Cerebellar Diseases Research Articles

Anti-Oxidant Drugs: Novelties and Clinical Implications in Cerebellar Ataxias.

Background: Hereditary cerebellar ataxias are a group of disorders characterized by heterogeneous clinical mani-festations, progressive clinical course, and diverse genetic causes. No disease modifying treatments are yet available for many of these disorders. Oxidative stress has been recurrently identified in different progressive cerebellar diseases, and it represents a widely investigated target for treatment.Objective: To review the main aspects and new perspectives of antioxidant therapy in cerebellar ataxias ranging from bench to bedside.Method: This article is a summary of the state-of-the-art on the use of antioxidant molecules in cerebellar ataxia treatments. It also briefly summarizes aspects of oxidative stress production and general characteristics of antioxidant compounds.Results: Antioxidants represent a vast category of compounds; old drugs have been extensively studied and modified in or-der to achieve better biological effects. Despite the vast body of literature present on the use of antioxidants in cerebellar atax-ias, for the majority of these disorders conclusive results on the efficacy are still missing.Conclusion: Antioxidant therapy in cerebellar ataxias is a promising field of investigations. To achieve the success in identi-fying the correct treatment more work needs to be done. In particular, a combined effort is needed by basic scientists in de-veloping more efficient molecules, and by clinical researchers together with patients communities, to run clinical trials in or-der to identify conclusive treatments strategies.

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”.

D-Cysteine promotes dendritic development in primary cultured cerebellar Purkinje cells via hydrogen sulfide production

Hydrogen sulfide and reactive sulfur species are regulators of physiological functions, have antioxidant effects against oxidative stresses, and are endogenously generated from l-cysteine. Recently, a novel pathway that generates hydrogen sulfide and reactive sulfur species from d-cysteine has been identified. d-Amino acid oxidase (DAO) is involved in this pathway and, among the various brain regions, is especially abundant in the cerebellum. d-Cysteine has been found to be a better substrate in the generation of hydrogen sulfide in the cerebellum than l-cysteine. Therefore, d-cysteine might be a novel neuroprotectant against cerebellar diseases such as spinocerebellar ataxia (SCA). However, it remains unknown if d-cysteine affects cerebellar Purkinje cells (PCs), which are important for cerebellar functions and are frequently degenerated in SCA patients. In the present study, we investigated whether the production of hydrogen sulfide from d-cysteine affects the dendritic development of cultured PCs. d-Cysteine was found to enhance the dendritic development of PCs significantly, while l-cysteine impaired it. The effect of d-cysteine was inhibited by simultaneous treatment with DAO inhibitors and was reproduced by treatment with 3-mercaptopyruvate, a metabolite of d-cysteine produced by the action of DAO, and disodium sulfide, a donor of hydrogen sulfide. In addition, hydrogen sulfide was immediately produced in cerebellar primary cultures after treatment with d-cysteine and 3-mercaptopyruvate. These findings suggest that d-cysteine enhances the dendritic development of primary cultured PCs via the generation of hydrogen sulfide.

Update on the Regulation of HIPK1, HIPK2 and HIPK3 Protein Kinases by microRNAs.

Here, we update our previous paper concerning the regulation of HIPK proteins expression by microRNAs (miRNAs), pointing out the most recent findings about new cellular mechanisms and diseases which are affected by the interplay between HIPKs and miRNAs. Recently, it has emerged that HIPKs and their related miRNAs are involved in diabetic nephropathy, gastric cancer chemoresistance, cervical cancer progression, and recombinant protein expression in cultured cells. Interestingly, circular RNAs (circRNAs) deriving from HIPK2 and HIPK3 loci also modulate cellular proliferation and viability by sponging several miRNAs, thus emerging as new putative therapeutic targets for diabetes-associated retinal vascular dysfunction, astrogliosis and cancer.

Cerebellar Ataxia in Children: A Clinical and MRI Approach to the Differential Diagnosis.

