Saccadic Movements in subjects with cerebellar disorders

Saccades are part of the electrooculography tests battery. The cerebellum has important connections with the brainstem and thalamic structures involved in the generation of saccades. Aim: to study saccadic movements in subjects with cerebellar disorders. Study Method: Prospective clinical study. Materials and Methods: 11 subjects with cerebellar disorders were selected, together with a control group with 27 normal subjects. The patients of both groups had their saccadic movements registered (fixed and randomized). We compared and quantitatively analyzed the responses from both groups. Results: We did not find any differences among the quantitative parameters between the two. Age and gender did not influence these values. Despite these findings, the morphologies of the saccadic curves were very different between the two groups. Conclusion: Quantitative parameters of horizontal saccades from individuals with cerebellar diseases do not differ from those presented by normal subjects. Gender and age also did not influence these parameters.

Cerebellar disorders in childhood: cognitive problems

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.

Consensus paper: the role of the cerebellum in perceptual processes.

Various lines of evidence accumulated over the past 30 years indicate that the cerebellum, long recognized as essential for motor control, also has considerable influence on perceptual processes. In this paper, we bring together experts from psychology and neuroscience, with the aim of providing a succinct but comprehensive overview of key findings related to the involvement of the cerebellum in sensory perception. The contributions cover such topics as anatomical and functional connectivity, evolutionary and comparative perspectives, visual and auditory processing, biological motion perception, nociception, self-motion, timing, predictive processing, and perceptual sequencing. While no single explanation has yet emerged concerning the role of the cerebellum in perceptual processes, this consensus paper summarizes the impressive empirical evidence on this problem and highlights diversities as well as commonalities between existing hypotheses. In addition to work with healthy individuals and patients with cerebellar disorders, it is also apparent that several neurological conditions in which perceptual disturbances occur, including autism and schizophrenia, are associated with cerebellar pathology. A better understanding of the involvement of the cerebellum in perceptual processes will thus likely be important for identifying and treating perceptual deficits that may at present go unnoticed and untreated. This paper provides a useful framework for further debate and empirical investigations into the influence of the cerebellum on sensory perception.

Examen neurológico

Se realizó un capítulo sobre la descripción del examen neurológico como herramienta principal en el abordaje del paciente con patología neurológica.

Ethanol intake-induced apoptosis in glial cells and axonal disorders in the cerebellar white matter of UChA rats (voluntary ethanol consumers)

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Selective loss of expression of glutamate GluR2/R3 receptor subunits in cerebellar tissue from a patient with olivopontocerebellar atrophy

Expression of the mRNAs encoding the astrocytic (EAAT1, EAAT2) and neuronal (EAAT3, EAAT4) excitatory amino acid transporters and the AMPA-type glutamate receptor subunits GluR2 and GluR3 was investigated in postmortem cerebellar extracts from a patient with olivopontocerebellar atrophy (OPCA) and in material from three age-matched controls. Decreased expression in the steady state level of EAAT4 mRNA in the OPCA sample was correlated with the selective loss of Purkinje cells. Neuropathological evaluation revealed reactive gliosis and concomitantly increased expression of the mRNA encoding astrocytic glial fibrillary acidic protein (GFAP). Expression of the mRNAs encoding the AMPA receptor subunits GluR2 and GluR3 subunits was found to be decreased in OPCA suggesting that excitotoxic mechanism could play a role in the pathogenesis of the selective neuronal cell death in this disorder.

Brain structure in movement disorders: a neuroimaging perspective.

Purpose of review: An overview of recent advances in structural neuroimaging and their impact on movement disorders research is presented. Recent findings: Novel developments in computational neuroanatomy and improvements in magnetic resonance image quality have brought further insight into the pathophysiology of movement disorders. Sophisticated automated techniques allow for sensitive and reliable in-vivo differentiation of phenotype/genotype related traits and their interaction even at presymptomatic stages of disease. Summary: Voxel-based morphometry consistently demonstrates well defined patterns of brain structure changes in movement disorders. Advanced stages of idiopathic Parkinson's disease are characterized by grey matter volume decreases in basal ganglia. Depending on the presence of cognitive impairment, volume changes are reported in widespread cortical and limbic areas. Atypical Parkinsonian syndromes still pose a challenge for accurate morphometry-based classification, especially in early stages of disease progression. Essential tremor has been mainly associated with thalamic and cerebellar changes. Studies on preclinical Huntington's disease show progressive loss of tissue in the caudate and cortical thinning related to distinct motor and cognitive phenotypes. Basal ganglia volume in primary dystonia reveals an interaction between genotype and phenotype such that brain structure changes are modulated by the presence of symptoms under the influence of genetic factors. Tics in Tourette's syndrome correlate with brain structure changes in limbic, motor and associative fronto-striato-parietal circuits. Computational neuroanatomy provides useful tools for in-vivo assessment of brain structure in movement disorders, allowing for accurate classification in early clinical stages as well as for monitoring therapy effects and/or disease progression.

