Degenerative Cerebellar Disease Research Articles

Effectiveness of Vestibular Rehabilitation for Patients with Degenerative Cerebellar Ataxia: A Retrospective Cohort Study.

Many patients with cerebellar ataxia have dizziness caused by oculomotor or peripheral vestibular deficits; however, there is little evidence supporting the use of vestibular rehabilitation for this population. The purpose of this study was to determine whether patients with degenerative cerebellar diseases improve following rehabilitation including vestibular exercises. A secondary aim was to identify variables associated with the outcomes. A retrospective chart review identified 42 ambulatory patients (23 men and 19 women; mean age = 54.5 ± 14.4 years) with cerebellar degeneration. Fourteen patients had ataxia only, twenty had ataxia and oculomotor abnormalities, and eight had ataxia with oculomotor and peripheral vestibular deficits. Patients received customized physical therapy including balance and gait training, as well as gaze stabilization and habituation exercises for vestibular hypofunction and motion-provoked dizziness. Primary outcome measures (Activities-specific Balance Confidence Scale, Tinetti Performance Oriented Mobility Assessment, Dynamic Gait index, and Sensory Organization Test) were evaluated at baseline and discharge. Patients improved (p < 0.05) on all outcome measures. Patients with vestibular deficits were seen for more visits compared to those with gait ataxia only (7.1 vs. 4.8 visits). This study provides evidence that patients with degenerative cerebellar disease improve in balance confidence, fall risk and sensory integration with therapy that includes vestibular rehabilitation.

Genetic Deletion of Thorase Causes Purkinje Cell Loss and Impaired Motor Coordination Behavior.

Thorase belongs to the AAA+ ATPase family, which plays a critical role in maintaining cellular homeostasis. Our previous work reported that Thorase was highly expressed in brain tissue, especially in the cerebellum. However, the roles of Thorase in the cerebellum have still not been characterized. In this study, we generated conditional knockout mice (cKO) with Thorase deletion in Purkinje cells. Thorase cKO mice exhibited cerebellar degenerative diseases-like behavior and significant impairment in motor coordination. Thorase deletion resulted in more Purkinje neuron apoptosis, leading to Purkinje cell loss in the cerebellum of Thorase cKO mice. We also found enhanced expression of the inflammatory protein ASC, IL-1β, IL-6 and TNF-α in the Thorase cKO cerebellum, which contributed to the pathogenesis of cerebellar degenerative disease. Our findings provide a better understanding of the role of Thorase in the cerebellum, which is a theoretical basis for Thorase as a therapeutic drug target for neurodegenerative diseases.

Real-Life Turning Movements Capture Subtle Longitudinal and Preataxic Changes in Cerebellar Ataxia.

Clinical and regulatory acceptance of upcoming molecular treatments in degenerative ataxias might greatly benefit from ecologically valid endpoints that capture change in ataxia severity in patients' real life. This longitudinal study aimed to unravel quantitative motor biomarkers in degenerative ataxias in real-life turning movements that are sensitive for changes both longitudinally and at the preataxic stage. Combined cross-sectional (n=30) and longitudinal (n=14, 1-year interval) observational study in degenerative cerebellar disease (including eight preataxic mutation carriers) compared to 23 healthy controls. Turning movements were assessed by three body-worn inertial sensors in three conditions: (1) instructed laboratory assessment, (2) supervised free walking, and (3) unsupervised real-life movements. Measures that quantified dynamic balance during turning-lateral velocity change (LVC) and outward acceleration-but not general turning measures such as speed, allowed differentiating ataxic against healthy subjects in real life (effect size δ=0.68), with LVC also differentiating preataxic against healthy subjects (δ=0.53). LVC was highly correlated with clinical ataxia severity (scale for the assessment and rating of ataxia [SARA] score, effect size ρ=0.79) and patient reported balance confidence (activity-specific balance confidence scale [ABC] score, ρ=0.66). Moreover, LVC in real life-but not general turning measures or the SARA score-allowed detecting significant longitudinal change in 1-year follow-up with high effect size (rprb =0.66). Measures of turning allow capturing specific changes of dynamic balance in degenerative ataxia in real life, with high sensitivity to longitudinal differences in ataxia severity and to the preataxic stage. They thus present promising ecologically valid motor biomarkers, even in the highly treatment-relevant early stages of degenerative cerebellar disease. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Neuroimaging of Pediatric Cerebellum in Inherited Neurodegenerative Diseases

