The core of the clinical syndrome of amyotrophic lateral sclerosis (ALS) is a progressive and typically rapid and uniformly fatal disintegration of the motor system, comprising upper motor neurons (UMNs) of the primary motor cortex and corticospinal tract (CST), brainstem nuclei and the lower motor neurons (LMNs) arising from the anterior horns of the spinal cord. While the spinal anterior horns and corticospinal tract superficially appear to bear the brunt of histopathology in ALS, it is clear that neurodegeneration extends to involve the extra-motor brain, preferentially involving the frontal and temporal lobes having clinical, histopathological and genetic overlap with frontotemporal dementia (FTD). There is a profound microglial and astrocytic component to pathology, with cortical hyperexcitability thought to be underpinned by changes in the balance of cortical inhibitory interneuronal influences. The marked clinical heterogeneity of the ALS-FTD spectrum, frequent diagnostic delay and reliance of therapeutic trials on survival as the primary outcome measure have made biomarker development a research priority. PET in paticular continues to provide to key mechanistic insights into pathogenesis at a uniquely systems-level.
