Gait bradykinesia: difficulty in switching posture/gait measured by the anatomical y-axis vector of the sole in Parkinson's disease.

This study in Parkinson's disease examined how spatiotemporal parameters in gait bradykinesia link to difficulty in terminating posture and initiating gait locomotion. 41 idiopathic Parkinson's disease patients and 15 age-matched healthy subjects participated in this study. After the patients fixated on a visual-fixation-target, gait was triggered by visual or vocal cue-stimulus. The LED instructed subjects to quickly achieve their own comfortable walking speed on a level floor. The posterior-anterior force of the y-axis vectors of sole relating to soleus and tibialis-anterior EMGs were examined. Step-gain was defined as the duration of the swing-phase relative that of the contralateral stance-phase. Dynamic-ratio was defined as the duration the fore-foot phase relative to that of the ipsilateral stance-phase as forward-oriented movement in each step. The pause in tonic soleus EMG was defined as the off-latency of posture (termination) and the onset of a tibialis-anterior EMG-burst as the on-latency of gait. In Parkinson's disease, soleus off-latencies were prolonged, whereas tibialis-anterior on-latencies were less prolonged. Unsynchronized off/on-latency differences correlated with spatiotemporal parameters of dynamic-ratios, step-gains, gait-initiation, and gait speed in gait bradykinesia. Delayed EMG off-latencies correlated with prolonged motor-latencies in gait bradykinesia as delayed initial backward body-shift. A delayed and deficient initial backward body-shift of y-axis vector was linked to each difficulty in terminating posture and initiating gait, changing to random gait akinesia. Gait bradykinesia in Parkinson's disease stemmed from unsynchronized off/on-latency EMG activities, linking to each difficulty in terminating posture and initiating gait synergic movement through an initial backward body-shift.

Gait bradykinesia in Parkinson's disease: a change in the motor program which controls the synergy of gait.

This study examined how gait bradykinesia is changed by the motor programming in Parkinson's disease. Thirty-five idiopathic Parkinson's disease patients and nine age-matched healthy subjects participated in this study. After the patients fixated on a visual-fixation target (conditioning-stimulus), the voluntary-gait was triggered by a visual on-stimulus. While the subject walked on a level floor, soleus, tibialis anterior EMG latencies, and the y-axis-vector of the sole-floor reaction force were examined. Three paradigms were used to distinguish between the off-/on-latencies. The gap-task: the visual-fixation target was turned off; 200 ms before the on-stimulus was engaged (resulting in a 200 ms-gap). EMG latency was not influenced by the visual-fixation target. The overlap-task: the on-stimulus was turned on during the visual-fixation target presentation (200 ms-overlap). The no-gap-task: the fixation target was turned off and the on-stimulus was turned on simultaneously. The onset of EMG pause following the tonic soleus EMG was defined as the off-latency of posture (termination). The onset of the tibialis anterior EMG burst was defined as the on-latency of gait (initiation). In the gap-task, the on-latency was unchanged in all of the subjects. In Parkinson's disease, the visual-fixation target prolonged both the off-/on-latencies in the overlap-task. In all tasks, the off-latency was prolonged and the off-/on-latencies were unsynchronized, which changed the synergic movement to a slow, short-step-gait. The synergy of gait was regulated by two independent sensory-motor programs of the off- and on-latency levels. In Parkinson's disease, the delayed gait initiation was due to the difficulty in terminating the sensory-motor program which controls the subject's fixation. The dynamic gait bradykinesia was involved in the difficulty (long off-latency) in terminating the motor program of the prior posture/movement.

A heterozygous missense mutation in adolescent-onset very long-chain acyl-CoA dehydrogenase deficiency with exercise-induced rhabdomyolysis.