In the study of cerebellar degenerative diseases, morphologic imaging (computed tomography, CT and magnetic resonance imaging, MRI) is the most common examination. From the clinical and genetic point of view, cerebellar degenerative diseases include heterogeneous conditions in which MRI may show isolated cerebellar atrophy or cerebellar atrophy associated with other cerebellar or supratentorial abnormalities. Neuroradiological progression is often observed. In congenital disorders of glycosylation (CDG), for example, MRI may be normal, may demonstrate mild cerebellar atrophy or, in the advanced stages of the disease, marked atrophy of the cerebellar hemispheres and vermis associated with the abnormal signal intensity of the cerebellar cortex and white matter and brainstem hypotrophy. In spinal cerebellar ataxias (SCAs), very rare in the pediatric population, MRI may demonstrate isolated cerebellar atrophy or cerebellar and brainstem atrophy. MRI shows characteristic findings in other diseases, strongly suggesting a distinct disorder, such as neuroaxonal dystrophy, ARSACS, ataxia-telangiectasia, or precise mitochondrial diseases. An example of neurodegenerative disorder with prenatal onset is pontocerebellar hypoplasia (PCH). PCH represents a group of neurodegenerative disorders characterized by microcephaly, early cerebellar hypoplasia, and variable atrophy of the cerebellum and ventral pons, genetically divided into several subtypes. Cerebellar hypoplasia visible on MRI is often the first sign that suggests the clinical diagnosis. In most cases, the PCH subtype may demonstrate a characteristic pattern distinguishable at MRI. Selective involvement of the cerebellum, sometimes accompanied by brainstem or supratentorial abnormalities in different combinations, may help restrict the differential diagnosis and may address the specific molecular screening.

Measurements of Hand Function in Degenerative Cerebellar Disease: A Case-Control Pilot Study.

The aim of the study was to determine the association of Nine Hole Peg Test, Box and Block Test, Jebsen-Taylor Hand Function Test, and kinematic measures of a simple reaching task with ataxia severity in adults with degenerative cerebellar disease. Fourteen adults with cerebellar degeneration were recruited, and ataxia severity was determined using the Scale for the Assessment and Rating of Ataxia. The median Scale for the Assessment and Rating of Ataxia score was used to divide participants into less and more severe ataxia groups. The two groups' average scores on the hand function tests were compared, and correlation of each test with ataxia severity was determined. The Nine Hole Peg Test, Box and Block Test, and Jebsen-Taylor Hand Function Test all differentiated between less and more severe ataxia groups, and the Nine Hole Peg Test performed with the participant's dominant hand had the highest correlation with ataxia severity (rs = 0.92, P < 0.01). Although accuracy, precision, and number of submovements were statistically different between healthy individuals and the more ataxic participant group, most kinematic measures were not significantly different between the less and more severe ataxic groups. Overall, our results indicate that all three clinical tests correlate with ataxia severity. Larger future studies should examine the reliability and validity of these hand function measures in adults with degenerative cerebellar disease.

