Pathoanatomy of Cerebellar Degeneration in Spinocerebellar Ataxia Type 2 (SCA2) and Type 3 (SCA3)

Scherzed, W.; Brunt, Ewout; Heinsen, Helmut; Vos, R A de; Seidel, Kay; Bürk, Katrin; Schöls, Lüdger; Auburger, Georg; Turco, Domenico Del; Deller, Thomas; Korf, Horst‐Werner; Dunnen, Wilfred F. A. den; Rüb, Udo

doi:10.1007/s12311-011-0340-8

Cited by 89 publications

(68 citation statements)

References 45 publications

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“…Recently, a study based on a 7-T MRI modality demonstrated that the CAG repeat length was not correlated with the atrophy of the cerebellar cortex or dentate nuclei (Stefanescu et al, 2015). In addition to those neuroimaging reports, a pathoanatomy study also demonstrated that the CAG repeat length was not correlated with the atrophy of the four deep cerebellar nuclei (fastigial nucleus, globose nucleus, emboliform nucleus and dentate nucleus) (Scherzed et al, 2012). …”

Section: Discussionmentioning

confidence: 85%

“…Especially, cerebellar nuclei are primarily affected at the beginning of the disease. Many neuropathology studies (Durr et al, 1996, Koeppen, 2005, Scherzed et al, 2012, Takiyama et al, 1994) have reported atrophy or neuronal loss in the cerebellar cortex, vermis, peduncles, and deep nuclei. Structural or functional degeneration of the cerebellum can be observed by different neuroimaging approaches including magnetic resonance imaging (MRI) volumetry (Eichler et al, 2011, Klockgether et al, 1998b, Reetz et al, 2013, Schulz et al, 2010, Stefanescu et al, 2015), diffusion tensor imaging (DTI) (Guimaraes et al, 2013), magnetic resonance spectroscopy (MRS) (Adanyeguh et al, 2015, Lirng et al, 2012, Wang et al, 2012), and position emission tomography (Wang et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

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CAG repeat length does not associate with the rate of cerebellar degeneration in spinocerebellar ataxia type 3

Huang¹,

Wu²,

Jao³

et al. 2017

NeuroImage: Clinical

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This cross-sectional study investigated the correlation between the CAG repeat length and the degeneration of cerebellum in spinocerebellar ataxia type 3 (SCA3) patients based on neuroimaging approaches. Forty SCA3 patients were recruited and classified into two subgroups according to their CAG repeat lengths (≥ 74 and < 74). We measured each patient's Scale for the Assessment and Rating of Ataxia (SARA) score, N-acetylaspartate (NAA)/creatine (Cr) ratios based on magnetic resonance spectroscopy (MRS), and 3-dimensional fractal dimension (3D-FD) values derived from magnetic resonance imaging (MRI) results. Furthermore, the 3D-FD values were used to construct structural covariance networks based on graph theoretical analysis. The results revealed that SCA3 patients with a longer CAG repeat length demonstrated earlier disease onset. However, the CAG repeat length did not significantly correlate with their SARA scores, cerebellar NAA/Cr ratios or cerebellar 3D-FD values. Network dissociation between cerebellar regions and parietal-occipital regions was found in SCA3 patients with CAG ≥ 74, but not in those with CAG < 74. In conclusion, the CAG repeat length is uncorrelated with the change of SARA score, cerebellar function and cerebellar structure in SCA3. Nevertheless, a longer CAG repeat length may indicate early structural covariance network dissociation.

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Section: Discussionmentioning

confidence: 85%

Section: Introductionmentioning

confidence: 99%

CAG repeat length does not associate with the rate of cerebellar degeneration in spinocerebellar ataxia type 3

Huang¹,

Wu²,

Jao³

et al. 2017

NeuroImage: Clinical

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“…Patients typically present first with progressive gait imbalance and speech difficulties, eventually developing occulomotor difficulties, spasticity, dystonia, and, ultimately, severe dysarthria and dysphagia [39]. Pathology in SCA3 is fairly widespread, and cell loss is apparent in the cerebellum [40], cerebral cortex [37], thalamus [41], basal ganglia, midbrain, pons, and medulla [42].…”

