Cerebellar Cognitive Affective Syndrome in Costa da Morte Ataxia (SCA36)

The Cerebellum - SCA36 is an autosomal dominant spinocerebellar ataxia (SCA) affecting many families from Costa da Morte, a northwestern region of Spain. It is caused by an intronic GGCCTG repeat...     

Cerebellar Atrophy in Patients with Subcortical-Type Vascular Cognitive Impairment

Recent studies suggest that the role of the cerebellum extends into cognitive regulation and that subcortical vascular dementia (SVaD) can result in cerebellar atrophy. However, there has been no evaluation of the cerebellar volume in the preclinical stage of SVaD. We aimed to compare cerebellar volume among patients with amnestic mild cognitive impairment (aMCI) and subcortical vascular mild cognitive impairment (svMCI) and evaluate which factors could have contributed to the cerebellar volume. Participants were composed of 355 patients with aMCI, svMCI, Alzheimer's disease (AD), and SVaD. Cerebellar volumes were measured using automated methods. A direct comparison of the cerebellar volume in SVaD and AD groups showed that the SVaD group had a statistically smaller cerebellar volume than the AD group. Additionally, the svMCI group had a smaller cerebellar volume than the aMCI group, with the number of lacunes (especially in the supratentorial regions) being associated with cerebellar volume. Cerebellar volumes were associated with some neuropsychological tests, digit span backward and ideomotor apraxia. These findings suggest that cerebellar atrophy may be useful in differentiating subtypes of dementia and the cerebellum plays a potential role in cognition.     

Cerebellar Stimulation in Ataxia

The cerebellum plays an important role in movement execution and motor control by modulation of the primary motor cortex (M1) through cerebello-thalamo-cortical connections. Transcranial magnetic stimulation (TMS) allows direct investigations of neural networks by stimulating neural structures in humans noninvasively. The motor evoked potential to single-pulse TMS of M1 is used to measure the motor cortical excitability. A conditioning stimulus over the cerebellum preceding a test stimulus of the contralateral M1 enables us to study the cerebellar regulatory functions on M1. In this brief review, we describe this cerebellar stimulation method and its usefulness as a diagnostic tool in clinical neurophysiology.     

Cerebellar Allografts Survive and Transiently Alleviate Ataxia in a Transgenic Model of Spinocerebellar Ataxia Type-1

Spinocerebellar ataxia type 1 (SCA-1) is one of several neurodegenerative diseases, including Huntington's disease, spinobulbar muscular atrophy, dentatorubral-pallidoluysian atrophy, and SCA-2, SCA-3, SCA-6, and SCA-7, each caused by an expanded number of CAG repeats in the coding region of their respective genes. The mechanism by which the resulting proteins are pathogenic is unknown. Clinical trials of neural transplants in Huntington's disease patients are under way. While initial reports are encouraging, definitive evidence of graft survival in patients despite the ongoing disease process is not possible with current imaging techniques. Transplants in primates have shown long-term survival of striatal grafts and recovery of function, but have used lesioning to model Huntington's phenotypically. Studies of striatal grafts in a transgenic mouse model of Huntington's have not yet shown a behavioral benefit. We describe a behavioral benefit of cerebellar grafts in a transgenic model of SCA-1 in which the ataxic phenotype results from expression of an expanded ataxin-1 protein. Mice were transplanted at an age when their ataxic phenotype is just becoming evident. Compared with sham-operated littermates, grafted mice showed better performance on multiple behavioral tests of cerebellar function. Differences persisted for 10 to 12 weeks posttransplant, after which there was a progressive decline in motor performance. At 20 weeks postsurgery, donor Purkinje cell survival was evident in 9 of 12 graft recipients. These results indicate that transplants can have behavioral benefits and grafts can survive long-term despite the ongoing pathological process in a brain actively expressing an expanded polyglutamine protein.     

Brain Imaging in Cerebellar Ataxia Associated with Autoimmune Polyglandular Syndrome Type 2

Autoimmune polyglandular syndrome (APS) type 2 (Schmidt syndrome) is a disorder characterized by a combination of autoimmune adrenal insufficiency, autoimmune thyroid disease, and type 1 autoimmune diabetes mellitus. We describe the first case of subacute cerebellar syndrome associated with APS type 2. Brain magnetic resonance imaging showed atrophy of the cerebellum and the vermis, as well as of the anterior pituitary gland. Magnetic resonance spectroscopy showed decreased N‐acetylaspartate/creatine ratio in the cerebellum and in the pons. Our findings expand the spectrum of neurological deficits in APS type 2 and underlines that cerebellar pathways may be a main target of the disorder.     

Cerebellar Volume Is Associated with Cognitive Decline in Mild Cognitive Impairment: Results from ADNI

The Cerebellum - Alzheimer’s disease (AD) is a disease with dysfunctional brain network. Previous studies found the cerebellar volume changes over the course of AD disease progression;...     

