Frontotemporal Pathology in Motor Neuron Disease Phenotypes: Insights From Neuroimaging

Frontotemporal involvement has been extensively investigated in amyotrophic lateral sclerosis (ALS) but remains relatively poorly characterized in other motor neuron disease (MND) phenotypes such as primary lateral sclerosis (PLS), progressive muscular atrophy (PMA), spinal muscular atrophy (SMA), spinal bulbar muscular atrophy (SBMA), post poliomyelitis syndrome (PPS), and hereditary spastic paraplegia (HSP). This review focuses on insights from structural, metabolic, and functional neuroimaging studies that have advanced our understanding of extra-motor disease burden in these phenotypes. The imaging literature is limited in the majority of these conditions and frontotemporal involvement has been primarily evaluated by neuropsychology and post mortem studies. Existing imaging studies reveal that frontotemporal degeneration can be readily detected in ALS and PLS, varying degree of frontotemporal pathology may be captured in PMA, SBMA, and HSP, SMA exhibits cerebral involvement without regional predilection, and there is limited evidence for cerebral changes in PPS. Our review confirms the heterogeneity extra-motor pathology across the spectrum of MNDs and highlights the role of neuroimaging in characterizing anatomical patterns of disease burden in vivo. Despite the contribution of neuroimaging to MND research, sample size limitations, inclusion bias, attrition rates in longitudinal studies, and methodological constraints need to be carefully considered. Frontotemporal involvement is a quintessential clinical facet of MND which has important implications for screening practices, individualized management strategies, participation in clinical trials, caregiver burden, and resource allocation. The academic relevance of imaging frontotemporal pathology in MND spans from the identification of genetic variants, through the ascertainment of presymptomatic changes to the design of future epidemiology studies.

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Motor neuron disease

10.1093/med/9780199568741.003.0232 ◽

2018 ◽

Author(s):

Martin R. Turner

Keyword(s):

Motor Neuron ◽

Motor Neuron Disease ◽

Motor Neurons ◽

Corticospinal Tract ◽

Muscular Atrophy ◽

Muscle Denervation ◽

Genetic Overlap ◽

Upper Motor Neurons ◽

Primary Lateral ◽

Lateral Sclerosis

Motor neuron disease (MND) is characterized by progressive muscular weakness due to simultaneous degeneration of lower and upper motor neurons (L/UMNs). Involvement of LMNs, arising from the anterior horns of the spinal cord and brainstem, leads to secondary wasting as a result of muscle denervation. Involvement of the UMNs of the motor cortex and corticospinal tract results in spasticity. In ~85% of cases, there is clear clinical involvement of both, and the condition is termed ‘amyotrophic lateral sclerosis’ (ALS; a term often used synonymously with MND). In ~13% of cases, there may be only LMN signs apparent, in which case the condition is termed ‘progressive muscular atrophy’, although such cases have a natural history that is to largely identical to that of ALS. In a very small group of patients (~2%), there are only UMN signs for at least the first 4 years, in which case the condition is termed ‘primary lateral sclerosis’; such cases have a uniformly slower progression. There is clinical, neuropathological, and genetic overlap between MND and some forms of frontotemporal dementia.

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Motor Neuron Disease (DRAFT)

10.1093/med/9780190650261.003.0018 ◽

2018 ◽

Author(s):

Tamara Kaplan ◽

Tracey Milligan

Keyword(s):

Spinal Muscular Atrophy ◽

Motor Neuron ◽

Motor Neuron Disease ◽

Muscular Atrophy ◽

Lower Motor Neuron ◽

Lateral Sclerosis

The video in this chapter explores motor neuron disease, including amytrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA). It discusses the signs of upper motor neuron (UMN) and lower motor neuron (LMN) pathology, as well as Kennedy disease.

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Types of Motor Neuron Diseases

10.1093/med/9780199937837.003.0022 ◽

2017 ◽

Author(s):

Nimish Thakore ◽

Erik P Pioro

Keyword(s):

Amyotrophic Lateral Sclerosis ◽

Spinal Muscular Atrophy ◽

Motor Neuron ◽

Motor Neuron Disease ◽

Motor Neurons ◽

Muscular Atrophy ◽

Motor Neuron Diseases ◽

The Subject ◽

Upper Motor Neurons ◽

Lateral Sclerosis

Disorders of lower motor neurons (LMNs, or anterior horn cells) and upper motor neurons (UMNs), jointly termed motor neuron disorders (MNDs), are diverse and numerous. The prototypical MND, namely amyotrophic lateral sclerosis (ALS), a relentlessly progressive lethal disorder of adults, is the subject of another section and will not be discussed further here. Other MNDs include spinal muscular atrophy (SMA), of which there are four types: Kennedy’s disease, Brown-Violetto-Van Laere, and Fazio-Londe syndromes, lower motor neuron disorders as part of neurodegenerations and secondary motor neuron disease as part of malignancy, radiation and infection.

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Case 19

10.1093/med/9780190603434.003.0023 ◽

2018 ◽

Author(s):

Bashar Katirji

Keyword(s):

Amyotrophic Lateral Sclerosis ◽

Motor Neuron ◽

Motor Neuron Disease ◽

Muscular Atrophy ◽

Multifocal Motor Neuropathy ◽

Lower Motor Neuron ◽

Motor Neuropathy ◽

Motor Neuron Degeneration ◽

Neuron Degeneration ◽

Lateral Sclerosis

Amyotrophic lateral sclerosis is a fatal neurological disorder, classically presenting with signs of upper motor neuron and lower motor neuron degeneration. Several motor neuron disease variants with purely upper or lower motor neuron degeneration exist. These includes primary lateral sclerosis, progressive muscular atrophy and progressive bulbar palsy. The diagnostic criteria, including El-Escorial criteria and its most recent Awaji revision, are not used in clinical practice and for research purposes. This case highlights the clinical features and electrodiagnostic characteristics of amyotrophic lateral sclerosis. The findings on nerve conduction studies and needle electromyography are emphasized in detail. The role of electrodiagnostic studies in the diagnosis of amyotrophic lateral sclerosis is to establish evidence of lower motor neuron degeneration, confirm its diffuse nature, and exclude treatable causes (such as multifocal motor neuropathy and mimickers of motor neuron disease such as chronic myopathies).

