Journal
TRANSLATIONAL NEURODEGENERATION
Volume 11, Issue 1, Pages -Publisher
BMC
DOI: 10.1186/s40035-022-00291-4
Keywords
Magnetic resonance imaging; Diffusion-weighted imaging; Neurodegeneration; Cerebrospinal fluid; Telomere
Categories
Funding
- National Health and Medical Research Council [1174040, 1140386]
- Ross Maclean Fellowship
- Brazil Family Program for Neurology
- Bethlehem Griffiths Research Foundation [BGRF2103]
- National Health and Medical Research Council of Australia [1174040, 1140386] Funding Source: NHMRC
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This study found that the glymphatic system is impaired in the early stages of amyotrophic lateral sclerosis (ALS), leading to progressive neurodegeneration and disrupted glymphatic function. This suggests that the glymphatic system could be a potential therapeutic target for ALS treatment.
Background: Multiple lines of evidence suggest possible impairment of the glymphatic system in amyotrophic lateral sclerosis (ALS). To investigate this, we used in vivo magnetic resonance imaging (MRI) to assess glymphatic function early in the course of disease in a transgenic mouse with doxycycline (Dox)-controlled expression of cytoplasmic human TDP-43 (hTDP-43 Delta NLS), mimicking the key pathology implicated in ALS. Methods: Adult TDP-43 transgenic and littermate monogenic control mice underwent longitudinal multimodal MRI one and three weeks after the cessation of Dox feed, together with weekly rotarod assessments of motor performance. Glymphatic function was assessed using dynamic contrast-enhanced MRI to track the clearance of an MR contrast agent injected into the cisterna magna. Results: Compared to their littermate controls, TDP-43 mice exhibited progressive neurodegeneration including that within the primary motor cortex, primary somatosensory cortex and corticospinal tract, significant weight loss including gastrocnemius atrophy, and shortened telomere length. Furthermore, in the presence of this ALS-like phenotype, these mice have significantly disrupted glymphatic function. Conclusions: Although the relationship between glymphatic clearance and ALS disease progression remains to be elucidated, these changes occurred very early in the disease course. This provides initial evidence to suggest that the glymphatic system might be a potential therapeutic target in the treatment of ALS.
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