小脑共济失调的过去、现在和未来

回顾小脑性共济失调的研究历史、分类,介绍脊髓小脑共济失调的病因机制和治疗方法。     

Sudden Stopping in Patients with Cerebellar Ataxia

Stopping during walking, a dynamic motor task frequent in everyday life, is very challenging for ataxic patients, as it reduces their gait stability and increases the incidence of falls. This study was conducted to analyse the biomechanical characteristics of upper and lower body segments during abrupt stopping in ataxic patients in order to identify possible strategies used to counteract the instability in the sagittal and frontal plane. Twelve patients with primary degenerative cerebellar ataxia and 12 age- and sex-matched healthy subjects were studied. Time–distance parameters, dynamic stability of the centre of mass, upper body measures and lower joint kinematic and kinetic parameters were analysed. The results indicate that ataxic patients have a great difficulty in stopping abruptly during walking and adopt a multi-step stopping strategy, occasionally with feet parallel, to compensate for their inability to coordinate the upper body and to generate a well-coordinated lower limb joint flexor–extensor pattern and appropriate braking forces for progressively decelerating the progression of the body in the sagittal plane. A specific rehabilitation treatment designed to improve the ability of ataxic patients to transform unplanned stopping into planned stopping, to coordinate upper body and to execute an effective flexion–extension pattern of the hip and knee joints may be useful in these patients in order to improve their stopping performance and prevent falls.     

The Cerebellar Cognitive Affective/Schmahmann Syndrome: a Task Force Paper

Sporadically advocated over the last two centuries, a cerebellar role in cognition and affect has been rigorously established in the past few decades. In the clinical domain, such progress is epitomized by the “cerebellar cognitive affective syndrome” (“CCAS”) or “Schmahmann syndrome.” Introduced in the late 1990s, CCAS reflects a constellation of cerebellar-induced sequelae, comprising deficits in executive function, visuospatial cognition, emotion–affect, and language, over and above speech. The CCAS thus offers excellent grounds to investigate the functional topography of the cerebellum, and, ultimately, illustrate the precise mechanisms by which the cerebellum modulates cognition and affect. The primary objective of this task force paper is thus to stimulate further research in this area. After providing an up-to-date overview of the fundamental findings on cerebellar neurocognition, the paper substantiates the concept of CCAS with recent evidence from different scientific angles, promotes awareness of the CCAS as a clinical entity, and examines our current insight into the therapeutic options available. The paper finally identifies topics of divergence and outstanding questions for further research.

     

Mesenchymal Stem Cells Ameliorate Cerebellar Pathology in a Mouse Model of Spinocerebellar Ataxia Type 1

Spinocerebellar ataxia type 1 (SCA1) is a progressive neurodegenerative disorder caused by the expansion of a polyglutamine tract in the ataxin-1 protein. To date, no fundamental treatments for SCA1 have been elucidated. However, some studies have shown that mesenchymal stem cells (MSCs) are partially effective in other genetic mouse models of cerebellar ataxia. In this study, we tested the efficacy of the intrathecal injection of MSCs in the treatment of SCA1 in transgenic (SCA1-Tg) mice. We found that intrathecal injection of only 3?×?10³ MSCs greatly mitigated the cerebellar neuronal disorganization observed in SCA1 transgenic mice (SCA1-Tg mice). Although the Purkinje cells (PCs) of 24-week-old nontreated SCA1-Tg mice displayed a multilayer arrangement, SCA1-Tg mice at a similar age injected with MSCs displayed monolayer PCs. Furthermore, intrathecal injection of MSCs suppressed the atrophy of PC dendrites in SCA1-Tg mice. Finally, behavioral tests demonstrated that MSCs normalized deficits in motor coordination in SCA1-Tg mice. Future studies should be performed to develop optimal protocols for intrathecal transplantation of MSCs in SCA1 model primates with the aim of developing applications for SCA1 patients.     

Cerebellar TMS in Treatment of a Patient with Cerebellar Ataxia: Evidence from Clinical, Biomechanics and Neurophysiological Assessments

We describe a patient with a probable diagnosis of idiopathic late-onset cerebellar atrophy who shows improvement of limb coordination, speech, and gait following 21 days of transcranial magnetic stimulation (TMS) applied to scalp regions presumably corresponding to the cerebellum. This case study provides, for the first time, a quantitative assessment of gait improvement in response to TMS therapy in ataxia, as well as neurophysiological evidence in support of modification of cerebellar-cortical interaction that may underlie some of the improvements.     

