Publications by authors named "Hiroshi Mitoma"

70 Publications

[Immune-Mediated Cerebellar Ataxias].

Authors:
Hiroshi Mitoma

Brain Nerve 2021 May;73(5):611-619

Department of Medical Education, Tokyo Medical University.

Autoimmune mechanisms insult the cerebellum, resulting in the development of cerebellar ataxias (CAs). These immune-mediated cerebellar ataxias (IMCAs) include gluten ataxia, postinfectious cerebellitis, paraneoplastic cerebellar degeneration (PCD), antiglutamate decarboxylase 65 antibody-associated CA (anti-GAD ataxia), and primary autoimmune cerebellar ataxia (PACA). Cell-mediated mechanisms are assumed to be involved in PCD, whereas accumulating evidence shows that anti-GAD antibodies decrease the amount of GABA released which leads to functional synaptic deficits. The therapeutic benefits of immunotherapies vary depending on the etiology of the disease. Early intervention is recommended while the cerebellar reserve can be preserved.
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http://dx.doi.org/10.11477/mf.1416201805DOI Listing
May 2021

Relationship between I-FP-CIT-SPECT and motor severity in drug-naive patients with Parkinson's disease.

J Neurol Sci 2021 Jul 6;426:117476. Epub 2021 May 6.

Department of Neurology, Tokyo Medical University, 6-7-1 Nishishinjuku, Shinjuku-ku, Tokyo 160-0023, Japan.

Introduction: Although functional imaging is useful for the diagnosis and pathophysiological evaluation of Parkinson's disease (PD), little is known about the relationship between functional imaging findings and PD clinical features. The objective of this study was to determine the relationship between I-FP-CIT-SPECT findings and motor symptoms, in particular gait disturbance.

Methods: The study included 46 drug-naive patients with early-stage PD. The specific binding ratios (SBRs) in the striatum and its subregions, namely anterior/posterior putamen and caudate nucleus, were calculated in patients who underwent I-FP-CIT-SPECT. Motor symptoms were evaluated using the modified Hoehn and Yahr (HY) stage and the Unified Parkinson's Disease Rating Scale (UPDRS) part III. Gait disturbance was evaluated by the mean gait cycle duration and the mean gait acceleration amplitude measured with a wearable sensor.

Results: The mean SBRs of the striatum and anterior putamen were significantly associated with the modified HY stage and UPDRS part III score. The mean SBR of the caudate nucleus was significantly associated with the UPDRS part III score. The mean striatal SBR was also significantly associated with the mean gait cycle duration and mean gait acceleration amplitude.

Conclusion: The mean striatal SBR, as determined by I-FP-CIT-SPECT, was significantly associated with motor severity and gait severity in drug-naive patients with PD.
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http://dx.doi.org/10.1016/j.jns.2021.117476DOI Listing
July 2021

Physiology of Cerebellar Reserve: Redundancy and Plasticity of a Modular Machine.

Int J Mol Sci 2021 Apr 30;22(9). Epub 2021 Apr 30.

Unité des Ataxies Cérébelleuses, Service de Neurologie, Médiathèque Jean Jacquy, CHU-Charleroi, 6000 Charleroi, Belgium.

The cerebellum is endowed with the capacity for compensation and restoration after pathological injury, a property known as cerebellar reserve. Such capacity is attributed to two unique morphological and physiological features of the cerebellum. First, mossy fibers that convey peripheral and central information run mediolaterally over a wide area of the cerebellum, resulting in the innervation of multiple microzones, commonly known as cerebellar functional units. Thus, a single microzone receives redundant information that can be used in pathological conditions. Secondly, the circuitry is characterized by a co-operative interplay among various forms of synaptic plasticity. Recent progress in understanding the mechanisms of redundant information and synaptic plasticity has allowed outlining therapeutic strategies potentiating these neural substrates to enhance the cerebellar reserve, taking advantage of the unique physiological properties of the cerebellum which appears as a modular and potentially reconfiguring brain structure.
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http://dx.doi.org/10.3390/ijms22094777DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8124536PMC
April 2021

LTDpathies: a Novel Clinical Concept.

Cerebellum 2021 Mar 22. Epub 2021 Mar 22.

Unité des Ataxies Cérébelleuses, Service de Neurologie, Médiathèque Jean Jacquy, CHU-Charleroi, 6000, Charleroi, Belgium.

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http://dx.doi.org/10.1007/s12311-021-01259-2DOI Listing
March 2021

Immune-Mediated Cerebellar Ataxias: Clinical Diagnosis and Treatment Based on Immunological and Physiological Mechanisms.

J Mov Disord 2021 Jan 12;14(1):10-28. Epub 2021 Jan 12.

Academic Department of Neurosciences, Royal Hallamshire Hospital, Sheffield, UK.

Since the first description of immune-mediated cerebellar ataxias (IMCAs) by Charcot in 1868, several milestones have been reached in our understanding of this group of neurological disorders. IMCAs have diverse etiologies, such as gluten ataxia, postinfectious cerebellitis, paraneoplastic cerebellar degeneration, opsoclonus myoclonus syndrome, anti-GAD ataxia, and primary autoimmune cerebellar ataxia. The cerebellum, a vulnerable autoimmune target of the nervous system, has remarkable capacities (collectively known as the cerebellar reserve, closely linked to plasticity) to compensate and restore function following various pathological insults. Therefore, good prognosis is expected when immune-mediated therapeutic interventions are delivered during early stages when the cerebellar reserve can be preserved. However, some types of IMCAs show poor responses to immunotherapies, even if such therapies are introduced at an early stage. Thus, further research is needed to enhance our understanding of the autoimmune mechanisms underlying IMCAs, as such research could potentially lead to the development of more effective immunotherapies. We underscore the need to pursue the identification of robust biomarkers.
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http://dx.doi.org/10.14802/jmd.20040DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7840241PMC
January 2021

The critical need to develop tools assessing cerebellar reserve for the delivery and assessment of non-invasive cerebellar stimulation.

