Variance of phenotypes of upper and lower motor neuron disease

Primary lateral sclerosis (PLS) is a rare neurodegenerative disorder traditionally characterised by progressive degeneration of upper motor neurons (UMNs), leading to spasticity, weakness, and loss of mobility. Historically, PLS has been regarded as a disease confined to the UMNs. However, accumulating evidence of cognitive and behavioural impairments, parkinsonian features, and subtle lower motor neuron (LMN) involvement challenges this narrow view and suggests a broader clinical spectrum overlapping with other motor neuron diseases (MNDs), particularly amyotrophic lateral sclerosis (ALS). This thesis investigates the diagnostic complexity, clinical heterogeneity, cognitive and behavioural involvement, long-term disease course, and genetic and pathological features of PLS, questioning its classification as a “pure” UMN disorder.
Part I addresses the diagnostic criteria of PLS and its differentiation from ALS and PLS mimics. A long-term natural history study demonstrates that PLS remains a diagnosis of exclusion and is frequently difficult to distinguish from ALS and hereditary spastic paraplegia (HSP). Some patients were reclassified during follow-up, underscoring the limitations of relying on clinical criteria alone. Disease progression was heterogeneous: patients with limb-only involvement showed slower progression, whereas bulbar involvement was associated with greater disability and an increased risk of conversion to ALS. The findings support the use of a four-year disease duration threshold to reduce misclassification, while highlighting the urgent need for biomarkers and advanced imaging techniques to improve early diagnostic accuracy.
Part II focuses on cognitive and behavioural impairment in PLS and its relationship to ALS and progressive muscular atrophy (PMA). A large case series shows that a small but relevant proportion of PLS patients meet criteria for frontotemporal dementia (FTD), while a substantial subset exhibits milder cognitive and behavioural deficits. Comprehensive neuropsychological and behavioural assessments reveal impairments in executive functioning, fluency, memory, and social cognition, with caregiver reports identifying behavioural changes consistent with behavioural variant FTD in a notable proportion of patients. Comparative analyses across PLS, ALS, and PMA demonstrate that cognitive and behavioural abnormalities are prevalent across the MND spectrum, challenging the concept of PLS and PMA as restricted phenotypes and supporting their inclusion within the FTD–MND continuum.
Part III explores neuropathological and genetic aspects of PLS. Neuropathological findings confirm predominant UMN degeneration but also reveal variable LMN involvement and non-motor pathology in some cases, in line with observed cognitive and behavioural features. TDP-43 pathology, a hallmark of ALS and FTD, is inconsistently present, suggesting partial overlap with ALS pathophysiology. Genetic analyses show that PLS is largely sporadic, with limited overlap with known ALS-associated mutations, including rare C9ORF72 repeat expansions, supporting both distinction from and relatedness to ALS within the broader MND spectrum.
In conclusion, this thesis demonstrates that PLS is a clinically and biologically heterogeneous disorder that extends beyond isolated UMN degeneration. Improved diagnostic criteria, systematic cognitive and behavioural assessment, and integration of pathological and genetic data are essential to refine disease classification, enhance diagnostic accuracy, and advance understanding of PLS within the MND spectrum.