Upper motor neuron‐predominant motor neuron disease presenting as atypical parkinsonism: A clinicopathological study
Department of Neuroscience, Mayo Clinic, Jacksonville, Florida, USA
Department of Neurology, Kansai Medical University, Osaka, Japan
Department of Pathology and Laboratory Medicine, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania, USA
Department of Neurology, Mayo Clinic, Jacksonville, Florida, USA
Department of Neurology, Fukuoka University, Fukuoka, Japan
Department of Pathology & Laboratory Medicine, University of Texas Health Science Center San Antonio, Texas, USA
Abstract
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by upper and lower motor neuron signs. There are, however, cases where upper motor neurons (UMNs) are predominantly affected, leading to clinical presentations of UMN‐dominant ALS or primary lateral sclerosis. Furthermore, cases exhibiting an UMN‐predominant pattern of motor neuron disease (MND) presenting with corticobasal syndrome (CBS) have been sparsely reported. This study aims to clarify the clinicopathological features of patients with UMN‐predominant MND. We reviewed 24 patients with UMN‐predominant MND with TDP‐43 pathology in the presence or absence of frontotemporal lobar degeneration. Additionally, we reviewed the medical records of patients with pathologically‐confirmed corticobasal degeneration (CBD) who received a final clinical diagnosis of CBS (n = 10) and patients with pathologically‐confirmed progressive supranuclear palsy (PSP) who received a final clinical diagnosis of PSP syndrome (n = 10). Of 24 UMN‐predominant MND patients, 20 had a clinical diagnosis of an atypical parkinsonian disorder, including CBS (n = 11) and PSP syndrome (n = 8). Only two patients had antemortem diagnoses of motor neuron disease. UMN‐predominant MND patients with CBS less frequently exhibited apraxia than those with CBD, and they were less likely to meet clinical criteria for possible or probable CBS. Similarly, UMN‐predominant MND patients with PSP syndrome less often met clinical criteria for probable PSP than PSP patients with PSP syndrome. Our findings suggest that UMN‐predominant MND can mimic atypical parkinsonism, and should be considered in the differential diagnosis of CBS and PSP syndrome, in particular when criteria are not met.
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Keywords: atypical parkinsonism, TDP‐43, upper‐motor‐neuron‐predominant motor neuron disease
Graphical
Heatmap and hierarchical clustering based on neuronal loss in 24 UMN‐predominant MND cases. Two distinct clusters are identified by hierarchical clustering based on neuronal loss. The heatmap reflects the severity of neuronal loss, and a color scale is given at the right. Missing data are shown in gray. Patients are represented with columns, and the study ID of each patient is provided. The main clinical features and diagnoses of each case are shown.
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Article notes
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Received 2024 Mar 5; Accepted 2024 Jun 26; Collection date 2025 Jan.
1.INTRODUCTION
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder that typically presents with upper and lower motor neuron signs. It is pathologically characterized by neuronal loss of upper and lower motor neurons as well as TDP‐43 positive neuronal cytoplasmic inclusion (NCI) and dystrophic neurites (DN) [1, 2]. ALS is commonly associated with upper and lower motor neuron deficits, but if neuronal loss of lower motor neurons is predominant, progressive muscular atrophy may be present. On the other hand, motor neuron disease (MND) with predominant neuronal loss of upper motor neurons (UMNs) may present with UMN dominant‐ALS and primary lateral sclerosis (PLS).
There have been relatively few reports of pathologically diagnosed pure UMN disease with TDP‐43 pathology, and detailed descriptions of clinical and neuropathologic features of such cases are scarce [3, 4, 5]. The core clinical features of UMN‐predominant MND are related to UMN signs [4, 6], such as spasticity, and hyperreflexia, but autopsy‐confirmed cases of UMN‐predominant MND have also been reported to present with atypical parkinsonism, such as progressive supranuclear palsy (PSP) syndrome and corticobasal syndrome (CBS) [7, 8, 9]. CBS and PSP syndrome are associated with various underlying pathologies, but most often tauopathies, including PSP and corticobasal degeneration (CBD). Less often, frontotemporal lobar degeneration (FTLD) with TDP‐43 pathology (FTLD‐TDP) has been reported in patients with CBS [10] or PSP syndrome [11].
The present study aims to investigate 24 patients with autopsy‐proven UMN‐predominant MND, dividing them into clinical subtypes based on the predominant clinical features. In this study, UMN‐predominant MND was defined as cases with UMN loss and corticospinal tract degeneration with minimal or no lower motor neuron pathology. We focus specifically on patients presenting with CBS due to UMN‐predominant MND (MND‐CBS) and those presenting with progressive supranuclear palsy syndrome due to UMN‐predominant MND (MND‐PSPS). To characterize the clinical features of MND‐CBS and MND‐PSPS, we compared them to patients who were clinically and pathologically diagnosed with CBD or PSP (CBD‐CBS or PSP‐PSPS). We also aimed to characterize the pathological features of UMN‐predominant MND by evaluating the distribution and severity of neuronal loss and TDP‐43 pathology, with a focus on TDP‐positive NCI and DN. To do this, we conducted cluster analysis based on the severity and topographical distributions of neuronal loss.
