Utility of serum neurofilament light chain and glial fibrillary acidic protein as diagnostic biomarkers of freezing of gait in Parkinson's disease.

Freezing of gait (FOG) is one of the most distressing features of Parkinson's disease (PD), increasing the risks of fractures and seriously affecting patients' quality of life. We aimed to examine the potential diagnostic roles of serum neurofilament light chain (NFL) and glial fibrillary acidic protein (GFAP) in PD patients with FOG (PD-FOG). We included 99 patients, comprising 54 PD patients without FOG (PD-NoFOG), 45 PD-FOG and 37 healthy controls (HCs). Our results indicated serum markers were significantly higher in PD-FOG and postural instability and gait difficulty (PIGD) motor subtype patients than in PD-NoFOG and non-PIGD subtype patients (P < 0.05), respectively. Patients with high concentrations of the markers NFL and GFAP had higher PIGD scores and greater FOG severity than those with low concentrations. Moreover, serum levels of both NFL and GFAP were significantly positively associated with age, FOG severity, PD-FOG status, and negatively associated with Mini-Mental State Examination (MMSE) scores. Logistic regression analysis identified serum levels of NFL and GFAP as independent risk factors for PD-FOG. Mediation analysis revealed that MMSE scores fully mediated the relationship between serum GFAP levels and FOG-Q scores, accounting for 33.33% of the total effects (indirect effect = 0.01, 95% CI 0.01-0.02). NFL levels differentiated PD-FOG from PD-NoFOG with reliable diagnostic accuracy (AUC 0.75, 95% CI 0.66-0.84), and the combination of NFL, GFAP, duration and MMSE scores demonstrated high accuracy (AUC 0.84, 95% CI 0.76-0.91). Our findings support the notion that NFL and GFAP may be potential biomarkers for the diagnosis of PD-FOG.

Spastic gait, intellectual disability and seizures due to a rare mutation causing hyperargininemia.

Hyperargininemia is an autosomal recessive disorder caused by a defect in the arginase I enzyme. We present a case of a 20-year-old male with severe spastic gait, intellectual disability and seizures. Metabolic tests revealed high levels of arginine in blood serum. Hyperargininemia was attributed to a likely pathogenic rare mutation of ARG1 gene [Chr6: g131905002_131905002 G>A (p.Arg308Gln) homozygous] detected in Whole Exome Sequencing resulting in deficiency in arginase I enzyme. Following the diagnosis, the patient has been treated with low protein diet, aminoacid and vitamin supplements. The accumulation of arginine, may contribute to the pathogenesis of severe neurological manifestations, however, low protein intake diet may lead to a favorable outcome. Therefore, clinicians should screen for hyperargininemia in early childhood in case of strong clinical suspicion.

Immunodeficiency, Centromeric Region Instability, and Facial Anomalies Syndrome (ICF) in a Boy with Variable Clinical and Immunological Presentations.

Immunodeficiency, centromeric instability, and facial anomalies (ICF) syndrome is a rare primary immunodeficiency disorder characterized by recurrent infections and low immunoglobulin levels due to variable combined immunodeficiency, and centromeric region instability, and facial dysmorphism. We describe a 12-year-old boy with recurrent respiratory tract infections, facial anomalies, scoliosis, and psychomotor retardation. He had recurrent pneumonia with low serum IgG and IgM levels during infancy and preschool age. Later at the age of 10, he developed recurrent ear infections. An IgA and IgM deficiency was found accompanied by a normal B-cell and T-cell count as well as an impaired candida-induced T-cell proliferation. Further evaluations revealed a missense mutation in the DNMT3B gene on chromosome 20. Chromosomal analysis showed a sunburst multi-radial feature on chromosome 1, which is a hallmark of ICF syndrome. The genetic mutation and chromosomal abnormality along with clinical findings are compatible with the diagnosis of ICF syndrome. To the best of our knowledge, this is the first time that scoliosis is observed in an ICF patient. The additional variable clinical symptoms in the case were the presence of spastic gait as well as hypogammaglobulinemia with immunoglobulin isotype switch at different ages.

