Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by degeneration of upper and lower motor neurons (1). The clinical picture of ALS is heterogeneous, including classic ALS, which is characterized by widespread muscle atrophy and corticospinal tract involvement, and flail arm syndrome, which is dominated by restricted muscle atrophy in both upper extremities. In addition, upper motor neuron-dominant ALS (UMND ALS) mainly involves upper motor neurons (UMNs), with only minor lower motor neuron (LMN) lesions (2, 3). Although these clinical phenotypes share similar pathological hallmarks, the prognosis is quite different, which suggests heterogeneity in ALS (4).

The prevalence of UMND ALS ranges from 6.5 to 22.2% among all ALS patients (5, 6). UMND ALS is generally considered to have an earlier disease onset, a better prognosis and a slower rate of progression than classic ALS (7). Previous studies have suggested that its better prognosis may be related to preservation of respiratory function (6). The subtle LMN damages differentiate UMND ALS from primary lateral sclerosis (PLS), which has a better prognosis. Despite the apparent differences, these three phenotypes (ALS, UMND ALS and PLS) still belong to a continuous spectrum of disorder (8).

Although the prognosis of UMND ALS is better than other ALS phenotypes, the severe spasticity caused by upper motor neuron damage has a significant impact on the activity of daily living, especially lower limb function and ambulatory abilities. Some studies also revealed that UMND ALS and PLS patients have gait instability and frequent falls in the early disease stage (9–11). These manifestations predominantly affect lower extremity function and cause the revised ALS functional rating scale (ALSFRS-R) score, especially the lower extremity part, to significantly decrease in the first few years of the disease.

The pathophysiological mechanism of postural instability in ALS patients is still not fully revealed. UMN lesions were suggested to be one of the major reasons for postural instability, but recent studies also indicate that frontal lobe dysfunction (premotor area, precentral gyrus, parietal lobule, dorsolateral prefrontal) also has an impact on motor dysfunction (12, 13). Some of these patients even have parkinsonism features such as bradykinesia and tremor (ALS-plus) (12, 14–17). There is no conclusion that postural instability represents a distinct feature of a subgroup of ALS patients rather than the consequence of more severe UMN signs in the lower limbs.

In this study, we describe the clinical features and the phenomenon of mismatch between the rate of lower extremity function decline and prognosis in patients with UMND ALS in a large ALS cohort. We compared these patients with matched classical ALS patients and discussed the early decline in motor function and the difference between UMND ALS with and without postural instability.

In the present study, we examined the characteristics of UMND ALS patients and the lower extremity functional decline in a large prospective recruitment cohort. In this cohort, the prevalence of UMND ALS was 9.0%, which is comparable with previous studies. The survival of UMND ALS was significantly better than that of classical ALS, and this result was consistent after multivariate modeling. This suggests that UMND ALS is an independent predictor for good prognosis. Moreover, the patient’s KCSS stage was significantly lower than that of classic ALS, suggesting that UMND ALS has a slower progression. There was no difference in the cognitive and behavioral changes, which is also mentioned in a previous paper (7).

Although the ALSFRS-R score and lower extremity strength of UMND ALS was significantly better than that of classical ALS when the disease was diagnosed, with a generally more favorable prognosis compared to ALS, the functional decline of the lower extremities was not significantly different from that of ALS in follow-up, suggesting rapid deterioration of spasticity and instability in the early disease stage. A study also showed that the ALSFRS-R lower extremity score was numerically lower than that of classical ALS in the early stage (6). The deterioration of lower limb function may also potentially arise from the gradual development of LMN damage in UMND ALS patients, although being a less likely scenario. However, lacking follow-up EMG data, we are unable to exclude this possibility, highlighting a need for future prospective cohort study. UMND ALS patients can be included in clinical trials according to new diagnostic criteria for ALS (e.g., Gold Coast criteria) (23). According to this study, they have a nonlinear decline and “ceiling effect” of ALSFRS-R scores in the first to second year after disease diagnosis. Therefore, more attention should be paid to the mismatch between early functional decline and survival in UMND ALS, as the ALSFRS-R decline is more widely used as the surrogate outcome in clinical trials.