2.METHODS
2.1.Case selection
We selected all patients from 2000 to 2021 with a pathological diagnosis of UMN‐predominant MND or FTLD with UMN‐predominant MND from the Mayo Clinic brain bank for neurodegenerative disorders. These brain autopsies were obtained with the consent of the legal next‐of‐kin and were considered exempt from human subject research. The Mayo Clinic brain bank operates under protocols approved by the Mayo Clinic Institutional Review Board. All cases underwent systematic and standardized neuropathologic evaluations, including data collection on concurrent pathologies, such as Alzheimer's disease neuropathologic changes [12]. UMN‐predominant MND was defined as cases with UMN loss, characterized by loss of Betz cell and gliosis of the motor cortex, and corticospinal tract degeneration, with minimal or no lower motor neuron pathology and no Bunina bodies. A total of 34 individuals with pathologic diagnoses of UMN‐predominant MND with TDP‐43 pathology and FTLD with UMN‐predominant MND with TDP‐43 pathology were identified. Of those, 24 cases (71%) were included who had adequate medical records and good to excellent antemortem clinical documentation by at least one neurologist. Fifteen out of 24 cases were documented by at least one specialist in movement disorders or motor neuron diseases, while the remaining nine were diagnosed by general neurologists. Two of the cases were previously reported [7, 13].
As control groups, we selected 10 patients with pathologically‐confirmed CBD who were given a clinical diagnosis of CBS and 10 patients with pathologically‐confirmed PSP who were given a clinical diagnosis of Richardson syndrome from the Mayo Clinic brain bank. Of the 10 patients with CBD‐CBS, 3 fulfilled criteria for probable CBS and 7 for possible CBS according to the criteria proposed by Armstrong et al. [14] All patients with PSP‐PSPS were judged to fulfill the criteria for probable PSP‐Richardson syndrome according to the International Parkinson and Movement Disorder Society's criteria for PSP [15]. The study design flow chart is shown in Figure 1.
2.2.Clinical assessment
Two neurologists (A.M., S.K.) extracted the following information from medical records collected throughout the course of the disease: sex, age at symptom onset, age at death, family history of neurologic disease, clinical diagnoses, initial symptoms categorized by the first system affected [16] (i.e., bulbar, upper extremities, lower extremities or cognitive dysfunction), signs and symptoms during the disease course and their timing, and neurologic findings as documented by a neurologist or movement disorder specialist. For each patient, a particular clinical symptom or sign was considered present if specifically stated in the clinical records. If clinical symptoms or signs were not described, they were considered to be absent for the purpose of this analysis. The following symptoms and neurologic signs were extracted from medical records: spasticity, hyperreflexia, Babinski sign, Hoffmann reflex, muscle weakness, fasciculations, dysarthria, dysphagia, parkinsonism (i.e., resting tremor, bradykinesia, or axial and limb rigidity), falls, early falls (defined as occurring within 3 years of symptomatic onset), ocular motor dysfunction, orobuccal or limb apraxia, myoclonus, dystonia, urinary urgency, memory loss, at least one of behavior features consistent with frontotemporal dementia, aphasia, neuropsychiatric symptoms (depression, anxiety, agitation), and pseudobulbar affect. Cognitive impairment was defined as short‐term memory loss, frontotemporal dementia, or other types of dementia recorded by a physician. The criteria proposed by Armstrong et al. [12] were used for TDP‐CBS. The Movement Disorder Society's criteria for PSP [13] were used for the diagnosis of TDP‐PSPS. The degree of levodopa responsiveness was recorded as no, partial, or good response. If available, electromyographic and imaging findings were reviewed. The information on symptoms was gathered from a combination of medical records, pathology records summarizing the clinical history, and a brain bank questionnaire filled out by a close relative. Findings not noted were considered negative. Of note, given the retrospective nature of the study, the quality of available medical records varied.
2.3.Neuropathologic assessment
Most of the brains were received with the left hemibrain fixed in 10% formalin and the right hemibrain frozen at −80°C. Formalin‐fixed brains underwent systematic and standardized sampling with neuropathologic evaluation by an experienced neuropathologist (D.W.D.). Paraffin‐embedded 5‐μm thick sections mounted on glass slides were stained with hematoxylin and eosin (H&E) and thioflavin S. H&E‐stained sections from the anterior horn in the spinal cord (at the cervicomedullary junction if no spinal cord was submitted), hypoglossal nucleus, putamen, globus pallidus, superior frontal gyrus, middle frontal gyrus, inferior parietal gyrus, superior temporal gyrus, and motor cortex were reviewed by three observers (A.M., S.K., D.W.D.) to assess neuronal loss on 4‐point semiquantitative scores (0 = absent; 1 = mild; 2 = moderate; 3 = severe; Supplementary Figure 1). Braak neurofibrillary tangle stage and Thal amyloid phase were assigned based upon lesion density and distribution with thioflavin S fluorescence microscopy according to published criteria [17, 18, 19]. Immunohistochemistry for phosphorylated‐TDP‐43 (pTDP‐43) (pS409/410, mouse monoclonal, 1:5000, Cosmo Bio, Tokyo, Japan) or TDP‐43 (MC2085, 1:3000, gift from Dr. Leonard Petrucelli, Mayo Clinic, FL) was performed on sections of the motor cortex, middle frontal cortex, temporal cortex, hippocampus, basal ganglia, basal forebrain, medulla, and spinal cord to establish a neuropathological diagnosis of UMN‐predominant MND. In addition, degeneration of upper and lower motor neurons, as well as corticospinal tract degeneration was assessed with a myelin stain (Luxol fast blue—periodic‐acid Schiff) and immunohistochemistry for microglia (IBA‐1, rabbit IG, 1:3000, Wako Chemicals, USA18). Bunina bodies were examined on H&E‐stained sections.
