Role of neurofilament aggregation in motor neuron disease

A major question in the pathogenesis of motor neuron disease is why motor neurons are selectively susceptible to mutations in widely expressed gene products. Reexamination of motor neuron degeneration due to alterations of neurofilament (NF) expression suggests that disruption of assembly with aggregation of the light neurofilament (NFL) protein may be an upstream event and contributing factor leading to the preferential degeneration of motor neurons. The implications of these findings are that aggregation of NFL is not only a triggering mechanism to account for the hallmark aggregates of NF protein in sporadic and familial forms of amyotrophic lateral sclerosis, but that aggregates of NFL may also promote aggregation of wildly expressed proteins that are destabilized by missense mutations, such as by mutations in superoxide dismutase-1 protein. This review examines the potential role of NFs in determining and promoting the preferential degeneration of motor neurons in motor neuron disease. The underlying premise is that motor neurons are selectively susceptible to alterations in NF expression, that alterations in NF expression lead to NF aggregates in motor neurons, and that elevated levels of NF aggregates provide a favorable microenvironment for the formation of neurotoxic aggregation and degeneration of motor neurons.     

Familial frontotemporal dementia with ubiquitin inclusion bodies and without motor neuron disease

Frontotemporal dementia (FTD) is the second most common degenerative dementia after Alzheimer’s disease and its Lewy body variant. Clinical pathology can be subdivided in three main neuropathological subtypes: frontal lobe dementia, Pick’s disease and FTD with motor neuron disease (MND), all characterised by distinct histological features. Until recently the presence of ubiquitin-positive intraneuronal inclusions in the dentate gyrus, and the temporal and frontal cortex was usually associated with the MND type. Such inclusions were also observed in a few sporadic cases of FTD without or with parkinsonism (FTDP) in the absence of MND. We present here clinical, neuropathological and immunohistochemical data about a Swiss FTD family with FTDP-like features but without MND. Spongiosis and mild gliosis were observed in the grey matter. No neurofibrillary tangles, Pick bodies, Lewy bodies, senile plaques or prion-positive signals were present. However, ubiquitin-positive intracytoplasmic inclusions were detected in various structures but predominantly in the dentate gyrus. These observations support the existence of a familial form of FTDP with ubiquitin-positive intracytoplasmic inclusions (Swiss FTDP family). Received: 8 November 1999 / Revised, accepted: 17 January 2000     

Human midsized neurofilament subunit induces motor neuron disease in transgenic mice

Aberrant accumulation of neurofilaments is a feature of human motor neuron diseases. Experimentally motor neuron disease can be induced in transgenic mice by overexpressing the mouse neurofilament light subunit (NF-L), the human heavy subunit (NF-H), or mouse peripherin. Here we describe that mice harboring a bacterial artificial chromosome (BAC) transgene containing the human midsized neurofilament subunit (NF-M) gene develop a progressive hind limb paralysis associated with neurofilamentous accumulations in ventral horn motor neurons and axonal loss in ventral motor roots. Biochemical studies revealed that all three mouse neurofilament subunits along with the human NF-M contributed to filament formation, although filaments contained less peripherin. In addition the endogenous mouse NF-M became less phosphorylated in the presence of the human protein and accumulated in the cell bodies of affected neurons even though phosphorylated human NF-M did not. Remaining motor axons contained an increased density of neurofilaments and morphometric studies showed that principally small myelinated axons were lost in the transgenic animals. Removing half of the mouse NF-M by breeding the transgene onto the mouse NF-M heterozygous null background offered no protection against the development of disease, arguing that the effect is not simply due to elevation of total NF-M. Collectively these studies argue that the human and mouse NF-M proteins exhibit distinct biochemical properties and within mouse neurons are not interchangeable and that indeed the human protein may be toxic to some mouse neurons. These studies have implications for the use of human neurofilament transgenic mice as models of amyotrophic lateral sclerosis.     

Peripherin and neurofilament protein coexist in spinal spheroids of motor neuron disease.