3 Hz postural tremor: A specific and sensitive sign of cerebellar dysfunction in patients with cerebellar ataxia

Objective3 Hz postural tremor was described in patients with anterior cerebellar lobe atrophy, however sensitivity and specificity of this sign in degenerative cerebellar diseases has not yet been evaluated. Our aim was to assess the 3 Hz tremor in patients with cerebellar ataxia, compare its sensitivity and specificity with other posturography parameters and to find out a correlation of intensity of 3 Hz tremor with ataxia severity. Methods30 patients with degenerative cerebellar ataxia, a control group of 30 patients with compensated peripheral vestibulopathy and 40 healthy volunteers were examined by posturography. 3 Hz tremor was assessed both qualitatively and quantitatively, its sensitivity and specificity were compared with other standard posturography parameters. Results3 Hz postural tremor was detected in 90% of patients with cerebellar ataxia, with 100% specificity and 90% sensitivity. The sensitivity and specificity of quantitative analysis of 3 Hz tremor was largely superior to standard posturography parameters when differentiating patients with cerebellar ataxia from vestibular impairment and healthy controls. Conclusion3 Hz postural tremor is highly sensitive and specific sign of cerebellar impairment in patients with cerebellar ataxia. SignificanceEvaluation of 3 Hz postural tremor should be a standard part of posturography examination when considering a cerebellar impairment.

Real-life gait assessment in degenerative cerebellar ataxia: Toward ecologically valid biomarkers.

With disease-modifying drugs on the horizon for degenerative ataxias, ecologically valid motor biomarkers are highly warranted. In this observational study, we aimed to unravel and validate markers of ataxic gait in real life by using wearable sensors. We assessed gait characteristics of 43 patients with degenerative cerebellar disease (Scale for the Assessment and Rating of Ataxia [SARA] 9.4 ± 3.9) compared with 35 controls by 3 body-worn inertial sensors in 3 conditions: (1) laboratory-based walking; (2) supervised free walking; (3) real-life walking during everyday living (subgroup n = 21). Movement analysis focused on measures of spatiotemporal step variability and movement smoothness. A set of gait variability measures was identified that allowed us to consistently identify ataxic gait changes in all 3 conditions. Lateral step deviation and a compound measure of spatial step variability categorized patients vs controls with a discrimination accuracy of 0.86 in real life. Both were highly correlated with clinical ataxia severity (effect size ρ = 0.76). These measures allowed detecting group differences even for patients who differed only 1 point in the clinical SARAposture&gait subscore, with highest effect sizes for real-life walking (d = 0.67). We identified measures of ataxic gait that allowed us not only to capture the gait variability inherent in ataxic gait in real life, but also to demonstrate high sensitivity to small differences in disease severity, with the highest effect sizes in real-life walking. They thus represent promising candidates for motor markers for natural history and treatment trials in ecologically valid contexts. This study provides Class I evidence that a set of gait variability measures, even if accessed in real life, correlated with the clinical severity of ataxia in patients with degenerative cerebellar disease.

Investigating the Clinical Significance and Research Discrepancies of Balance Training in Degenerative Cerebellar Disease: A Systematic Review.

The aims of this study were to understand the clinical significance of balance training in degenerative cerebellar disease and to analyze inconsistencies among published data. Five databases were searched from inception to October 8, 2019. Cochrane guidelines informed review methods, and Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines were followed. The Australian National Health and Medical Research Council Evidence Hierarchy, PEDro scale, and Joanna Briggs Institute Critical Appraisal Tools were used to evaluate methodological quality. Outcome measures examined included ataxia severity, gait speed, and balance. Fourteen articles were identified that met inclusion criteria. The quality of evidence was moderate to high, with recent articles being of higher quality. Nine of 12 articles showed statistical improvements in ataxia severity (reduction ranging from 1.4 to 2.8 in the Scale for the Assessment and Rating of Ataxia points), three of eight showed statistical improvements in gait speed (average increase of 0.1 m/sec), and six of nine showed improvements in balance measures (average increase of 1.75 in Berg Balance Scale and 1.5 in Dynamic Gait Index). Most studies showed statistical and clinically significant ataxia severity improvements in subjects who performed balance training. The amount of balance challenge and frequency of training were important factors in determining the extent of training benefit. Gait speed may also improve if walking exercises are included in the balance training, but more studies need to be conducted. Balance measures statistically improved with training, but these improvements did not meet criteria for clinical significance. Complete the self-assessment activity and evaluation online at http://www.physiatry.org/JournalCME CME OBJECTIVES: Upon completion of this article, the reader should be able to: (1) Describe the cause(s) of discrepancies in the literature regarding the benefits of balance training in degenerative cerebellar disease; (2) Determine if benefits from balance training are clinically meaningful for individuals with cerebellar degeneration; and (3) Understand the best practices gleaned from the current literature regarding balance training for these diseases. Advanced ACCREDITATION: The Association of Academic Physiatrists is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.The Association of Academic Physiatrists designates this Journal-based CME activity for a maximum of 1.0 AMA PRA Category 1 Credit(s)™. Physicians should only claim credit commensurate with the extent of their participation in the activity.