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Dissociated leg muscle atrophy in amyotrophic lateral sclerosis/motor neuron disease: the ‘split-leg’ sign

Scientific Reports ◽

10.1038/s41598-020-72887-7 ◽

2020 ◽

Vol 10 (1) ◽

Author(s):

Young Gi Min ◽

Seok-Jin Choi ◽

Yoon-Ho Hong ◽

Sung-Min Kim ◽

Je-Young Shin ◽

...

Keyword(s):

Amyotrophic Lateral Sclerosis ◽

Motor Neuron ◽

Motor Neuron Disease ◽

Muscle Atrophy ◽

Rating Scale ◽

Muscular Atrophy ◽

Compound Muscle Action Potential ◽

Healthy Controls ◽

Abductor Hallucis ◽

Lateral Sclerosis

Abstract Disproportionate muscle atrophy is a distinct phenomenon in amyotrophic lateral sclerosis (ALS); however, preferentially affected leg muscles remain unknown. We aimed to identify this split-leg phenomenon in ALS and determine its pathophysiology. Patients with ALS (n = 143), progressive muscular atrophy (PMA, n = 36), and age-matched healthy controls (HC, n = 53) were retrospectively identified from our motor neuron disease registry. We analyzed their disease duration, onset region, ALS Functional Rating Scale-Revised Scores, and results of neurological examination. Compound muscle action potential (CMAP) of the extensor digitorum brevis (EDB), abductor hallucis (AH), and tibialis anterior (TA) were reviewed. Defined by CMAPEDB/CMAPAH (SIEDB) and CMAPTA/CMAPAH (SITA), respectively, the values of split-leg indices (SI) were compared between these groups. SIEDB was significantly reduced in ALS (p < 0.0001) and PMA (p < 0.0001) compared to the healthy controls (HCs). SITA reduction was more prominent in PMA (p < 0.05 vs. ALS, p < 0.01 vs. HC), but was not significant in ALS compared to the HCs. SI was found to be significantly decreased with clinical lower motor neuron signs (SIEDB), while was rather increased with clinical upper motor neuron signs (SITA). Compared to the AH, TA and EDB are more severely affected in ALS and PMA patients. Our findings help to elucidate the pathophysiology of split-leg phenomenon.

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Reliable and efficient scale to assess upper motor neuron disease burden in amyotrophic lateral sclerosis

Muscle & Nerve ◽

10.1002/mus.26764 ◽

2019 ◽

Vol 61 (4) ◽

pp. 508-511 ◽

Cited By ~ 3

Author(s):

Colin Quinn ◽

Christyn Edmundson ◽

Nabila Dahodwala ◽

Lauren Elman

Keyword(s):

Amyotrophic Lateral Sclerosis ◽

Motor Neuron ◽

Motor Neuron Disease ◽

Disease Burden ◽

Lateral Sclerosis

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Motor neuron disease in vitro: the use of cultured motor neurons to study amyotrophic lateral sclerosis

European Journal of Pharmacology ◽

10.1016/s0014-2999(00)00560-4 ◽

2000 ◽

Vol 405 (1-3) ◽

pp. 285-295 ◽

Cited By ~ 22

Author(s):

P.R Bär

Keyword(s):

Amyotrophic Lateral Sclerosis ◽

Motor Neuron ◽

Motor Neuron Disease ◽

Motor Neurons ◽

Lateral Sclerosis

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LanCL1 promotes motor neuron survival and extends the lifespan of amyotrophic lateral sclerosis mice

Cell Death and Differentiation ◽

10.1038/s41418-019-0422-6 ◽

2019 ◽

Vol 27 (4) ◽

pp. 1369-1382 ◽

Cited By ~ 4

Author(s):

Honglin Tan ◽

Mina Chen ◽

Dejiang Pang ◽

Xiaoqiang Xia ◽

Chongyangzi Du ◽

...

Keyword(s):

Amyotrophic Lateral Sclerosis ◽

Motor Neuron ◽

Motor Neurons ◽

Neuronal Survival ◽

Disease Onset ◽

Alternative Mechanism ◽

Specific Expression ◽

Motor Neuron Survival ◽

Lateral Sclerosis

Abstract Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive loss of motor neurons. Improving neuronal survival in ALS remains a significant challenge. Previously, we identified Lanthionine synthetase C-like protein 1 (LanCL1) as a neuronal antioxidant defense gene, the genetic deletion of which causes apoptotic neurodegeneration in the brain. Here, we report in vivo data using the transgenic SOD1G93A mouse model of ALS indicating that CNS-specific expression of LanCL1 transgene extends lifespan, delays disease onset, decelerates symptomatic progression, and improves motor performance of SOD1G93A mice. Conversely, CNS-specific deletion of LanCL1 leads to neurodegenerative phenotypes, including motor neuron loss, neuroinflammation, and oxidative damage. Analysis reveals that LanCL1 is a positive regulator of AKT activity, and LanCL1 overexpression restores the impaired AKT activity in ALS model mice. These findings indicate that LanCL1 regulates neuronal survival through an alternative mechanism, and suggest a new therapeutic target in ALS.

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