Cerebellar cortical layers: in vivo visualization with structural high-field-strength MR imaging.

Purpose: To perform in vivo imaging of the cerebellum with an in-plane resolution of 120 mm to observe its cortical granular and molecular layers by taking advantage of the high signal-to-noise ratio and the increased magnetic susceptibility-related contrast available at high magnetic field strength such as 7 T. Materials and Methods: The study was approved by the institutional review board, and all patients provided written consent. Three healthy persons (two men, one woman; mean age, 30 years; age range, 28-31 years) underwent MR imaging with a 7-T system. Gradient-echo images (repetition time msec/echo time msec, 1000/25) of the human cerebellum were acquired with a nominal in-plane resolution of approximately 120 mum and a section thickness of 1 mm. Results: Structures with dimensions as small as 240 mum, such as the granular and molecular layers in the cerebellar cortex, were detected in vivo. The detection of these structures was confirmed by comparing the contrast obtained on T2*-weighted and phase images with that obtained on images of rat cerebellum acquired at 14 T with 30 mum in-plane resolution. Conclusion: In vivo cerebellar imaging at near-microscopic resolution is feasible at 7 T. Such detailed observation of an anatomic area that can be affected by a number of neurologic and psychiatric diseases, such as stroke, tumors, autism, and schizophrenia, could potentially provide newer markers for diagnosis and follow-up in patients with such pathologic conditions. (c) RSNA, 2010.

Outcome of severe unilateral cerebellar hypoplasia.

Aim: Complete or subtotal absence of one cerebellar hemisphere is exceptional; only single cases have been described. We aimed to assess the long-term outcome in children with severe unilateral cerebellar hypoplasia (UCH). Method: As part of a retrospective study we describe neuroimaging features, clinical findings, and cognitive outcomes of seven children with UCH (five males, two females; age at first magnetic resonance imaging [MRI]: median 1y 3mo, range 9d-8y 10mo; age at latest follow-up: median 6y 6mo, range 2y 3mo-14y 11mo). Results: One child had abnormalities on prenatal MRI at 21 weeks' gestation. The left cerebellar hemisphere was affected in five children, and the right hemisphere in two children. The vermis was involved in five children. The volume of the posterior fossa was variable. At the latest follow-up, neurological findings included truncal ataxia and muscular hypotonia in five children, limb ataxia in three patients, and head nodding in two patients. Three children had learning disability*, five had speech and language disorders, and one had a severe behavioural disorder. Interpretation: Severe UCH is a residual change after a disruptive prenatal cerebellar insult, most likely haemorrhagic. The outcome is variable, ranging from almost normal development to marked developmental impairment. Ataxia is a frequent but not a leading sign. It seems that involvement of the cerebellar vermis is often, but not consistently, associated with a poorer cognitive outcome, whereas an intact vermis is associated with normal outcome and no truncal ataxia.

Fetal alcohol spectrum disorders in Finnish children and adolescents : diagnosis, cognition, behavior, adaptation and brain metabolic alterations

