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Query: UMLS:C0004134 (ataxia)
 15,886 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

High-resolution structural magnetic resonance imaging (MRI) has become a powerful tool in human cerebellar lesion studies. Structural MRI is helpful to analyse the localisation and extent of cerebellar lesions and to determine possible extracerebellar involvement. Functionally meaningful correlations between a cerebellar lesion site and behavioural data can be obtained both in subjects with degenerative as well as focal cerebellar disorders. In this review, examples are presented which demonstrate that MRI-based lesion-symptom mapping is helpful to study the function of cerebellar cortex and cerebellar nuclei. Behavioural measures were used which represent two main areas of cerebellar function, that is, motor coordination and motor learning. One example are correlations with clinical data which are in good accordance with the known functional compartmentalisation of the cerebellum in three sagittal zones: In patients with cerebellar cortical degeneration ataxia of stance and gait was correlated with atrophy of the medial (and intermediate) cerebellum, oculomotor disorders with the medial, dysarthria with the intermediate and limb ataxia with atrophy of the intermediate and lateral cerebellum. Similar findings were obtained in patients with focal lesions. In addition, in patients with acute focal lesions, a somatotopy in the superior cerebellar cortex was found which is in close relationship to animal data and functional MRI data in healthy control subjects. Finally, comparison of data in patients with acute and chronic focal lesions revealed that lesion site appears to be critical for motor recovery. Recovery after lesions to the nuclei of the cerebellum was less complete. Another example which extended knowledge about functional localisation within the cerebellum is classical conditioning of the eyeblink response, a simple form of motor learning. In healthy subjects, learning rate was related to the volume of the cortex of the posterior cerebellar lobe. In patients with focal cerebellar lesions, acquisition of eyeblink conditioning was significantly reduced in lesions including the cortex of the superior posterior lobe, but not the inferior posterior lobe. Disordered timing of conditioned eyeblink responses correlated with lesions of the anterior lobe. Findings are in good agreement with the animal literature. Different parts of the cerebellar cortex may be involved in acquisition and timing of conditioned eyeblink responses in humans. These examples demonstrate that MRI-based lesion-symptom mapping is helpful to study the contribution of functionally relevant cerebellar compartments in motor control and recovery in patients with cerebellar disease. In addition, information about the function of cerebellar cortex and nuclei can be gained.
Cerebellum 2008
PMID:Lesion-symptom mapping of the human cerebellum. 1894 30

Over the last decade, increasing evidence of cognitive functions of the cerebellum during development and learning processes could be ascertained. Posterior fossa malformations such as cerebellar hypoplasia or Joubert syndrome are known to be related to developmental problems in a marked to moderate extent. More detailed analyses reveal special deficits in attention, processing speed, visuospatial functions, and language. A study about Dandy Walker syndrome states a relationship of abnormalities in vermis lobulation with developmental problems. Further lobulation or volume abnormalities of the cerebellum and/or vermis can be detected in disorders as fragile X syndrome, Downs's syndrome, William's syndrome, and autism. Neuropsychological studies reveal a relation of dyslexia and attention deficit disorder with cerebellar functions. These functional studies are supported by structural abnormalities in neuroimaging in these disorders. Acquired cerebellar or vermis atrophy was found in groups of children with developmental problems such as prenatal alcohol exposure or extreme prematurity. Also, focal lesions during childhood or adolescence such as cerebellar tumor or stroke are related with neuropsychological abnormalities, which are most pronounced in visuospatial, language, and memory functions. In addition, cerebellar atrophy was shown to be a bad prognostic factor considering cognitive outcome in children after brain trauma and leukemia. In ataxia teleangiectasia, a neurodegenerative disorder affecting primarily the cerebellar cortex, a reduced verbal intelligence quotient and problems of judgment of duration are a hint of the importance of the cerebellum in cognition. In conclusion, the cerebellum seems to play an important role in many higher cognitive functions, especially in learning. There is a suggestion that the earlier the incorrect influence, the more pronounced the problems.
Cerebellum 2008
PMID:Cerebellar disorders in childhood: cognitive problems. 1905 77

