The Epidemiology of Primary Lateral Sclerosis: Results from a Population-Based Cohort.

9. Upper motor neuron dysfunction and neuropsychological profile in PLS: Another entrant on the ALS-FTD spectrum

Using diffusion tensor (DT) magnetic resonance imaging (MRI), damage to brain intrahemispheric and interhemispheric connections was assessed in 26 sporadic primary lateral sclerosis (PLS) patients compared with 28 sporadic amyotrophic lateral sclerosis (ALS) patients with similar disability and 35 healthy controls. DT MRI diagnostic accuracy in distinguishing the two motor neuron disease (MND) variants was tested. PLS and ALS patients showed a distributed pattern of abnormalities of the motor system, including the corticospinal tracts and corpus callosum (CC). PLS versus ALS patients showed a more severe damage to the motor CC fibers and subcortical white matter (WM) underlying the primary motor cortices. Both patient groups showed an extra-motor damage, which was more severe in PLS. This did not appear to be driven by longer disease duration in PLS. In PLS patients, damage to the CC mid-body correlated with the severity of upper motor neuron clinical burden. CC fractional anisotropy values had the highest accuracy in distinguishing PLS from controls and ALS. PLS and ALS share an overlapped pattern of WM abnormalities. This underscores that PLS, despite its distinct clinical phenotype and long survival, still lies within the wider MND spectrum. Whether CC diffusivity may be a novel marker to increase confidence in an early diagnostic separation of PLS from ALS still needs to be investigated.

Hereditary spastic paraplegia (HSP) is a group of genetic neurodegenerative diseases characterised by upper motor neuron (UMN) impairment of the lower limbs. The differential diagnosis with primary lateral sclerosis (PLS) and amyotrophic lateral sclerosis (ALS) can be challenging. As microglial iron accumulation was reported in the primary motor cortex (PMC) of ALS cases, here we assessed the radiological appearance of the PMC in a cohort of HSP patients using iron-sensitive MR imaging and compared the PMC findings among HSP, PLS, and ALS patients. We included 3-T MRI scans of 23 HSP patients, 7 PLS patients with lower limb onset, 8 ALS patients with lower limb and prevalent UMN onset (UMN-ALS), and 84 ALS patients with any other clinical picture. The PMC was visually rated on 3D T2*-weighted images as having normal signal intensity, mild hypointensity, or marked hypointensity, and differences in the frequency distribution of signal intensity among the diseases were investigated. The marked hypointensity in the PMC was visible in 3/22 HSP patients (14%), 7/7 PLS patients (100%), 6/8 UMN-ALS patients (75%), and 35/84 ALS patients (42%). The frequency distribution of normal signal intensity, mild hypointensity, and marked hypointensity in HSP patients was different than that in PLS, UMN-ALS, and ALS patients (p < 0.01 in all cases). Iron-sensitive imaging of the PMC could provide useful information in the diagnostic work - up of adult patients with a lower limb onset UMN syndrome, as the cortical hypointensity often seen in PLS and ALS cases is apparently rare in HSP patients. • The T2* signal intensity of the primary motor cortex was investigated in patients with HSP, PLS with lower limb onset, and ALS with lower limb and prevalent UMN onset (UMN-ALS) using a clinical 3-T MRI sequence. • Most HSP patients had normal signal intensity in the primary motor cortex (86%); on the contrary, all the PLS and the majority of UMN-ALS patients (75%) had marked cortical hypointensity. • The T2*-weighted imaging of the primary motor cortex could provide useful information in the differential diagnosis of sporadic adult-onset UMN syndromes.