Alzheimer's type neuropathologic change was based on the consensus criteria for the neuropathologic diagnosis of Alzheimer's disease [20]. Lewy‐related pathology was assessed by α‐synuclein immunohistochemistry (NACP, rabbit polyclonal, 1:3000, Mayo Clinic) in the amygdala, basal forebrain, brainstem, cingulate gyrus, and temporal lobe, and classified as the brainstem, limbic, and diffuse types [21]. Hippocampal sclerosis was assessed on H&E stained sections of the hippocampus as previously described [22]. Argyrophilic grain disease was assessed with phosphorylated‐tau immunohistochemistry (CP13, mouse monoclonal, 1:1000 from the late Dr. Peter Davies, Feinstein Institute, North Shore Hospital, NY or AT8, mouse monoclonal, 1:2500, DAKO, Carpinteria, CA) in the amygdala. A diagnosis of aging‐related tau astrogliopathy (ARTAG) was associated with variable thorn‐shaped astrocytes or granular/fuzzy astrocytes in subependymal, subpial, perivascular, gray matter, and white matter. The presence of a C9orf72 repeat expansion was assessed using p62/sequestosome‐1 immunohistochemistry (p62 lck ligand, mouse monoclonal, 1:250, BD Transduction, USA) [23].
2.4.Assessment of TDP‐43 pathology
TDP‐43 immunohistochemistry was performed on paraffin‐embedded tissue sections of the spinal cord, medulla, a basal ganglia section that includes nucleus accumbens and corpus striatum, a basal forebrain section that includes lentiform nucleus, basal nucleus of Meynert and amygdala, superior frontal cortex, middle frontal cortex, inferior parietal cortex, superior temporal cortex, and motor cortex with anti‐phosphorylated‐TDP‐43 antibody (pS409/410, mouse monoclonal, 1:5000, Cosmo Bio). In addition to formal diagnostic evaluations, slides were reviewed by two observers (A.M., S.K.) who agreed on the presence of TDP‐43 immunoreactivity in affected brain regions and characterized as NCI, DN, or neuronal intranuclear inclusions. The severity of TDP‐43 pathology was graded semi‐quantitatively on a five‐point scale (0 = absent, 1 = rare, 2 = mild, 3 = moderate, 4 = severe) as previously reported (Supplementary Figure 2) [24].
2.5.Assigning FTLD‐TDP subtype
Each case was assigned an FTLD‐TDP subtype based on published criteria [25, 26, 27]. Type A is characterized by abundant NCI and short DN in neocortical layer II and presence of lentiform neuronal intranuclear inclusions in most cases. Also, type A cases often have fine neurites in CA1. Type B is characterized by abundant NCI and few DN in all cortical layers and the dentate gyrus. The NCI often has diffuse granular cytoplasmic TDP‐43 immunoreactivity. Type C is characterized by abundant long DN and few NCI in all cortical layers and moderate to frequent Pick body‐like NCI in the dentate gyrus. In addition to standard types, some cases had a mixture of features of both Types A and B. Cases were assigned “unclassified” when TDP‐43 positive structures were very sparse and insufficient to confidently assign a subtype.
2.6.Statistical methods
All statistical analyses were performed using R version 4.0.5 (The R Foundation for Statistical Computing, Vienna, Austria) and EZR (Saitama Medical Center, Jichi Medical University Saitama, Japan), which is a graphical interface for R [28]. A Fisher's exact test was performed for group comparisons of categorical data, as appropriate. Analysis of t test or one‐way ANOVA test were used for analyses of continuous variables, as appropriate. Hierarchical cluster analysis using Euclidean distance and average linkage clustering was performed on patient and region‐specific variables reflecting the severity of the neuronal loss or TDP‐43 pathology as previously reported [24].
2.7.Genetic analyses
We performed genetic analyses in UMN‐predominant MND cases for whom frozen brain tissue was available (n = 22). Genomic DNA was extracted from frozen brain tissue using standard procedures. For C9orf72, a 2‐step protocol was employed, consisting of a fluorescent PCR fragment‐length analysis and a repeat‐primed PCR [29]. Additionally, all cases were screened for intermediate repeats in ATXN2, as described elsewhere [30]. Moreover, Sanger sequencing was done to exclude mutations in GRN (all exons), SOD1 (all exons), TARDBP (exon 6), and FUS (exon 5, 6, 14, and 15). In brief, amplicons were generated using a PCR, followed by a sequencing reaction with the BigDye Terminator v3.1 Cycle Sequencing Kit (Applied Biosystems, Carlsbad, CA), and then run on an ABI 3730 Genetic Analyzer (Applied Biosystems). Sequence analysis was performed using Sequencher 5.3 software (Gene Codes, Michigan). Genotyping for APOE alleles (single nucleotide polymorphism [SNP] rs429358 [C___3084793_20] and rs7412 [C____904973_10]), GRN (SNP rs5848 [C___7452046_20]), TMEM106B (SNP rs3173615 [C___27465458_10]), UNC13A (SNP rs12608932 [C__43881386_10], and rs12973192 [C__11514504_10]) was performed using a TaqMan SNP genotyping assay (Applied Biosystems). Genotype calls were obtained with QuantStudio Real‐Time PCR Software v1.2 (Applied Biosystems).
3.RESULTS
3.1.Demographic and pathologic features
Of 24 patients with a pathological diagnosis of UMN‐predominant MND, 11 (46%) had an antemortem clinical diagnosis of CBS, 8 (33%) had a clinical diagnosis of PSP and 2 (8%) had a clinical diagnosis of MND, including ALS (n = 1) or frontotemporal dementia with MND (n = 1). Three (13%) had a clinical diagnosis of other disorders, including frontotemporal dementia (n = 2) or multiple system atrophy (n = 1) (Figure 1). Table 1 summarizes demographic and pathologic features of all UMN‐predominant MND patients and compares them by clinical diagnostic group (i.e., CBS, PSP syndrome, MND, and others). The average age at symptom onset was 64 ± 9 years, and the average disease duration was 5 ± 5 years. There were no significant differences in the proportion of men or women in the four groups and no differences for age at onset, disease duration, family history of parkinsonism or dementia among the groups. Pathologic features, including brain weight, Braak neurofibrillary tangle stage, Thal amyloid phase, and frequencies of hippocampal sclerosis, Lewy‐related pathology, argyrophilic grain disease, and ARTAG did not differ among the groups. There were no C9orf72 repeat expansion carriers based upon p62 immunohistochemistry.
