␣-Tocopherol transfer protein (␣-TTP) maintains the concentration of serum ␣-tocopherol (vitamin E), one of the most potent fat-soluble antioxidants, by facilitating ␣-tocopherol export from the liver. Mutations of the ␣-TTP gene are linked to ataxia with isolated vitamin E deficiency (AVED). We produced a model mouse of AVED by deleting the ␣-TTP gene, which showed ataxia and retinal degeneration after 1 year of age. Because the brain ␣-TTP functions in maintaining ␣-tocopherol levels in the brain, ␣-tocopherol was completely depleted in the ␣-TTP ؊͞؊ mouse brain, and the neurological phenotype of ␣-TTP ؊͞؊ mice is much more severe than that of wild-type mice when maintained on an ␣-tocopherol-deficient diet. Lipid peroxidation in ␣-TTP ؊͞؊ mice brains showed a significant increase, especially in degenerating neurons. ␣-Tocopherol supplementation suppressed lipid peroxidation and almost completely prevented the development of neurological symptoms. This therapy almost completely corrects the abnormalities in a mouse model of human neurodegenerative disease. Moreover, ␣-TTP ؊͞؊ mice may prove to be excellent animal models of delayed onset, slowly progressive neuronal degeneration caused by chronic oxidative stress.A taxia with isolated vitamin E deficiency (AVED) is an autosomal recessive disease, the phenotype of which is often indistinguishable from Friedreich ataxia (1), the most common hereditary ataxia in Europe and United States. We cloned the ␣-tocopherol transfer protein (␣-TTP) gene (2) and identified mutations on the ␣-TTP gene in patients with AVED (3, 4). Later, we found those same mutations on the ␣-TTP gene to be a cause of retinitis pigmentosa as well (5, 6). ␣-TTP is expressed in the brain and retina as well as in the liver, and its function still remains unclear (6, 7). Therefore, it is not known whether ␣-tocopherol deficiency is the only cause for neuronal degeneration of AVED. Here we produced a model mouse of AVED by deleting the ␣-TTP gene. The mice showed ataxia and retinal degeneration after 1 year of age, and these symptoms were reversed after ␣-tocopherol supplementation.The brain is thought to be particularly vulnerable to oxidative stress (8), and accumulating evidence suggests that oxidative stress is involved in the pathogenesis of neurodegenerative diseases including Alzheimer's disease and amyotrophic lateral sclerosis (8,9). In animal models, neuronal cell death has been induced by free radical-producing chemicals, such as paraquat (10) or N-methy-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP; ref. 11), or by knocking out the manganese superoxide dismutase gene (12). These experimentally induced neuronal degenerations develop acutely within several days and differ therefore from the cell death that occurs in human neurodegenerative diseases, which are characterized by delayed onset and slow progression over years or decades. We discuss whether the ␣-TTP Ϫ͞Ϫ mouse serves as a mouse model of age-related neuronal degeneration arising from chronic oxidative stress. Materials and MethodsG...

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Previous studies suggest that in amyotrophic lateral sclerosis (ALS) the abductor pollicis brevis (APB) and first dorsal interosseous (FDI) are more severely involved than abductor digiti minimi (ADM). To elucidate the pattern, frequency, extent, and specificity of such dissociated muscle atrophy in ALS, compound muscle action potentials recorded from APB, FDI, and ADM were analyzed in 77 ALS patients, 171 normal controls, and 196 disease controls. Compared with normal controls, ALS patients had a reduced APB/ADM amplitude ratio (P < 0.001) and FDI/ADM ratio (P < 0.001), whereas patients with other anterior horn diseases showed similar APB/ADM and FDI/ADM ratios to normal values. Decreased APB/ADM ratio was found in 41% of ALS patients, 5% of normal controls, and 4% of disease controls. Prominent muscle atrophy in APB and FDI, with relatively preserved ADM, appears to be specific to ALS. Dissociated hand muscle atrophy presumably reflects part of the pathophysiology and supports the diagnosis of ALS.