Cerebellum Ataxias 2021 Jan 4;8(1). Epub 2021 Jan 4.

Department of Medical Education, Tokyo Medical University, Tokyo, 160-0023, Japan.

Non-invasive cerebellar stimulation (NICS) aims to modulate cerebello-cerebral loops and cerebro-spinal loops, both for research and clinical applications. It is of paramount importance to establish and validate morphological and functional tools to quantify cerebellar reserve, defined as the capacity for restoration and compensation to pathology of the cerebellum. Using NICS without efforts to estimate cerebellar reserve will end up in conflicting results due to the very high heterogeneity of cerebellar disorders encountered in daily practice.
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http://dx.doi.org/10.1186/s40673-020-00126-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7784008PMC
January 2021

Dysmetria and Errors in Predictions: The Role of Internal Forward Model.

Int J Mol Sci 2020 Sep 20;21(18). Epub 2020 Sep 20.

Faculty of Information Technology, Tokyo City University, Tokyo 158-8557, Japan.

The terminology of cerebellar dysmetria embraces a ubiquitous symptom in motor deficits, oculomotor symptoms, and cognitive/emotional symptoms occurring in cerebellar ataxias. Patients with episodic ataxia exhibit recurrent episodes of ataxia, including motor dysmetria. Despite the consensus that cerebellar dysmetria is a cardinal symptom, there is still no agreement on its pathophysiological mechanisms to date since its first clinical description by Babinski. We argue that impairment in the predictive computation for voluntary movements explains a range of characteristics accompanied by dysmetria. Within this framework, the cerebellum acquires and maintains an internal forward model, which predicts current and future states of the body by integrating an estimate of the previous state and a given efference copy of motor commands. Two of our recent studies experimentally support the internal-forward-model hypothesis of the cerebellar circuitry. First, the cerebellar outputs (firing rates of dentate nucleus cells) contain predictive information for the future cerebellar inputs (firing rates of mossy fibers). Second, a component of movement kinematics is predictive for target motions in control subjects. In cerebellar patients, the predictive component lags behind a target motion and is compensated with a feedback component. Furthermore, a clinical analysis has examined kinematic and electromyography (EMG) features using a task of elbow flexion goal-directed movements, which mimics the finger-to-nose test. Consistent with the hypothesis of the internal forward model, the predictive activations in the triceps muscles are impaired, and the impaired predictive activations result in hypermetria (overshoot). Dysmetria stems from deficits in the predictive computation of the internal forward model in the cerebellum. Errors in this fundamental mechanism result in undershoot (hypometria) and overshoot during voluntary motor actions. The predictive computation of the forward model affords error-based motor learning, coordination of multiple degrees of freedom, and adequate timing of muscle activities. Both the timing and synergy theory fit with the internal forward model, microzones being the elemental computational unit, and the anatomical organization of converging inputs to the Purkinje neurons providing them the unique property of a perceptron in the brain. We propose that motor dysmetria observed in attacks of ataxia occurs as a result of impaired predictive computation of the internal forward model in the cerebellum.
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http://dx.doi.org/10.3390/ijms21186900DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7555030PMC
September 2020

Fundamental Mechanisms of Autoantibody-Induced Impairments on Ion Channels and Synapses in Immune-Mediated Cerebellar Ataxias.

Int J Mol Sci 2020 Jul 13;21(14). Epub 2020 Jul 13.

Unité des Ataxies Cérébelleuses, Service de Neurologie, Médiathèque Jean Jacquy, CHU-Charleroi, 6000 Charleroi, Belgium.

In the last years, different kinds of limbic encephalitis associated with autoantibodies against ion channels and synaptic receptors have been described. Many studies have demonstrated that such autoantibodies induce channel or receptor dysfunction. The same mechanism is discussed in immune-mediated cerebellar ataxias (IMCAs), but the pathogenesis has been less investigated. The aim of the present review is to evaluate what kind of cerebellar ion channels, their related proteins, and the synaptic machinery proteins that are preferably impaired by autoantibodies so as to develop cerebellar ataxias (CAs). The cerebellum predictively coordinates motor and cognitive functions through a continuous update of an internal model. These controls are relayed by cerebellum-specific functions such as precise neuronal discharges with potassium channels, synaptic plasticity through calcium signaling pathways coupled with voltage-gated calcium channels (VGCC) and metabotropic glutamate receptors 1 (mGluR1), a synaptic organization with glutamate receptor delta (GluRδ), and output signal formation through chained GABAergic neurons. Consistently, the association of CAs with anti-potassium channel-related proteins, anti-VGCC, anti-mGluR1, and GluRδ, and anti-glutamate decarboxylase 65 antibodies is observed in IMCAs. Despite ample distributions of AMPA and GABA receptors, however, CAs are rare in conditions with autoantibodies against these receptors. Notably, when the autoantibodies impair synaptic transmission, the autoimmune targets are commonly classified into three categories: release machinery proteins, synaptic adhesion molecules, and receptors. This physiopathological categorization impacts on both our understanding of the pathophysiology and clinical prognosis.
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http://dx.doi.org/10.3390/ijms21144936DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7404345PMC
July 2020

Medical and Paramedical Care of Patients With Cerebellar Ataxia During the COVID-19 Outbreak: Seven Practical Recommendations of the COVID 19 Cerebellum Task Force.

