Brain stem and cerebellum volumetric analysis of Machado Joseph disease patients

Abstract

Machado-Joseph disease, or spinocerebellar ataxia type 3(MJD/SCA3), is the most frequent late onset spinocerebellar ataxia and results from a CAG repeat expansion in the ataxin-3 gene. Previous studies have found correlation between atrophy of cerebellum and brainstem with age and CAG repeats, although no such correlation has been found with disease duration and clinical manifestations. In this study we test the hypothesis that atrophy of cerebellum and brainstem in MJD/SCA3 is related to clinical severity, disease duration and CAG repeat length as well as to other variables such as age and ICARS (International Cooperative Ataxia Rating Scale). Whole brain high resolution MRI and volumetric measurement with cranial volume normalization were obtained from 15 MJD/ SCA3 patients and 15 normal, age and sex-matched controls. We applied ICARS and compared the score with volumes and CAG number, disease duration and age. We found significant correlation of both brain stem and cerebellar atrophy with CAG repeat length, age, disease duration and degree of disability. The Spearman rank correlation was stronger with volumetric reduction of the cerebellum than with brain stem. Our data allow us to conclude that volumetric analysis might reveal progressive degeneration after disease onset, which in turn is linked to both age and number of CAG repeat expansions in SCA 3. Key words: CAG expansion, Machado-Joseph disease, MJD/SCA3, spinocerebellar ataxia, volumetry.Análise volumétrica de cerebelo e tronco cerebral de pacientes com doença de Machado Joseph RESUMO Doença de Machado-Joseph, ou ataxia espinocerebelar tipo 3 (MJD/SCA3) é ataxia espinocerebelar de início tardio mais frequente e resulta de uma expansão da repetição CAG no gene da ataxina-3. Estudos precedentes encontraram correlação entre a atrofia do cerebelo e do tronco cerebral com a idade e número de expansões CAG. Tais correlações não foram encontradas em relação ao tempo de doença ou manifestações clínicas. Neste estudo testamos a hipótese de que a atrofia do cerebelo e do tronco encefálico em MJD/SCA3 está relacionada à gravidade clínica, duração da doença e número de repetições CAG, bem como com outras variáveis como a idade e a ICARS (escala cooperativa internacional de avaliação de ataxias). Foram realizados estudos de imagem pela ressonância magnética de alta resolução e volumetria com normalização de volume craniano de 15 pacientes portadores de MJD/SCA3 e 15 controles pareados por idade e sexo. Nós aplicamos a ICARS e correlacionamos com o escore de volumes e número de CAG, duração da doença e idade. Encontramos correlação significativa entre atrofia de tronco cerebral e cerebelo com duração da doença, repetição CAG, idade e grau de acometimento da doença. O índice de correlação de Spearman foi maior em relação à atrofia de cerebelo do que à atrofia de tronco. Nossos dados permitem concluir que a análise volumétrica pode revelar degeneração progressiva após o início da doença que, por sua vez, está ligada à idade e número de expansões CAG em SCA 3...

Antisense oligonucleotide therapy rescues aggresome formation in a novel spinocerebellar ataxia type 3 human embryonic stem cell line

“…We also observed the formation of high molecular weight ATXN3 aggregates throughout neuronal differentiation, including in derived SCA3-NPC and mature SCA3-CN. Though there is evidence for involvement of the frontal, parietal, temporal, occipital and limbic lobes in SCA3 58,59 , the degree of neuronal loss in these regions is significantly less severe than in brainstem and cerebellar nuclei 60 . Because cortical regions likely play less of a role in the progressive deterioration of motor control in SCA3 patients, differentiated forebrain cortical neurons may not be the best cellular model in which to study SCA3 disease processes.…”

The merit of proton magnetic resonance spectroscopy in the longitudinal assessment of spinocerebellar ataxias and multiple system atrophy-cerebellar type

“…Progressive reduction in the cerebellar volume, correlating with disease duration and age, has been documented in patients with MSA-C [ 31 ], SCA2 [ 32 ], SCA3 [ 33 ] and SCA6 [ 34 ]. In SCA2, the presence of pre-symptomatic region-specific atrophy was observed and a possible developmental component to the pathomechanisms was once proposed [ 32 ].…”

MR Imaging of SCA3/MJD

“…In addition, a previous study using multimodal MR imaging-based analyses in a large cohort of patients and presymptomatic subjects showed that volume measurements were more sensitive than SARA (Reetz et al, 2013), which provides a strong empirical basis for using these objective neuroimaging biomarkers to supplement ataxia assessment scales in the evaluation of clinical outcomes. Some neuroimaging studies have demonstrated an inverse correlation between the CAG repeats length and the volume of brainstem, cerebellum, and basal ganglia (Yoshizawa et al, 2003;Schulz et al, 2010;Camargos et al, 2011;Peng et al, 2019), whereas some failed to reveal a significant association between the CAG repeat expansion and the volume changes in the specific brain region (Burk et al, 1996;Klockgether et al, 1998;Eichler et al, 2011;Goel et al, 2011;Guimarães et al, 2013;Stefanescu et al, 2015;Huang et al, 2017). Apart from these neuroimaging reports, a pathoanatomic study also disclosed no correlation between the degeneration of the cerebellar Purkinje cell layer or the deep cerebellar nuclei with the CAG repeat length (Scherzed et al, 2012).…”