Effect of Sertoli Cell Transplantation on Reducing Neuroinflammation-Induced Necroptosis and Improving Motor Coordination in the Rat Model of Cerebellar Ataxia Induced by 3-Acetylpyridine.

To date, no certain cure has been found for patients with degenerative cerebellar disease. In this trial, we examined the in vivo and in vitro neuroprotective effects of Sertoli cells (SCs) on alleviating the symptoms of cerebellar ataxia. Testicular cells from an immature male rat were isolated and characterized by immunocytochemical analysis for somatic cell markers (anti-Mullerian hormone, vimentin). The protein assessment had already confirmed the expression of neurotrophic factors of glial cell line-derived neurotrophic factor (GDNF) and vascular endothelial factor (VEGF). In vitro neuroprotective impact of SCs was determined after exposing PC12 cells to Sertoli cell-conditioned media (SC-CM) and H2O2, simultaneously. Afterwards, ataxia rat models were induced by a single dose of 3-AP (3-acetylpyridin), and 3days later, SCs were bilaterally implanted. Motor and neuromuscular activity test were conducted following SC transplantation. Finally, immunohistochemistry against RIPK3 and Iba-1 was done in our generation. The in vivo results revealed substantial improvement in neuromuscular response, while ataxia group exhibited aggravated condition over a 28-day period. Our results suggested enhanced motor function and behavioral characteristics due to the ability of SCs to suppress necroptosis and consequently extend cell survival. Nevertheless, more studies are required to affirm the therapeutic impacts of SC transplantation in human cerebellar ataxia. In vitro data indicated cell viability was increased as a result of SC-CM with a significant reduction in ROS.

Extinction of cognitive associations is preserved in patients with cerebellar disease.

In the present study extinction and renewal of cognitive associations were assessed in two experiments in participants with focal and degenerative cerebellar disease. Using a predictive learning task, participants had to learn by trial and error the relationships between food items and the occurrence of stomach trouble in a hypothetical patient. In the first experiment, focus was on renewal effects. Participants with chronic cerebellar stroke (n=14; mean age 50.9±12years), participants with degenerative cerebellar disease (n=16; mean age 58±12years), age-, sex-, and education matched controls (n=20; mean age 53.7±10.8years) and young controls (n=19; mean age 23.2±2.7years) were tested. Acquisition and extinction of food-stomach trouble associations took part in two different contexts (represented by restaurants). In a subsequent test phase, food stimuli were presented in both contexts and no feedback was given. This allowed testing for renewal of the initially acquired associations in the acquisition context. Acquisition and extinction learning were not significantly different between groups. Significant renewal effects were present in young controls only. In the second experiment, focus was on extinction. To control for age effects, 19 young participants with chronic surgical lesions of the cerebellum (mean age 25.6±6.1years), and 24 age-, sex- and education-matched healthy controls were tested. Acquisition and extinction of food-stomach trouble associations took part in the same context. In the extinction phase, the relationship with stomach trouble was reversed in some of the food items. Acquisition and extinction learning were not significantly different between groups. The main finding of the present study was preserved extinction of learned cognitive associations in participants with chronic cerebellar disease. Findings agree with previous observations in the literature that cognitive abnormalities are frequently absent or weak in adults with cerebellar disease. This does not exclude a contribution of the cerebellum to extinction of learned associations. For example, findings may be different in more challenging cognitive tasks, and in participants with acute cerebellar disease with no time for compensation.