Front Neurol 2020 22;11:516. Epub 2020 May 22.

Ataxia Center, Cognitive Behavioral Neurology Unit, Laboratory for Neuroanatomy and Cerebellar Neurobiology, Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, United States.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV2), the cause of the current pandemic coronavirus disease 2019 (COVID-19), primarily targets the respiratory system. Some patients also experience neurological signs and symptoms ranging from anosmia, ageusia, headache, nausea, and vomiting to confusion, encephalitis, and stroke. Approximately 36% of those with severe COVID-19 experience neurological complications. The virus may enter the central nervous system through the olfactory nerve in the nasal cavity and damage neurons in the brainstem nuclei involved in the regulation of respiration. Patients with cerebellar ataxia (CA) are particularly vulnerable to severe outcome if they contract COVID-19 because of the complexity of their disease, the presence of comorbidities, and their use of immunosuppressive therapies. Most CA patients burdened by progressive neurologic deficits have substantially impaired mobility and other essential functions, for which they rely heavily on ambulatory services, including rehabilitation and psychosocial care. Cessation of these interventions because of isolation restrictions places the CA patient population at risk of further deterioration. This international panel of ataxia experts provides recommendations for neurologists caring for patients with CA, emphasizing a pro-active approach designed to maintain their autonomy and well-being: continue long-term medications, promote rehabilitation efforts, utilize the technology of virtual visits for regular contact with healthcare providers, and pay attention to emotional and psychosocial health. Neurologists should play an active role in decision-making in those CA cases requiring escalation to intensive care and resuscitation. Multi-disciplinary collaboration between care teams is always important, and never more so than in the context of the current pandemic.
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http://dx.doi.org/10.3389/fneur.2020.00516DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7274029PMC
May 2020

Management of Patients with Cerebellar Ataxia During the COVID-19 Pandemic: Current Concerns and Future Implications.

Cerebellum 2020 Aug;19(4):562-568

Ataxia Center, Cognitive Behavioral Neurology Unit, Laboratory for Neuroanatomy and Cerebellar Neurobiology, Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.

The current worldwide severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic that causes coronavirus disease 2019 (COVID-19) has brought some medical systems to the brink of collapse. This crisis is also negatively impacting the care of patients with non-COVID-19 conditions, including those with cerebellar ataxia (CA). Older patients with CA and those with immune-mediated ataxias on immunosuppressive medication are potentially at high risk of developing serious complications of the infection, although it is also possible that immunosuppressive agents may provide a defense against cytokine storm. This has implications for even greater attention to preventing contracting the disease through physical distancing and/or isolation. The CA patient population is also at higher risk because of the neurological complexities of their underlying disorder and the comorbid medical illnesses that often accompany the genetic ataxias. As the disruption of social patterns and healthcare delivery in response to the crisis continues, interruption of rehabilitation, speech and language therapy, and face-to-face consultations threatens to have a negative impact on the course and well-being of CA patients. Mental and physical health is also potentially at greater risk because the prevailing uncertainty and anxiety may be superimposed upon cerebellum-specific neuropsychological challenges. We identify and review some of the short- and long-term consequences of this global pandemic for the community of ataxia patients and their families and for the clinical and academic neurologists/ataxiologists caring for these patients. This includes the recognition that telemedicine has emerged as a principle means of caregiver-patient contact and that neurological manifestations of COVID-19 including those specific to cerebellar neurobiology are increasingly recognized and will require close surveillance and monitoring. This COVID-19 Cerebellum Task Force consensus provides some guidance on how we may approach this uncertain time and consider preparing for the new realities we face in CA patient care once this acute crisis has passed.
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http://dx.doi.org/10.1007/s12311-020-01139-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7220536PMC
August 2020

Analysis of non-invasive gait recording under free-living conditions in patients with Parkinson's disease: relationship with global cognitive function and motor abnormalities.

BMC Neurol 2020 Apr 29;20(1):161. Epub 2020 Apr 29.

Department of Neurology, Tokyo Medical University, 6-7-1 Nishishinjuku, Shinjuku-ku, Tokyo, 160-0023, Japan.

Background: We investigated the gait characteristics of patients with Parkinson's disease (PD), under free-living conditions, using a wearable device, and assessed their relationships with global cognitive function and motor abnormalities.

Methods: The study subjects comprised patients with PD aged < 80 years, with a Mini-Mental State Examination (MMSE) score of ≥20, free of any motor complications. A wearable sensor with a built-in tri-axial accelerometer was waist-mounted on each patient, and continuous, 24-h records were obtained. The mean gait cycle duration and mean gait acceleration amplitude, under free-living conditions, were computed and analyzed to determine their relationship with disease duration, MMSE score, Unified Parkinson's Disease Rating Scale (UPDRS) Part III score, and postural instability and gait difficulty (PIGD) score.

Results: The study included 106 consecutive patients with PD. The mean gait cycle duration was 1.18 ± 0.12 s, which was similar to that of the normal controls. However, the mean gait acceleration amplitude of PD patients (1.83 ± 0.36 m/s) was significantly lower than that of the control (p < 0.001). In PD patients, the mean gait acceleration amplitude correlated with the MMSE (β = 0.197, p = 0.028), UPDRS Part III (β = - 0.327, p < 0.001), and PIGD (β = - 0.235, p = 0.008) scores.