[Peripheral neuropathy with hypervitaminosis B6 caused by self-medication]. / Neuropathie périphérique avec hypervitaminose B6 provoquée par l'automédication.

INTRODUCTION: Vitamin B6 is contained in a number of over-the-counter drugs and vitamin supplements. It may cause severe neurological troubles in case of overdosage. CASE REPORT: We report the case of a 92-year-old women with gait disorders. A diagnosis of peripheral neuropathy with both motor and sensitive deficits was established and investigated. Blood level of vitamin B6 was measured to investigate a potential deficiency. Unexpectedly, the results showed hypervitaminosis B6, which appears to be due to self-administration of an over-the-counter drug containing vitamin B6. Discontinuation of this drug was associated with decrease in vitamin B6 level as well as gait improvement. We also discuss the toxicity of vitamin B6. CONCLUSION: Hypervitaminosis B6 remains a possible cause of peripheral neuropathy and it may be caused by self-administration of over-the-counter vitamin-containing drugs.

High ultrasensitive serum C-reactive protein may be related to freezing of gait in Parkinson's disease patients.

C-reactive protein (CRP) is a biomarker of systemic inflammation that has been linked to accelerated decline in walking speed in older adults. The aim of the present study was to compare the CRP levels of PD patients with vs patients without freezing of gait (FOG). Patients and controls participating in the COPPADIS-2015 study that performed blood extraction for determining molecular serum biomarkers were included. Patients with FOG were identified as those with a score of 1 or greater on item-3 of the Freezing of Gait Questionnaire (FOG-Q). Immunoassay was used for determining ultrasensitive CRP (US-CRP) level (mg/dL). In the PD group (n = 225; 61.8 ± 9.5 years old, 61.8% males), 32% of the patients presented FOG but none in the control group (n = 65; 60.3 ± 6.1 years old, 56.9% males) (p < 0.0001). Differences in US-CRP level were significant in patients with FOG vs patients without FOG and vs controls (0.31 ± 0.52 vs 0.16 ± 0.21 vs 0.21 ± 0.22; p = 0.04). Significant differences were also observed between patients with vs without FOG (p = 0.001) but not between patients and controls (p = 0.163). US-CRP level was related to FOG (OR = 4.369; 95% CI 1.105-17.275; p = 0.036) along with H&Y (OR = 2.974; 95% CI 1.113-7.943; p = 0.030) and non-motor symptoms burden (NMSS total score; OR = 1.017; 95% CI 1.005-1.029; p = 0.006) after adjusting for age, gender, disease duration, equivalent daily levodopa dose, number of non-antiparkinsonian drugs per day, motor fluctuations, cognition, motor phenotype, and chronic use of anti-inflammatory drugs. The present study suggests that serum US-CRP level is related to FOG in PD patients. Inflammation could be linked to FOG development.

Association of Serum Indirect Bilirubin Concentrations with Motor Subtypes of Parkinson's Disease.

INTRODUCTION: We aimed to investigate the change of serum indirect bilirubin (IBIL) concentrations in patients with Parkinson's disease (PD) and whether IBIL concentrations were associated with the motor subtypes of PD. METHODS: A case-control study was performed to evaluate differences in bilirubin concentrations between 78 PD subjects and 78 controls. Venous blood samples were collected, and total bilirubin (TBIL), direct bilirubin (DBIL), and IBIL concentrations were analyzed between PD subjects and controls. PD patients were classified into three motor subtypes: tremor-dominant (TD), intermediate (I), and postural instability and gait disorder (PIGD). It was evaluated whether there were differences in IBIL concentrations between the different motor subtypes and between motor subtypes and controls. RESULTS: PD patients had lower IBIL concentrations compared to controls (6.51 ± 4.03 vs. 10.82 ± 4.61, p< 0.001). There was no significant difference in IBIL concentrations between PD males and PD females (6.66 ± 3.64 vs. 6.22 ± 4.79, p =0.655). IBIL concentrations had negative relationships with levodopa-equivalent daily dose (LEDD) (R = -0.452, p < 0.001) and positive relationships with tremor score (R = 0.360, p = 0.001). IBIL concentrations were significantly lower for PIGD than for TD subtype (4.88 ± 4.03 vs. 9.00 ± 4.15, p< 0.001). The lower IBIL concentrations in PD compared to controls were mainly driven by the PIGD patients. CONCLUSIONS: PD subjects showed lower levels of IBIL compared to controls. Higher IBIL levels were associated with TD motor subtype in PD, which could be related to the antioxidative properties of IBIL.