: The cerebellum has long been recognized as a fundamental structure in motor coordination. Structural cerebellar abnormalities and diseases involving the cerebellum are relatively common in children. The not always specific clinical presentation of ataxia, incoordination, and balance impairment can often be a challenge to attain a precise diagnosis. Continuous advances in genetic research and moreover the constant development in neuroimaging modalities, particularly in the field of magnetic resonance imaging, have promoted a better understanding of cerebellar diseases and led to several modifications in their classification in recent years. Thorough clinical and neuroimaging investigation is recommended for proper diagnosis. This review outlines an update of causes of cerebellar disorders that present clinically with ataxia in the pediatric population. These conditions were classified in 2 major groups, namely genetic malformations and acquired or disruptive disorders recognizable by neuroimaging and subsequently according to their features during the prenatal and postnatal periods.

Medical Comorbidities in Bipolar Disorder.

Bipolar disorder (BD) medical comorbidity presents significant clinical and public health concerns with serious impact on health. The aim of this article is to present an updated narrative review of original research articles (case control, longitudinal cohort, and cross-sectional studies) and meta-analyses published in English language journals from January 2013 to May 2017 focusing on general medical comorbidity in BD, including the added risks of iatrogenic factors relevant to the treatment of BD. We found numerous patterns of association between BD and various medical disorders involving multiple organ systems. One pattern indicated reciprocal increase in the rate of each comorbid condition, such as an increased rate of BD in asthma or migraine, and likewise an increase in the rate of asthma or migraine in patients with BD. A second pattern was a predominantly unidirectional increase in the rate of BD in patients with certain medical disorders, such as multiple sclerosis or cerebellar diseases. A third pattern was a predominantly unidirectional increased rate of medical disorders in patients with BD. One study suggested the potential involvement of genetic mechanisms for the association between BD and migraine. Most of the studies had cross-sectional or retrospective designs, and many relied on analysis of large administrative databases inviting multiple potential biases. Our review highlights the association between BD and a variety of medical disorders. Further research is needed to elucidate the potential underlying etiopathological mechanisms that contribute to observed comorbidities. The results of this review also emphasize the need for comprehensive screening for medical disorders in BD and for adoption of an integrated model of care to address these complex comorbidities.

A case of cerebellar ataxia associated with VZV infection.

The varicella zoster virus (VZV) is a neurotropic virus that becomes latent in the sensory ganglia, but later causes various neurologic complications such as meningitis, encephalitis, myelitis, meningoencephalitis, cranial neuropathy, and peripheral neuropathy [1]. While acute cerebellitis is one of the most frequent acute cerebellar diseases associated with VZV in childhood, VZV rarely causes cerebellitis in adults, with or without skin manifestations, and only a few isolated cases of adult VZV cerebellitis have been reported. We report a case of acute cerebellitis associated with VZV infection after a herpetic rash in an 80-year-old male. Functional imaging of his cerebellum showed high blood perfusion during the acute stage of the disease, though perfusion decreased in the subacute stage.

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.

Calcium Signaling, PKC Gamma, IP3R1 and CAR8 Link Spinocerebellar Ataxias and Purkinje Cell Dendritic Development.

BackgroundSpinocerebellar ataxias (SCAs) are a group of cerebellar diseases characterized by progressive ataxia and cerebellar atrophy. Several forms of SCAs are caused by missense mutations or deletions in genes related to calcium signaling in Purkinje cells. Among them, spinocerebellar ataxia type 14 (SCA14) is caused by missense mutations in PRKCG gene which encodes protein kinase C gamma (PKCγ). It is remarkable that in several cases in which SCA is caused by point mutations in an individual gene, the affected genes are involved in the PKCγ signaling pathway and calcium signaling which is not only crucial for proper Purkinje cell function but is also involved in the control of Purkinje cell dendritic development. In this review, we will focus on the PKCγ signaling related genes and calcium signaling related genes then discuss their role for both Purkinje cell dendritic development and cerebellar ataxia.MethodsResearch related to SCAs and Purkinje cell dendritic development is reviewed.ResultsPKCγ dysregulation causes abnormal Purkinje cell dendritic development and SCA14. Carbonic anhydrase related protein 8 (Car8) encoding CAR8 and Itpr1 encoding IP3R1were identified as upregulated genes in one of SCA14 mouse model. IP3R1, CAR8 and PKCγ proteins are strongly and specifically expressed in Purkinje cells. The common function among them is that they are involved in the regulation of calcium homeostasis in Purkinje cells and their dysfunction causes ataxia in mouse and human. Furthermore, disruption of intracellular calcium homeostasis caused by mutations in some calcium channels in Purkinje cells links to abnormal Purkinje cell dendritic development and the pathogenesis of several SCAs.ConclusionOnce PKCγ signaling related genes and calcium signaling related genes are disturbed, the normal dendritic development of Purkinje cells is impaired as well as the integration of signals from other neurons, resulting in abnormal development, cerebellar dysfunction and eventually Purkinje cell loss.