The spinocerebellar ataxia type 23 locus was identified in 2004 based on linkage analysis in a large, two-generation Dutch family. The age of onset ranged 43-56 years and the phenotype was characterized by a slowly progressive, isolated ataxia. Neuropathological examination revealed neuronal loss in the Purkinje cell layer, dentate nuclei, and inferior olives. Ubiquitin-positive intranuclear inclusions were found in nigral neurons, but were considered to be Marinesco bodies. The disease locus on chromosome 20p13-12.3 was found to span a region of approximately 6 Mb of genomic DNA, containing 97 known or predicted genes. To date, no other families have been described that also map to this SCA locus. Direct sequencing of the coding regions of 21 prioritized candidate genes did not reveal any disease-causing mutation. Apparently, the SCA23 gene is a disease gene with a different function than the genes that have been associated with other known SCA types. Work to elucidate the chromosomal organization of the SCA23 locus will eventually discover the responsible disease gene.
Cerebellum 2009 Jun
PMID:Spinocerebellar ataxia type 23: a genetic update. 1908 25

The morphogenetic factor Sonic hedgehog (SHH) has been discovered as one of the masterplayers in cerebellar patterning and was subjected to intensive investigation during the last decade. During early postnatal development, this continuously secreted cholesterol-modified protein drives the expansion of the largest neuronal population of the brain, the granular cells. Moreover, it acts on Bergmann glia differentiation and would potentially affect Purkinje cells homeostasis at adult age. The cerebellar cortex constituted an ideal developmental model to dissect out the upstream mechanisms and downstream targets of this complex pathway. Its deep understanding discloses some of the mechanistic disorders underlying pediatric tumorigenesis, congenital ataxia, and mental retardation. Therapeutical use of its regulators has been consolidated on murine transgenic models and is now considered as a realistic human clinical application. Here, we will review the most recent advances made in the comprehensive understanding of SHH involvement in cerebellar development and pathology.
Cerebellum 2009 Sep
PMID:SHH pathway and cerebellar development. 1922 9

Different subunits of the Kv3 subfamily of voltage-gated potassium (Kv) channels (Kv3.1-Kv3.4) are expressed in distinct neuronal subpopulations in the cerebellum. Behavioral phenotypes in Kv3-null mutant mice such as ataxia with prominent hypermetria and heightened alcohol sensitivity are characteristic of cerebellar dysfunction. Here, we review how the unique biophysical properties of Kv3-type potassium channels, fast activation and fast deactivation that enable cerebellar neurons to generate brief action potentials at high frequencies, affect firing patterns and influence cerebellum-mediated behavior.
Cerebellum 2009 Sep
PMID:The role of Kv3-type potassium channels in cerebellar physiology and behavior. 1924 32

For the first time, synchrotron rapid-scanning X-ray fluorescence (RS-XRF) was used to simultaneously localize and quantify iron, copper, and zinc in spinal cord and brain in a case of spinocerebellar ataxia (SCA). In the normal medulla, a previously undescribed copper enrichment was seen associated with spinocerebellar fibers and amiculum olivae. This region was virtually devoid of all metals in the SCA case. Regions with neuronal loss and gliosis in the cerebellar cortex, inferior olivary, and dentate nuclei and areas showing loss of myelinated fibers were also low in all metals in SCA compared to control. In contrast, the ventral columns of the spinal cord that exhibited only moderate myelin pallor had increased metal levels. Iron and zinc were also elevated in the globus pallidus pars externa in SCA relative to control. We hypothesize that metals increase as part of the initial neurodegenerative process, but once degeneration is advanced, the metal levels drop. This implies a role for multiple metals in SCA neurodegeneration, but further study is required to establish a causative role. We suggest that if these findings are generally true of at least some cases of SCA, not only iron but also copper and zinc should be considered as possible therapeutic targets.
Cerebellum 2009 Sep
PMID:Synchrotron X-ray fluorescence reveals abnormal metal distributions in brain and spinal cord in spinocerebellar ataxia: a case report. 1930 49