| Total | CBS | PSPS | MND | Others | p‐Value a | |
|---|---|---|---|---|---|---|
| Demographic features | ||||||
| Number | 24 | 11 | 8 | 2 | 3 | |
| Male | 63% (15) | 55% (6) | 75% (6) | 50% (1) | 67% (2) | 0.92 |
| Age at onset | 64 ± 9 | 60 ± 8 | 69 ± 6 | 66 ± 0.7 | 66 ± 9 | 0.12 |
| Age at death | 69 ± 8 | 65 ± 7 | 73 ± 5 | 68 ± 0.7 | 76 ± 11 | 0.056 |
| Disease duration | 5.1 ± 5.0 | 5.2 ± 2.0 | 4.1 ± 2.9 | 2.0 ± 1.4 | 9.5 ± 14 | 0.37 |
| FHx of MND | 0 | 0 | 0 | 0 | 0 | |
| FHx of parkinsonism | 13% (3) | 18% (2) | 13% (1) | 0% (0) | 0% (0) | 1 |
| FH of dementia | 38% (9) | 27% (3) | 25% (2) | 100% (2) | 67% (2) | 0.17 |
| Pathologic features | ||||||
| Brain weight, grams | 1150 ± 151 | 1146 ± 127 | 1180 ± 162 | 1220 ± 28 | 990 ± 296 | 0.42 |
| Hippocampal sclerosis | 8% (2) | 9% (1) | 13% (1) | 0% (0) | 0% (0) | 1.0 |
| Braak stage, median (IQR) | II (I, II) | II (I, II) | II (I, II) | 0 (0, 0) | II (II, II) | 0.34 |
| Thal phase, median (IQR) | 2 (1, 2) | 1 (0, 2) | 0 (0, 2) | 0 (0, 0) | 0 (0, 0) | 0.38 |
| Lewy‐related pathology | 21% (5) | 46% (5) | 0% (0) | 0% (0) | 0% (0) | 0.14 |
| AGD | 0% (0) | 0% (0) | 0% (0) | 0% (0) | 0% (0) | |
| ARTAG | 42% (10) | 27% (3) | 50% (4) | 50% (1) | 67% (2) | 0.59 |
3.2.Clinical features of pathologically diagnosed UMN‐predominant MND
Table 2 lists the frequency of clinical features in autopsy‐confirmed UMN‐predominant MND. UMN signs were recorded in 75% of all cases. The most common clinical symptoms were dysarthria (92%), followed by parkinsonism (75%), dysphagia (71%), early falls (67%), urinary urgency (54%), and spasticity (50%). The frequencies of each clinical feature varied among the four groups. Parkinsonism was frequently observed in MND‐CBS (73%), MND‐PSPS (100%), and others (67%), but not in MND. An asymmetric presentation was observed in 91% of MND‐CBS. Ocular motor dysfunction was frequent in MND‐PSPS (75%). All patients with MND had muscle fasciculations. Ten patients underwent electromyography, and four of them had abnormal findings. Chronic neurogenic changes were observed in two patients, and minimal acute neurogenic changes were noted in two patients but judged to be within normal limits by the clinician of record. Fluorodeoxyglucose (FDG) positron emission tomography (PET) was available for one case (case 21), which showed bilateral hypometabolism in the posterior frontal and medial frontal lobes. After a retrospective assessment of clinical features, none of the patients were judged to fulfill research criteria for either probable PLS or definite PLS [31] nor clinically pure PLS [32].
| Total | CBS | PSPS | MND | Other | p‐Value a | |
|---|---|---|---|---|---|---|
| Bulbar signs | 33% (8) | 27% (3) | 38% (3) | 50% (1) | 33% (1) | 1.0 |
| Upper extremities | 21% (5) | 36% (4) | 13% (1) | 0% (0) | 0% (0) | 0.55 |
| Lower extremities | 46% (11) | 55% (6) | 38% (3) | 50% (1) | 33% (1) | 0.92 |
| Cognitive | 13% (3) | 0% (0) | 25% (2) | 0% (0) | 33% (1) | 0.2 |
| UMN signs | 75% (18) | 91% (10) | 50% (4) | 100% (2) | 67% (2) | 0.18 |
| Spasticity | 50% (12) | 66% (7) | 38% (3) | 50% (1) | 33% (1) | 0.74 |
| Hyperreflexia | 67% (16) | 82% (9) | 50% (4) | 100% (2) | 33% (1) | 0.23 |
| Babinski reflex | 63% (15) | 73% (8) | 38% (3) | 100% (2) | 67% (2) | 0.38 |
| Hoffmann reflex | 17% (4) | 27% (3) | 0% (0) | 0% (0) | 33% (1) | 0.27 |
| Weakness | 63% (15) | 66% (7) | 63% (5) | 100% (2) | 33% (1) | 0.69 |
| Fasciculation | 21% (5) | 18% (2) | 13% (1) | 100% (2) | 0% (0) | 0.074 |
| Dysarthria | 92% (22) | 100% (11) | 88% (7) | 100% (2) | 67% (2) | 0.26 |
| Dysphagia | 71% (17) | 82% (9) | 63% (5) | 100% (2) | 33% (1) | 0.32 |
| Parkinsonism | 75% (18) | 73% (8) | 100% (8) | 0% (0) | 67% (2) | 0.035 |
| Early falls | 67% (16) | 55% (6) | 75% (6) | 100% (2) | 67% (2) | 0.77 |
