| dc.description.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. | en |
