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Background <p>The <i>ATXN2</i> gene contains a polymorphic CAG-rich region encoding a polyglutamine tract in ataxin- 2. Normal alleles have fewer than 27 CAG repeats, 27–34 repeats pose a risk for ALS (<i>ATXN2</i>-ALS), and &gt; 34 repeats cause spinocerebellar ataxia type 2 (SCA2). The striking phenotypic differences between these two <i>ATXN2-</i>related conditions are not yet fully understood.</p> Objective <p>To characterize and compare the distinguishing radiological signatures of <i>ATXN2</i>-ALS, SCA2, sporadic ALS (sALS) and healthy controls in vivo using quantitative computational neuroimaging techniques.</p> Methods <p>Four groups were defined: healthy controls (<i>n</i> = 34), sALS (<i>n</i> = 17), <i>ATXN2</i>-ALS (<i>n</i> = 16), and SCA2 (<i>n</i> = 17). Cortical, subcortical, brainstem, cerebellar and spinal regions were segmented based on T1-weighted data using validated segmentation tools and their volumes estimated. Group-specific morphometric data were correlated with cerebral <i>ATXN2</i> expression maps from the Allen Human Brain Atlas.</p> Results <p>Study groups were age and sex-matched. sALS, <i>ATXN2</i>-ALS and SCA2 have distinct structural CNS signatures, with disease burden restricted to the precentral gyri in the sALS group, to the spinal cord and brainstem in the <i>ATXN2</i>-ALS group and more diffusely distributed in the subcortical structures in the SCA2 group. Brain <i>ATXN2</i> expression correlated with the structural signature of SCA2, but not with that of <i>ATXN2</i>-ALS.</p> Conclusions <p>Neuroimaging signatures differ in <i>ATXN2</i>-ALS and SCA2, indicating distinct mechanisms of <i>ATXN2</i>-mediated neurodegeneration. sALS and <i>ATXN2</i>-ALS also exhibit distinct patterns of CNS involvement. The unique imaging signatures and clinical profiles along the spectrum of ATXN2-related disorders raise important questions regarding the pathophysiology of the disease and have practical clinical ramifications.</p>

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Distinct patterns of cerebral and spinal pathology along the spectrum of ATXN2-related disorders

  • 期刊论文

  • 发表日期：

    2025年4月9日

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  • Paulo Schneider Wolmer,
  • Fabrício Castro de Borba,
  • Thiago Junqueira Ribeiro de Rezende,
  • Carelis González-Salazar,
  • José Luiz Pedroso,
  • Orlando Graziani Povoas Barsottini,
  • Jana Kleinerova,
  • Peter Bede,
  • Wilson Marques Jr.,
  • Marcondes Cavalcante França Jr.

摘要

Background

The ATXN2 gene contains a polymorphic CAG-rich region encoding a polyglutamine tract in ataxin- 2. Normal alleles have fewer than 27 CAG repeats, 27–34 repeats pose a risk for ALS (ATXN2-ALS), and > 34 repeats cause spinocerebellar ataxia type 2 (SCA2). The striking phenotypic differences between these two ATXN2-related conditions are not yet fully understood.

Objective

To characterize and compare the distinguishing radiological signatures of ATXN2-ALS, SCA2, sporadic ALS (sALS) and healthy controls in vivo using quantitative computational neuroimaging techniques.

Methods

Four groups were defined: healthy controls (n = 34), sALS (n = 17), ATXN2-ALS (n = 16), and SCA2 (n = 17). Cortical, subcortical, brainstem, cerebellar and spinal regions were segmented based on T1-weighted data using validated segmentation tools and their volumes estimated. Group-specific morphometric data were correlated with cerebral ATXN2 expression maps from the Allen Human Brain Atlas.

Results

Study groups were age and sex-matched. sALS, ATXN2-ALS and SCA2 have distinct structural CNS signatures, with disease burden restricted to the precentral gyri in the sALS group, to the spinal cord and brainstem in the ATXN2-ALS group and more diffusely distributed in the subcortical structures in the SCA2 group. Brain ATXN2 expression correlated with the structural signature of SCA2, but not with that of ATXN2-ALS.

Conclusions

Neuroimaging signatures differ in ATXN2-ALS and SCA2, indicating distinct mechanisms of ATXN2-mediated neurodegeneration. sALS and ATXN2-ALS also exhibit distinct patterns of CNS involvement. The unique imaging signatures and clinical profiles along the spectrum of ATXN2-related disorders raise important questions regarding the pathophysiology of the disease and have practical clinical ramifications.