Alcohol consumption during pregnancy can potentially affect the developing fetus in devastating ways, leading to a range of physical, neurological, and behavioral alterations most accurately termed Fetal Alcohol Spectrum Disorders (FASD). Despite the fact that it is a preventable disorder, prenatal alcohol exposure today constitutes a leading cause of intellectual disability in the Western world. In Western countries where prevalence studies have been performed the rates of FASD exceed, for example, autism spectrum disorders, Down’s syndrome and cerebral palsy. In addition to the direct effects of alcohol, children and adolescents with FASD are often exposed to a double burden in life, as their neurological sequelae are accompanied by adverse living surroundings exposing them to further environmental risk. However, children with FASD today remain remarkably underdiagnosed by the health care system. This thesis forms part of a larger multinational research project, The Collaborative Initiative on Fetal Alcohol Spectrum Disorders (the CIFASD), initiated by the National Institute of Alcohol Abuse and Alcoholism (NIAAA) in the U.S.A. The general aim of the present thesis was to examine a cohort of children and adolescents growing up with fetal alcohol-related damage in Finland. The thesis consists of five studies with a broad focus on diagnosis, cognition, behavior, adaptation and brain metabolic alterations in children and adolescents with FASD. The participants consisted of four different groups: one group with histories of prenatal exposure to alcohol, the FASD group; one IQ matched contrast group mostly consisting of children with specific learning disorder (SLD); and two typically-developing control groups (CON1 and CON2). Participants were identified through medical records, random sampling from the Finnish national population registry and email alerts to students. Importantly, the participants in the present studies comprise a group of very carefully clinically characterized children with FASD as the studies were performed in close collaboration with leading experts in the field (Prof. Edward Riley and Prof. Sarah Mattson, Center for Behavioral Teratology, San Diego State University, U.S.A; Prof. Eugene Hoyme, Sanford School of Medicine, University of South Dakota, U.S.A.). In the present thesis, the revised Institute of Medicine diagnostic criteria for FASD were tested on a Finnish population and found to be a reliable tool for differentiating among the subgroups of FASD. A weighted dysmorphology scoring system proved to be a valuable additional adjunct in quantification of growth deficits and dysmorphic features in children with FASD (Study 1). The purpose of Study 2 was to clarify the relationship between alcohol-related dysmorphic features and general cognitive capacity. Results showed a significant correlation between dysmorphic features and cognitive capacity, suggesting that children with more severe growth deficiency and dysmorphic features have more cognitive limitations. This association was, however, only moderate, indicating that physical markers and cognitive capacity not always go hand in hand in individuals with FASD. Behavioral problems in the FASD group proved substantial compared to the typically developing control group. In Study 3 risk and protective factors associated with behavioral problems in the FASD group were explored further focusing on diagnostic and environmental factors. Two groups with elevated risks for behavioral problems emerged: length of time spent in residential care and a low dysmorphology score proved to be the most pervasive risk factor for behavioral problems. The results underscore the clinical importance of appropriate services and care for less visibly alcohol affected children and highlight the need to attend to children with FASD being raised in institutions. With their background of early biological and psychological impairment compounded with less opportunity for a close and continuous caregiver relationship, such children seem to run an especially great risk of adverse life outcomes. Study 4 focused on adaptive abilities such as communication, daily living skills and social skills, in other words skills that are important for gradually enabling an independent life, maintain social relationships and allow the individual to become integrated into society. The results showed that adaptive abilities of children and adolescents growing up with FASD were significantly compromised compared to both typically-developing peers and IQ-matched children with SLD. Clearly different adaptive profiles were revealed where the FASD group performed worse than the SLD group, who in turn performed worse than the CON1 group. Importantly, the SLD group outperformed the FASD group on adaptive behavior in spite of comparable cognitive levels. This is the first study to compare adaptive abilities in a group of children and adolescents with FASD relative to both a contrast group of IQ-matched children with SLD and to a group of typically-developing peers. Finally, in Study 5, through magnetic resonance spectroscopic imaging (MRS) evidence of longstanding neurochemical alterations were observed in adolescents and young adults with FASD related to alcohol exposure in utero 14-20 years earlier. Neurochemical alterations were seen in several brain areas: in frontal and parietal cortices, corpus callosum, thalamus and frontal white matter areas as well as in the cerebellar dentate nucleus. The findings are compatible with neuropsychological findings in FASD. Glial cells seemed to be more affected than neurons. In conclusion, more societal efforts and resources should be focused on recognizing and diagnosing FASD, and supporting subgroups with elevated risk of poor outcome. Without adequate intervention children and adolescents with FASD run a great risk of marginalization and social maladjustment, costly not only to society but also to the lives of the many young people with FASD.

Does modulation of the endocannabinoid system have potential therapeutic utility in cerebellar ataxia?

Cerebellar ataxias represent a spectrum of disorders which are, however, linked by common symptoms of motor incoordination and are typically associated with deficient in Purkinje cell firing activity and, often, degeneration. Cerebellar ataxias currently lack a curative agent. The endocannabinoid (eCB) system includes eCB compounds and their associated metabolic enzymes, together with cannabinoid receptors, predominantly the cannabinoid CB1 receptor (CB1R) in the cerebellum; activation of this system in the cerebellar cortex is associated with deficits in motor coordination characteristic of ataxia, effects which can be prevented by CB1R antagonists. Of further interest are various findings that CB1R deficits may also induce a progressive ataxic phenotype. Together these studies suggest that motor coordination is reliant on maintaining the correct balance in eCB system signalling. Recent work also demonstrates deficient cannabinoid signalling in the mouse ‘ducky2J’ model of ataxia. In light of these points, the potential mechanisms whereby cannabinoids may modulate the eCB system to ameliorate dysfunction associated with cerebellar ataxias are considered.

