MRI Signal Abnormalities of the Inferior Olivary Nuclei in Spinocerebellar Ataxia Type 2

Yoshii, Fumihito; Tomiyasu, Hitoshi; Watanabe, Ryuta; Ryo, Masafuchi

doi:10.1159/000481303

Cited by 5 publications

(4 citation statements)

References 17 publications

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“…Our results, however, demonstrate that inhibitory innervation to the IO in SCA1-KI mice is both structurally and functionally intact. Though some limited occurrence of HOD in the context of SCA has been previously reported (Yoshii et al, 2017), this study constitutes the first description of a robust HOD-like phenotype in the proven absence of inhibitory deafferentation.…”

Section: Discussionmentioning

confidence: 61%

Increased intrinsic membrane excitability is associated with hypertrophic olivary degeneration in spinocerebellar ataxia type 1

Morrison,

Huang,

Handler

et al. 2023

Preprint

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One of the characteristic areas of brainstem degeneration across multiple spinocerebellar ataxias (SCAs) is the inferior olive (IO), a medullary nucleus that plays a key role in motor learning. In addition to its vulnerability in SCAs, the IO is also susceptible to a distinct pathology known as hypertrophic olivary degeneration (HOD). Clinically, HOD has been exclusively observed after lesions in the brainstem disrupt inhibitory afferents to the IO. Here, for the first time, we describe HOD in another context: spinocerebellar ataxia type 1 (SCA1). Using the genetically-precise SCA1 knock-in mouse model (SCA1-KI; both sexes used), we assessed SCA1-associated changes in IO neuron structure and function. Concurrent with degeneration, we found that SCA1-KI IO neurons are hypertrophic, exhibiting early dendrite lengthening and later somatic expansion. Unlike in previous descriptions of HOD, we observed no clear loss of IO inhibitory innervation; nevertheless, patch-clamp recordings from brainstem slices reveal that SCA1-KI IO neurons are hyperexcitable. Rather than synaptic disinhibition, we identify increases in intrinsic membrane excitability as the more likely mechanism underlying this novel SCA1 phenotype. Specifically, transcriptome analysis indicates that SCA1-KI IO hyperexcitability is associated with a reduced medullary expression of ion channels responsible for spike afterhyperpolarization (AHP) in IO neurons - a result that has a functional consequence, as SCA1-KI IO neuron spikes exhibit a diminished AHP. These results reveal membrane excitability as a potential link between disparate causes of IO degeneration, suggesting that HOD can result from any cause, intrinsic or extrinsic, that increases excitability of the IO neuron membrane.

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Section: Discussionmentioning

confidence: 61%

Increased intrinsic membrane excitability is associated with hypertrophic olivary degeneration in spinocerebellar ataxia type 1

Morrison,

Huang,

Handler

et al. 2023

Preprint

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“…10 In addition, one patient with spinocerebellar ataxia type 2 showed bilateral inferior olivary hypertrophy on MRI findings. 20 Severity of neuronal loss in the dentate nucleus may not by itself contribute to inferior olivary hypertrophy, because it is unusual 6 in dentatorubral-pallidoluysian atrophy, Machado-Joseph disease, or any other neurodegenerative diseases, in which severe neurodegeneration can occur in the dentate nucleus. In addition, the MRI and histological findings can be changed sequentially in the course of inferior olivary degeneration.…”