Neurological disorders represent a large share of the disease burden worldwide, and the incidence of age-related forms will continue to rise with life expectancy. Gene targeting has been and will remain a valuable approach to the generation of clinically relevant mouse models from which to elucidate the underlying molecular basis. However, as the aetiology of the majority of these conditions is still unknown, a reverse approach based on large-scale random chemical mutagenesis is now being used in an attempt to identify new genes and associated signalling pathways that control neuronal cell death and survival. Here, we review the characterisation of a novel model of autosomal dominant cerebellar ataxia which shows general growth retardation and develops adult-onset region-specific Purkinje cell loss as well as cataracts and defects in early T-cell maturation. We have previously established that the mutated protein Af4, which is a member of the AF4/LAF4/FMR2 (ALF) family of transcription cofactors frequently translocated in childhood leukaemia, undergoes slower proteasomal turnover through the ubiquitin pathway and abnormally accumulates in Purkinje cells of the cerebellum. We have also shown that Af4 functions as part of a large multiprotein complex that stimulates RNA polymerase II elongation and mediates chromatin remodelling during transcription. With the forthcoming identification of the gene targets that trigger Purkinje cell death in the robotic cerebellum, and the functional conservation among the ALF proteins, the robotic mouse promises to deliver important insights into the pathogenesis of human ataxia, but also of mental retardation to which FMR2 and LAF4 have been linked.
Cerebellum 2009 Sep
PMID:The robotic mouse: understanding the role of AF4, a cofactor of transcriptional elongation and chromatin remodelling, in purkinje cell function. 1934 Apr 90

A spontaneous model of cerebellar ataxia in the Syrian hamster is described. Breeding data indicate that the condition is hereditary and that the mode of inheritance is autosomal recessive. Homozygotes are smaller in size than the wild-type but have a normal appearance. Mutants show a moderate ataxia beginning at 7 weeks of age. Although affected adults exhibit significant atrophy in the cerebellum, other parts of the brain appear relatively normal by light microscopy. Mutants lose almost all Purkinje cells by 18 months of age and exhibit a moderate reduction in granule cell density, probably as a consequence of the primary loss of Purkinje cells. In the homozygous hamster brain, Nna1 expression is suppressed, similar to that previously observed in Purkinje cell degeneration (pcd) mutant mice. A phenotypic comparison of ataxic hamsters with the pcd mutant mice suggests that the influence of the causal allele in ataxic hamsters is considerably milder than most of the alleles found in the mutant mice.
Cerebellum 2009 Sep
PMID:The ataxic Syrian hamster: an animal model homologous to the pcd mutant mouse? 1946 16

Tyrosine phosphorylation is a powerful mechanism of modulation for proliferation, differentiation, and functioning of neurons. The protein products of the neuronal mouse gene PTPRR are physiological regulators of mitogen-activated protein kinase (MAPK) activities. PTPRR(-/-) mice display deficits of motor coordination and balance skills. PTPRR gene orthologues are found in many vertebrates. Recent observations suggest that the human episodic ataxia 2 (EA2) and spinocerebellar ataxia types 6 (SCA6), 12 (SCA12), and 14 (SCA14) might be associated with impaired phosphorylation levels of cerebellum calcium channels and receptors. The concept that MAPK signaling is a key process in tuning synaptic plasticity in cerebellar circuits is now emerging, with numerous implications for understanding cerebellar functions and cerebellar disorders.
Cerebellum 2009 Jun
PMID:PTPRR, cerebellum, and motor coordination. 1948 25

Traumatic brain injury (TBI) is a major cause of morbidity and mortality worldwide. Studies of human TBI demonstrate that the cerebellum is sometimes affected even when the initial mechanical insult is directed to the cerebral cortex. Some of the components of TBI, including ataxia, postural instability, tremor, impairments in balance and fine motor skills, and even cognitive deficits, may be attributed in part to cerebellar damage. Animal models of TBI have begun to explore the vulnerability of the cerebellum. In this paper, we review the clinical presentation, pathogenesis, and putative mechanisms underlying cerebellar damage with an emphasis on experimental models that have been used to further elucidate this poorly understood but important aspect of TBI. Animal models of indirect (supratentorial) trauma to the cerebellum, including fluid percussion, controlled cortical impact, weight drop impact acceleration, and rotational acceleration injuries, are considered. In addition, we describe models that produce direct trauma to the cerebellum as well as those that reproduce specific components of TBI including axotomy, stab injury, in vitro stretch injury, and excitotoxicity. Overall, these models reveal robust characteristics of cerebellar damage including regionally specific Purkinje cell injury or loss, activation of glia in a distinct spatial pattern, and traumatic axonal injury. Further research is needed to better understand the mechanisms underlying the pathogenesis of cerebellar trauma, and the experimental models discussed here offer an important first step toward achieving that objective.
Cerebellum 2009 Sep
PMID:Models of traumatic cerebellar injury. 1949 1


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