Gait instability in valproate-treated patients: Call to measure ammonia levels.

OBJECTIVE: Hyperammonemia induced by valproate (VPA) treatment may lead to several neurological and systemic symptoms as well as to seizure exacerbation. Gait instability and recurrent falls are rarely mentioned as symptoms, especially not as predominant ones. METHODS: We report five adult patients with frontal lobe epilepsy (FLE) who were treated with VPA and in whom a primary adverse effect was unstable gait and falls. RESULTS: There were four males and one female patients with FLE, 25-42-year-old, three following epilepsy surgery. All of them were treated with antiepileptic drug polytherapy. Gait instability with falls was one of the principal sequelae of the treatment. Patients also exhibited mild encephalopathy (all patients) and flapping tremor (three patients) that developed following the addition of VPA (three patients) and with chronic VPA treatment (two patients). VPA levels were within the reference range. Serum ammonia levels were significantly elevated (291-407 µmole/L, normal 20-85) with normal or slightly elevated liver enzymes. VPA dose reduction or discontinuation led to the return of ammonia levels to normal and resolution of the clinical symptoms, including seizures, which disappeared in two patients and either decreased in frequency or became shorter in duration in the other three. CONCLUSIONS: Gait instability due to hyperammonemia and VPA treatment is probably under-recognized in many patients. It can develop when the VPA levels are within the reference range and with normal or slightly elevated liver enzymes.

Slow gait, white matter characteristics, and prior 10-year interleukin-6 levels in older adults.

OBJECTIVE: To examine the relationship between gait speed and prior 10 years interleukin-6 (IL-6) burden in older adults. We then assessed whether white matter characteristics influence this relationship. METHODS: In 179 community-dwelling older adults, gait speed was assessed on an automated walkway and serum IL-6 was assayed on ELISA. Concurrently, white matter characteristics were assessed on MRI by quantifying volume of white matter hyperintensities (WMH), a marker of small vessel disease, and normal-appearing white matter on fractional anisotropy (NAWM-FA), a marker of axonal integrity. IL-6 was assayed at regular intervals at gait assessment and over the prior 10 years and estimates of sustained 10-year IL-6 exposure and the rate of change in IL-6 over 10 years were obtained. Multivariate linear regressions were used to examine the relationships among sustained IL-6 exposure, rate of change in IL-6, gait speed, and white matter characteristics. RESULTS: In this sample (age 83 years, 58% female, 41% black, gait speed 0.9 m/s), higher sustained IL-6 levels, but not the rate of change in IL-6 or IL-6 at gait assessment, was significantly related to slower gait (ß = -0.27, p < 0.001) and to higher WMH (ß = 0.23, p = 0.002), but not NAWM-FA, withstanding covariate adjustments. WMH accounted for 30% attenuation in the relationship between higher sustained IL-6 levels and slower gait speed (p = 0.043) in the mediation analyses. CONCLUSIONS: Sustained exposure to high IL-6 over 10 years rather than the rate of change in IL-6 or an isolated high IL-6 level may adversely affect gait speed by influencing cerebral WMH.

Gait characteristics in older adults with diabetes and impaired fasting glucose: The Rotterdam Study.