| Oculomotor | 42% (10) | 27% (3) | 75% (6) | 50% (1) | 0% (0) | 0.065 |
| Asymmetry | 54% (13) | 91% (10) | 38% (3) | 0% (0) | 0% (0) | 0.002 |
| Apraxia | 33% (8) | 55% (6) | 25% (2) | 0% (0) | 0% (0) | 0.25 |
| Myoclonus | 13% (3) | 18% (2) | 13% (1) | 0% (0) | 0% (0) | 1 |
| Dystonia | 25% (6) | 46% (5) | 13% (1) | 0% (0) | 0% (0) | 0.26 |
| Urinary urgency | 54% (13) | 82% (9) | 38% (3) | 100% (2) | 0% (0) | 0.018 |
| L‐DOPA responsive | 0% (0/14) | 0% (0/8) | 0% (0/4) | 0% (0/1) | 0% (0/1) | |
| Cognitive impairment | 42% (10) | 46% (5) | 25% (2) | 50% (1) | 67% (2) | 0.62 |
| Memory loss | 42% (10) | 46% (5) | 50% (4) | 50% (1) | 0% (0) | 0.52 |
| bvFTD features | 21% (5) | 9% (1) | 25% (2) | 50% (1) | 33% (1) | 0.36 |
| Aphasia | 21% (5) | 27% (3) | 13% (1) | 0% (0) | 33% (1) | 0.78 |
| Depression/anxiety | 54% (13) | 55% (6) | 50% (4) | 50% (1) | 67% (2) | 1 |
| Agitation | 38% (9) | 36% (4) | 50% (4) | 50% (1) | 0% (0) | 0.52 |
| Pseudobulbar affect | 21% (5) | 18% (2) | 25% (2) | 50% (1) | 0% (0) | 0.69 |
| EMG (n = 10) | 40% (4/10) | 40% (2/5) | 33% (1/3) | 0% (0) | 100% (1/1) | 1 |
| Chronic neurogenic | 20% (2/10) | 40% (2/5) | 0% (0/3) | 0% (0) | 0% (0/1) | 0.67 |
| Acute neurogenic | 0% (0/10) | 0% (0/5) | 0% (0/3) | 0% (0) | 0% (0/1) |
3.3.Comparing pathologically diagnosed UMN‐predominant MND versus CBD‐CBS
We next compared clinical features of MND‐CBS with CBD‐CBS (Table 3). All patients with CBD‐CBS met Armstrong's criteria of possible or probable CBS, whereas only two MND‐CBS met the criteria for probable CBS, and four met the criteria for possible CBS. All CBD‐CBS patients had asymmetrical limb apraxia and parkinsonism. In contrast, only six of 11 patients with MND‐CBS had apraxia, which was less frequent compared to CBD‐CBS (55% vs. 100%; p = 0.035). There were no significant differences in sex, age at onset, age at death, disease duration, asymmetry, early falls, oculomotor dysfunction, parkinsonism, or UMN signs between MND‐CBS and CBD‐CBS.
| MND‐CBS (n = 11) | CBD‐CBS (n = 10) | p‐Value a | |
|---|---|---|---|
| Male | 55% (6) | 50% (5) | 1 |
| Age of onset, years | 60 ± 8 | 65 ± 10 | 0.24 |
| Age of death, years | 65 ± 8 | 72 ± 9 | 0.11 |
| Disease duration, months | 5.2 ± 2 | 6.6 ± 3 | 0.25 |
| Asymmetrical presentation | 90% (10) | 100% (10) | 1 |
| Early falls | 55% (6) | 50% (5) | 1 |
| Ocular motor dysfunction | 27% (3) | 20% (2) | 1 |
| Apraxia | 55% (6) | 100% (10) | 0.035 |
| Parkinsonism | 73% (8) | 100% (10) | 0.21 |
| Upper motor neuron signs | 90% (10) | 70% (7) | 0.31 |
| Armstrong criteria | 0.07 | ||
| Probable CBS | 18% (2) | 30% (3) | |
| Possible CBS | 36% (4) | 70% (7) |
3.4.Comparing pathologically diagnosed UMN‐predominant MND versus PSP‐PSPS
We also compared clinical features of MND‐PSPS to PSP‐PSPS patients (Table 4). All patients with PSP‐PSPS met the Movement Disorder Society's criteria of probable PSP‐Richardson syndrome, while only four MND‐PSPS met the probable PSP‐ Richardson syndrome. One patient fulfilled criteria for possible PSP with predominant ocular motor dysfunction, two met criteria for suggestive PSP with predominant postural instability, and one met criteria for suggestive PSP with predominant frontal presentation. The disease duration was lower in MND‐PSPS compared to PSP‐PSPS (4.0 ± 3 vs. 7.0 ± 3 years; p = 0.05). Although the frequency of oculomotor dysfunction was not different between the two groups, the frequency of eye movement dysfunction specifically defined in the Movement Disorder Society's criteria for PSP (i.e., vertical supranuclear gaze palsy and slow velocity of vertical saccades) was higher in PSP‐PSPS than in MND‐PSPS, but this was not significant (100% vs 63%, p = 0.07). Other features did not appear to differ between the two groups.