Amyloid beta-peptide activates nuclear factor-kappa B through an N-methyl-D-aspartate signaling pathway in cultured cerebellar cells

Amyloid P-peptide (A beta) likely causes functional alterations in neurons well prior to their death. Nuclear factor-kappa B (NF-kappa B), a transcription factor that is known to play important roles in cell survival and apoptosis, has been shown to be modulated by A beta in neurons and glia, but the mechanism is unknown. Because A beta has also been shown to enhance activation of N-methyl-D-aspartate (NMDA) receptors, we investigated the role of NMDA receptor-mediated intracellular signaling pathways in A beta-induced NF-kappa B activation in primary cultured rat cerebellar cells. Cells were treated with different concentrations of A beta 1-40 (1 or 2 mu M) for different periods (6, 12, or 24 hr). MK-801 (NMDA antagonist), manumycin A and FTase inhibitor 1 (farnesyltransferase inhibitors), PP1 (Src-family tyrosine kinase inhibitor), PD98059 [mitogen-activated protein kinase (MAPK) inhibitor], and LY294002 [phosphatidylinositol 3-kinase (PI3-k) inhibitor] were added 20 min before A beta treatment of the cells. A beta induced a time- and concentration-dependent activation of NF-kappa B (1 mu M, 12 hr); both p50/p65 and p50/p50 NF-kappa B dimers were involved. This activation was abolished by MK-801 and attenuated by manumycin A, FTase inhibitor 1, PP1, PD98059, and LY294002. AP at 1 mu M increased the expression of inhibitory protein I kappa B, brain-derived neurotrophic factor, inducible nitric oxide synthase, tumor necrosis factor-alpha, and interleukin-1 beta as shown by RTPCR assays. Collectively, these findings suggest that AP activates NF-kappa B by an NMDA-Src-Ras-like protein through MAPK and PI3-k pathways in cultured cerebellar cells. This pathway may mediate an adaptive, neuroprotective response to A beta. (c) 2007 Wiley-Liss, Inc.

Cerebellar Pathology Does Not Impair Performance on Identification or Categorization Tasks

In comparison to the basal ganglia, prefrontal cortex, and medial temporal lobes, the cerebellum has been absent from recent research on the neural substrates of categorization and identification, two prominent tasks in the learning and memory literature. To investigate the contribution of the cerebellum to these tasks, we tested patients with cerebellar pathology (seven with bilateral degeneration, six with unilateral lesions, and two with midline damage) on rule-based and information-integration categorization tasks and an identification task. In rule-based tasks, it is assumed that participants learn the categories through an explicit reasoning process. In information-integration tasks, optimal performance requires the integration of information from multiple stimulus dimensions, and participants are typically unaware of the decision strategy. The identification task, in contrast, required participants to learn arbitrary, color-word associations. The cerebellar patients performed similar to matched controls on all three tasks and performance did not vary with the extent of cerebellar pathology. Although the interpretation of these null results requires caution, these data contribute to the current debate on cerebellar contributions to cognition by providing boundary conditions on understanding the neural substrates of categorization and identification, and help define the functional domain of the cerebellum in learning and memory.

Accumulation of protease-resistant prion protein (PrP) and apoptosis of cerebellar granule cells in transgenic mice expressing a PrP insertional mutation

We have generated lines of transgenic mice that express a mutant prion protein (PrP) containing 14 octapeptide repeats whose human homologue is associated with an inherited prion dementia. These mice develop a neurological illness with prominent ataxia at 65 or 240 days of age, depending on whether the transgene array is, respectively, homozygous or hemizygous. Starting from birth, mutant PrP is converted into a protease-resistant and detergent-insoluble form that resembles the scrapie isoform of PrP, and this form accumulates dramatically in many brain regions throughout the lifetime of the mice. As PrP accumulates, there is massive apoptosis of granule cells in the cerebellum. Our analysis provides important insights into the molecular pathogenesis of inherited prion disorders in humans.