AIMS: To investigate the association of diabetes mellitus and impaired fasting glucose with gait in the general middle-aged and elderly population. METHODS: We performed a cross-sectional study on 3019 participants from the population-based Rotterdam Study (aged >45years, 54% women). The presence of diabetes mellitus and impaired fasting glucose was evaluated by measuring serum glucose levels and by documenting anti-diabetic treatment. Participants underwent gait analysis using an electronic walkway. Thirty gait variables were summarized into five independent gait domains for normal walking (Rhythm, Variability, Phases, Pace and Base of Support), one for turning (Turning) and one for walking heel to toe (Tandem), which were averaged into Global Gait. Linear regression analyses were performed to determine the association of diabetes, impaired fasting glucose and continuous glucose levels within the normal range with gait. RESULTS: Diabetes mellitus was associated with worse Global Gait (Z-score difference -0.19, 95% confidence interval (CI) -0.30; -0.07), worse Pace (-0.20, 95% CI -0.30; -0.10) and worse Tandem (-0.21, 95% CI -0.33; -0.09), after adjusting for age, sex, height and weight. The association with Tandem remained significant after additional adjustment for cardiovascular risk factors. Impaired fasting glucose and continuous glucose levels within the normal range were not associated with any of the gait domains. CONCLUSION: In our population-based study diabetes mellitus was associated with worse Global Gait, which was mostly reflected in Pace and Tandem. These associations were partly driven by other cardiovascular risk factors, emphasizing the importance of optimal control of cardiovascular risk factor profiles in patients with diabetes.

Chronic Hyponatremia Causes Neurologic and Psychologic Impairments.

Hyponatremia is the most common clinical electrolyte disorder. Once thought to be asymptomatic in response to adaptation by the brain, recent evidence suggests that chronic hyponatremia may be linked to attention deficits, gait disturbances, risk of falls, and cognitive impairments. Such neurologic defects are associated with a reduction in quality of life and may be a significant cause of mortality. However, because underlying diseases such as adrenal insufficiency, heart failure, liver cirrhosis, and cancer may also affect brain function, the contribution of hyponatremia alone to neurologic manifestations and the underlying mechanisms remain unclear. Using a syndrome of inappropriate secretion of antidiuretic hormone rat model, we show here that sustained reduction of serum sodium ion concentration induced gait disturbances; facilitated the extinction of a contextual fear memory; caused cognitive impairment in a novel object recognition test; and impaired long-term potentiation at hippocampal CA3-CA1 synapses. In vivo microdialysis revealed an elevated extracellular glutamate concentration in the hippocampus of chronically hyponatremic rats. A sustained low extracellular sodium ion concentration also decreased glutamate uptake by primary astrocyte cultures, suggesting an underlying mechanism of impaired long-term potentiation. Furthermore, gait and memory performances of corrected hyponatremic rats were equivalent to those of control rats. Thus, these results suggest chronic hyponatremia in humans may cause gait disturbance and cognitive impairment, but these abnormalities are reversible and careful correction of this condition may improve quality of life and reduce mortality.

Elevated C-reactive protein is associated with sensory gating deficit in schizophrenia.

Sensory and cognitive impairments and inflammatory processes are contributing factors to the pathogenesis of schizophrenia. A previous study found that an elevated CRP level (≥5mg/L) was associated with higher cognitive impairments in schizophrenia. We aimed to investigate the association between an elevated CRP level and sensory impairments defined by a sensory gating deficit (abnormal P50 suppression) in 55 outpatients. Fifteen patients (27.3%) had an elevated CRP level that was associated with higher rate of sensory gating deficit (60% vs. 12.5%, p<0.001). This is the first study suggesting a relationship between sensory gating deficit and inflammatory processes in schizophrenia.

Effects of manganese from a commercial multi-trace element supplement in a population sample of Canadian patients on long-term parenteral nutrition.

BACKGROUND: Long-term parenteral nutrition (PN) can be associated with micronutrient deficiency or toxicity depending on supplementation. Recently, hypermanganesemia and potential neurological toxicity were reported. The aim of this study was to assess the effect of manganese supplementation in a sample of patients on long-term PN receiving manganese (Mn) as part of a multi-trace element (TE) supplement. METHODS: A convenience sample of 16 patients underwent clinical and blood biochemical measurements as well as magnetic resonance imaging (MRI) of the brain. Descriptive statistics were performed. RESULTS: The mean daily Mn supplementation was 7.28 ± 0.97 µmol/d (400 ± 53 µg/d), which was within the American Medical Association Nutrition Advisory Group guidelines of 2.73-14.56 µmol/d (150-800 µg/d) but exceeded the American Society for Parenteral and Enteral Nutrition (A.S.P.E.N.) 2002 recommendations of 1.09-1.82 µmol/d (60-100 µg/d). The mean whole blood Mn level was 1.38 ± 0.29 times the upper limit of normal (ULN), and 8 of 14 patients with blood measurements had Mn levels above ULN. On MRI, 81% of patients had high signals on T1-weighted images assumed to be Mn deposits in their basal ganglia. Two patients with positive MRI (15%) had a clinical diagnosis of Parkinson disease. Multiple neuropsychiatric complaints were reported, including depression (66%), lack of concentration (42%), memory disturbances (17%), and gait instability (8%). CONCLUSION: These results suggest that Mn status is elevated in these patients. Manganese supplementation should be used with caution in patients receiving long-term PN, and attention should be paid to the Mn content of multi-TE supplements.