Chapter 19 - Neuro-ophthalmologic assessment and investigations in children and adults with cerebellar diseases

In this chapter, we present the bedside assessment and laboratory tests that are available for the neuro-ophthalmologic evaluation of children and adults with cerebellar diseases. In the evaluation of a patient with cerebellar dysfunction, recognizing the pattern of ocular motor and / or vestibular impairment is often a key step to the correct diagnosis. The cerebellum is very important in processing a wide range of different eye movements, including angular vestibulo-ocular reflexes, otolith-ocular reflexes, fixation and gaze holding, smooth pursuit eye movements, saccadic eye movements, optokinetic response, ocular alignment, and vergence. Quantitative eye movement recording is now widely available in specialized clinics and medical practices, especially for testing the vestibulo-ocular reflexes. We describe the approach for assessing specific eye movements linked to cerebellar function, discuss appropriate eye movement laboratory tests, and summarize recent related research findings. In addition, for each laboratory test, we discuss its advantages, disadvantages, indications, and interpretations. Furthermore, we provide differential diagnoses for specific ocular motor and vestibular abnormalities such as slow saccades or impaired vestibulo-ocular reflexes.

Chapter 25 - Neurotransplantation therapy

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.

Chapter 15 - Epigenetic cerebellar diseases

Epigenetics is a growing field of knowledge that is changing our understanding of pathologic processes. For many cerebellar disorders, recent discoveries of epigenetic mechanisms help us to understand their pathophysiology. In this chapter, a short explanation of each epigenetic mechanism (including methylation, histone modification, and miRNA) is followed by references to those cerebellar disorders in which relevant epigenetic advances have been made. The importance of normal timing and distribution of methylation during neurodevelopment is explained. Abnormal methylation and altered gene expression in the developing cerebellum have been related to neurodevelopmental disorders such as autism, Rett syndrome, and fragile X syndrome. DNA packaging by histones is another important epigenetic mechanism in cerebellar functioning. Current knowledge of histone abnormalities in cerebellar diseases such as Friedreich ataxia and spinocerebellar ataxias is reviewed, including implications for new therapeutic approaches to these degenerative diseases. Finally, micro RNAs, the third mechanism to modulate DNA expression, and their role in normal cerebellar development and disease are described. Understanding how genetic and epigenetic mechanisms interact not only in normal cerebellar development but also in disease is a great challenge. However, such understanding will lead to promising new therapeutic possibilities as is already occurring in other areas of medicine.

Epidemiological, clinical, and genotype characterization of spinocerebellar ataxia type in families in Buriram province, northeast Thailand

Abstract Background In Thais, the most prevalent type of spinocerebellar ataxia (SCA) is type 3, most commonly known as Machado–Joseph disease (MJD), followed by SCA type 1 (SCA1), SCA2, and SCA6. Objectives To describe the epidemiological, clinical, and genotypic features of SCA in northeastern Thailand and to study 2 associations: between syndromic features and the genotype of SCA, and between health determinants and scores on the scale for the assessment and rating of ataxia (SARA). Methods We conducted a cross-sectional study of 24 patients with autosomal dominant SCA from 13 families recruited from Buriram province in northeast Thailand between December 2009 and January 2014. Patients provided a clinical history and were examined by a neurologist. DNA was extracted from the peripheral blood of each patient. We analyzed associations between the type of SCA and sex, age, family history, clinical features, any underlying disease, age at onset, body weight, smoking status, family history, alcohol consumption, head injury history, and SARA. Results Seven of the families were positive for SCA1 and 6 for MJD. There were 24 index patients from these autosomal dominant SCA families, including 13 with SCA1 and 11 with MJD. Their average age was 43.7 years (range 20–72 years), whereas their average age at disease onset was 36.9 years (range 18–59 years). Pyramidal signs between MJD and SCA1 were not significantly different. Extrapyramidal features appeared uncommon. Horizontal nystagmus and upward gaze paresis were significantly associated with MJD. There were no significant differences in demographic data between the groups with SARA scores ≥15 or <15. Conclusions MJD and SCA1 were the 2 adult-onset cerebellar degenerative diseases found in Buriram province. Clinical clues for differentiating between them were upward gaze paresis and horizontal nystagmus, which were significantly more common in MJD.