Very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency is characterized by impaired mitochondrial ß-oxidation of fatty acids. The fatty acid oxidation plays a significant role in energy production especially in skeletal muscle. VLCAD is one of four acyl-CoA dehydrogenases with different-chain length specificity and catalyzes the initial step in mitochondrial ß-oxidation of fatty acids. While the clinical phenotypes in neonates and infants are described as severe, adolescent-onset or adult-onset VLCAD deficiency has a more benign course with only skeletal muscle involvement. These myopathic phenotypes are characterized by episodic muscle weakness and rhabdomyolysis triggered by fasting and strenuous exercise. We report a male teenager who manifested repeated episodes of rhabdomyolysis immediately after exertional exercise. Rhabdomyolysis was diagnosed based on the marked elevation of serum creatine kinase and myoglobinuria. Acylcarnitine analysis by tandem mass spectrometry (MS/MS) revealed elevation of serum tetradecenoylcarnitine (C14:1-AC), which represents an abnormal acylcarnitine profile associated with the mitochondrial ß-oxidation defect. High performance liquid chromatographic analysis showed decreased production of 2-hexadecenoyl-CoA (C16:1) from palmitoyl-CoA (C16:0), indicating the defect of VLCAD activity. Direct sequencing of the acyl-CoA dehydrogenase, very long-chain gene (ACADVL) that codes VLCAD revealed a heterozygous mutation (c.1242G>C) in exon 12 (E414D), which is a novel mutation in myopathic-type VLCAD deficiency. Because VLCAD functions as a homodimer, we assume that this heterozygous mutation may exhibit dominant-negative effect. This patient remains asymptomatic thereafter by avoiding exertional exercise. The findings of reduction of enzyme activity and clinical features associated with this novel missense mutation of VLCAD are discussed.

Autoantibodies against HSP70 family proteins were detected in the cerebrospinal fluid from patients with multiple sclerosis.

We evaluated the specific IgG antibodies against heat shock proteins (HSPs) in cerebrospinal fluids (CSF) from patients with multiple sclerosis (MS). ELISA was employed to examine IgG antibodies against ten HSPs (HSP27, alphaA and alphaB crystallins, HSP60, CCT, Mycobacterium bovis HSP65, Escherichia coli GroEL, HSP70, HSC70 and HSP90) in CSF from 30 patients with MS, and 25 patients with motor neuron diseases (MND). Significantly higher antibody titers against HSP70 and HSC70 proteins were found in CSF obtained from patients with MS as compared with MND independent of CSF total protein, IgG concentrations and IgG indices, respectively. The antibody titers against HSP70 were indicated to be significantly higher in the progressive cases than in cases of remission. The results suggest that IgG antibodies against specific types of HSPs especially HSP70 family proteins (HSP70 and HSC70) in CSF may play an important role in the pathophysiology of MS through the modification of immune response and cytoprotective functions of molecular chaperons.

Single nucleotide polymorphisms and functional analysis of MxA promoter region in multiple sclerosis.

OBJECTIVE: Interferons (IFNs)-inducible myxovirus resistance protein A (MxA) has recently been used as an indirect marker of neutralizing antibody against IFN in patients with multiple sclerosis (MS). On the other hand, MxA inhibits the replication of viruses by means of modifying cellular function, including apoptotic pathway. Our objective is to investigate the genetic and pathological role of MxA in patients with MS. METHODS: We examined SNPs of MxA promoter region in 67 patients with MS. Moreover, to elucidate the functional roles of SNPs, we conducted Luciferase assay with pGL3-basic vector including patient-derived or artificially mutated MxA promoter region. RESULTS: A significantly higher frequency of the haplotype with -88T and -123A, which correlates with over-expression of MxA, was observed in MS. Moreover, we elucidated novel findings showing that nt -88 played a leading part with type I IFNs and that nt -123 played the same role independently without type I IFNs, respectively. CONCLUSION: SNPs on MxA promoter region may play an important role in the pathophysiology of MS and provide a novel strategy for the therapeutic resolutions of MS.

Cerebrospinal fluids containing anti-HSP70 autoantibodies from multiple sclerosis patients augment HSP70-induced proinflammatory cytokine production in monocytic cells.

Anti-heat shock protein 70 (HSP70) autoantibodies are found in cerebrospinal fluids (CSF) from patients with multiple sclerosis. These autoantibodies cross-reacted not only with HSP70 and heat shock cognate protein 70 (HSC70), but also with a bacterial homologue, DnaK. CSF with a high anti-HSP70 autoantibody titer enhanced HSP70-induced proinflammatory cytokine and chemokine production in the human monocytic cell line, THP-1. Thus, anti-HSP70 autoantibodies in the CSF of multiple sclerosis patients may play a pathophysiological role in enhancing inflammation.