Lower Motor Neuron Systems Research Articles

Neuropathological profile of long-duration amyotrophic lateral sclerosis in military Veterans.

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder affecting both the upper and lower motor neurons. Although ALS typically leads to death within 3 to 5years after initial symptom onset, approximately 10% of patients with ALS live more than 10years after symptom onset. We set out to determine similarities and differences in clinical presentation and neuropathology in persons with ALS with long vs. those with standard duration. Participants were United States military Veterans with a pathologically confirmed diagnosis of ALS (n=179), dichotomized into standard duration (<10years) and long-duration (≥10years). The ALS Functional Rating Scale-Revised (ALSFRS-R) was administered at study entry and semi-annually thereafter until death. Microglial density was determined in a subset of participants. long-duration ALS occurred in 76 participants (42%) with a mean disease duration of 16.3years (min/max=10.1/42.2). Participants with long-duration ALS were younger at disease onset (P=0.002), had a slower initial ALS symptom progression on the ALSFRS-R (P<0.001) and took longer to diagnose (P<0.002) than standard duration ALS. Pathologically, long-duration ALS was associated with less frequent TDP-43 pathology (P<0.001). Upper motor neuron degeneration was similar; however, long-duration ALS participants had less severe lower motor neuron degeneration at death (P<0.001). In addition, the density of microglia was decreased in the corticospinal tract (P=0.017) and spinal cord anterior horn (P=0.009) in long-duration ALS. Notably, many neuropathological markers of ALS were similar between the standard and long-duration groups and there was no difference in the frequency of known ALS genetic mutations. These findings suggest that the lower motor neuron system is relatively spared in long-duration ALS and that pathological progression is likely slowed by as yet unknown genetic and environmental modifiers.

Association between oxidative stress and microRNA expression pattern of ALS patients in the high-incidence area of the Kii Peninsula

Amyotrophic lateral sclerosis (ALS) is a progressive degenerative disorder of the upper and lower motor neuron systems. The high incidence of ALS in the southern part of the Kii Peninsula of Japan (K-ALS) was reported in the 1960s, but it has gradually decreased to the worldwide average. Although causes of the high incidence of ALS in this area are unknown, our previous studies suggested that environmental factors, including essential mineral deficiency and increased metal-induced oxidative stress, play a role in its development. Recently, it has been reported that microRNAs (miRNA) contribute to the degeneration of nervous system such as ALS. The aim of this study is to explore specific miRNAs in K-ALS and evaluate relationships between oxidative stress. We comprehensively analyzed serum miRNAs and examined urinary 8-hydroxy-2′-deoxyguanosine (8-OHdG), serum Cu/Zn superoxide dismutase (SOD) and serum Nɛ-hexanoyl lysin (HEL) as oxidative stress markers in the patients with K-ALS, sporadic ALS (S-ALS), residents in this area (K-residents) and controls from another area. The expression levels of miR-92a-3p and miR-486-5p in the patients with K-ALS were significantly higher than those in controls. The HEL levels were significantly higher in the patients with K-ALS than in those with S-ALS and controls. The expression levels of miR-92a-3p and miR-486-5p were not correlated with the levels of HEL. A set of high levels of miR-92a-3p, miR-486-5p and serum HEL may be a useful biomarker for K-ALS in the Kii Peninsula. The findings should be further studied by a large number of subjects.

Neuropathology of Amyotrophic Lateral Sclerosis

The basic neuropathology of amyotrophic lateral sclerosis (ALS) is defined as the involvement of the upper motor neurons system (UMN) and the lower motor neuron system (LMN), with variable degree and combination. The characteristic pathological feature of sporadic ALS is cytoplasmic mislocalization of nuclear TDP-43 and aggregation of abnormally phosphorylated TDP-43 inclusions in cytoplasm in LMN, UMN and glial cells. TDP-43 inclusions correlate with cell loss and distribute beyond the UMN and LMN system. It has been proposed that phosphorylated TDP-43 (pTDP-43) disseminates in a sequential pattern along the motor pathways, as suggested by the hypothesis of corticofugal ('prion-like') propagation of misfolded proteins in ALS.

