The clinical and neuroimaging profiles of primary lateral sclerosis: a longitudinal research study

Abstract

Primary Lateral Sclerosis (PLS) is a progressive, idiopathic upper motor neuron (UMN) disease. Clinically, PLS is defined by the presence of spasticity and associated UMN signs without concurrent evidence of lower motor neuron degeneration. However, the detailed phenotype, rate of progression, and the risk of transition to amyotrophic lateral sclerosis (ALS) are inadequately understood. Studies have been limited by small sample sizes, retrospective design, absence of genetic testing, patient attrition and a lack of standardised clinical assessments. Without a well-defined clinical phenotype or validated biomarkers, diagnostic criteria for PLS have required a minimum duration of four years for diagnosis. Clinical trials in PLS are long-awaited. Given the paucity of post-mortem studies in PLS, advanced neuroimaging methods are uniquely placed to explore its neuroanatomic signature, particularly with respect to extra-motor and early-stage changes. The main objective of this study is to describe, in detail, the clinical and neuroimaging characteristics of PLS.

In this prospective research study, 43 PLS patients participated in a longitudinal clinical study of PLS over a two-year period, including standardised neurological assessments and genetic analysis. A total of 40 PLS patients also underwent 3T MRI. Imaging profiles in PLS were compared to 117 ALS patients and 100 healthy controls. Whole-brain and region-of-interest analyses were undertaken to evaluate patterns of cortical grey matter and white matter degeneration in both motor and extra-motor regions. Additionally, volumetric, morphometric, segmentation and vertex-wise analyses were carried out in the three study groups to evaluate the integrity of subcortical grey matter structures. Finally, the clinical and imaging characteristics of early PLS were explored in patients meeting the newly defined category of probable PLS .In the clinical study, no PLS patients were lost to follow-up. None tested positive for ALS or hereditary spastic paraplegia-related genetic mutations. Notably, no PLS patients developed features suggestive of ALS during the follow-up period and no deaths occurred. Mean duration at baseline assessment was 9.5 years. Several distinctive phenotypic characteristics were observed. Symptom onset was in the lower limbs in all but one patient and lower limb symptoms remained predominant in all, regardless of symptom duration. A large majority required a mobility aid and frequent falls were almost universal. Despite prolonged symptom duration, and in contrast with ALS, no PLS patient had severe dysarthria requiring assistive devices or severe dysphagia requiring gastrostomy. Previous studies in PLS have commented on mild muscle weakness and symmetry of clinical signs in PLS using a subjective, qualitative approach. These observations were confirmed in this study using standardised analysis. Significant correlations were observed between both regional UMN burden and reduced tapping-rates and corresponding level of functional impairment, confirming the close association of clinical signs and symptoms in PLS. The pre-study ALSFRS-R rate of progression (slope) in the group as a whole was 0.15 per month. However, when stratified according to symptom duration, longer duration at baseline was associated with a much slower rate of progression. Importantly, this difference in progression rate based on symptom duration at baseline was also observed in the prospective follow-up period. This has important implications for patient stratification in clinical trials of PLS. The comprehensive imaging analysis demonstrates that disease burden in the motor cortex in PLS is more medial than in ALS, consistent with its lower limb symptom- predominance. PLS is also associated with considerable cerebellar white and grey matter degeneration, sparing of the post-central gyrus and preferential involvement of the body and splenium of the corpus callosum. Clinical measures revealed anatomically meaningful correlations with imaging metrics in a somatotopic distribution. Significant thalamic, caudate, and hippocampal atrophy was detected in PLS based on both volumetric and vertex analyses. Significant volume reductions were also identified in the accumbens nuclei. Hippocampal atrophy in PLS is dominated by dentate gyrus, hippocampal tail and CA4 subfield volume reductions. Voxel-wise analyses revealed anterior cingulate, dorsolateral prefrontal, insular, opercular, orbitofrontal and bilateral mesial temporal grey matter changes and white matter alterations in the fornix, brainstem, temporal lobes, and cerebellum. Extra-motor clinical manifestations were dominated by verbal fluency deficits, language deficits, apathy and pseudobulbar affect. Finally, in the comparison of early stage (probable) PLS and long-established (definite) PLS, lower limb function, UMN burden and cortical thickness measurements were indistinguishable, despite considerably longer duration in the latter group. These findings confirm distinctive clinical and neuropathological features and indicate that successful clinical trials of disease- modifying drugs in PLS should include patients at a much earlier point than the four- year symptom duration required by existing diagnostic criteria.