Spinocerebellar Ataxia Types 1, 2, 3 and 6: the Clinical Spectrum of Ataxia and Morphometric Brainstem and Cerebellar Findings

To assess the clinical spectrum of ataxia and cerebellar oculomotor deficits in the most common spinocerebellar ataxias (SCAs), we analysed the baseline data of the EUROSCA natural history study, a multicentric cohort study of 526 patients with either spinocerebellar ataxia type 1, 2, 3 or 6. To quantify ataxia symptoms, we used the Scale for the Assessment and Rating of Ataxia (SARA). The presence of cerebellar oculomotor signs was assessed using the Inventory of Non-Ataxia Symptoms (INAS). In a subgroup of patients, in which magnetic resonance images (MRIs) were available, we correlated MRI morphometric measures with clinical signs on an exploratory basis. The SARA subscores posture and gait (items 1-3), speech (item 4) and the limb kinetic subscore (items 5-8) did not differ between the genotypes. The scores of SARA item 3 (sitting), 5 (finger chase) and 6 (nose-finger test) differed between the subtypes whereas the scores of the remaining items were not different. In SCA1, ataxia symptoms were correlated with brainstem atrophy and in SCA3 with both brainstem and cerebellar atrophy. Cerebellar oculomotor deficits were most frequent in SCA6 followed by SCA3, whereas these abnormalities were less frequent in SCA1 and SCA2. Our data suggest that vestibulocerebellar, spinocerebellar and pontocerebellar circuits in SCA1, SCA2, SCA3 and SCA6 are functionally impaired to almost the same degree, but at different anatomical levels. The seemingly low prevalence of cerebellar oculomotor deficits in SCA1 and SCA2 is most probably related to the defective saccadic system in these disorders.     

The Reciprocal Cerebellar Circuitry in Human Hereditary Ataxia

Clinicoanatomic correlation in the spinocerebellar ataxias (SCA) and Friedreich’s ataxia (FRDA) is difficult as these diseases differentially affect multiple sites in the central and peripheral nervous systems. A new way to study cerebellar ataxia is the systematic analysis of the “reciprocal cerebellar circuitry” that consists of tightly organized reciprocal connections between Purkinje cells, dentate nuclei (DN), and inferior olivary nuclei (ION). This circuitry is similar to but not identical with the “cerebellar module” in experimental animals. Neurohumoral transmitters operating in the circuitry are both inhibitory (γ-aminobutyric acid in corticonuclear and dentato-olivary fibers) and excitatory (glutamate in olivocerebellar or climbing fibers). Glutamatergic climbing fibers also issue collaterals to the DN. The present study applied five immunohistochemical markers in six types of SCA (1, 2, 3, 6, 7, 17), genetically undefined SCA, FRDA, and FRDA carriers to identify interruptions within the circuitry: calbindin-D28k, neuron-specific enolase, glutamic acid decarboxylase, and vesicular glutamate transporters 1 and 2. Lesions of the cerebellar cortex, DN, and ION were scored according to a guide as 0 (normal), 1 (mild), 2 (moderate), and 3 (severe). Results of each of the five immunohistochemical stains were examined separately for each of the three regions. Combining scores of each anatomical region and each stain yielded a total score as an indicator of pathological severity. Total scores ranged from 16 to 38 in SCA-1 (nine cases); 22 to 39 in SCA-2 (six cases); 9 to 15 in SCA-3 (four cases); and 13 and 25 in SCA-6 (two cases). In single cases of SCA-7 and SCA-17, scores were 16 and 31, respectively. In two genetically undefined SCA, scores were 36 and 37, respectively. In nine cases of FRDA, total scores ranged from 11 to 19. The low scores in SCA-3 and FRDA reflect selective atrophy of the DN. The FRDA carriers did not differ from normal controls. These observations offer a semiquantitative assessment of the critical role of the DN in the ataxic phenotype of SCA and FRDA while other parts of the circuitry appear less important.     

Upper Body Kinematics in Patients with Cerebellar Ataxia

Although abnormal oscillations of the trunk are a common clinical feature in patients with cerebellar ataxia, the kinematic behaviour of the upper body in ataxic patients has yet to be investigated in quantitative studies. In this study, an optoelectronic motion analysis system was used to measure the ranges of motion (ROMs) of the head and trunk segments in the sagittal, frontal and yaw planes in 16 patients with degenerative cerebellar ataxia during gait at self-selected speed. The data obtained were compared with those collected in a gender-, age- and gait speed-matched sample of healthy subjects and correlated with gait variables (time-distance means and coefficients of variation) and clinical variables (disease onset, duration and severity). The results showed significantly larger head and/or trunk ROMs in ataxic patients compared with controls in all three spatial planes, and significant correlations between trunk ROMs and disease duration and severity (in sagittal and frontal planes) and time-distance parameters (in the yaw plane), and between both head and trunk ROMs and swing phase duration variability (in the sagittal plane). Furthermore, the ataxic patients showed a flexed posture of both the head and the trunk during walking. In conclusion, our study revealed abnormal motor behaviour of the upper body in ataxic patients, mainly resulting in a flexed posture and larger oscillations of the head and trunk. The results of the correlation analyses suggest that the longer and more severe the disease, the larger the upper body oscillations and that large trunk oscillations may explain some aspects of gait variability. These results suggest the need of specific rehabilitation treatments or the use of elastic orthoses that may be particularly useful to reduce trunk oscillations and improve dynamic stability.