Psychomotor deficits associated with hyponatremia: a retrospective analysis.

Hyponatremia (serum sodium concentration [Na+] < 136 mEq/L) is a potentially life-threatening condition. Recent evidence (Renneboog, Musch, Vandemergel, Manto, & Decaux, 2006) shows that even mild hyponatremia is associated with disorders of balance/gait. This retrospective analysis explored the influence of serum [Na+] on neuropsychological (NP) measurements at baseline from 44 patients with chronic hyponatremia who participated in an efficacy and safety study of an experimental compound over a decade ago. Group mean serum [Na+] was 124.8 ± 4.9 mEq/L. Age-adjusted partial correlations were computed between serum [Na+] and NP measurements, 39% of which were statistically significant--all involving psychomotor functioning. These findings replicate and extend previous observations that psychomotor deficits are, at least in part, associated with hyponatremia in these patients. While chronic hyponatremia is known to have deleterious effects on quality of life, motor and gait disturbances represent manifestations of mild hyponatremia that have until now gone unrecognized. A new class of medication, vasopressin antagonists, has been shown to correct hyponatremia. It will be important to explore the effects of correcting hyponatremia on psychomotor functioning in individuals with hyponatremia.

Biology of gait control: vitamin D involvement.

BACKGROUND: Adverse neuromuscular events have been described in case of low serum 25-hydroxyvitamin D (25OHD) concentrations, suggesting that vitamin D may be involved in gait stability. The objective of this cross-sectional study was to examine the association between stride-to-stride variability of stride time (STV) and serum 25OHD concentration in adults aged 65 years and older. METHODS: STV and 25OHD concentration were assessed in 411 community-dwelling older adults (mean age 70.4 ± 1.8 years, 57.9% women). The following established 25OHD thresholds were used: severe 25OHD insufficiency <10 ng/mL, moderate 10-30 ng/mL, and normal >30 ng/mL. Age, number of drugs used per day, use of psychoactive drugs, depressive symptoms, cognitive decline, history of falls, distance visual acuity, lower limb proprioception, center of mass (CoM) motion, and walking speed were considered as potential confounders. RESULTS: A total of 16.6% (n = 68) of subjects had severe 25OHD insufficiency, 70.3% (n = 289) moderate insufficiency, and 13.1% (n = 54) normal concentrations. In the full adjusted and the stepwise backward linear regression models, high STV (worse performance) was associated with severe 25OHD insufficiency (p = 0.028 and p = 0.044, respectively), high CoM motion (p = 0.031 and p = 0.014, respectively), and low lower limb proprioception score (p = 0.017 and p = 0.008, respectively). The stepwise backward regression model also showed that high STV was associated with female gender (p = 0.041). CONCLUSIONS: Low serum 25OHD concentrations were associated with high STV reflecting a disturbed gait control. This association could be explained by a possible action of vitamin D on different components involved in gait control.

Plasma iron levels appraised 15 days after spinal cord injury in a limb movement animal model.