Conclusions: The gait rhythm of PD patients is preserved at levels similar to those of normal subjects. However, the mean gait acceleration amplitude was significantly reduced in patients with PD. The results indicate that gait acceleration amplitude correlates with the severity of motor disorders and global cognitive function.
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http://dx.doi.org/10.1186/s12883-020-01729-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7189597PMC
April 2020

Diagnostic Criteria for Primary Autoimmune Cerebellar Ataxia-Guidelines from an International Task Force on Immune-Mediated Cerebellar Ataxias.

Cerebellum 2020 Aug;19(4):605-610

Tokyo Medical University, Tokyo, Japan.

Aside from well-characterized immune-mediated ataxias with a clear trigger and/or association with specific neuronal antibodies, a large number of idiopathic ataxias are suspected to be immune mediated but remain undiagnosed due to lack of diagnostic biomarkers. Primary autoimmune cerebellar ataxia (PACA) is the term used to describe this later group. An International Task Force comprising experts in the field of immune ataxias was commissioned by the Society for Research on the Cerebellum and Ataxias (SRCA) in order to devise diagnostic criteria aiming to improve the diagnosis of PACA. The proposed diagnostic criteria for PACA are based on clinical (mode of onset, pattern of cerebellar involvement, presence of other autoimmune diseases), imaging findings (MRI and if available MR spectroscopy showing preferential, but not exclusive involvement of vermis) and laboratory investigations (CSF pleocytosis and/or CSF-restricted IgG oligoclonal bands) parameters. The aim is to enable clinicians to consider PACA when encountering a patient with progressive ataxia and no other diagnosis given that such consideration might have important therapeutic implications.
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http://dx.doi.org/10.1007/s12311-020-01132-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7351847PMC
August 2020

Cerebellar Scholars' Challenging Time in COVID-19 Pandemia.

Cerebellum 2020 Jun;19(3):343-344

Unité des Ataxies Cérébelleuses, Service de Neurologie, CHU-Charleroi, 6000, Charleroi, Belgium.

Novel coronavirus, SARS-CoV2, has caused pandemic of highly contagious disease called coronavirus disease 2019 (COVID-19), with epicenters in China, Italy, Spain, and the USA. Primarily affecting the human respiratory system, SARS-CoV2 has some impact on the human brain, but apparently minimal on the cerebellum, at least so far. Neurological involvement in the acute phase appears to manifest with confusion, dizziness, impaired consciousness, propensity to develop acute strokes, anosmia, hypogeusia, ataxia, epilepsy, and neuralgia. Cerebellar scholars are facing a time of uncertainty. Telemedicine has suddenly emerged as an alternative to follow patients. There is an urgent need to develop novel platforms to assess and follow ataxic patients remotely, especially because cerebellar patients often require ambulatory care to maintain their autonomy.
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http://dx.doi.org/10.1007/s12311-020-01131-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7161715PMC
June 2020

Assessment and Rating of Motor Cerebellar Ataxias With the Kinect v2 Depth Sensor: Extending Our Appraisal.

Front Neurol 2020 11;11:179. Epub 2020 Mar 11.

Movement Disorders Project, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan.

Current assessment of patients with cerebellar disorders is based on conventional neurological examination that is dependent on subjective judgements. Quantitative measurement of cerebellar ataxias (CAs) is essential for assessment of evidence-based treatments and the monitoring of the progress or recovery of diseases. It may provide us a useful tool to navigate future treatments for ataxia. We developed a Kinect v2. sensor system with a novel algorithm to measure and evaluate movements for two tests of Scale for the Assessment and Rating of Ataxia (SARA): the nose-finger test and gait. For the nose-finger test, we evaluated and compared accuracy, regularities and smoothness in the movements of the index finger and the proximal limbs between cerebellar patients and control subjects. For the task of walking, we evaluated and compared stability between the two groups. The precision of the system for evaluation of movements was smaller than 2 mm. For the nose-finger test, the mildly affected patients tended to show more instability than the control subjects. For a severely affected patient, our system quantified the instability of movements of the index finger using kinematic parameters, such as fluctuations and average speed. The average speed appears to be the most sensitive parameter that contrasts between patients with CAs and control subjects. Furthermore, our system also detected the adventitious movements of more proximal body parts, such as the elbow, shoulder and head. Assessment of walking was possible only in patients with mild CAs. They demonstrated large sways and compensatory wide stances. These parameters appeared to show higher accuracy than SARA. This examiner-independent device measures movements of the points of interest of SARA more accurately than eye and further provides additional information about the ataxic movements (e.g., the adventitious movements of the elbow, shoulder and head in the nose-finger test and the wide-based walking with large oscillation in the gait task), which is out of the scope of SARA. Our new system enables more accurate scoring of SARA and further provides additional information that is not currently evaluated with SARA. Therefore, it provides an easier, more accurate and more systematic description of CAs.
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http://dx.doi.org/10.3389/fneur.2020.00179DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7078683PMC
March 2020

Recent Advances in the Treatment of Cerebellar Disorders.

Brain Sci 2019 Dec 23;10(1). Epub 2019 Dec 23.

Service de Neurologie, Unité des Ataxies Cérébelleuses, CHU-Charleroi, 6000 Charleroi, Belgium.