Differential motor neuron involvement in progressive muscular atrophy: a comparative study with amyotrophic lateral sclerosis

ObjectiveProgressive muscular atrophy (PMA) is a clinical diagnosis characterised by progressive lower motor neuron (LMN) symptoms/signs with sporadic adult onset. It is unclear whether PMA is simply a clinical phenotype...

Lower Motor Neuron Involvement in TAR DNA-Binding Protein of 43 kDa–Related Frontotemporal Lobar Degeneration and Amyotrophic Lateral Sclerosis

TAR DNA-binding protein of 43 kDa (TDP-43) plays a major role in the pathogenesis of frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). Although a pathological continuity between FTLD and ALS has been suggested, the neuropathological changes of the lower motor neuron (LMN) systems have not been assessed in TDP-43-associated FTLD (FTLD-TDP), to our knowledge. To investigate a pathological continuity between FTLD-TDP and ALS by comparing their respective neuropathological changes in the motor neuron system. A retrospective clinical medical record review and a semiquantitative neuropathological evaluation of the cranial motor nerve nuclei and spinal cord were conducted at autopsy. We included 43 patients with sporadic FTLD-TDP, type A, B, or C, from 269 consecutively autopsied patients with TDP-43 proteinopathy. Patients were categorized as having FTLD without ALS, FTLD-ALS (onset of FTLD symptoms/signs preceded those of ALS), or ALS-FTLD (onset of ALS symptoms/signs preceded those of FTLD). Neuronal TDP-43 pathological changes and neuronal loss. Forty-three patients were included in the clinical analysis, and 29 from whom spinal cords were obtained were included in the neuropathological analysis. Survival time was significantly shorter in the FTLD-ALS and ALS-FTLD groups than in the FTLD without ALS group (P < .001). At neuropathological examination, 89% of patients in the FTLD without ALS group showed aggregations of TDP-43 in the spinal motor neurons. The LMN loss was most severe in ALS-FTLD, followed by FTLD-ALS and FTLD without ALS. All the patients with type A or C FTLD-TDP were included in the FTLD without ALS group, and all those with type B pathological changes were in the FTLD-ALS or the ALS-FTLD group. Lower motor neuron loss and TDP-43-positive skeinlike inclusions were observed in all pathological subtypes. The LMN systems of FTLD-TDP frequently exhibit neuropathological changes corresponding to ALS. Thus, a pathological continuity between FTLD-TDP and ALS is supported at the level of the LMN system.

著明な筋痙攣・線維束性収縮をともない抗voltage gated potassium channel（VGKC）複合体抗体が高値であった筋萎縮性側索硬化症の1剖検例

The patient was a 55-year-old male who had prominent fasciculation and muscle cramps. Muscle weakness and atrophy of the trunk, respiratory system, and extremities gradually progressed. On the basis of these features, we diagnosed this patient as having amyotrophic lateral sclerosis (ALS), however, the upper motor neuron signs were not significant. Following the detection of the anti-voltage gated potassium channel (VGKC) complex antibody at 907.5 pM (normal < 100 pM) and repetitive discharge in a nerve conduction study, immunotherapy with intravenous immunoglobulin, methylprednisolone (mPSL), double filtration plasmapheresis (DFPP), ciclosporin, and rituximab was introduced. mPSL and DFPP showed only tentative effectiveness for fasciculation and muscle cramps, respectively. Thereafter, muscle weakness progressed. The patient died of type II respiratory failure at the age of 57 years, about 2 years after the onset of the disease. At autopsy, a histopathological diagnosis of ALS with lower-motor-predominant degeneration was made. Characteristic cellular features, including Bunina bodies in the remaining lower motor neurons and phosphorylated TAR DNA-binding protein 43-kDa (pTDP-43)-immunopositive inclusions in both upper and lower motor neuron systems, were evident. At present, an immunological role of the anti-VGKC complex antibody in the development of cramp-fasciculation syndrome has been speculated. In this ALS patient, the antibodies might be associated with pathomechanisms underlying the characteristic symptoms.