Maturation of Human Pluripotent Stem Cell-Derived Cerebellar Neurons in the Absence of Co-culture

The cerebellum plays a critical role in all vertebrates, and many neurological disorders are associated with cerebellum dysfunction. A major limitation in cerebellar research has been the lack of adequate disease models. As an alternative to animal models, cerebellar neurons differentiated from pluripotent stem cells have been used. However, previous studies only produced limited amounts of Purkinje cells. Moreover, in vitro generation of Purkinje cells required co-culture systems, which may introduce unknown components to the system. Here we describe a novel differentiation strategy that uses defined medium to generate Purkinje cells, granule cells, interneurons, and deep cerebellar nuclei projection neurons, that self-formed and differentiated into electrically active cells. Using a defined basal medium optimized for neuronal cell culture, we successfully promoted the differentiation of cerebellar precursors without the need for co-culturing. We anticipate that our findings may help developing better models for the study of cerebellar dysfunctions, while providing an advance toward the development of autologous replacement strategies for treating cerebellar degenerative diseases.

Phase I randomized single-blinded controlled study investigating the potential benefit of aerobic exercise in degenerative cerebellar disease

Objectives: To investigate whether people with cerebellar degeneration can perform rigorous aerobic exercise and to assess the clinical impact of training. Design: Randomized single-blinded controlled, feasibility study comparing aerobic training to no training. Setting: Home intervention, assessments conducted at an academic medical center. Subjects: Twenty individuals with cerebellar degeneration caused by a range of genetic disorders. Intervention: Aerobic training consisted of four weeks of stationary bicycle training, five times per week for 30-minute sessions. Intensity ranged from 65% to 80% of the participant’s maximal heart rate determined during cardiopulmonary exercise testing. Main measures: Primary outcome measure was change in the Scale for the Assessment and Rating of Ataxia scores. Recruitment rate, adherence, drop-out, and adverse events were also determined. The treatment was considered technically feasible if participants achieved target training frequency, duration, and intensity. Results: The 20 participants mean age was 50 years (standard deviation 15.65 years) and average Scale for the Assessment and Rating of Ataxia score was 9.6 (standard deviation 3.13). Ten participants were randomized to aerobic training and 10 to no training. Seven participants in the aerobic group attained target training duration, frequency, and intensity. There was a mean reduction in ataxia severity of 2.1 points (standard deviation 1.26) with four weeks of aerobic training, whereas ataxia severity increased by 0.3 (standard deviation 0.62) in the control group over the same period. Walking speed, balance measures, and fitness also improved in individuals who performed aerobic exercise. Conclusions: Rigorous aerobic training is feasible in people with cerebellar degeneration. Improvements in ataxia, balance, and gait are promising.

Health-related quality of life and depressive symptoms in Friedreich ataxia.

Friedreich ataxia (FRDA) is a chronic, progressive and highly disabling cerebellar degenerative disease. Despite this, little attention has been paid to the health-related quality of life (HRQOL) in this disease. The aim of the present study was to assess FRDA patients' perception of HRQOL and to determine the influence of depression, and demographic and clinical variables. The sample consisted of 62 patients with genetically confirmed FRDA. The SF-36 Health Survey was used to assess HRQOL. Depressive symptoms were evaluated with the Beck Depression Inventory-II. FRDA patients' mean scores were significantly lower than the values for the Spanish population in all SF36 dimensions. Average z scores ranged from - 5.5 in physical functioning to - 0.48 in mental health. Age and clinical variables were significant predictors of HRQOL in only several dimensions, whereas BDI scores were able to predict a significant percentage of variance in all SF36 dimensions, except physical functioning. Our study demonstrates the high impact of Friedreich ataxia on quality of life. This impact does not only occur in those aspects most related to motor disability but it is also present in non-motor dimensions. Depressive symptomatology is the most relevant variable for predicting quality of life.