| MND‐PSPS (n = 8) | PSP‐PSPS (n = 10) | p‐Value a | |
|---|---|---|---|
| Male | 75% (6) | 40% (4) | 0.19 |
| Age of onset, years | 69 ± 6 | 67 ± 8 | 0.62 |
| Age of death, years | 73 ± 5 | 74 ± 7 | 0.67 |
| Disease duration, years | 4.1 ± 3 | 7.0 ± 3 | 0.052 |
| Asymmetrical presentation | 38% (3) | 30% (3) | 1 |
| Early falls | 75% (6) | 90% (9) | 0.56 |
| Ocular motor dysfunction | 75% (6) | 100% (10) | 0.18 |
| Apraxia | 25% (2) | 20% (2) | 1 |
| Parkinsonism | 100% (8) | 100% (10) | |
| Upper motor neuron signs | 50% (4) | 40% (4) | 1 |
| PSP criteria | 0.02 | ||
| Probable PSP | 50% (4) | 100% (10) | |
| Possible PSP | 13% (1) | 0% (0) | |
| Suggestive of PSP | 38% (3) | 0% (0) |
3.5.Distribution of neuronal loss in UMN‐predominant MND
All cases of UMN‐predominant MND had corticospinal tract degeneration in the internal capsule and brainstem with the Luxol fast blue combined with periodic acid‐Schiff and IBA‐1 immunohistochemistry. We also examined the distribution of neuronal loss in various regions of the central nervous system. Neuronal loss and gliosis were more severe in the motor cortex than in brainstem motor neurons or anterior horn cells at the cervicospinal junction in all cases. Seven patients had moderate‐to‐severe neuronal loss in the superior frontal cortex, middle frontal cortex, superior temporal cortex, inferior parietal cortex, putamen, or globus pallidus, while the other patients had no or mild neuronal loss in these regions. The entire brain was fixed in one case (Case 8). Neuronal loss in the superior temporal gyrus, inferior parietal gyrus, putamen, and globus pallidus was more severe on the right side (contralateral to the symptoms) than on the left side (Supplementary Table 1).
3.6.Topographical distribution, severity, morphology of TDP‐43 pathology, and FTLD‐TDP subtypes
The frequency and severity of TDP‐43 pathology in 12 brain regions are summarized in Supplementary Tables 2 and 3. The motor cortex (100%), superior frontal cortex (83%), superior temporal cortex (74%), middle frontal cortex (74%), inferior parietal cortex (65%), and putamen (87%) often had NCI, while NCI was less common in anterior horn cells (30%), hypoglossal nucleus (21%), substantia nigra (29%), subthalamic nucleus (21%), and globus pallidus (17%). NCI and DN were frequent in the cerebral cortex and putamen, but less in subcortical nuclei and brainstem. The frequency of NCI and DN were consistent within each region. The only exception was anterior horn cells at the cervicospinal junction, where DN was frequent (70%), but NCI (30%) was less common. Representative images of TDP‐43 pathology are shown in Figure 2. The motor cortex was consistently affected in all cases. NCIs were seen in all layers in most cases (Figure 2A,C). Three cases had NCI predominantly in layer II (Figure 2B,D). Most of the cases had abundant NCI and less DN (Figure 2E), while five cases had abundant NCI and DN (Figure 2F), and only one case had abundant DN and less NCI. The NCI in the putamen were mostly granular and less often dense (Figure 2I). Mild TDP‐43 pathology was also observed in the hypoglossal nucleus (Figure 2J), anterior horn cells (Figure 2K), substantia nigra, subthalamic nucleus, and globus pallidus. Very rarely, round neuronal intranuclear inclusions were observed (Figure 2L).
We attempted to fit the observed pathology into FTLD‐TDP subtypes [26]. Type B was most frequent (13; 54%), followed by Type A (4; 17%) and Type C (1; 4%). Two cases (8%) had a mix of Types A and B, and 4 (17%) cases were unclassifiable due to minimal TDP‐43 pathology.
3.7.Cluster analysis based on neuronal loss and clinicopathologic association
Hierarchical cluster analysis suggested two distinct clusters based on neuronal loss‐limited (n = 20) and neuronal loss‐extended (n = 4)—as shown in Figure 3. In the neuronal loss‐extended cluster, severe neuronal loss in the superior temporal gyrus was observed in all cases. The major clinical features of each cluster are provided in Figure 3. The average disease duration was longer for patients in neuronal loss‐extended than in neuronal loss‐limited. Cognitive dysfunction was more frequent in neuronal loss‐extended than in neuronal loss‐limited. The frequency of UMN signs, fasciculation, early falls, ocular motor dysfunction, apraxia, parkinsonism, and aphasia, as well as the final clinical diagnosis was not different between the two clusters.
3.8.Genetic analysis
We performed genetic analyses to determine whether UMN‐predominant MND patients had well‐known mutations or genetic risk factors linked to ALS or FTLD‐TDP. No mutations were detected in C9orf72, GRN, SOD1, TARDBP, or FUS. We did, however, observe two UMN‐predominant MND patients (9%) with ATXN2 repeats in the intermediate range (31 repeats). Genotype frequencies for APOE, GRN, TMEM106B, and UNC13A are specified in Supplementary Table 4.
4.DISCUSSION
In the present study, we demonstrated that patients with pathologically‐confirmed UMN‐predominant MND can present with atypical parkinsonism, such as CBS and PSP syndrome. Asymmetrical UMN‐predominant MND with TDP‐43 pathology most frequently resembled CBS, while symmetrical UMN‐predominant MND most often mimicked PSP syndrome. We found that atypical parkinsonism caused by UMN‐predominant MND and tauopathies (i.e., CBD and PSP) might have distinct clinical characteristics.