A Music Therapy Treatment Protocol for Acquired Dysarthria Rehabilitation

ABSTRACT: Dysarthria is a common form of speech impairment, affecting 20-50% of stroke patients and 10-60% of traumatic brain injury patients (Sellers, Hughes, & Langhorne, 2002). Very little research has been conducted on the effect of treatments for dysarthria and even less has been reported on rehabilitative music therapy interventions. In the current climate of evidence-based practice (Edwards, 2002) the music therapy profession needs to develop and rigorously test interventions designed to address specific disorders such as dysarthria. This paper discusses theoretical foundations for the use of singing interventions to treat dysarthria and presents a music therapy dysarthria treatment protocol incorporating vocal and respiratory exercises and therapeutic singing. Publications on the use of music therapy in neurorehabilitation have increased considerably in recent years. However, a recent review of this literature (Gilbertson, 2004) found mainly descriptions of clinical approaches and treatment practices in neurorehabilitation with little outcome-based evidence for treatment. Limitations reported in this review include inconsistencies or omissions in recording neurodiagnostics, applications of other concurrent therapies, assessment tools used, and time elapsed between injury and therapeutic music intervention (Gilbertson, 2004). So far, only a small body of music therapy research exists in the area of communication rehabilitation. Preliminary findings have indicated that music therapy techniques, such as singing and vocal training, can assist in rehabilitation of communication disorders (Adamek, Gervin, & Shiraishi, 2000; Cohen, 1992); however, further research on particular music therapy interventions to address specific communication disorders is needed. The purpose of this paper is to present and discuss a music therapy protocol to treat the various symptoms of acquired dysarthria, including intelligibility, rate of speech, communication efficiency, fluency and naturalness. The findings of case study research assessing the efficacy of this protocol are published elsewhere in greater detail (Tamplin, 2008). It is important to understand the neurophysical factors of dysarthria that inform music therapy intervention and influence treatment outcomes. These will also influence clinical decisions such as the choice of musical material used, the selection of appropriate music therapy techniques, the length and frequency of intervention, and the method of evaluation chosen. Dysarthria Dysarthria refers to a group of motor speech disorders involving disturbances in control of the speech musculature as a result of nervous system damage (Abbs & De Paul, 1989). There is a particularly high incidence of dysarthria following acquired brain injury as dysarthria may result from damage to a number of areas in the brain including the upper or lower motor neuron system, the cerebellum, the extrapyramidal system or a combination of these (Sarno, Buonaguro, & Levita, 1986; Sellars et al., 2002). Clinical presentation may include impairments in the movement and coordination of speech musculature in terms of strength and tone, and impairments in range, timing, speed and steadiness of movement (Darley, Aronson, & Brown, 1975). In particular, dysarthria is often characterized by reduced verbal intelligibility, voice volume or range, abnormal rate of speech, and poor prosody, which in combination often impair speech naturalness. The sequelae of dysarthria and its neurological foundations distinguish it from other neurological speech and language disorders such as apraxia and aphasia. These higher-level representational communication disorders are associated with temporal lobe lesions in the language dominant hemisphere. Aphasia is a neurological language processing disorder involving difficulty formulating and/or interpreting words and sentences (Brookshire, 2003). Apraxia is primarily a motor planning problem and not a problem with the muscles themselves; thus, the apraxic speakers' articulation and prosody are abnormal, but phonation and resonance are usually unaffected (Brookshire, 2003). …

Expression of insulin‐like growth factor‐II and leukemia inhibitory factor antibody immunostaining on the ionized calcium‐binding adaptor molecule 1‐positive microglias in the spinal cord of amyotrophic lateral sclerosis patients

