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Objective <p>Investigate associations between brain pathology (pTDP-43 inclusions and microglial activation) and cognitive and behavioural impairment in patients with amyotrophic lateral sclerosis (ALS).</p> Methods <p>Based on comprehensive neuropsychological examination and behavioural assessment, 21 ALS patients of whom post mortem brain tissue was obtained, were classified as having 1) no cognitive and/or behavioural impairment (pure motor ALS), 2) mild cognitive and/or behavioural impairment (ALSci/bi), and 3) ALS with behavioural variant frontotemporal dementia (ALS-bvFTD). Immunohistochemical staining of pTDP-43 and HLA-DR-defined microglial activation was semi-quantitatively assessed in grey and/or white matter of the prefrontal cortex, thalamus, hippocampus, and motor cortex.</p> Results <p>Fourteen patients had pure motor ALS, four patients had ALSci/bi, and three patients had ALS-bvFTD. pTDP-43 pathology in the grey matter of the prefrontal cortex and <i>gyrus dentatus</i> differed between groups, especially between pure motor ALS and ALS-bvFTD. For each extra-motor brain region, pTDP-43 severity was highest in patients with ALS-bvFTD and lowest in patients with pure motor ALS, with ALSci/bi in between. This pattern was not observed for microglial activation. Associations between white matter pTDP-43 severity and cognitive/behavioural impairment were less robust than those in grey matter.</p> Conclusion <p>Severity of cognitive and/or behavioural impairment in ALS is related to severity of pTDP-43 pathology, in particular in the grey matter of extra-motor brain regions; we did not detect a clear association with microglial activation.</p>

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Associations of cognitive and behavioural impairment in ALS with brain pathology: pTDP-43 versus microglial activation

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年5月15日

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  • Hanneke M. J. Slaghekke,
  • Rosanne Govaarts,
  • Lucia Mesarosova,
  • Angelika Mühlebner,
  • Emma Beeldman,
  • Marianne de Visser,
  • Michael A. van Es,
  • Leonard H. van den Berg,
  • Anneke J. van der Kooi,
  • Yolande A. L. Pijnenburg,
  • Eleonora Aronica,
  • Joost Raaphorst

摘要

Objective

Investigate associations between brain pathology (pTDP-43 inclusions and microglial activation) and cognitive and behavioural impairment in patients with amyotrophic lateral sclerosis (ALS).

Methods

Based on comprehensive neuropsychological examination and behavioural assessment, 21 ALS patients of whom post mortem brain tissue was obtained, were classified as having 1) no cognitive and/or behavioural impairment (pure motor ALS), 2) mild cognitive and/or behavioural impairment (ALSci/bi), and 3) ALS with behavioural variant frontotemporal dementia (ALS-bvFTD). Immunohistochemical staining of pTDP-43 and HLA-DR-defined microglial activation was semi-quantitatively assessed in grey and/or white matter of the prefrontal cortex, thalamus, hippocampus, and motor cortex.

Results

Fourteen patients had pure motor ALS, four patients had ALSci/bi, and three patients had ALS-bvFTD. pTDP-43 pathology in the grey matter of the prefrontal cortex and gyrus dentatus differed between groups, especially between pure motor ALS and ALS-bvFTD. For each extra-motor brain region, pTDP-43 severity was highest in patients with ALS-bvFTD and lowest in patients with pure motor ALS, with ALSci/bi in between. This pattern was not observed for microglial activation. Associations between white matter pTDP-43 severity and cognitive/behavioural impairment were less robust than those in grey matter.

Conclusion

Severity of cognitive and/or behavioural impairment in ALS is related to severity of pTDP-43 pathology, in particular in the grey matter of extra-motor brain regions; we did not detect a clear association with microglial activation.