Primary lateral sclerosis (PLS) is an ultrarare upper motor neuron syndrome with a prognosis unique from classical ALS. The study of PLS is complicated by its rarity and the difficulty distinguishing PLS from ALS. We present data from a 1-year prospective follow-up study on PLS and efforts to distinguish it from ALS. Seventy-six PLS participants enrolled in this prospective natural history study. EMG studies, blood neurofilament light chain levels (NfLs), and demographic characteristics were obtained at baseline. At 1-year follow-up, repeat EMG studies were conducted to determine which participants fulfilled criteria for ALS. Baseline characteristics were then compared to determine features that predict reclassification. Seventy participants completed 1-year follow-up. Five of the 70 were reclassified to ALS (7.1%). Those reclassified had higher trends in baseline blood NfL levels (91.4 vs. 34.0 pg/mL, p = 0.13) and shorter symptom duration (39 vs. 69 months in the PLS group, p = 0.15). Reclassification was noted in both probable and definite PLS participants. All cases with a symptomatic duration of less than 2 years retained the PLS phenotype (5 of 5). NfL levels over 90 pg/mL predicted reclassification with 94% specificity and 60% sensitivity. No other features predicted reclassification to ALS. In our population, reclassification of PLS to ALS occurred at a low frequency at 1 year follow-up (7.1%). Baseline NfL was the strongest predictor in differentiating UMN dominant ALS from PLS at 1-year follow-up. Based on our data, we propose EMG and NfL criteria for enrollment in future PLS trials.

Involvement of Keap1/Nrf2 and the antioxidant defence in cytoprotective effects induced by cannabis polyphenols in SH-SY5Y neuronal cells.

Trajectory of Mobility Function Decline for People With Motor Neuron Disease.

To quantify riluzole use in New Zealand, identify factors associated with its use and explore reasons for non-use. In 2025, people in New Zealand diagnosed with MND were invited to self-complete questionnaires. Data were collected via Qualtrics, exported to Excel and analysed using descriptive and inferential statistics. Respondents with progressive muscular atrophy or primary lateral sclerosis diagnoses were excluded from this analysis. Of 115 respondents, 55 (48%) were currently taking riluzole, 14 (12%) had taken it previously and 42 (36%) had never taken it. Common reasons for non-use included riluzole not being offered and concerns about lack of effectiveness and/or side effects. Uptake was lower with bulbar onset than limb onset (p<0.05). People with ALS in New Zealand have low uptake of riluzole, despite its survival benefits. Prescribers and people with ALS need up-to-date information about riluzole's benefit-risk profile to increase uptake and confidence in prescription and use. Liquid riluzole is needed in New Zealand to aid uptake.

TDP-43 proteinopathies, such as frontotemporal degeneration (FTLD) and amyotrophic lateral sclerosis (ALS), are classified into five neuropathological subtypes, Types A to E, according to the morphology of TDP-43 inclusions. Recent cryo-electron microscopy analysis of FTLD-TDP cases demonstrated that TDP-43 filaments composing the inclusions are structurally different depending on the subtype, and remarkably, co-assembled heteromeric filaments of TDP-43 and annexin A11 (ANXA11) were identified in Type C. Therefore, the involvement of ANXA11 in TDP-43 proteinopathy should be further examined. Here, we pathologically and biochemically analyzed four cases of primary lateral sclerosis-phenotype FTLD/motor neuron disease (MND) with TDP-43 pathology (PLS-TDP), and found that ANXA11 co-localizes with FTLD-TDP Type A pathology in PLS-TDP. Immunoblot analysis of the PLS-TDP cases revealed that the banding patterns of C-terminal and chymotrypsin-resistant fragments of TDP-43 are distinct from those of FTLD-TDP Types A, B and C. In addition, the N-terminal fragments of ANXA11 appear to be different from those of FTLD-TDP Type C. Filaments extracted from PLS-TDP cases were TDP-43- and ANXA11-immunopositive, suggesting the presence of TDP-ANXA11 heteromeric filaments. These results suggest that co-aggregation of ANXA11 and TDP-43 may serve as a neuropathological and biochemical indicator distinguishing PLS from ALS in FTLD/MND.Supplementary InformationThe online version contains supplementary material available at 10.1186/s40478-025-02210-w.

BackgroundAmyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterised by progressive muscle weakness and ultimately death from respiratory failure. Heterogeneity in disease trajectories and outcomes among patients with ALS (pwALS) is influenced by healthcare access, rehabilitation, and palliative care, but real-world data on demographic and clinical characteristics remain scarce in many countries, including Austria.ObjectivesTo characterise the demographic, clinical, and genetic landscape of pwALS in Austria.MethodsIn this retrospective cohort study, we included pwALS diagnosed according to the Gold Coast criteria and treated at two large tertiary referral centres. Demographic, clinical, and genetic data were extracted from the local ALS registries, and survival was determined via linkage with Statistik Austria, censored in December 2023.ResultsA total of 341 patients with motor neuron disease were included (44.9% female), of whom 5% were diagnosed with primary lateral sclerosis and 2.9% with progressive muscular atrophy. Among pwALS (n = 314), spinal onset was most common (67.2%), followed by bulbar onset (29.6%) and respiratory onset (2.5%). Median survival from symptom onset was 36.0 months (IQR 20.0–74.0), with age at onset (HR 1.04, 95% CI 1.02–1.05; p < 0.0001), diagnostic delay (HR 0.97, 95% CI 0.96–0.98; p < 0.0001), and PEG tube placement (HR 0.72, 95% CI 0.50–1.00; p = 0.0478) as the only independent predictors of survival. (Likely) pathogenic variants were identified in 5.5% of patients, including two in SOD1 and one each in C9orf72, OPTN, TARDBP, and FUS.ConclusionsThis study provides the first comprehensive description of the demographic, clinical, and genetic characteristics of pwALS in Austria, offering valuable real-world insight into disease presentation and genetic diversity.Supplementary InformationThe online version contains supplementary material available at 10.1007/s00415-025-13614-y.

Motor neuron disease (MND) represents a broad and heterogeneous group of disorders involving the upper or lower motor neurons, represented mainly by amyotrophic lateral sclerosis (ALS), primary lateral sclerosis (PLS), progressive muscular atrophy (PMA) and progressive bulbar palsy (PBP). Primary motor neuronopathies are characterized by progressive degenerative loss of anterior horn cell motoneurons (lower motor neurons) or loss of giant pyramidal Betz cells (upper motor neurons). Rare atypical variants of MND-ALS include flail arm syndrome (FA), flail leg syndrome (FL), facial-onset sensory and motor neuronopathy (FOSMN), finger extension weakness and downbeat nystagmus motor neuron disease (FEWDON-MND) and long-standing and juvenile MND-ALS. In this article, we present a review of diagnostic criteria and the differential diagnosis for MND, focusing on ALS.

We describe two patients with variably protease-sensitive prionopathy (VPSPr) who developed progressive upper motor neuron symptoms, insomnia, behavioral and cognitive decline, compatible with primary lateral sclerosis associated with frontotemporal dementia (FTD). Neuropathology revealed a spongiform encephalopathy with frontotemporal and pronounced thalamic involvement, associated with fine synaptic abnormal prion protein conformer (PrPSc) deposits, microplaques, and intraneuronal aggregates. Western blot analysis revealed a characteristic VPSPr proteolytic profile, lacking the diglycosylated band. Both patients were methionine homozygous at PRNP codon 129 and carried no pathogenic mutations. These cases illustrate that VPSPr can present with a prominent motor neuron syndrome and FTD features.

In this retrospective case series, we present two patients with primary lateral sclerosis (PLS) and spasticity-related gait impairment. Both patients were assessed with 6-min walk tests (6MWT) and timed up and go (TUG) at baseline and after 4 weeks of oral levetiracetam. Following levetiracetam therapy, Patient 1 improved 27.3% (148.5 to 189 m) on 6MWT and 26.1% (23-17 s) on TUG. Patient 2 improved 18% (90 m in 4:29 min to 112 m in 6 min) on 6MWT and 10% (46-41 s) on TUG. Larger prospective trials of levetiracetam for spasticity and gait may be considered in PLS.