There are currently no imaging or blood diagnostic biomarkers that can differentiate amyotrophic lateral sclerosis (ALS) from primary lateral sclerosis (PLS) patients early in their disease courses. Our objective is to examine whether patients with PLS can be differentiated from ALS reliably by using plasma lipidome profile and supervised machine learning. 40 ALS and 28 PLS patients derived from the Multicenter Cohort study of Oxidative Stress (COSMOS) and 28 healthy control volunteers (CTR) were included. ALS, PLS, and CTR were matched by age and sex. Plasma samples were obtained after overnight fasting. Lipids were extracted from the plasma samples and analyzed using liquid chromatography/mass spectrometry to obtain relative concentrations of 392 lipid species. The lipid data were partitioned into training and testing datasets randomly. An elastic net algorithm was trained using cross-validation to classify PLS vs ALS and PLS vs CTR. Final accuracy was evaluated in the testing dataset. The elastic net model trained with labeled PLS and ALS training lipid dataset demonstrated accuracy (number classified correctly/total number), sensitivity, and specificity of 100% in classifying PLS vs ALS in the unlabeled testing lipid dataset. Similarly, the elastic net model trained with labeled PLS and CTR training lipid datasets demonstrated accuracy, sensitivity, and specificity of 88% in classifying PLS vs CTR in the unlabeled testing lipid dataset. Our study suggests PLS patients can be accurately distinguished from ALS and CTR by combining lipidome profile and supervised machine learning without clinical information.

Primary lateral sclerosis (PLS) has been regarded as a rare, extreme form of amyotrophic lateral sclerosis (ALS). Like ALS, it is a clinical diagnosis without established biomarkers. We sought to explore loss of cerebral myelin in relation to clinical features, including cognitive impairment, in cases of both ALS and PLS.A novel MRI sequence (mcDESPOT) sensitive to water pools within myelin and intra- and extra-cellular spaces was applied to 23 ALS patients, seven PLS patients and 12 healthy controls, with interval follow-up in 15 ALS and four PLS patients.Results demonstrated that PLS patients were distinguished by widespread cerebral myelin water fraction reductions, independent of disease duration and clinical upper motor neuron burden. ALS patients showed a significant increase in intra- and extra-cellular water, indirectly linked to neuroinflammatory activity. Limited measures of cognitive impairment in the ALS group were associated with myelin changes within the anterior corpus callosum and frontal lobe projections. Longitudinal changes were only significant in the PLS group. In conclusion, in this exploratory study, myelin imaging has potential to distinguish PLS from ALS, and may have value as a marker of extramotor involvement. PLS may be a more active cerebral pathological process than its rate of clinical deterioration suggests.

Structural imaging differences and longitudinal changes in primary lateral sclerosis and amyotrophic lateral sclerosis☆

Primary lateral sclerosis (PLS) is a motor neuron disease (MND) which mainly affects upper motor neurons. Within the MND spectrum, PLS is much more slowly progressive than amyotrophic laterals sclerosis (ALS). `Classical` ALS is characterized by catabolism and abnormal energy metabolism preceding onset of motor symptoms, and previous studies indicated that the disease progression of ALS involves hypothalamic atrophy. Very limited weight loss is observed in patients with PLS, which raises the question of whether there are also less hypothalamic alterations. The purpose of this study was to quantitatively investigate the hypothalamic volume in a group of PLS patients and to compare it with ALS and controls. Recently, we have introduced automatic hypothalamic quantification method based on the use of convolutional neural network (CNN) to reduce human variability and enhance analysis robustness. This CNN of U-Net architecture was applied for automatic segmentation of the hypothalamus and intracranial volume (ICV) to allow adjustments of the hypothalamic volume between subjects with different head sizes respectively. Automatic segmentation and volumetric analysis were performed in high resolution T1 weighted MRI volumes (acquired on a 1.5 T MRI scanner) of 46 PLS patients in comparison to 107 healthy controls and 411 `classical` ALS patients, respectively. Significant hypothalamic volume reduction was observed in PLS (818 ± 73 mm3) when compared to controls (852 ± 77 mm3); significant hypothalamic volume reduction was also confirmed in ALS (823 ± 84 mm3), in support of previous studies. No significant differences were found in normalized hypothalamic volumes between ALS patients and PLS patients at the group level. This unbiased CNN-based hypothalamus volume quantification study demonstrated similarly reduced hypothalamus volume in PLS and ALS patients, despite the clinical phenotypic differences.