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Gait analysis is used widely in clinical practice to evaluate abnormal gait caused by disease. Conventionally, medical professionals use motion capture systems or make visual observations to evaluate a patient's gait. Recent biomedical engineering studies have proposed easy-to-use gait analysis methods employing wearable sensors with inertial measurement units (IMUs). IMUs placed on the shanks just above the ankles allow for long-term gait monitoring because the participant can walk with or without shoes during the analysis. To the knowledge of the authors, no IMU-based gait analysis method has been reported that estimates stride length, gait speed, stride duration, stance duration, and swing duration simultaneously. In the present study, we tested a proposed gait analysis method that uses IMUs attached on the shanks to estimate foot trajectory and temporal gait parameters. Our proposed method comprises two steps: stepwise dissociation of continuous gait data into multiple steps and three-dimensional trajectory estimation from data obtained from accelerometers and gyroscopes. We evaluated this proposed method by analyzing the gait of 19 able-bodied participants (mean age 23.9 years, 9 men and 10 women). Wearable sensors were attached on the participants' shanks, and we measured three-axis acceleration and three-axis angular velocity with the sensors to estimate foot trajectory during walking. We compared gait parameters estimated from the foot trajectory obtained with the proposed method and those measured with a motion capture system. Mean accuracy (± standard deviation) was 0.054 ± 0.031 m for stride length, 0.034 ± 0.039 m/s for gait speed, 0.002 ± 0.020 s for stride duration, 0.000 ± 0.017 s for stance duration, and 0.002 ± 0.024 s for swing duration. These results suggest that the proposed method is suitable for gait analysis, whereas there is a room for improvement of its accuracy and further development of this IMU-based gait analysis method will enable us to use such systems for clinical gait analysis.

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Objective-Transcranial double magnetic stimulation on the motor cortex was used to investigate central motor tract function in 16 patients with amyotrophic lateral sclerosis, five with spinal muscular atrophy, and 16 age matched normal controls. Methods-Surface EMG responses were recorded from the relaxed abductor pollicis brevis (APB) muscle. Results-Responses to test stimuli were markedly attenuated by a subthreshold conditioning stimulus given at a condition-test (C-T) interval of 1-4 ms in normal controls and patients with spinal muscular atrophy, but attenuation was mild in patients with amyotrophic lateral sclerosis. In the normal controls this suppression was caused by activation of the intracortical inhibitory mechanism because responses to electrical test stimuli and the H wave were not suppressed by the same magnetic subthreshold conditioning stimulus. In amyotrophic lateral sclerosis the effect of the conditioning cortical stimulus on the H wave was also in the normal range. Conclusion-The intracortical inhibitory mechanism may be impaired in patients with amyotrophic lateral sclerosis. SubjectsSixteen patients with amyotrophic lateral sclerosis (eight men and eight women, mean (SD) age 63-4 (6 5) years, duration of illness 13-5 (9.7) months), five with spinal muscular atrophy (five men; age 55-5 (5-9), duration of illness 12-0 (8&7) years), and 16 age matched normal controls were studied. Selection of patients with amyotrophic lateral sclerosis was based on the following criteria: (1) progressive muscular weakness and atrophy; (2) fasciculations of the affected muscles; (3) clinical signs of pyramidal tract lesion; (4) abnormal needle EMG results characteristic of anterior horn cell disease; (5) absence of sensory signs; sphincter abnormalities, and dementia; (6) absence of conduction block and abnormal temporal dispersion; (7) motor evoked potential (MEP) at rest > 1 mV without temporal dispersion and normal threshold stimulation intensity at rest that produces MEP; (8) MEP latency on electric cortical stimulation of low intensity shorter by more than 1 0 ms than that in magnetic stimulation for the selection of patients in which magnetic stimuli activate I waves. Selection of patients with spinal muscular atrophy was based on slowly progressive muscular weakness and atrophy without clinical signs of pyramidal tract lesion, as well as on criteria (4)-(8) for amyotrophic lateral sclerosis.

Humoral immune response to glutamic acid decarboxylase (GAD) has been implicated in the pathogenesis of stiff‐man syndrome and cerebellar ataxia, but the underlying pathomechanism is unclear. Using a whole‐cell patch‐clamp technique with rat cerebellar slices, we found that immunoglobulins present in the cerebrospinal fluid of an ataxic patient acted presynaptically to cause a selective suppression of GABAergic transmission. This synaptic depression was most likely elicited by an autoantibody to GAD. Ann Neurol 1999;46:263–267