Amyotrophic lateral sclerosis (ALS) is a progressive degenerative disease involving the upper and lower motor neuron systems. Activated microglia are reported to enhance motor neuron death by secreting neurotoxic cytokines in SOD1-transgenic mice. Recent studies have provided evidence that chronic stimulation leads microglia to acquire an anti-inflammatory phenotype, characterized by activated morphology and induction of neuroprotective and immunoregulatory molecules. However, little information is available on the protective functions of microglia in the ALS spinal cord. To investigate the roles of microglia in ALS, we examined the appearance of ionized calcium-binding adaptor molecule 1-positive (Iba1-positive) microglia as correlated to the disease duration and immunohistochemical expression of neurogrowth factors in the ALS spinal cord. In this study, the number of Ibal-positive rod-like microglia significantly increased in the ALS spinal cord compared to controls. The number of ramified microglia was positively correlated with the number of normal-looking neurons and clinical duration of ALS patients; however, the number of rod-like microglia was not correlated with that of abnormal neurons, nor with the clinical duration of the disease. Some rod-like microglia were positive for anti-insulin-like growth factor-II (IGF II) and anti-leukemia inhibitory factor (LIF) immunostaining. Motor neurons in the ALS spinal cords also showed immunore-activity for IGF-II, LIF and the receptors of IGF-II and LIE Taken together, these findings suggest that at least some microglia might have a protective effect on motor neurons in the ALS spinal cord. Neuroprotective and/or neurotoxic effects of microglia on motor neurons should be further studied.

TDP-43 immunoreactivity in neuronal inclusions in familial amyotrophic lateral sclerosis with or without SOD1 gene mutation

Recently, 43-kDa TAR DNA-binding protein (TDP-43) was identified as a component of ubiquitinated inclusions (UIs) in sporadic amyotrophic lateral sclerosis (SALS). To clarify whether TDP-43 immunoreactivity is present in neuronal inclusions in familial ALS (FALS), we examined immunohistochemically the brains and spinal cords from four cases of FALS, two with Cu/Zn superoxide dismutase (SOD1) gene mutation and two without, together with three cases of SALS and three control subjects, using two antibodies, one polyclonal and one monoclonal, against TDP-43. Neuropathologically, the SOD1-related FALS cases were characterized by Lewy body-like hyaline inclusions (LBHIs) in the lower motor neurons. On the other hand, the SOD1-unrelated FALS cases showed degeneration restricted to the upper and lower motor neuron systems, with Bunina bodies (BBs) and UIs in the lower motor neurons, being indistinguishable from SALS. No cytoplasmic TDP-43 immunoreactivity was observed in the control subjects or SOD1-related FALS cases; LBHIs were ubiquitinated, but negative for TDP-43. UIs observed in the SALS and SOD1-unrelated FALS cases were clearly positive for TDP-43. BBs were negative for this protein. Interestingly, in these SALS and FALS cases, glial cells were also found to have cytoplasmic TDP-43-positive inclusions. These findings indicate that the histological and molecular pathology of SALS can occur as a phenotype of FALS without SOD1 mutation.

Familial amyotrophic lateral sclerosis: a SOD1-unrelated Japanese family of bulbar type with Bunina bodies and ubiquitin-positive skein-like inclusions in lower motor neurons

We describe a new family with adult onset amyotrophic lateral sclerosis (FALS), in which the disease was characterized clinically by relatively rapid progression of bulbar symptoms. Gene analysis of Cu/Zn superoxide dismutase (SOD1) performed in one patient showed no mutations. Autopsy of another patient demonstrated degenerative changes restricted to the upper and lower motor neuron systems; no evident changes were observed in the posterior column, Clarke's column or spinocerebellar tracts. The presence of Bunina bodies and ubiquitin-positive skein-like inclusions in the lower motor neuron was of considerable interest. Cases of FALS with such pathological features are quite rare in the literature. Identification of the gene responsible for the disease is desirable in order to shed further light on the molecular pathology of not only familial, but also sporadic, ALS.

Is motor neuron disease‐inclusion dementia aforme frusteof amyotrophic lateral sclerosis with dementia? An autopsy case further supporting the disease concept

We report the autopsy findings of a 62-year-old man who exhibited progressive FTD 10 years before the appearance of muscle weakness and wasting, and who died approximately 11 years after onset of the symptoms. Degeneration and atrophy of the frontal and temporal lobes, which contained ubiquitin-positive neuronal inclusions and dystrophic neurites, were evident. Circumscribed degeneration affecting the hippocampal CA1-subiculum border zone was also a feature. Moreover, degeneration was present in both the upper and lower motor neuron systems, the latter being more severely affected. A few lower motor neurons were found to contain the cytoplasmic inclusions characteristic of ALS (i.e. Bunina bodies and ubiquitin-positive skeins). Also of interest was the presence of pallidonigroluysian atrophy, which appeared to be responsible for the chorea-like involuntary movements that developed in this patient approximately 2 months before death. The clinical and pathological features of our patient further support the idea that motor neuron disease-inclusion dementia (MND-ID), which has been classified as a pathological subgroup of FTD, is a forme fruste of ALS with dementia. In other words, if patients with MND-ID live long enough, they may develop ALS.