Pathologically‐diagnosed UMN‐predominant MND is typically considered to be a clinical presentation of PLS characterized by UMN signs and the absence of lower motor neuron signs, or UMN‐dominant ALS [4, 6, 33]. PLS is a selective neurodegenerative disorder, primarily affecting the central motor system, and characterized by a slow progression [34]. Importantly, PLS is used as a term for clinical diagnosis [29]. In most patients with PLS, initial symptoms begin insidiously in the lower extremities and can be accompanied by falls [31]. In addition to motor symptoms, changes in urinary frequency are often observed in PLS [16, 34]. In our autopsy series, 46% of the patients had initial symptoms in lower extremities, 67% had early falls, and 54% had urinary urgency, which are features commonly associated with PLS. PLS often has a long disease course, with some patients surviving for more than 20 years [16, 32, 35], but the average duration in our series was only 5 years. Interestingly, most patients in our study had neurologic features in addition to or instead of UMN signs, such as parkinsonism, ocular motor dysfunction, apraxia, and cognitive dysfunction. Non‐motor neuron features including parkinsonism, sensory abnormalities, ocular motor dysfunction, and cognitive dysfunction have been reported in 10–39% of PLS patients, and is sometimes classified as “PLS plus” [9, 36, 37]. PLS plus is defined as patients with predominant UMN signs who also have a clinical, laboratory, or pathological evidence of dementia, parkinsonism, or sensory tract abnormalities [32]. In retrospect, at least 18 patients in our study may have fallen in the PLS plus category. Non‐motor neuron signs in PLS may often lead to a diagnosis of other diseases; therefore, PLS plus may be underdiagnosed.
Clinicopathologic correlation studies on PLS plus are limited but have shown inconsistent results. Since moderate‐to‐severe neuronal loss in the substantia nigra is essential for parkinsonism [38], the substantia nigra is a focus in patients presenting with parkinsonism. A case report of such a patient had neuronal loss in the substantia nigra, in addition to corticospinal tract degeneration and neuronal loss in the motor cortex [39]. Other case reports have not confirmed involvement of the substantia nigra [40]. MND patients with substantia nigra or Pallido‐Nigro‐Luysian degeneration were also reported as TDP‐43 positive MND with parkinsonism [8, 41]. In our cohort, there was no or only mild neuronal loss in the globus pallidus, subthalamic nucleus, and substantia nigra. Only one case had a moderate neuronal loss in the putamen. Previous reports showed a more accumulation of pospho‐TDP‐43 in the substantia nigra in patients with FTLD‐TDP with movement disorders compared to patients without movement disorders [42]. In our cases, there was no correlation between severity of NCI in the putamen and substantia nigra and parkinsonism. Almost all cases in our study had no obvious histopathologic correlates for parkinsonism; therefore, it is possible that pyramidal signs and symptoms may have been misinterpreted as parkinsonism. In contrast, all patients in the neuronal loss‐extended cluster with severe neuronal loss in the superior temporal gyrus had cognitive dysfunction. This finding is consistent with a study that reported an association between cognitive dysfunction and frontotemporal atrophy in PLS [43].
Although the clinicopathologic subtypes of FTLD‐TDP have been well established, clinicopathologic subtypes of UMN‐predominant MND have not been studied. While there are correlations between the FTLD‐TDP pathological subtypes with causal gene mutations and clinical phenotypes [25], less is known about UMN‐predominant MND. Most of our cases had pathology similar to type B (54%), but some had pathology similar to type A (17%). Of particular interest were cases in which the subtype was difficult to assign, including cases with a combination of features of both type A and type B (8%). Only one case had features similar to type C (4%). These frequencies of TDP‐43 subtypes were different from a previous neuropathologic study of FTLD‐PLS by Kobayashi et al. who found that 10 of 16 cases of FTLD‐PLS had findings consistent with Type C [43]. In ALS, cluster analysis using semiquantitative measures of TDP‐43 pathology revealed that patients with extended TDP‐43 pathology were associated with cognitive decline and C9orf72 repeat expansions [44]; however, these findings were not observed in UMN‐predominant MND. It is worth reiterating that in many cases it was difficult to classify UMN‐predominant MND into specific FTLD‐TDP subtypes, in part because they had features of more than one subtype, especially patients with mixed A and B subtypes [26]. These results suggest that UMN‐predominant MND and FTLD with UMN‐predominant MND have pathological features that may be distinct from FTLD‐MND, which is strongly associated with Type B [25]. Further studies are needed on additional series of autopsy confirmed UMN‐predominant MND patients.
Surprisingly, 55% of MND‐CBS patients had apraxia, although CBS has not been considered a characteristic feature of UMN‐predominant MND. To investigate the regions that correlated with apraxia, we examined neuronal loss in the inferior parietal and superior frontal cortices [45]. Only two of eight patients with apraxia had moderate neuronal loss in these areas (25%). When we applied clinical diagnostic criteria to the individual cases, five of 11 cases of MND‐CBS did not meet the criteria for CBS (45%). MND‐PSPS was also different from typical PSP‐PSPS in that they had a shorter disease duration and lower frequency of vertical gaze palsy that is typical of PSP‐PSPS. All cases of PSP‐PSPS met criteria for probable PSP‐Richardson syndrome, while only half of MND‐PSPS met criteria for probable or possible PSP. It should be noted that possible and suggestive PSP is a general term that captures a heterogeneous clinical syndrome, including PSP with predominant ocular motor dysfunction, PSP with predominant parkinsonism, and PSP with a predominant frontal presentation.
In this study, many UMN‐predominant MND patients were clinically diagnosed with atypical parkinsonism. In a report of tau‐positive corticospinal tract degeneration with mild neuronal loss in the substantia nigra, subthalamic nucleus, and globus pallidus, the clinical diagnosis was PSP or CBS in 75% of cases. Common features of these cases were parkinsonism with bradykinesia, rigidity, and postural instability in addition to upper motor neuron signs. Corticospinal tract degeneration may mimic PSP or CBS, regardless of the accumulated proteins [46]. Moreover, a short disease duration in UMN‐predominant MND may make it difficult to consider pure UMN disease such as PLS, which is generally considered to have a long disease duration [32], as a differential diagnosis. For diagnostic purposes, neuroimaging may be useful. The ratio of corticospinal tract/superior cerebellar peduncle measured by diffusion tensor imaging has been suggested as a marker to differentiate PSP from PLS [47]. Hypometabolism in the primary motor cortex was observed in PLS and ALS patients with UMN symptoms in the FDG PET [48, 49]. Further research on biomarkers will be needed to improve antemortem diagnostic accuracy of UMN diseases.
