Fast Progression in Amyotrophic Lateral Sclerosis Is Associated With Greater TDP-43 Burden in Spinal Cord

Area of Science:

• Neuropathology
• Neurodegenerative Diseases
• Motor Neuron Diseases

Background:

• Amyotrophic lateral sclerosis (ALS) diagnosis relies on upper and lower motor neuron pathologies.
• Understanding the impact of pathology burden on ALS progression is crucial.

Purpose of the Study:

• To investigate the association between the burden of TDP-43 proteinopathy in specific CNS regions and clinical features of ALS.
• To explore correlations between C9orf72 expansion and clinicopathological findings in ALS.

Main Methods:

• Retrospective analysis of 38 ALS patient autopsy cases.
• Blinded assessment of TDP-43 pathology burden in motor cortex, hypoglossal nucleus, and lumbar cord.
• Correlation of pathological findings with clinical data including progression rate, survival, and symptom onset.

Main Results:

• Significant association between higher TDP-43 burden in the lumbar cord and hypoglossal nucleus with faster disease progression and reduced survival (p < 0.02).
• No correlation found between TDP-43 burden and severity of neuronal loss in the motor cortex.
• C9orf72 expansion linked to shorter disease duration (p < 0.001) but not specific regional TDP-43 pathology.

Conclusions:

• Lower motor neuron TDP-43 burden is a significant predictor of rapid ALS progression and poorer survival.
• TDP-43 in the spinal cord and brainstem warrants further investigation as a potential biomarker for ALS.
• C9orf72 expansion influences disease duration independently of regional TDP-43 pathology in this cohort.