Introduction: Slow vital capacity (SVC) and forced vital capacity (FVC) are the most frequent used tests evaluating respiratory function in amyotrophic lateral sclerosis (ALS). No previous study has determined their interchangeability.Objective: To evaluate SVC-FVC correlation in ALS.Methods: Consecutive definite/probable ALS and primary lateral sclerosis (PLS) patients (2000-2014) in whom respiratory tests were performed at baseline/4-6months later were included. All were evaluated with revised ALS functional rating scale, the ALSFRS respiratory (R-subscore) and bulbar subscores, SVC, FVC, maximal inspiratory (MIP) and expiratory (MEP) pressures. SVC-FVC correlation was analysed by Pearson product-moment correlation test. Paired t-test compared baseline/follow-up values. Multilinear regression analysis modelled the relationship between tested variables.Results: We included 592 ALS (332 men, mean onset age 62.6 ± 11.8 years, mean disease duration 15.4 ± 15 months) and 19 PLS (11 men, median age 54 years, median disease duration 5.5 years) patients. SVC and FVC predicted values decreased 2.15%/month and 2.08%/month, respectively. FVC and SVC were strongly correlated. Both were strongly correlated with MIP and MEP and moderately correlated with R-subscore for the all population and spinal-onset patients, but weakly correlated for bulbar-onset patients.Conclusions: FVC and SVC were strongly correlated and declined similarly. This correlation was preserved in bulbar-onset ALS and in spastic PLS patients.

Primary lateral sclerosis (PLS) has been traditionally viewed as a distinct upper motor neuron condition (UMN) but is increasingly regarded as a sub-phenotype within the amyotrophic lateral sclerosis (ALS) spectrum. Despite established diagnostic criteria, formal diagnosis can be challenging and the protracted diagnostic journey and uncertainty about longer-term prognosis cause considerable distress to patients and caregivers. PLS patients are invariably excluded from ALS clinical trials, while PLS pharmacological trials are lacking. There remains an unmet need for diagnostic biomarkers for upper motor neuron predominant conditions and prognostic indicators regarding prognosis, survival, and risk of conversion to ALS. Validated biomarkers will not only have implications for individualized patient care but also serve as outcome measures in pharmaceutical trials. Given the paucity of post-mortem studies in PLS, novel pathological insights are generally inferred from state-of-the-art imaging studies. Computational neuroimaging has already contributed significantly to the characterization of PLS-associated pathology in vivo and has underscored the role of neuro-inflammation, the presence of extra-motor changes, and confirmed pathological patterns similar to ALS. This systematic review assesses the current state of PLS research across clinical, neuroimaging and neuropathological domains from a combined clinical and academic perspective. We discuss patterns of pathological overlap with other ALS phenotypes, examine if the biological processes of PLS warrant therapeutic strategies distinct from ALS, and evaluate the evidence that classes PLS as a distinct clinico-pathological entity.

FV7. Tract of interest-based DTI analysis in upper and lower motor neuron disease variants of ALS

The prevalence of psychiatric disorders in primary lateral sclerosis (PLS) is currently unknown. In the present study, we compared the prevalence of psychiatric illness in patients with PLS and amyotrophic lateral sclerosis (ALS). We hypothesized that if the psychosocial stress of motor neuron disease predisposes patients to depressive disorders, patients with ALS (with a poorer prognosis and more disability than patients with PLS) should have a higher prevalence of depressive disorders than patients with PLS. We administered the gold standard of psychiatric assessment, the SCID, to 19 PLS and 13 ALS patients. We found a prevalence of current depressive disorders in PLS patients that was, by a non-significant trend, lower than that of ALS patients. The prevalence of current depressive disorders in the ALS patients was higher than previously reported and similar to that observed in non-neurological medical disorders. Other psychiatric disorders were rare. In conclusion, depressive disorders were the most commonly observed psychiatric disorders in both PLS and ALS. By a non-significant trend, the PLS patients had a lower current prevalence of depressive disorders than the ALS patients. These data are consistent with the hypothesis that the psychosocial stress of MND is a risk factor for depression.