UBQLN2 is located on Xp11.21 and encodes the ubiquilin 2 protein involved in protein homeostasis. Heterozygous or hemizygous missense variants in UBQLN2 cause amyotrophic lateral sclerosis (ALS). In addition, rare cases of primary lateral sclerosis (PLS) and spastic paraplegia (SPG) associated with UBQLN2 variants have also been reported. Here, we report four male patients in a family with SPG carrying a hemizygous missense UBQLN2 variant (NM_013444.4:c.1442G>T, p.(Gly481Val)). These patients showed childhood-onset lower limb spasticity, progressing to gait disturbance. The mean onset age (11 years) was earlier than that of previous ALS (49.6 years), SPG (29 years) and PLS (25.5 years) cases, and their progression was slower than in ALS or PLS. Literature review reveals Pro506 missense variants are associated with various motor neuron disease phenotypes, with some SPG patients progressing to ALS. Therefore, we consider that careful follow-up is warranted for UBQLN2-related SPG patients.

Motor band sign in 18F-FDG PET/CT studies: a biomarker of degenerative upper motor neuron disease? A study of three cases and literature review.

PCR167 Outcome Measures Relevant for Assessing Health-Related Quality of Life and Utility in Primary Lateral Sclerosis (PLS)

SA49 Health-Related Quality of Life Impacts of Living With Primary Lateral Sclerosis (PLS): The Development of a Conceptual Model

CO189 Primary Lateral Sclerosis (PLS): A Targeted Literature Review of Symptoms, Progression, and Outcomes to Inform Evidence Gaps for Rare Neurological Disorders

FTLD-TDP type A pathology co-localized with annexin A11 in primary lateral sclerosis cases

There is a lack of information about startle reflex (SR) in primary lateral sclerosis (PLS). This study examined the presence and prevalence of SR in PLS and compared findings with amyotrophic lateral sclerosis (ALS). 46 PLS and 54 ALS participants were assessed through structured interviews in this cross-sectional study. Fisher's exact test was used to compare reported SR prevalence. Multivariable linear regression was utilized to study associations between disease group and SR frequency in response to sudden stimuli. SR differed markedly between the two groups, with a higher prevalence in PLS (93.5%) than ALS (20.4%; p < 0.001). Among ALS patients, SR was present in all upper motor neuron (UMN)-predominant cases, which accounted for 54.5% of the SR-positive ALS group, but only 10.4% of probable/definite ALS cases. In SR-positive patients, response frequency to sudden stimuli exceeded 60% in both ALS and PLS, most often triggered by auditory stimuli. Younger age, shorter disease duration, and PLS diagnosis were associated with more frequent SR. SR is significantly more common in PLS than in ALS. Notably, UMN-predominant ALS, although limited in number, showed a higher prevalence of SR (6 out of 6, 100%), indicating that predominant UMN involvement may be a key determinant of SR across both conditions. These hypothesis-generating findings suggest that SR may serve as a novel clinical marker in PLS and UMN-predominant ALS, warranting further validation through prospective studies.