Speech treatment improves dysarthria in multisystemic ataxia: a rater-blinded, controlled pilot-study in ARSACS.

We aimed to provide proof-of-principle evidence that intensive home-based speech treatment can improve dysarthria in complex multisystemic degenerative ataxias, exemplified by autosomal recessive spastic ataxia Charlevoix-Saguenay (ARSACS). Feasibility and piloting efficacy of speech training specifically tailored to cerebellar dysarthria was examined through a 4-week program in seven patients with rater-blinded assessment of intelligibility (primary outcome) and naturalness and acoustic measures of speech (secondary outcomes) performed 4 weeks before, immediately prior to, and directly after training (intraindividual control design). Speech intelligibility and naturalness improved post treatment. This provides piloting evidence that ataxia-tailored speech treatment might be effective in degenerative cerebellar disease.

Depression disorder in patients with cerebellar damage: Awareness of the mood state.

BackgroundAlthough depressive symptoms are often reported to be comorbid with degenerative cerebellar diseases, the role of the cerebellum in depressive disorder needs to be elucidated. To address this aim, we investigated self-perception of the negative mood state in patients with cerebellar pathology and depressive symptoms. MethodsThirty-eight patients with cerebellar damage (10 with depressive symptoms – CB-DP and 28 with no depressive symptoms – CB-nDP), 11 subjects with depressive disorders without cerebellar damage (DP) and 29 healthy controls (CTs) were enrolled. A device for self-monitoring of the mood state (MoMo) and validated scales such as the Profile of Mood States questionnaire (POMS), the Self-Report Symptom Inventory-Revised (SCL-90-R) and the Hamilton Depression Rating Scale (HDRS) were used to evaluate depressive symptoms. ResultsBoth CB-DP and DP patients showed higher scores than CTs on the POMS and SCL-90-R for depressive factors and on the HDRS. DP patients showed a lower frequency of ‘good’ mood and a higher frequency of ‘bad’ mood than CTs when using the MoMo device. However, although the two depressed populations showed comparable scores on these validated scales, CB-DP patients showed impaired self-awareness of the mood experience in ‘the here and now’, as evidenced by the absence of significant differences, compared with CTs, in the subjective mood evaluation performed with the MoMo device. LimitationsThe number of CB patients and inhomogeneity across MRI scans were study limitations. ConclusionCerebellar dysfunction might slow the data integration necessary for mood state awareness, resulting in difficulty of depressed CB patients in explicitly recognizing their mood “in the here and now”.

Astrocytes restore connectivity and synchronization in dysfunctional cerebellar networks

Evidence suggests that astrocytes play key roles in structural and functional organization of neuronal circuits. To understand how astrocytes influence the physiopathology of cerebellar circuits, we cultured cells from cerebella of mice that lack the ATM gene. Mutations in ATM are causative of the human cerebellar degenerative disease ataxia-telangiectasia. Cerebellar cultures grown from Atm-/- mice had disrupted network synchronization, atrophied astrocytic arborizations, reduced autophagy levels, and higher numbers of synapses per neuron than wild-type cultures. Chimeric circuitries composed of wild-type astrocytes and Atm-/- neurons were indistinguishable from wild-type cultures. Adult cerebellar characterizations confirmed disrupted astrocyte morphology, increased GABAergic synaptic markers, and reduced autophagy in Atm-/- compared with wild-type mice. These results indicate that astrocytes can impact neuronal circuits at levels ranging from synaptic expression to global dynamics.