Various etiopathologies affect the cerebellum, resulting in the development of cerebellar ataxias (CAs), a heterogeneous group of disorders characterized clinically by movement incoordination, affective dysregulation, and cognitive dysmetria. Recent progress in clinical and basic research has opened the door of the ''era of therapy" of CAs. The therapeutic rationale of cerebellar diseases takes into account the capacity of the cerebellum to compensate for pathology and restoration, which is collectively termed cerebellar reserve. In general, treatments of CAs are classified into two categories: cause-cure treatments, aimed at arresting disease progression, and neuromodulation therapies, aimed at potentiating cerebellar reserve. Both forms of therapies should be introduced as soon as possible, at a time where cerebellar reserve is still preserved. Clinical studies have established evidence-based cause-cure treatments for metabolic and immune-mediated CAs. Elaborate protocols of rehabilitation and non-invasive cerebellar stimulation facilitate cerebellar reserve, leading to recovery in the case of controllable pathologies (metabolic and immune-mediated CAs) and delay of disease progression in the case of uncontrollable pathologies (degenerative CAs). Furthermore, recent advances in molecular biology have encouraged the development of new forms of therapies: the molecular targeting therapy, which manipulates impaired RNA or proteins, and the neurotransplantation therapy, which delays cell degeneration and facilitates compensatory functions. The present review focuses on the therapeutic rationales of these recently developed therapeutic modalities, highlighting the underlying pathogenesis.
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http://dx.doi.org/10.3390/brainsci10010011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7017280PMC
December 2019

Association of daily physical activity with cognition and mood disorders in treatment-naive patients with early-stage Parkinson's disease.

J Neural Transm (Vienna) 2019 12 30;126(12):1617-1624. Epub 2019 Sep 30.

Department of Neurology, Tokyo Medical University, 6-7-1 Nishishinjuku, Shinjuku-ku, Tokyo, 160-0023, Japan.

To determine the association of daily physical activity with cognition, mood disorders, and olfactory function in treatment-naive patients with early-stage Parkinson's disease (PD). The study subjects were 52 treatment-naive patients with early-stage PD (< 80 years). Daily physical activity was measured using a wearable sensor with a built-in triaxial accelerometer, and its association with cognition [mini-mental state examination (MMSE), clock-drawing test (CDT), frontal assessment battery (FAB), and behavioral assessment of the dysexecutive syndrome (BADS)], depressive symptoms [Beck Depression Inventory-Second Edition (BDI-II)], apathy [Starkstein Apathy Scale (AS)], and olfactory function [Odor Stick Identification Test for the Japanese (OSIT-J)] was analyzed using multiple linear regression after adjustment for age, sex, and education status. The daily physical activity (0.42 ± 0.11 m/s) of the PD group was significantly lower than that of healthy controls (p < 0.001). Moreover, the daily physical activity of the PD group was significantly associated with FAB (β = 0.337, p = 0.027) and BADS (β = 0.374, p = 0.017) scores, but not with MMSE, CDT, BDI-II, AS, and OSIT-J scores. The daily physical activity is significantly reduced in treatment-naive patients with early-stage PD, and the low activity correlates with frontal/executive function.
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http://dx.doi.org/10.1007/s00702-019-02085-xDOI Listing
December 2019

Contribution of the Cerebellum to Predictive Motor Control and Its Evaluation in Ataxic Patients.

Front Hum Neurosci 2019 26;13:216. Epub 2019 Jun 26.

School of Medicine, University of Washington, Seattle, WA, United States.

Goal-directed movements are predictive and multimodal in nature, especially for moving targets. For instance, during a reaching movement for a moving target, humans need to predict both motion of the target and movement of the limb. Recent computational studies show that the cerebellum predicts current and future states of the body and its environment using internal forward models. Sensory feedback signals from the periphery have delays in reaching the central nervous system, ranging between tens to hundreds of milliseconds. It is well known in engineering that feedback control based on time-delayed inputs can result in oscillatory and often unstable movements. In contrast, the brain predicts a current state from a previous state using forward models. This predictive mechanism most likely underpins stable and dexterous control of reaching movements. Although the has long been suggested as loci of various forward models, few methods are available to evaluate accuracy of the forward models in patients with cerebellar ataxia. Recently, we developed a non-invasive method to analyze receipt of motor commands in terms of movement kinematics for the wrist joint ( ratio). In the present study, we have identified two components (F1 and F2) of the smooth pursuit movement. We found that the two components were in different control modes with different ratios. The major F1 component in a lower frequency range encodes both velocity and position of the moving target ( ratio) to synchronize movement of the wrist joint with motion of the target in a manner. The minor F2 component in a higher frequency range is biased to position control in order to generate intermittent small step-wise movements. In cerebellar patients, the F1 component shows a selective decrease in the ratio, which is correlated with decrease in accuracy of the pursuit movement. We conclude that the ratio of the F1 component provides a unique parameter to evaluate accuracy of the predictive control. We also discuss the pathophysiological and clinical implications for clinical ataxiology.
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http://dx.doi.org/10.3389/fnhum.2019.00216DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6608258PMC
June 2019

The Classification of Autosomal Recessive Cerebellar Ataxias: a Consensus Statement from the Society for Research on the Cerebellum and Ataxias Task Force.

Cerebellum 2019 Dec;18(6):1098-1125

Axe Neurosciences, CHU de Québec-Université Laval, Québec, QC, Canada.