In this population-based study, we described the epidemiology of primary lateral sclerosis (PLS) in northern Italy and compared the clinical characteristics of patients with PLS to those with predominant upper motor neuron (PUMN) involvement and classic amyotrophic lateral sclerosis (ALS). Patients from the PARALS registry diagnosed with probable or definite PLS between 2007 and 2021 were included. Crude annual incidence rates were calculated, along with age- and sex-specific rates. A survival analysis was performed to identify prognostic factors at diagnosis. Covariates included sex, age at onset, site of onset, diagnostic delay, forced vital capacity (FVC), change in ALS Functional Rating Scale (ΔFRS), and change in body mass index (ΔBMI). A total of 57 PLS patients (2.7%) were included, with a crude incidence rate of 0.084 per 100,000 person-years. Compared to PUMN and classic ALS, PLS patients were younger (median onset age 63.5 years, interquartile range [IQR] 54.9-70.4) and predominantly female (male-to-female ratio 0.58). Bulbar onset occurred in 11 cases (19.3%), all of whom later developed spinal symptoms. At censoring, 38 patients (66.7%) were still alive (median survival 8.3 years, IQR 5.7-12.3), corresponding to a point prevalence of 0.89 per 100,000. Survival was significantly associated with age at onset (hazard ratio [HR] 1.17, 95% confidence interval [CI]: 1.05-1.33, p = 0.001), male sex (HR 4.41, 95% CI: 1.24-15.6, p = 0.02), and FVC at diagnosis (HR 0.95, 95% CI: 0.93-0.98, p = 0.006). PLS was confirmed to be rarer than other ALS phenotypes. Patients had a higher age at onset than previously reported and a female predominance. Sex, age at onset, and respiratory function were key prognostic factors. ANN NEUROL 2026;99:606-613.

Recent studies suggest that primary lateral sclerosis (PLS) may have a genetic component. In this work, we performed a next-generation sequencing (NGS) analysis in order to explore the genetic architecture of PLS in a cohort of Italian patients. NGS was conducted to analyze 228 genes associated with amyotrophic lateral sclerosis (ALS), hereditary spastic paraplegia (HSP), and parkinsonian syndromes (PS) in a cohort of PLS patients diagnosed between 2003 and 2021 at our center. All patients were also screened for C9orf72 hexanucleotide repeat expansion (C9orf72-HRE) by repeat-primed PCR. Genetic variants were classified according to the ACMG criteria. In our study, including 47 PLS patients, we detected 22 rare variants in 17 patients, including 8 likely pathogenic or pathogenic variants and 14 variants of uncertain significance. Four patients carried more than one variant. Among the variants identified, 18 (81.8%) were found in ALS-associated genes. Variants in TBK1 were associated with extra-motor involvement. Although the majority of the PLS patients in our cohort tested negative for an expanded panel of genes associated with ALS, HSP and PS, in 36.2% of the cases, a genetic variant was identified and it mostly belongs to genes associated with ALS, including a C9orf72 expansion and a rare SOD1 variant. Based on these results, we emphasize the need for genetic screening in PLS patients. Further studies on the genetic background are necessary to better understand the complex pathomechanism of each phenotype within the MND-FTD spectrum disorder.

Objective: Primary Lateral Sclerosis (PLS) is a progressive neurodegenerative disease with no current therapy. So far, the lack of a specific evaluation instrument has been a barrier for clinical trials. The Primary Lateral Sclerosis Functional Rating Scale (PLSFRS) is a novel tool designed to specifically assess disease progression and functional impairment in patients with PLS. We sought to translate and validate the PLSFRS to the Spanish language. Methods: We back-translated the PLSFRS scale to Spanish and assessed a cohort of 10 PLS patients by two independent raters. Both inter- and intrarater reliability were evaluated, with assessments conducted through both in-person and over-the-phone interviews. Results: The PLSFRS demonstrated excellent inter- and intrarater reliability for the total score (ICC = 0.90–1.00) and for most subdomains (ICC > 0.90). Agreement between in-clinic and over-the-phone assessments was similarly strong. Squared weighted kappa coefficients for individual items indicated substantial to almost perfect agreement. Bland–Altman analysis revealed no significant systematic bias, with mean differences close to zero and acceptable limits of agreement. Conclusion: This study demonstrates high reliability for the Spanish version of the PLSFRS scale.

Primary Lateral Sclerosis (PLS) is an ultra-rare disorder characterized by the selective degeneration of upper motor neurons. Here, we report the generation and validation of two human induced pluripotent stem cell (iPSC) lines derived from unrelated male and female donors without any known family history of PLS or identifiable genetic risk factors. Aside from a juvenile subtype, PLS is predominantly idiopathic, and existing animal models fail to replicate its clinical features. As such, these iPSC lines offer a valuable resource for studying sporadic, adult-onset PLS-the most prevalent form of the disease.