Amyotrophic lateral sclerosis with prolonged survival and degeneration of the spinocerebellar tracts, substantia nigra and dentatorubral system

We report on a case of sporadic amyotrophic lateral sclerosis (ALS) with prolonged, respirator‐assisted survival and clinical signs limited to the upper and lower motor neuron systems. Autopsy revealed degeneration of the upper and lower neuron systems and Bunina bodies, both characteristic of ALS. In addition, we found degeneration of the spinocerebellar tracts, the substantia nigra and the dentatorubral system. Our case is an additional example of multisystem degeneration in ALS associated with prolonged, respirator‐assisted survival. These findings suggest that sporadic ALS comprises heterogeneous subgroups with patterns of degeneration that depend, in part, on survival time.

Neuropathology of sporadic amyotrophic lateral sclerosis of long duration

We performed post-mortem examinations of three patients with progressive neurogenic amyotrophy of long duration. One patient had been clinically diagnosed as having sporadic amyotrophic lateral sclerosis (ALS) and two had been diagnosed with progressive spinal muscular atrophy (PSMA). The disease durations were 10, 17 and 20 years, respectively, and all of the patients died of respiratory failure with no artificial respiratory support. In all of the patients, both the upper and lower motor neuron systems were affected; degeneration of the former was definite, but was milder than that usually encountered in sporadic ALS patients, and the histopathology of the latter was identical to that of sporadic ALS. Light microscopy revealed Bunina bodies, which are characteristic of sporadic ALS, in the remaining anterior horn cells of each patient. In addition, ubiquitin-positive skein-like inclusions were also identified, immunohistochemically, in the remaining anterior horn cells of each patient. Neuron counts indicated that the number of neurons was preserved in Clarke's column in these patients, but was significantly reduced in the intermediolateral nucleus, compared with control subjects. Based on these findings, we think that these three patients, with long disease durations, were affected by essentially the same underlying disease process as that of sporadic, classical ALS. Moreover, we question the neuropathological occurrence of sporadic ALS without involvement of the upper motor neuron system, namely, pure PSMA or lower motor neuron disease. © 1997 Elsevier Science B.V. All rights reserved.

Progressive degeneration of motor nerve terminals in GAD mutant mouse with hereditary sensory axonopathy.

The evolution of motor nerve degeneration was examined in gracile axonal dystrophy (GAD) mutant mice, which develop initial sensory ataxia and subsequent motor paresis. Using the anterior gracilis (AG) muscle, which is innervated at two discrete and well-separated endplate zones, we demonstrated that axonal degeneration occurred first at motor nerve terminals in the distal endplate zone, and then extended gradually from the distal to the more proximal parts of affected axons in the intra-muscular nerve trunk. In contrast to the degeneration in the distal zone, active degeneration was less marked in the proximal endplate zone and, furthermore, most terminal axons had begun to produce regenerating sprouts. Ventral horn cells were histologically normal, even at advanced stages. These results indicate that, as previously observed in sensory nerves, dying back degeneration progresses later in the lower motor neuron system, even within one muscle. The mechanism(s) influencing the activation of axonal regeneration are discussed. This mutant mouse will be a useful model for the study of regenerating phenomena in dying back degeneration of genetically compromised motor neurons, as well as for the study of the pathogenesis of hereditary sensory and motor neuropathies in man.

Observations on the Clinical Assessment of Patients with Motor Neuron Disease: Experience with a TRH Analogue

The need for improved assessment techniques in order to monitor the action of substances active in upper and lower motor neuron systems in motor neuron disease is discussed. A long-acting TRH analogue is shown to have detectable acute effects on bulbar symptoms, particularly speech, tone, fasciculations, and muscle force. Endocrine surveillance is essential in studies with TRH and analogues.