Hiroshi Mitoma

Accelerometry-Based Gait Analysis and Its Application to Parkinson's Disease Assessment— Part 1: Detection of Stride Event

Gait analysis is widely recognized as a promising tool for obtaining objective information on the walking behavior of Parkinsons disease (PD) patients. It is especially useful in clinical practices if gait properties can be captured with minimal instrumentation that does not interfere with the subjects usual behavioral pattern under ambulatory conditions. In this study, we propose a new gait analysis system based on a trunk-mounted acceleration sensor and automatic gait detection algorithm. The algorithm identifies the acceleration signal with high intensity, periodicity, and biphasicity as a possible gait sequence, from which gait peaks due to stride events are extracted by utilizing the cross-correlation and anisotropy properties of the signal. A total of 11 healthy subjects and 12 PD patients were tested to evaluate the performance of the algorithm. The result indicates that gait peaks can be detected with an accuracy of more than 94%. The proposed method may serve as a practical component in the accelerometry-based assessment of daily gait characteristics.

Consensus Paper: Neuroimmune mechanisms of cerebellar ataxias

In the last few years, a lot of publications suggested that disabling cerebellar ataxias may develop through immune-mediated mechanisms. In this consensus paper, we discuss the clinical features of the main described immune-mediated cerebellar ataxias and address their presumed pathogenesis. Immune-mediated cerebellar ataxias include cerebellar ataxia associated with anti-GAD antibodies, the cerebellar type of Hashimoto’s encephalopathy, primary autoimmune cerebellar ataxia, gluten ataxia, Miller Fisher syndrome, ataxia associated with systemic lupus erythematosus, and paraneoplastic cerebellar degeneration. Humoral mechanisms, cell-mediated immunity, inflammation, and vascular injuries contribute to the cerebellar deficits in immune-mediated cerebellar ataxias.

Guidelines for treatment of immune-mediated cerebellar ataxias

Immune-mediated cerebellar ataxias include gluten ataxia, paraneoplastic cerebellar degeneration, GAD antibody associated cerebellar ataxia, and Hashimoto’s encephalopathy. Despite the identification of an increasing number of immune-mediated cerebellar ataxias, there is no proposed standardized therapy. We evaluated the efficacies of immunotherapies in reported cases using a common scale of daily activity. The analysis highlighted the importance of removal of autoimmune triggering factors (e.g., gluten or cancer) and the need for immunotherapy evaluation (e.g., corticosteroids, intravenous immunoglobulin, immunosuppressants) and adaptation according to each subtype.

Disease-specific monoclonal antibodies targeting glutamate decarboxylase impair GABAergic neurotransmission and affect motor learning and behavioral functions

Autoantibodies to the smaller isoform of glutamate decarboxylase (GAD) can be found in patients with type 1 diabetes and a number of neurological disorders, including stiff-person syndrome, cerebellar ataxia and limbic encephalitis. The detection of disease-specific autoantibody epitopes led to the hypothesis that distinct GAD autoantibodies may elicit specific neurological phenotypes. We explored the in vitro/in vivo effects of well-characterized monoclonal GAD antibodies. We found that GAD autoantibodies present in patients with stiff person syndrome (n = 7) and cerebellar ataxia (n = 15) recognized an epitope distinct from that recognized by GAD autoantibodies present in patients with type 1 diabetes mellitus (n = 10) or limbic encephalitis (n = 4). We demonstrated that the administration of a monoclonal GAD antibody representing this epitope specificity; (1) disrupted in vitro the association of GAD with γ-Aminobutyric acid containing synaptic vesicles; (2) depressed the inhibitory synaptic transmission in cerebellar slices with a gradual time course and a lasting suppressive effect; (3) significantly decreased conditioned eyelid responses evoked in mice, with no modification of learning curves in the classical eyeblink-conditioning task; (4) markedly impaired the facilitatory effect exerted by the premotor cortex over the motor cortex in a paired-pulse stimulation paradigm; and (5) induced decreased exploratory behavior and impaired locomotor function in rats. These findings support the specific targeting of GAD by its autoantibodies in the pathogenesis of stiff-person syndrome and cerebellar ataxia. Therapies of these disorders based on selective removal of such GAD antibodies could be envisioned.

Independent Regulation of the Cycle and Acceleration in Parkinsonian Gait Analyzed by a Long-Term Daily Monitoring System

Background: Few reports have objectively assessed gait patterns of Parkinson’s disease (PD) patients in their daily lives. We investigated the mean gait cycle and mean gait acceleration using a portable gait rhythmogram (PGR). Method: We continuously recorded PGR measurements for 24 h in 64 PD patients with the ability to independently engage in activities of daily living. Results: There was no significant difference in the mean gait cycle between PD patients and normal controls. However, the mean gait cycle was significantly faster in PD patients in the modified Hoehn and Yahr stage 1.5 than those in stages 2.5–3.0. The mean gait acceleration in PD patients was significantly less than in normal controls, but there were no significant differences among the stage groups. Conclusion: The results suggest that the cycle and acceleration of gait movements are controlled independently and that disturbances in these movements have different clinical courses in PD.