While most cases of PLS are bilateral and symmetrical, unilateral or asymmetrical features of UMN degeneration have been reported [16, 50]. The first such case was reported by Mills in 1900 [51], and has been termed Mills syndrome. Mills syndrome is thought to be a rare variant of PLS; however, due to a paucity of reports, it is not well recognized by neurologists. Although Mills syndrome has been considered rare, a recent study has shown that 21% of PLS patients (9/43) had the hemiparetic variant or Mills syndrome [16]. In our present study, 13 out of 24 cases (54%) of UMN‐predominant MND had an asymmetrical clinical presentation, supporting the fact that asymmetrical clinical presentation is fairly common in patients with UMN‐predominant MND.
It is interesting to note that the genetic underpinnings of UMN‐predominant MND remain largely unknown. In our present study, we examined well‐known causative and risk genes; however, no pathogenic mutations were detected. We did discover two patients who carried intermediate ATXN2 repeats, which are associated with an increased risk of ALS and FTLD‐MND with TDP‐43 pathology [52, 53, 54]. Previous research has suggested that suppression of ataxin‐2 may reduce TDP‐43 pathology and could improve lifespan and motor function [55]. Deficiency of ATXN2 ortholog, Pbp1, appears to protect against TDP‐43 toxicity‐induced autophagy reduction [56]. In spite of these findings, little is known about the exact mechanisms underlying the relationship between ATXN2 and ALS. Our study suggests that intermediate ATXN2 repeats might represent a risk factor for UMN‐predominant MND but, given the relatively low number of patients examined, larger independent studies are needed.
There are some limitations to the present study. First, we were unable to assess the laterality of pathology because only one hemi‐brain was available for the pathologic assessment in all but one case. In addition, not all neuropathologic analyses were on the side predicted to have more severe pathology (i.e., contralateral to clinically most affected side). Second, clinical information was limited in some cases because of the retrospective nature of this brain bank study. To evaluate possible clinical correlates of neuronal loss and TDP‐43 pathology and clinical features associated with antemortem diagnoses, it will be important to evaluate patients who come to an autopsy from prospective clinical studies. Third, the sample size was relatively small to identify significant differences in clinicopathologic features between clusters. This approach using a larger sample size may define clinicopathologic subtypes of UMN‐predominant MND, analogous to the ALS‐FTLD‐TDP spectrum. The future validation study for clinicopathological feature of UMN‐predominant MND is needed.
In conclusion, the present study indicates that UMN‐predominant MND with TDP‐43 pathology can mimic atypical parkinsonism, especially CBS and PSP syndrome; therefore, UMN‐predominant MND should be considered in the differential diagnosis in these disorders, especially for patients who do not meet criteria for clinically probable CBS or PSP syndrome. The findings of our study also emphasize the need for further clinical, biomarker, and genetic studies of UMN‐predominant MND.
FUNDING INFORMATION
This study was supported in part by The Rainwater Charitable Foundation and Target ALS, the Albertson Parkinson's Research Foundation, and the Spastic Paraplegia Foundation, Inc., as well as NIH grants P30‐AG062677, U54‐NS100693, P01‐AG03949, R01‐AG062348, 1U19AG063911, RF1‐NS123052, R01‐NS121125, and FAIN: U19AG063911. AM reports fellowships from the Japanese Society of Neurology, and the Katano Foundation.
CONFLICT OF INTEREST STATEMENT
M.E.M. served as a paid consultant for Avid Radiopharmaceuticals. Z.K.W. is partially supported by Mayo Clinic Center for Regenerative Medicine, the gifts from the Donald G. and Jodi P. Heeringa Family, and the Haworth Family Professorship in Neurodegenerative Diseases fund. Z.K.W. serves as PI or Co‐PI on Biohaven Pharmaceuticals, Inc. (BHV4157‐206 and BHV3241‐301), Neuraly, Inc. (NLY01‐PD‐1), and Vigil Neuroscience, Inc. (VGL101‐01.001 and VGL101‐01.002) grants. He serves as Co‐PI of the Mayo Clinic APDA Center for Advanced Research and as an external advisory board member for the Vigil Neuroscience, Inc. All other authors report no competing interests.
Supporting information
ACKNOWLEDGMENTS
We would like to thank the patients and their families who donated brains to help further the scientific understanding of neurodegeneration. The authors would also like to acknowledge Virginia Phillips, Jo A. Landino Garcia, and Ariston L. Librero (Mayo Clinic, Jacksonville) for histologic support, Monica Castanedes‐Casey (Mayo Clinic, Jacksonville) for immunohistochemistry support. Rachel LaPaille‐Harwood provides valuable outreach to families wishing to donate brains to the Mayo Clinic brain bank. We thank Audrey Strongosky for her assistance in data collection and coordinating care related to this study. This work supported by a grant of the Japanese Society of Neurology.
Untitled section
Murakami A, Koga S, Fujioka S, White AE, Bieniek KF, Sekiya H, et al. Upper motor neuron‐predominant motor neuron disease presenting as atypical parkinsonism: A clinicopathological study. Brain Pathology. 2025;35(1):e13286. 10.1111/bpa.13286
Contributor Information
Shunsuke Koga, Email: shunsuke.koga@pennmedicine.upenn.edu.
Dennis W. Dickson, Email: dickson.dennis@mayo.edu.
DATA AVAILABILITY STATEMENT
Data that support the findings of this study are available from the corresponding author upon request.
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Associated Data
Supplementary Materials
Data Availability Statement
Data that support the findings of this study are available from the corresponding author upon request.