Validity and reliability of the International Cooperative Ataxia Rating Scale (ICARS) and the Scale for the Assessment and Rating of Ataxia (SARA) in multiple sclerosis patients with ataxia

BackgroundAtaxia is an extremely common problem in multiple sclerosis (MS) patients. Thus, appropriate scales are required for detailed assessment of this issue. The aim of our study was to investigate the reliability and validity of the Turkish version of the International Cooperative Ataxia Rating Scale (ICARS) and Scale for the Assessment and Rating of Ataxia (SARA), which are widely used in ataxia evaluation in the context of other cerebellar diseases. MethodThis cross-sectional study included 80 MS patients with Kurtzke cerebellar functional system score (C-FSS) greater than zero and slight pyramidal involvement. The Expanded Disability Status Scale (EDSS), C-FSS, and Berg Balance Scale (BBS) were administered. SARA and ICARS were assessed on first admission by two physical therapists. Seven days later, second assessments were repeated in same way for reliability. ResultsIntra-rater and inter-rater reliability were found to be high for both ICARS and SARA (p< 0.001) The Cronbach's α coefficients were 0.922 and 0.921 for SARA (reviewer 1 and reviewer 2 respectively) and 0.952 and 0.952 for ICARS (reviewer 1 and reviewer 2, respectively). There were no floor or ceiling effects determined for either scale except for item 17 of ICARS (p= 0.055). The EDSS total score had significant correlations with both SARA and ICARS (rho: 0.557 and 0.707, respectively). C-FSS had moderate correlation with SARA and high correlation with ICARS (rho: 0.469 and 0.653, respectively). BBS had no significant correlation with SARA and ICARS. (rho: –0.048 and –0.008 respectively). According to the area under the curve (AUC) value, ICARS is the best scale to discriminate mild and moderate ataxia. (AUC: 0.875). Factor analyses of ICARS showed that the rating results were determined by five different factors that did not coincide with the ICARS sub-scales. ConclusionOur study demonstrated that ICARS and SARA are both reliable in MS patients with ataxia. Although ICARS has some structural problems, it seems to be more valid given its high correlations with EDSS and C-FSS. SARA also can be preferred as a brief assessment.

Epidemiology of Cerebellar Diseases and Therapeutic Approaches.

Diseases involving the cerebellum occur relatively commonly in children and adults around the globe. Many factors influence their epidemiology including geography, ethnicity, consanguinity, and the methodology used to ascertain patients. In addition, reliable epidemiological data rely heavily on accurate disease classification. Continuous advances in genetic research and neuroimaging modalities have resulted in improved understanding of cerebellar diseases and have led to several revisions in their classification. Recent global epidemiological studies on ataxia reported an estimated overall prevalence rate of 26/100,000 in children, a prevalence rate of dominant hereditary cerebellar ataxia of 2.7/100,000, and a prevalence rate of recessive hereditary cerebellar ataxia of 3.3/100,000. The management of cerebellar diseases is multidisciplinary and multimodal. General supportive and symptomatic therapies should be initiated. Genetic counseling should be offered, where appropriate. Few drugs, specific motor rehabilitation programs, and noninvasive cerebellar stimulation for the treatment of ataxia have been developed and seem to show early promise, but more studies are needed to replicate and fine-tune their benefits further. Some disease-specific treatments are available. For example, acetazolamide or 4-aminopyridine for patients with episodic ataxia type 2 and vitamin E for patients with ataxia caused by vitamin E deficiency.

