TDP-43 pathology and cognition in ALS: A prospective clinicopathologic correlation study

Area of Science:

• Neuroscience
• Neuropathology
• Clinical Neurology

Background:

• Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease.
• TDP-43 proteinopathy is a hallmark of ALS, but its relationship with cognitive decline is not fully understood.
• A systematic spread of TDP-43 pathology throughout the central nervous system (CNS) in ALS has been proposed.

Purpose of the Study:

• To investigate the association between cognitive functioning and the extent and neuroanatomic distribution of TDP-43 pathology in ALS patients.
• To explore clinicopathologic correlations between TDP-43 pathology and cognitive status.

Main Methods:

• Postmortem CNS tissue from 18 ALS patients was analyzed.
• Patients were stratified into three cognitive groups: cognitively not impaired, cognitively impaired, and ALS-frontotemporal dementia (FTD).
• Detailed prospective neuropsychological testing was performed.

Main Results:

• Cognition closely correlates with TDP-43 pathology extent in non-primary motor areas.
• A striking difference in TDP-43 pathology was observed between ALS-FTD and other cognitive groups.
• Absence of Alzheimer pathology and lack of correlation in primary motor regions support the specificity of findings.

Conclusions:

• TDP-43 pathology progression and distribution differ in ALS-FTD compared to ALS without FTD.
• These findings highlight the importance of TDP-43 distribution in understanding cognitive decline in ALS.