. Serum G-CSF and TNF-α levels were significantly higher in MMN patients presenting with focal demyelination including conduction block than in patients without any focal demyelination. CONCLUSIONS: Proinflammatory cytokines may contribute to peripheral nerve demyelination in MMN.