There is currently no accepted classification of autosomal recessive cerebellar ataxias, a group of disorders characterized by important genetic heterogeneity and complex phenotypes. The objective of this task force was to build a consensus on the classification of autosomal recessive ataxias in order to develop a general approach to a patient presenting with ataxia, organize disorders according to clinical presentation, and define this field of research by identifying common pathogenic molecular mechanisms in these disorders. The work of this task force was based on a previously published systematic scoping review of the literature that identified autosomal recessive disorders characterized primarily by cerebellar motor dysfunction and cerebellar degeneration. The task force regrouped 12 international ataxia experts who decided on general orientation and specific issues. We identified 59 disorders that are classified as primary autosomal recessive cerebellar ataxias. For each of these disorders, we present geographical and ethnical specificities along with distinctive clinical and imagery features. These primary recessive ataxias were organized in a clinical and a pathophysiological classification, and we present a general clinical approach to the patient presenting with ataxia. We also identified a list of 48 complex multisystem disorders that are associated with ataxia and should be included in the differential diagnosis of autosomal recessive ataxias. This classification is the result of a consensus among a panel of international experts, and it promotes a unified understanding of autosomal recessive cerebellar disorders for clinicians and researchers.
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http://dx.doi.org/10.1007/s12311-019-01052-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6867988PMC
December 2019

Efficacy of istradefylline for gait disorders with freezing of gait in Parkinson's disease: A single-arm, open-label, prospective, multicenter study.

Expert Opin Pharmacother 2019 Aug 28;20(11):1405-1411. Epub 2019 May 28.

h Department of Neurology , Juntendo University Shizuoka Hospital , Izunokuni , Japan.

: Gait disorders are common in Parkinson's disease patients who respond poorly to dopaminergic treatment. Blockade of adenosine A receptors is expected to improve gait disorders. Istradefylline is a first-in-class selective adenosine A receptor antagonist with benefits for motor complications associated with Parkinson's disease. : This multicenter, open-label, single-group, prospective interventional study evaluated changes in total gait-related scores of the Part II/III Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) and Freezing of Gait Questionnaire (FOG-Q) in 31 Parkinson's disease patients treated with istradefylline. Gait analysis by portable gait rhythmogram was performed. : MDS-UPDRS Part III gait-related total scores significantly decreased at Weeks 4-12 from baseline with significant improvements in gait, freezing of gait, and postural stability. Significant decreases in MDS-UPDRS Part II total scores and individual item scores at Week 12 indicated improved daily living activities. At Week 12, there were significant improvements in FOG-Q, new FOG-Q, and overall movement per 48 h measured by portable gait rhythmogram. Adverse events occurred in 7/31 patients. : Istradefylline improved gait disorders in Parkinson's disease patients complicated with freezing of gait, improving their quality of life. No unexpected adverse drug reactions were identified. : UMIN-CTR (UMIN000020288).
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http://dx.doi.org/10.1080/14656566.2019.1614167DOI Listing
August 2019

Critical Thinking and Scientific Writing Skills of Non-Anglophone Medical Students: a Model of Training Course.

J Korean Med Sci 2019 Jan 4;34(3):e18. Epub 2019 Jan 4.

Department of Medical Education, Tokyo Medical University, Tokyo, Japan.

There are currently very limited reports on the strengths and weaknesses of Japanese medical students in processing (i.e., searching, reading, synthesizing, writing, editing, refining) and presenting medical content based on scholarly journal articles. We developed and offered a 3-week group independent research course in English as a summer elective named "Improving Medical English Skills and Creating English Medical Content (PPT and video) Based on Medical Journal Articles" to our fourth-year Japanese medical students who follow a 6-year medical curriculum as the target audience. Herein, we describe the specific strengths and weaknesses of 6 students who chose and completed the course. Thereafter, we assessed the possible reasons underlying these weaknesses, pondered on the potential implications of such weaknesses on the critical thinking, logical reasoning, and communication skills of Japanese medical students, and suggested approaches to further enhance these skills. The assessments, implications, and suggestions given may provide medical educators new insights on how to newly organize educational and clinical programs to address such weaknesses, improve searching, reading, writing, editing, and presentation skills, enhance critical thinking and logical reasoning abilities, and gain in-depth knowledge essential for effectively appraising and communicating medical content.
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http://dx.doi.org/10.3346/jkms.2019.34.e18DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6335120PMC
January 2019

Improving Scientific Writing Skills and Publishing Capacity by Developing University-Based Editing System and Writing Programs.

J Korean Med Sci 2019 Jan 28;34(1):e9. Epub 2018 Dec 28.

Department of Medical Education, Tokyo Medical University, Tokyo, Japan.

Scholarly article writing and publishing in international peer-reviewed journals can become an overwhelming task for many medical, nursing, and healthcare professionals in a university setting, especially in countries whose native language is not English. To help improve their scientific writing skills and publishing capacity, a university-based editing system and writing programs can be developed as educational platforms. These are delivered by a team of specialist editors composed of tenured faculty members who have a strong medical background and extensive experience in teaching courses on medical research, editing, writing, and publishing. For the editing system, the specialist editors provide comprehensive editing, personalized consultation, full editorial support after peer review, guidance with online submissions/resubmissions, and detailed editorial review at different stages of the manuscript writing. In addition, the specialist editors can develop writing programs such as medical writing and editing internships, academic courses in medical writing or research study designs and reporting standards, special interactive lectures and sessions on predatory publishing, seminars on updated editorial guidance of global editorial associations, academic visits on medical writing and editing, medical writing mentoring program, networking programs in scholarly communication, and publication resources in medical writing and scholarly publishing. These editing system and writing programs can serve as integrated platforms for improving scientific writing skills and publishing capacity by providing continuing education in medical writing, editing, publishing, and publication ethics.
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http://dx.doi.org/10.3346/jkms.2019.34.e9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6318442PMC
January 2019

Task Force Paper On Cerebellar Transplantation: Are We Ready to Treat Cerebellar Disorders with Cell Therapy?