An expandable embryonic stem cell-derived Purkinje neuron progenitor population that exhibits in vivo maturation in the adult mouse cerebellum

The directed differentiation of patient-derived induced pluripotent stem cells into cell-type specific neurons has inspired the development of therapeutic discovery for neurodegenerative diseases. Many forms of ataxia result from degeneration of cerebellar Purkinje cells, but thus far it has not been possible to efficiently generate Purkinje neuron (PN) progenitors from human or mouse pluripotent stem cells, let alone to develop a methodology for in vivo transplantation in the adult cerebellum. Here, we present a protocol to obtain an expandable population of cerebellar neuron progenitors from mouse embryonic stem cells. Our protocol is characterized by applying factors that promote proliferation of cerebellar progenitors. Cerebellar progenitors isolated in culture from cell aggregates contained a stable subpopulation of PN progenitors that could be expanded for up to 6 passages. When transplanted into the adult cerebellum of either wild-type mice or a strain lacking Purkinje cells (L7cre-ERCC1 knockout), GFP-labeled progenitors differentiated in vivo to establish a population of calbindin-positive cells in the molecular layer with dendritic trees typical of mature PNs. We conclude that this protocol may be useful for the generation and maturation of PNs, highlighting the potential for development of a regenerative medicine approach to the treatment of cerebellar neurodegenerative diseases.

Blood Supply to the Human Dentate Nucleus by Cerebellar Arteries

The major roles of human cerebellum are balancing and planning, initiation, and modulation of voluntary movements. In addition, the cerebellum is known to be related with the cognitive function. The dentate nucleus is the largest deep nucleus in human cerebellum. The dentate nucleus is known to have somatotopic arrangement in itself in relation with the upper limb and lower limb. Series of cognitive function tests revealed that the areas for different cognitive domains are located in specific arrangement in the dentate nucleus as well. However, the mapping of arterial supply to each regions of the dentate nucleus by cerebellar arteries has not been clarified anatomically. The aims of this study are to clarify the arterial territories in the dentate nucleus and to match them with the known somatotopy and the arrangement of cognitive area in the dentate nucleus which should be useful for research and clinical situation of various cerebellar diseases. Fourteen cerebellar hemispheres from seven adult cadavers were used in this study. Red‐colored radio‐opaque silicon dye was injected into the vertebral arteries or their branches supplying the cerebellum. Computed tomographs of the cerebellar hemispheres were taken. The cerebellar hemispheres were sliced into sections of 5 mm thickness. The sliced cerebellar hemispheres were stained by Mulligan method. The stained sections were microdissectioned under surgical microscopes. Most of the dentate nuclei were mainly supplied by three or four direct branches of superior cerebellar arteries and two or three direct branches of posterior inferior cerebellar arteries. Between the known suppliers to the dentate nucleus, the superior cerebellar artery is more dominant for dorsal side of the dentate nucleus, whereas the dominant artery for the ventral side of the dentate nucleus is the posterior inferior cerebellar artery.

Treating SCA1 Mice with Water-Soluble Compounds to Non-Specifically Boost Mitochondrial Function.

Mitochondrial dysfunction plays a significant role in the aging process and in neurodegenerative diseases including several hereditary spinocerebellar ataxias and other movement disorders marked by progressive degeneration of the cerebellum. The goal of this protocol is to assess mitochondrial dysfunction in Spinocerebellar ataxia type 1 (SCA1) and assess the efficacy of pharmacological targeting of metabolic respiration via the water-soluble compound succinic acid to slow disease progression. This approach is applicable to other cerebellar diseases and can be adapted to a host of water-soluble therapies. Ex vivo analysis of mitochondrial respiration is used to detect and quantify disease-related changes in mitochondrial function. With genetic evidence (unpublished data) and proteomic evidence of mitochondrial dysfunction in the SCA1 mouse model, we evaluate the efficacy of treatment with the water-soluble metabolic booster succinic acid by dissolving this compound directly into the home cage drinking water. The ability of the drug to pass the blood brain barrier can be deduced using high performance liquid chromatography (HPLC). The efficacy of these compounds can then be tested using multiple behavioral paradigms including the accelerating rotarod, balance beam test and footprint analysis. Cytoarchitectural integrity of the cerebellum can be assessed using immunofluorescence assays that detect Purkinje cell nuclei and Purkinje cell dendrites and soma. These methods are robust techniques for determining mitochondrial dysfunction and the efficacy of treatment with water-soluble compounds in cerebellar neurodegenerative disease.