The effect of intensive physical therapy with repetitive transcranial magnetic stimulation in patients with degenerative cerebellar disease

The studies of repetitive transcranial magnetic stimulation (rTMS) of the brain have demonstrated the modulation of cortical excitability. Combination of rTMS with physical therapy (PT) might affect the therapeutic effects for movement disorders. The aim of this study was to investigate the effect of combination of intensive PT with rTMS in patients with degenerative cerebellar disease. Twelve patients with degenerative cerebellar disease participated in the study. The rTMS and PT were carried out five days a week for three weeks. The gait parameters were determined using a three-dimensional motion analysis system, and the total length and the velocity of the center of pressure (COP) in standing position using a stabilometer and the International Cooperative Ataxia Rating Scale (ICARS) were assessed in all patients before and after the intervention. The changes in the walking speed, step width, the total length of the COP and the velocity of the COP in standing position were not significant. The amplitude of the lateral head and body sway when walking were reduced after intervention ( P < 0.01) and the ICARS was improved after the intervention ( P < 0.01). The correlations between the duration of disease and the improvement of walking speed and step width were not significant. The correlations between the disease severity and the improvement of walking speed and step width were significant. In our study, combination of intensive PT and rTMS conferred positive effects on the dynamic balance in patients with degenerative cerebellar disease in earlier stages of the disease.

A quantitative study of “empty baskets” in essential tremor and cerebellar degenerative diseases (P6.054)

A quantitative study of “empty baskets” in essential tremor and cerebellar degenerative diseases (P6.054)

Physiological and Morphological Principles Underpinning Recruitment of the Cerebellar Reserve.

Background: In order to optimize outcomes of novel therapies for cerebellar ataxias (CAs), it is desirable to start these therapies while declined functions are restorable: i.e. while the so-called cere-bellar reserve remains.Objective: In this mini-review, we tried to define and discuss the cerebellar reserve from physiological and morphological points of view.Method: The cerebellar neuron circuitry is designed to generate spatiotemporally organized outputs, re-gardless of the region. Therefore, the cerebellar reserve may be defined as a mechanism to restore its proper input-output organization of the cerebellar neuron circuitry, when it is damaged. Then, the follow-ing four components are essential for recruitment of the cerebellar reserve: operational local neuron cir-cuitry; proper combination of mossy fiber inputs to be integrated; climbing fiber inputs to instruct favor-able reorganization of the integration; deep cerebellar nuclei to generate reorganized outputs.Results: We discussed three topics related to these resources, 1) principles of generating organized cere-bellar outputs, 2) redundant mossy fiber inputs to the cerebellum, 3) plasticity of the cerebellar neuron circuitry.Conclusion: To make most of the cerebellar reserve, it is desirable to start any intervention as early as possible when the cerebellar cell loss is minimal or even negligible. Therefore, an ideal future therapy for degenerative cerebellar diseases should start before consuming the cerebellar reserve at all. In the meantime, our real challenge is to establish a reliable method to identify the decrease in the cerebellar re-serve as early as possible.

Long-Term Development of Embryonic Cerebellar Grafts in Two Strains of Lurcher Mice.

For many degenerative cerebellar diseases, currently, no effective treatment that would substantially restore cerebellar functions is available. Neurotransplantation could be a promising therapy for such cases. Nevertheless, there are still severe limitations for routine clinical use. The aim of the work was to assess volume and morphology and functional impact on motor skills of an embryonic cerebellar graft injected in the form of cell suspension in Lurcher mutant and wild-type mice of the B6CBA and C3H strains after a 6-month survival period. The grafts survived in the majority of the mice. In both B6CBA and C3H Lurcher mice, most of the grafts were strictly delimited with no tendency to invade the host cerebellum, while in wild-type mice, graft-derived Purkinje cells colonized the host's cerebellum. In C3H Lurcher mice, but not in B6CBA Lurchers, the grafts had smaller volume than in their wild-type counterparts. C3H wild-type mice had significantly larger grafts than B6CBA wild-type mice. No positive effect of the transplantation on performance in the rotarod test was observed. The findings suggest that the niche of the Lurcher mutant cerebellum has a negative impact on integration of grafted cells. This factor seems to be limiting for specific functional effects of the transplantation therapy in this mouse model of cerebellar degeneration.