Cerebellum 2019 Jun;18(3):575-592

Department of Neurology, CHU-Charleroi, 6000, Charleroi, Belgium.

Restoration of damaged central nervous system structures, functional recovery, and prevention of neuronal loss during neurodegenerative diseases are major objectives in cerebellar research. The highly organized anatomical structure of the cerebellum with numerous inputs/outputs, the complexity of cerebellar functions, and the large spectrum of cerebellar ataxias render therapies of cerebellar disorders highly challenging. There are currently several therapeutic approaches including motor rehabilitation, neuroprotective drugs, non-invasive cerebellar stimulation, molecularly based therapy targeting pathogenesis of the disease, and neurotransplantation. We discuss the goals and possible beneficial mechanisms of transplantation therapy for cerebellar damage and its limitations and factors determining outcome.
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http://dx.doi.org/10.1007/s12311-018-0999-1DOI Listing
June 2019

The Era of Cerebellar Therapy.

Curr Neuropharmacol 2019 ;17(1):3-6

Service de Neurologie, CHUCharleroi, Charleroi, Belgium.

Major advances in our understanding of the neurology/pathology, anatomy/physiology, and molecular biology of the cerebellum have opened a new door for cerebellar ataxias (CAs). We have now entered in the 'era of therapies'. Cures are knocking at the door. We discuss the hot topics in the therapeutic protocols available for CAs, including aminopyridines, noninvasive cerebellar stimulation, anti-oxidant drugs and therapies for immune-mediated cerbellar ataxias (IMCAs), topics emphasized in this issue. The history of the cerebellum is a typical example of the importance of apparently divergent and multi-disciplinary approaches.
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http://dx.doi.org/10.2174/1570159X1701181129111212DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6341497PMC
April 2019

Anti-GAD Antibodies and the Cerebellum: Where Do We Stand?

Cerebellum 2019 Apr;18(2):153-156

University of Washington, School of Medicine, Seattle, WA, 98109, USA.

Anti-GAD65 antibodies (anti-GAD65 Abs) are associated with cerebellar ataxia (CA). The significance of anti-GAD65 Abs has been a focus of debates. Since GAD65 is intracellularly located and associated with type 1 diabetes mellitus and different clinical neurological phenotypes such as CA, stiff-person syndrome, and epilepsy, some researchers have argued that anti-GAD65 Abs have no pathogenic roles. On the other hand, recent physiological studies in vitro and in vivo have elucidated that binding of GAD65 by anti-GAD65 Abs elicits loss of GAD65 functions pertaining GABA release with an epitope dependence, leading to the development of CA. Internalization of autoantibodies has been also clarified. These studies provide substantial evidence of the pathogenesis of anti-GAD65 Abs in CA. We also discuss methodological problems in the identification of anti-GAD65 Abs.
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http://dx.doi.org/10.1007/s12311-018-0986-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6443918PMC
April 2019

Cerebellar Cortex as a Therapeutic Target for Neurostimulation.

Cerebellum 2018 Dec;17(6):777-787

Service de Neurologie, Médiathèque Jean Jacquy, CHU-Charleroi, Charleroi, Belgium.

Non-invasive stimulation of the cerebellum is growingly applied both in the clinic and in research settings to modulate the activities of cerebello-cerebral loops. The anatomical location of the cerebellum, the high responsiveness of the cerebellar cortex to magnetic/electrical stimuli, and the implication of the cerebellum in numerous cerebello-cerebral networks make the cerebellum an ideal target for investigations and therapeutic purposes. In this mini-review, we discuss the potentials of cerebellar neuromodulation in major brain disorders in order to encourage large-scale sham-controlled research and explore this therapeutic aid further.
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http://dx.doi.org/10.1007/s12311-018-0976-8DOI Listing
December 2018

Consensus paper: Decoding the Contributions of the Cerebellum as a Time Machine. From Neurons to Clinical Applications.

Cerebellum 2019 Apr;18(2):266-286

Department of Psychology and Neuroscience, Duke University, Durham, NC, USA.

Time perception is an essential element of conscious and subconscious experience, coordinating our perception and interaction with the surrounding environment. In recent years, major technological advances in the field of neuroscience have helped foster new insights into the processing of temporal information, including extending our knowledge of the role of the cerebellum as one of the key nodes in the brain for this function. This consensus paper provides a state-of-the-art picture from the experts in the field of the cerebellar research on a variety of crucial issues related to temporal processing, drawing on recent anatomical, neurophysiological, behavioral, and clinical research.The cerebellar granular layer appears especially well-suited for timing operations required to confer millisecond precision for cerebellar computations. This may be most evident in the manner the cerebellum controls the duration of the timing of agonist-antagonist EMG bursts associated with fast goal-directed voluntary movements. In concert with adaptive processes, interactions within the cerebellar cortex are sufficient to support sub-second timing. However, supra-second timing seems to require cortical and basal ganglia networks, perhaps operating in concert with cerebellum. Additionally, sensory information such as an unexpected stimulus can be forwarded to the cerebellum via the climbing fiber system, providing a temporally constrained mechanism to adjust ongoing behavior and modify future processing. Patients with cerebellar disorders exhibit impairments on a range of tasks that require precise timing, and recent evidence suggest that timing problems observed in other neurological conditions such as Parkinson's disease, essential tremor, and dystonia may reflect disrupted interactions between the basal ganglia and cerebellum.The complex concepts emerging from this consensus paper should provide a foundation for further discussion, helping identify basic research questions required to understand how the brain represents and utilizes time, as well as delineating ways in which this knowledge can help improve the lives of those with neurological conditions that disrupt this most elemental sense. The panel of experts agrees that timing control in the brain is a complex concept in whom cerebellar circuitry is deeply involved. The concept of a timing machine has now expanded to clinical disorders.
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http://dx.doi.org/10.1007/s12311-018-0979-5DOI Listing
April 2019

