Primary Lateral Sclerosis and Amyotrophic Lateral Sclerosis: Unraveling Clinical and Biological Distinctions

Primary Lateral Sclerosis (PLS) and Amyotrophic Lateral Sclerosis (ALS) are both progressive neurogenerative disorders classified within the Motor Neuron Disease Spectrum. PLS is characterized by selective degeneration of upper motor neuron (UMN), leading predominantly to spasticity and muscle weakness without lower motor neuron (LMN) involvement. In contrast ALS involves the degeneration of both upper and lower motor neurons, resulting in a combination of spasticity, muscle atrophy, and widespread weakness. Clinically, PLS typically presents a more indolent progression with milder symptoms and longer survival compared to the rapidly progressive and fatal course of ALS. Despite overlapping features, the distinct pathological mechanisms and prognostic outcomes of PLS and ALS remain incompletely understood, complicating diagnosis and management. The aim of this study is to compare the clinical and biological characteristics of PLS and ALS patients to highlight the differences, evaluating the prognosis and course of the disease. A retrospective observational study was conducted in the tertiary neuromuscular center of Modena. We collected detailed phenotypic profiles and biological features of patients at diagnosis. Additionally, we analyzed the concentrations of neuroinflammation and neurodegeneration biomarkers in serum and cerebrospinal fluid (CSF) to explore potential biological distinctions between the two conditions. We enrolled 319 patients, 31 with PLS diagnosis and 288 with ALS diagnosis. Mean age at onset is 56.55 years for PLS and 60.42 years for ALS patient with a mean diagnostic delay of 37.81 months and 12.27 months respectively. 84% of PLS patients had a spinal onset of diseases and no one had a respiratory onset; 73% of ALS patients had a spinal onset and 25% a bulbar one. Fifty-eight percent of patients with PLS exhibited dyslipidemia as a comorbidity, compared to 29% of ALS patients (p 0.001). Among PLS patients, only 13% required non-invasive ventilation and 10% underwent nutritional support placement, compared to 54% and 43% of ALS patients, respectively. Both interventions were initiated significantly later from symptom onset in the PLS group. Serum and CSF levels of heavy neurofilaments (NfH) were significantly higher in ALS compared to PLS (p 0.005 and p 0.020), and also CSF levels of NfL were lower in PLS patients (p 0.008). Serum levels of neurogranin were significantly lower in PLS patients (p 0.035), instead serum UCHL1 levels were higher in PLS patients with value approaching statistical significance. The lower concentrations of NfH in serum and CSF observed in SLP compared with ALS could reflect a slower and less widespread neurodegenerative process in SLP. The differences in serum levels of neurogranin and UCHL1 between SLP and ALS, on the other hand, could indicate the involvement of different biomolecular mechanisms in the neurodegeneration characteristic of this clinical entity. The study highlighted some significant clinical and biological differences between PLS and ALS. These findings underscore the importance of further research in this field, with the aim of identifying more accurate biomarkers for each disease. A more accurate understanding of these biomolecular factors could enable the development of targeted therapies tailored to the clinical phenotype of patients.