Section: Sca3 (Machado-joseph Disease)mentioning

confidence: 99%

The Role for Alterations in Neuronal Activity in the Pathogenesis of Polyglutamine Repeat Disorders

Chopra

Shakkottai

2014

Neurotherapeutics

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Polyglutamine diseases are a class of neurodegenerative diseases that share an expansion of a glutamineencoding CAG tract in the respective disease genes as a central hallmark. In all of these diseases there is progressive degeneration in a select subset of neurons, and the mechanisms behind this degeneration remain unclear. Emerging evidence from animal models of disease has identified abnormalities in synaptic signaling and intrinsic excitability in affected neurons, which coincide with the onset of symptoms and precede apparent neuropathology. The appearance of these early changes suggests that altered neuronal activity might be an important component of network dysfunction and that these alterations in network physiology could contribute to symptoms of disease. Here we review abnormalities in neuronal function that have been identified in both animal models and patients, and highlight ways in which these changes in neuronal activity may contribute to disease symptoms. We then review the literature supporting an emerging role for abnormalities in neuronal activity as a driver of neurodegeneration. Finally, we identify common themes that emerge from studies of neuronal dysfunction in polyglutamine disease.

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“…For example, in many of the spinocerebellar ataxias (SCAs), there is marked PC loss [16-22], whereas in ET, PC loss is more subtle and difficult to detect [23, 24], leading us to hypothesize that the primary problem in ET is one that is a stressor to PCs but not to a degree that always overwhelms this type of neuron. To our knowledge, although torpedoes have been observed, they have not been systematically quantified in the SCAs.…”

Section: Introductionmentioning

confidence: 99%

Torpedo Formation and Purkinje Cell Loss: Modeling their Relationship in Cerebellar Disease

et al. 2014

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Background Torpedo formation and Purkinje cell (PC) loss represent standard and inter-related cerebellar responses to injury. Surprisingly, the nature of their relationship has not been carefully characterized across a range of normal and disease states. Are brains with more torpedoes expected to have fewer PCs? We quantified torpedoes and PCs in four groups: essential tremor (ET), spinocerebellar ataxia (SCA), multiple system atrophy-cerebellar (MSA-C), and controls. Methods Brains from 100 individuals (58 ET, 27 controls, 7 SCA, 8 MSA-C) were available at the New York Brain Bank. After complete neuropathological assessment, a standard parasagittal neocerebellar block was harvested, a 7-μm thick section was stained with Luxol Fast Blue/Hematoxylin and Eosin, and torpedoes and PCs were quantified. Results For a given PC count, SCA and MSA-C cases often had higher torpedo counts than ET cases or controls. Furthermore, the relationship between torpedo and PC counts was complex. The correlation between torpedo and PC counts was negative in ET cases (i.e., individuals with more torpedoes had fewer PCs [i.e., more PC loss]) whereas the relationship was positive in MSA-C cases (i.e., individuals with fewer PCs [i.e., more PC loss] had fewer torpedoes). Patients with SCA showed both patterns. When all diagnostic groups were combined, the correlation was best fit by a quadratic (i.e. parabolic) model rather than a simple linear model; this model incorporated data on the negative correlation in ET cases, the mixed results in SCA cases, and the positive correlation in MSA-C cases (r = 0.636). Conclusions The relationship between torpedo and PC counts was complex and heterogeneous across a range of cerebellar disease states, and was best characterized by a quadratic rather than a simple model. With more severe cerebellar disease, torpedoes can be quite numerous, and are likely a common feature of surviving PCs, but eventually, dramatic loss of PC leads to a paradoxical reduction in observable torpedoes.

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Pathoanatomy of Cerebellar Degeneration in Spinocerebellar Ataxia Type 2 (SCA2) and Type 3 (SCA3)

Cited by 89 publications

References 45 publications

CAG repeat length does not associate with the rate of cerebellar degeneration in spinocerebellar ataxia type 3

CAG repeat length does not associate with the rate of cerebellar degeneration in spinocerebellar ataxia type 3

The Role for Alterations in Neuronal Activity in the Pathogenesis of Polyglutamine Repeat Disorders

Torpedo Formation and Purkinje Cell Loss: Modeling their Relationship in Cerebellar Disease

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