Immune-mediated Cerebellar Ataxias: Practical Guidelines and Therapeutic Challenges.

Curr Neuropharmacol 2019 ;17(1):33-58

University of Washington, School of Medicine, Seattle, WA 98109, United States.

Immune-mediated cerebellar ataxias (IMCAs), a clinical entity reported for the first time in the 1980s, include gluten ataxia (GA), paraneoplastic cerebellar degenerations (PCDs), antiglutamate decarboxylase 65 (GAD) antibody-associated cerebellar ataxia, post-infectious cerebellitis, and opsoclonus myoclonus syndrome (OMS). These IMCAs share common features with regard to therapeutic approaches. When certain factors trigger immune processes, elimination of the antigen( s) becomes a priority: e.g., gluten-free diet in GA and surgical excision of the primary tumor in PCDs. Furthermore, various immunotherapeutic modalities (e.g., steroids, immunoglobulins, plasmapheresis, immunosuppressants, rituximab) should be considered alone or in combination to prevent the progression of the IMCAs. There is no evidence of significant differences in terms of response and prognosis among the various types of immunotherapies. Treatment introduced at an early stage, when CAs or cerebellar atrophy is mild, is associated with better prognosis. Preservation of the "cerebellar reserve" is necessary for the improvement of CAs and resilience of the cerebellar networks. In this regard, we emphasize the therapeutic principle of "Time is Cerebellum" in IMCAs.
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http://dx.doi.org/10.2174/1570159X16666180917105033DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6341499PMC
April 2019

Characteristics of apathy in treatment-naïve patients with Parkinson's disease.

Int J Neurosci 2019 Jan 29;129(1):16-21. Epub 2018 Nov 29.

a Department of Neurology , Tokyo Medical University , Shinjuku-ku , Tokyo , Japan.

Introduction: Although apathy is a common psychiatric symptom of Parkinson's disease (PD), there are many unknown aspects of its pathology. This study aimed to investigate the characteristics of apathy in treatment-naïve patients with early-stage PD.

Methods: Fifty treatment-naïve patients with early-stage PD were divided into 1 of 2 groups-apathetic or non-apathetic-based on Starkstein Apathy Scale (AS) scores. Cognitive function, depressive symptoms, olfactory function, and motor severity were compared between the two groups using validated assessment scales. Multiple linear regression was performed to assess the association between AS scores and clinical parameters.

Results: Apathy (AS score ≥16) was observed in 13 (26%) patients. Assessment scale scores (Beck Depression Inventory-Second Edition [p < .004]; modified Hoehn & Yahr stage [p = .039]; Unified Parkinson's Disease Rating Scale part III [p < .001]) were significantly higher in apathetic patients than in non-apathetic patients. Significant association between these scale scores and AS score was also evident (all p ≤ .001). There were no significant differences in the test scores derived from several other validated scales.

Conclusion: Apathy was observed in 26% of treatment-naïve patients with early-stage PD. Significant association between apathy and motor severity was found, suggesting that dysfunction of the dopaminergic pathway is involved in the pathology of apathy.
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http://dx.doi.org/10.1080/00207454.2018.1503184DOI Listing
January 2019

Editorial: Advances in Therapies of Cerebellar Disorders.

CNS Neurol Disord Drug Targets 2018 ;17(3):157-160

Service de Neurologie, CHU-Charleroi, 6000 Charleroi, Belgium, and Service des Neurosciences, University of Mons, 7000 Mons, Belgium.

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http://dx.doi.org/10.2174/187152731703180619151532DOI Listing
July 2019

Neurotransplantation therapy.

Handb Clin Neurol 2018 ;155:379-391

Department of Medical Education, Tokyo Medical University, Tokyo, Japan.

Neurotransplantation may be a promising approach for therapy of cerebellar diseases characterized by a substantial loss of neurons. Neurotransplantation could rescue neurons from degeneration and maintain cerebellar reserve, facilitate cerebellar compensation, or help reconstruct damaged neural circuits by cell substitution. These mechanisms of action can be of varying importance according to the type of cerebellar disease. Neurotransplantation therapy in cerebellar ataxias is still at the stage of experimental studies. There is currently little knowledge regarding cerebellar patients. Nevertheless, data provided by experiments in animal models of cerebellar degeneration and both clinical studies and experiences in patients with other neurologic diseases enable us to suggest basic principles, expectations, limitations, and future directions of neurotransplantation therapy for cerebellar diseases.
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http://dx.doi.org/10.1016/B978-0-444-64189-2.00025-1DOI Listing
October 2018