Abstract
Degeneration of the primary motor cortex is a defining feature of amyotrophic lateral sclerosis (ALS), which is associated with the accumulation of microscopic protein aggregates in neurons and glia. However, little is known about the quantitative burden and pattern of motor cortex proteinopathies across ALS genotypes. We combined quantitative digital image analysis with multi-level generalized linear modelling in an independent cohort of 82 ALS cases to explore the relationship between genotype, total proteinopathy load and cellular vulnerability to aggregate formation. Primary motor cortex phosphorylated (p)TDP-43 burden and microglial activation were more severe in sporadic ALS-TDP disease than C9-ALS. Oligodendroglial pTDP-43 pathology was a defining feature of ALS-TDP in sporadic ALS, C9-ALS and ALS with OPTN, HNRNPA1 or TARDBP mutations. ALS-FUS and ALS-SOD1 showed less cortical proteinopathy in relation to spinal cord pathology than ALS-TDP, where pathology was more evenly spread across the motor cortex-spinal cord axis. Neuronal pTDP-43 aggregates were rare in GAD67+ and Parvalbumin+ inhibitory interneurons, consistent with predominant accumulation in excitatory neurons. Finally, we show that cortical microglia, but not astrocytes, contain pTDP-43. Our findings suggest divergent quantitative, genotype-specific vulnerability of the ALS primary motor cortex to proteinopathies, which may have implications for our understanding of disease pathogenesis and the development of genotype-specific therapies.
Highlights
The term ‘selective vulnerability’ describes the differential susceptibility of cells or anatomically defined systems to disease pathomechanisms
We found a strong positive correlation between the extent of p62 and phosphorylated TDP-43 (pTDP-43) in sporadic amyotrophic lateral sclerosis (ALS) [Pearson r(16) = 0.61, p = 0.006](Fig. 2j), this relationship was not observed in C9-ALS to the same degree [Pearson r(14) = 0.53, p = 0.03](Fig. 2j), reflecting the existence of p62-positive, pTDP-43negative dipeptide repeat proteins produced as a consequence of the Chromosome 9 open reading frame 72 (C9ORF72) expansion
We found a trend for highest CD68 reactivity in the corticospinal tract of C9-ALS cases, this did not reach statistical significance compared with sporadic ALS-TDP cases (p = 0.91; Fig. 3h.) We found no relationship between pTDP-43 and CD68 in the anterior horn (Fig. 4j)
Summary
The term ‘selective vulnerability’ describes the differential susceptibility of cells or anatomically defined systems to disease pathomechanisms. While ALS patients commonly present with a combination of LMN and pyramidal signs, the nature of disease initiation and progression between the spinal cord and cortex remains unclear. Attempts to identify a histological correlate for this hypothesis using human tissue have produced conflicting results [30, 48, 55], compounded by neuropathological assessment often being confined to subjective readouts of disease burden which are a source of bias and potentially increase type I error. Digital image analysis algorithms have previously been used to accurately quantify TDP-43 pathology more objectively [35, 86], and the combination of quantitative disease indicators and genetic architecture can be used to produce neuropathological endophenotypes independent of relatively crude clinical readouts, which may not be up-to-date during the terminal phase of the illness [2, 18, 53]
Sign-in/Register to view highlights & summary 
Published Version (
Free)
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call