The current definition of UMND ALS is still empirical and debated (24). In this study, we also explored the possible heterogenicity of this ALS subtype. UMND ALS patients with gait instability or repeated falls (UMND ALS plus) account for 2.5% of all ALS patients and 28.0% of overall UMND ALS patients. UMND ALS plus has an earlier onset age, higher incidence of lower extremity onset, a lower ALSFRS-R score and a more advanced disease stage than pure UMND ALS. KCSS staging and ALSFRS-R score in patients with UMND ALS plus do not differ from those in matched classic ALS, suggesting a more rapid progression of disease that differs from pure UMND ALS. However, the lower motor neuron damage in this phenotype is relatively mild, resulting in a significantly better prognosis. The rapid decline in ALSFRS-R in UMND ALS can be attributed mainly to the UMND ALS plus subgroup, which has more severe lower extremity dysfunction. The difference on age and site of onset between UMND ALS plus and pure UMND ALS cannot be explained by differences on UMN signs or different disease stages. In addition, these two groups are stratified based on the presence of gait disturbances at diagnosis, indicating an early feature of the disease, with some patients even presenting with falls as their chief complaint. This suggests that the differences are not merely reflections of different phases of the same disease but rather implying distinct disease behaviors. Whether UMND ALS plus represents a distinct subgroup of ALS patients deserves further investigation.

The present study also showed that UMND ALS plus had a more severe (higher PUMNS score) and widespread (higher KCSS stages) UMN symptoms, consistent with a previous study (17), suggesting a more severe involvement of primary motor cortex against pure UMND ALS. However, we cannot rule out the possibility of coincidental extrapyramidal symptoms that may also contribute to lower limb dysfunction. Postural instability or backward falls have been reported in early-stage ALS, especially in UMND ALS and PLS. The premotor cortex (supplementary motor area), superior parietal lobule, and basal ganglia involvement have been speculated to be responsible for gait disorders (12, 25). Extrapyramidal features are not typical of ALS. Notably, a subset of tauopathies can also present with prominent UMN symptoms with concomitant extrapyramidal manifestations (26), similar to the UMND ALS plus in this study. Globular glial tauopathy (GGT) is a rare 4-repeat tauopathy with clinical manifestations that can mimic ALS (27). TDP-43 pathology with comorbid Tau pathology, on the other hand, is not uncommon in neurodegenerative diseases and may affect clinical manifestations. Whether Tau pathology accounts for extrapyramidal manifestations in UMND ALS plus patients still require further pathology and follow-up study. Therefore, we speculate that UMND ALS plus has widespread pathology in the brain, and the balance disturbance may be caused by a combination of severe upper motor neuron damage and extensive extra-motor brain region involvement. This hypothesis needs further pathological and neuroimaging study.

The main limitation of this study is the absence of prospective clinical follow-up, especially the assessment for lower motor neuron. Future longitudinal studies on UMND ALS would have better clarified the reason for the apparent faster progression and more significant functional decline in the UMND ALS plus subgroup. Another limitation is its baseline parameter imbalance. Although propensity score matching eliminated some of the imbalance, it also reduced representation for this cohort. During the recruitment course of this cohort, the diagnostic criteria for PLS was updated. Nonetheless, the ALS patients included in our research presented with acute and chronic denervation in at least one muscle, which still does not meet the revised diagnostic criteria for PLS (28). Given the extensive duration of the study, there is a possibility of bias in the electrophysiological data. Moreover, differentiating early-stage PLS from UMND ALS remains inherently difficult. While we cannot exclude the possibility that a minority of UMND ALS cases in this study might ultimately be diagnosed as PLS, this scenario is considered unlikely, as the UMND ALS proportion in our study aligns with prior cohorts and exhibits poorer survival outcomes compared to typical PLS. Additional limitation is that the recognition of balance disorder and gait instability in this study is based on the medical history and neurological examination, and there is no objective evaluation of balance (such as the Berg balance scale). Hence, the prevalence of UMND ALS plus patients may be underestimated. Neuroimaging, follow-up EMG, genetic and biomarker profiles were also unavailable in the current cohort and this could be clarified in future prospective cohorts. Hence, the pathophysiological mechanisms of UMND ALS cannot be addressed in this study.

In summary, UMND ALS accounts for 9.0% of all ALS patients with a favorable prognosis. However, these patients have a rapid decline in lower extremity function in the early disease stage. A subgroup of these patients with frequent falls or postural instability has an earlier disease onset and their motor function declines as fast as classic ALS. Whether these patients represent a distinct subgroup of ALS deserves further investigation.

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

The studies involving humans were approved by the Ethics Committee of Peking University Third Hospital (IRB No. 00006761). The studies were conducted in accordance with the local legislation and institutional requirements. The participants provided their written informed consent to participate in this study.

XYL: Writing – original draft, Funding acquisition, Formal analysis. LC: Writing – review & editing, Methodology, Data curation. SY: Writing – review & editing, Formal analysis. XXL: Writing – review & editing. YZ: Writing – review & editing. DF: Writing – review & editing, Supervision, Methodology, Funding acquisition, Conceptualization.