ACCELEROMETRY-BASED LONG-TERM MONITORING OF MOVEMENT DISORDERS: FROM DIURNAL GAIT BEHAVIOR TO NOCTURNAL BED MOBILITY

Accelerometry-based motion analysis is widely recognized as a promising tool in health care and medical settings since it is unobtrusive, inexpensive, and capable of providing useful information on human movement disorders. Patients suffering from neurological diseases such as Parkinsons disease (PD) often exhibit a combination of multiple motion symptoms during everyday activities. Thus, there is a need in clinical practice to capture as many types of abnormal movements as possible with minimal instrumentation that does not interfere with the subjects usual behavioral patterns. This paper presents the prospect of total health monitoring with a single accelerometer-based technique. The behavior of a PD patient was continuously recorded for a period of 36 h using a portable device with a triaxial accelerometer worn on the waist. Data were analyzed by newly developed computer programs to extract relevant movement parameters that might underlie pathological motor performance. We found that the state of the...

Ambulatory Gait Behavior in Patients With Dementia: A Comparison With Parkinson’s Disease

Accelerometry-based gait analysis is a promising approach in obtaining insightful information on the gait characteristics of patients with neurological disorders such as dementia and Parkinsons disease (PD). In order to improve its practical use outside the laboratory or hospital, it is required to design new metrics capable of quantifying ambulatory gait and their extraction procedures from long-term acceleration data. This paper presents a gait analysis method developed for such a purpose. Our system is based on a single trunk-mounted accelerometer and analytical algorithm for the assessment of gait behavior that may be context dependent. The algorithm consists of the detection of gait peaks from acceleration data and the analysis of multimodal patterns in the relationship between gait cycle and vertical gait acceleration. A set of six new measures can be obtained by applying the algorithm to a 24-h motion signal. To examine the performance and utility of our method, we recorded acceleration data from 13 healthy, 26 PD, and 26 mild cognitive impairment or dementia subjects. Each patient group was further classified into two, comprising 13 members each, according to the severity of the disease, and the gait behavior of the five groups was compared. We found that the normal, PD, and MCI/dementia groups show characteristic walking patterns which can be distinguished from one another by the developed gait measure set. We also examined conventional parameters such as gait acceleration, gait cycle, and gait variability, but failed to reproduce the distinct differences among the five groups. These findings suggest that the proposed gait analysis may be useful in capturing disease-specific gait features in a community setting.

Deficits in Scaling of Gait Force and Cycle in Parkinsonian Gait Identified by Long-Term Monitoring of Acceleration with the Portable Gait Rhythmogram

To examine the range of gait acceleration and cycle in daily walking of patients with Parkinsons disease (PD), we compared the gait of 40 patients with PD and 17 normal controls by using a newly developed long-term monitoring device that extracts gait-related accelerations from overall movements-related accelerations. The range of change in gait acceleration, relative to the control, was less than 75% in 12 patients. The range of change in gait cycle was less than 75% in 8 patients. The range of changes in both parameters was less than 75% in 4 patients. The results suggest narrow changes in gait parameters in PD.

How Far Do the Complaints of Patients with Parkinson’s Disease Reflect Motor Fluctuation? Quantitative Analysis Using a Portable Gait Rhythmogram

In advanced-stage Parkinsons disease (PD), motor fluctuation is a frequent and disabling problem. Assessment of motor fluctuation depends on patients subjective self-statement. We examined whether the subjective fluctuation matched the objective motor fluctuation defined by gait disorders. Using a new device, the portable gait rhythmogram, we recorded gait cadence and acceleration continuously over the 24-hour period in 54 patients with PD and 17 normal controls, for the quantitative evaluation of motor fluctuation. The patients were asked to estimate motor fluctuation every hour. In 44 of 54 patients, changes in the cadence were associated with simultaneous changes in acceleration. We examined the subjective fluctuation in these 44 patients who were confirmed to have motor fluctuation. Nineteen (82.7%) of 23 patients who felt no fluctuation showed distinct gait disorders. During off time, they walked with marked short or bradykinetic stepping. No matching changes were observed in either the cadence or acceleration in 11 (52.4%) of 21 patients who perceived motor fluctuation. No synchronization was noted in 30 (68.2%) of the 44 patients, between the times of subjectively assessed motor fluctuation and those of quantitative analysis of gait disorder. This discrepancy suggests that the objective continuous recording of the cadence and acceleration is necessary to understand motor fluctuation.

Pathogenic Roles of Glutamic Acid Decarboxylase 65 Autoantibodies in Cerebellar Ataxias

Reports suggesting a pathogenic role of autoantibodies directed against glutamic acid decarboxylase 65 (GAD65Abs) in cerebellar ataxias (CAs) are reviewed, and debatable issues such as internalization of antibodies by neurons and roles of epitopes are discussed. GAD65 is one of two enzymes that catalyze the conversion of glutamate to the inhibitory neurotransmitter gamma-aminobutyric acid (GABA). A pathogenic role of GAD65Ab in CAs is suggested by in vivo and in vitro studies. (1) Intracerebellar administration of cerebrospinal fluid (CSF) immunoglobulins (IgGs) obtained from GAD65Ab-positive CA patients impairs cerebellar modulation of motor control in rats. (2) CSF IgGs act on terminals of GABAergic neurons and decrease the release of GABA in cerebellar slices from rats and mice. (3) Absorption of GAD65Ab by recombinant GAD65 diminishes the above effects, and monoclonal human GAD65Ab (b78) mimic the effects of CSF IgGs in vivo and in vitro. Studies using GAD65-KO mice confirm that the target molecule is GAD65. (4) Notably, the effects of GAD65Ab depend on the epitope specificity of the monoclonal GAD65Ab. Taken together, these results indicate that epitope-specific GAD65Ab-induced impairment of GABA release is involved in the pathogenesis of GAD65Ab-positive CA and support the early detection of GAD65Ab-associated CA to initiate immunotherapy before irreversible neuronal death in the cerebellum.