STUDY DESIGN: Experimental, controlled trial. OBJECTIVES: The purpose of this study was to evaluate plasma iron and transferrin levels in a limb movement animal model with spinal cord injury (SCI). SETTING: Universidade Federal de São Paulo, Departamento de Psicobiologia. METHODS: In all, 72 male Wistar rats aged 90 days were divided into four groups: (1) acute SCI (1 day, SCI1), (2) 3 days post-SCI (SCI3), (3) 7 days post-SCI (SCI7) and (4) 15 days post-SCI (SCI15). Each of these groups had corresponding control (CTRL) and SHAM groups. Plasma iron and transferrin levels of the different groups were analyzed using a one-way analysis of variance (ANOVA) followed by Tukey's test. RESULTS: We found a significant reduction in iron plasma levels after SCI compared with the CTRL group: SCI1 (CTRL: 175±10.58 µg dl(-1); SCI: 108.28±11.7 µg dl(-1)), SCI3 (CTRL: 195.5±11.00 µg dl(-1); SCI: 127.88±12.63 µg dl(-1)), SCI7 (CTRL: 186±2.97 µg dl(-1); SCI: 89.2±15.39 µg dl(-1)) and SCI15 (CTRL: 163±5.48 µg dl(-1); SCI: 124.44±10.30 µg dl(-1)) (P<0.05; ANOVA). The SHAM1 group demonstrated a reduction in iron plasma after acute SCI (CTRL: 175±10.58 µg dl(-1); SHAM: 114.60±7.81 µg dl(-1)) (P<0.05; ANOVA). CONCLUSION: Reduced iron metabolism after SCI may be one of the mechanisms involved in the pathogenesis of sleep-related movement disorders.

Proinflammatory modulation of the surface and cytokine phenotype of monocytes in patients with acute Charcot foot.

OBJECTIVE: Despite increased information on the importance of an inappropriate inflammatory response in the acute Charcot process, there has been no previous attempt to define the specific pathways that mediate its pathogenesis. Here, the role played by monocytes was analyzed. RESEARCH DESIGN AND METHODS: The immune phenotype of peripheral monocytes was studied by fluorescence-activated cell sorter analysis comparing patients with acute Charcot (n = 10) in both the active and recovered phase, diabetic patients with neuropathy (with or without osteomyelitis), and normal control subjects. RESULTS: When compared with diabetic control subjects and healthy subjects, monocytes from acute Charcot patients showed a proinflammatory immune phenotype characterized by increased production of proinflammatory cytokines, reduced secretion of anti-inflammatory cytokines, increased expression of surface costimulatory molecules, and increased resistance to serum withdrawal-induced apoptosis. In addition, the pattern of circulating cytokines confirmed activation of proinflammatory cytokines. No modulation of the monocyte phenotype was documented in diabetic control subjects and healthy subjects, thus indicating that the proinflammatory alterations of monocytes are specific and causative of acute Charcot. CONCLUSIONS: Together, these data provide evidence for the role of proinflammatory changes in the immune phenotype of monocytes in the pathogenesis of acute Charcot. These alterations may explain the abnormally intense and prolonged inflammatory response that characterizes this disorder and may represent a potential therapeutic target for specific pharmacological interventions.

ABO blood groups, grass pea preparation, and neurolathyrism in Ethiopia.

An exploratory study was conducted in the rural Estie district of Ethiopia in 1997 to identify the role of ABO blood group, rhesus factor, and type of grass pea (Lathyrus sativus) diet in the susceptibility to neurolathyrism. Five-hundred study subjects (250 cases and 250 controls) were examined and interviewed, and had their ABO and rhesus blood groups determined. The majority (86%) of the cases were males. Blood group O was the most common in the patients and controls followed by groups A, B, and AB. The vast majority of the study subjects were rhesus-positive. The gravy (Shiro) grass pea preparation was consumed by 91.6% of the study population, boiled (Nifiro) by 86%, and roasted (Kollo) by 56.4%. Almost half (48%) of the cases had consumed grass pea for > 4 months compared to 8% of controls (P < 0.001). There was a significant association between the risk for neurolathyrism and the consumption of boiled (adjusted odds ratio [AOR] = 98.4) and roasted (AOR = 55.62) forms of grass pea. There was no risk of paralysis associated with consumption of the gravy form of grass pea (AOR = 0.40, 95% confidence interval 0.1-2.0). Blood group O remained significantly associated with the disease after adjusting for age, type of grass pea preparation consumed, and duration of consumption (AOR = 2.90).