Tongue's motor evoked potentials in the diagnosis of Primary Lateral Sclerosis (PLS): Preliminary report

110. Tongue’s motor evoked potentials in the diagnosis of Primary Lateral Sclerosis (PLS): Preliminary report

<h3>Objective:</h3> We studied the association of changes in body mass index (BMI) with disease progression among amyotrophic lateral sclerosis (ALS) and primary lateral sclerosis (PLS) Multicenter Cohort Study of Oxidative Stress (COSMOS) study participants, prospectively followed up to 24 months. <h3>Background:</h3> Weight loss is a poor prognostic factor in ALS. However, less is known about weight change in PLS. <h3>Design/Methods:</h3> Participants had a confirmed diagnosis of ALS or PLS and completed baseline and at least one follow-up visit. The rate of BMI change (ΔBMI) and total revised ALS functional rating scale change (ΔALSFRS-r) were calculated between baseline and the first follow-up. Correlation between ΔBMI and ΔALSFRS-r were assessed using Pearson correlation among ALS and PLS participants separately. The demographics and proportion of participants with swallowing dysfunction at baseline and significant weight loss were compared between ALS and PLS groups using chi-square test. Cox proportional hazard models examined the association between significant weight loss (ΔBMI&lt;−1kg/m2/year) and survival in ALS, adjusted for other prognostic factors. <h3>Results:</h3> 279 ALS and 37 PLS participants were included. Mean age of ALS and PLS were both 60 years and 61% male. At baseline, swallowing dysfunction was more frequent in the PLS (78% vs 48%, p&lt;0.001) while significant weight loss was more frequent in the ALS (53% vs 19%, p&lt;0.001). ΔBMI and ΔALSFRS-r correlated significantly in ALS (r=0.3, p&lt;0.0001) but not in PLS (r= −0.21, p=0.2). Significant weight loss was associated with increased risk of death (hazard ratio 2.08, p&lt;0.0001) in ALS after adjusting for age, disease-duration, bulbar-onset, diagnostic-certainty, riluzole-intake, forced vital capacity, baseline BMI, baseline ALSFRS-r and ΔALSFRS-r. <h3>Conclusions:</h3> In ALS, significant weight loss is a strong independent prognostic factor for survival and rate of BMI change correlates with faster functional decline. In contrast, significant weight loss is infrequent in PLS despite a high prevalence of swallowing dysfunction. <b>Disclosure:</b> Dr. Lee has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Alexion. Dr. Lee has received personal compensation in the range of $0-$499 for serving as a Consultant for Amylyx. Dr. Lee has received personal compensation in the range of $0-$499 for serving on a Scientific Advisory or Data Safety Monitoring board for Regeneron. The institution of Dr. Lee has received research support from Myasthenia Gravis Foundation of America. The institution of Dr. Lee has received research support from CReATe consortium/American Brain Foundation. Dr. Mitsumoto has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Eli Lilly. Pam Factor-Litvak has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for ICF. Pam Factor-Litvak has received personal compensation in the range of $10,000-$49,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Frontiers Publishing. The institution of Pam Factor-Litvak has received research support from NIH. Prof. Nieves has received personal compensation in the range of $5,000-$9,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Bone Health and Osteoporosis Foundation. The institution of Prof. Nieves has received research support from Radius Pharmaceuticals. Prof. Nieves has received personal compensation in the range of $0-$499 for serving as a DSMB member with NIH.

Identical patterns of cortico-efferent tract involvement in primary lateral sclerosis and amyotrophic lateral sclerosis: A tract of interest-based MRI study