Section: Discussionmentioning

confidence: 99%

An autopsy case of corticobasal degeneration with inferior olivary hypertrophy

et al. 2021

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We report autopsy results of a female patient who was confirmed pathologically as having corticobasal degeneration (CBD). This patient presented with progressive gait disturbance at the age of 66 years, and subsequently showed parkinsonism with a right-sided predominance and dementia. She was clinically diagnosed as having possible corticobasal syndrome without palatal myoclonus throughout the disease course. An autopsy at 72 years of age revealed that neuronal loss with gliosis was severe in the substantia nigra and the portion from hippocampal cornu ammonis (CA1) region to the parahippocampal gyrus, and mild-tomoderate in the basal ganglia, thalamus, red nucleus, dentate nucleus, and cerebral cortices, predominantly in the frontal lobe. Myelin pallor was observed in the pyramidal tract of the brainstem and central tegmental tract. Neurodegenerative or axonal degenerative findings were observed predominantly on the left side, except for the dentate nucleus, which was more affected on the right side. The inferior olivary nucleus exhibited hypertrophic degeneration predominantly on the left side. The topography of neurodegeneration was likely to correspond to the dentate nucleus and inferior olivary nucleus. Phosphorylated tauimmunoreactive pretangles, neurofibrillary tangles, coiled bodies, and threads were diffusely observed in the whole brain. The distribution of tau deposits was prominent in the deeper affected lesions of the dentate nucleus and inferior olivary nucleus. Inferior olivary hypertrophy is unusual in patients with CBD. It is highly possible that the neurodegeneration of the inferior olivary nucleus followed that of the dentate nucleus in our patient. Moreover, these results indicate not only the severity of neurodegenerative changes, but also that of tau deposition that could be related to the topography of the projections of the dentatoolivary pathway. Tau propagation and subsequent neurodegeneration along the fiber connections may have occurred. Our results support the possibility that progression of CBD lesions can be mediated by tau propagation.

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“…In SCA2 patients, MRI reveals olivopontocerebellar atrophy, pontine brainstem volume loss before clinical onset, diffuse spin-spin relaxation time (T2) high signal in pons, middle cerebellar peduncles and cerebellar white matter with "hot cross bun" sign, and thalamus and parietal cortical atrophy in advanced phases, whereas in terms of the volume of the pontine brainstem and cerebellum, diffusion tensor imaging indexes of the brainstem and cerebellum are the most promising imaging measures to monitor disease progression in SCA2 [76,77]. Recent MRI studies have shown the hypertrophy of the inferior olivary nuclei in SCA2 patients that represents a unique feature of SCA2 compared with other hereditary SCAs [78]. A special kind of diffusion-weighted MRI, diffusion-tensor imaging (DTI), has revealed the microstructural changes associated with the pontocerebellar degeneration in SCA2 and has shown that the median value of the mean diffusivity might be a marker for SCA2 progression [79] and may account for the specificity of the cognitive symptomatology observed in SCA2 patients [80].…”

Section: Cerebellar Atrophy In Sca2mentioning

confidence: 99%

Molecular Mechanisms and Therapeutics for Spinocerebellar Ataxia Type 2

Egorova

Bezprozvanny

2019

Neurotherapeutics

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The effective therapeutic treatment and the disease-modifying therapy for spinocerebellar ataxia type 2 (SCA2) (a progressive hereditary disease caused by an expansion of polyglutamine in the ataxin-2 protein) is not available yet. At present, only symptomatic treatment and methods of palliative care are prescribed to the patients. Many attempts were made to study the physiological, molecular, and biochemical changes in SCA2 patients and in a variety of the model systems to find new therapeutic targets for SCA2 treatment. A better understanding of the uncovered molecular mechanisms of the disease allowed the scientific community to develop strategies of potential therapy and helped to create some promising therapeutic approaches for SCA2 treatment. Recent progress in this field will be discussed in this review article.

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MRI Signal Abnormalities of the Inferior Olivary Nuclei in Spinocerebellar Ataxia Type 2

Cited by 5 publications

References 17 publications

Increased intrinsic membrane excitability is associated with hypertrophic olivary degeneration in spinocerebellar ataxia type 1

Increased intrinsic membrane excitability is associated with hypertrophic olivary degeneration in spinocerebellar ataxia type 1

An autopsy case of corticobasal degeneration with inferior olivary hypertrophy

Molecular Mechanisms and Therapeutics for Spinocerebellar Ataxia Type 2

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