We have compared the immunolocalization of neurofilament protein (NF) with two other neuronal-specific intermediate filament proteins in large spinal axonal swellings (spheroids) of motor neuron disease and controls. All spheroids labeled each of the three different subunits of NF, the low, middle, and high molecular weight polypeptides. In doublelabel immunofluorescence, 300 axonal swellings were immunostained for NF, and 87% of them contained the intermediate protein peripherin. The pattern of immunostaining of NF and peripherin was indistinguishable at a high resolution viewed in 1 microns optical sections by confocal microscopy. A minority of the spheroids contained alpha-internexin, another intermediate protein, but it was weakly immunoreactive. The immunostaining of axonal swellings was similar for all epitopes tested in motor neuron disease and control subjects. The findings suggest that peripherin as well as neurofilament protein are major components of the proliferated intermediate filaments in spheroids.     

An autopsy case of atypical infantile motor neuron disease with hyaline intraneuronal inclusions

We describe a 5-year-old boy who had had a progressive motor weakness with bulbar palsy and spasticity of the lower extremities since age 3 years and who died of bronchopneumonia after about two and a half years of the illness. Neuropathologic examination revealed combined degenerative processes in the upper and lower motor neurons, the spinocerebellar and olivocerebellar systems, and the ventral thalamic nuclei. Lewy body-like intraneuronal hyaline inclusions, which ultrastructurally showed irregular accumulations of trilaminar membranous profiles, were detected in the spinal anterior horn, Clarke's dorsal nucleus, facial nerve nucleus, inferior olivary nucleus, and substantia nigra. This case could be considered as a unique form in the group of the infantile motor neuron diseases associated with multi-systemic degenerations in the central nervous system.     

Dementia with motor neuron disease

Dementia with motor neuron disease has been described as a new clinicopathologic entity and more than 100 cases have been reported in Japan since 1964. The clinicopathologic criteria in the diagnosis of dementia with motor neuron disease are: (i) frontotemporal lobe‐type dementia with insidious onset, mostly in the presenile period; (ii) neurogenic muscular wasting during the course of the illness (amyotrophic lateral sclerosis‐ or SPMA‐like symptoms); (iii) duration from the onset of illness to death of 2–5 years (average, 30.6 months); (iv) both extrapyramidal symptoms and definite sensory deficits are present less commonly; (v) no characteristic abnormalities in the cerebrospinal fluid or electroencephalogram on screening; (vi) no known parental consanguinity or familial occurrence; and (vii) non‐specific, mild to slight degenerative changes in the frontotemporal cortex, hypoglossal nuclei and spinal cord, and frequently in the substantia nigra. Dementia with motor neuron disease is characterized by ubiquitin‐immunoreactive intraneuronal inclusions in cortical layer II and hypocampal dentate granule cells.     

泛素阳性包涵体在运动神经元病的表达

目的：探讨泛素阳性包涵体在运动神经病（MND）中枢神经系统的分布、成分及与神经细胞变性的关系。方法：对5例MND和9例非神经系统变性病对照患者脑和脊髓进行苏木素－伊红、快蓝和Bodian常规染色,抗－泛素、抗－tau蛋白、抗－胶质纤维酸性蛋白和抗－神经丝蛋白抗体免疫组化染色。结果：5例MND抗泛素免疫组化染色在其中4例细胞 质内发现单线－线团样包涵体、透明包涵体、路易体样包涵体和不规则包涵体、相应前角细胞存在轻中度变性。3例海马颗粒细胞内出现泛素阳性包涵体。1例患者脊髓前角细胞内少数泛素阳性包涵体抗神经丝蛋白染色也阳性,各种泛不阳性包涵体抗tau蛋白及胶质纤维酸性蛋白染色为阴性,结论脊髓前角细胞质内的泛素阳性包涵体是MND较为特异的免疫病理改变,不同类型包涵体之间可能存在一定的演变规律,与相应神经细胞的变性相关。少数泛素阳性包涵体含有神经丝蛋白成分,海马颗粒细胞内出现泛素阳性包涵休提示此病同时累及非运动系统,并可能 与MND临床上智能或精神异常有关。     

运动神经元病162例的节段性运动神经传导测定分析

目的探讨运动神经元病(motor neuron d isease,MND)常规节段运动神经传导和位移技术检测的特点。方法对162例MND患者和60名健康对照进行常规节段运动神经传导测定,同时对部分神经采用位移技术测定,并进行分析比较。结果(1)健康人常规节段运动神经传导测定显示:近端与远端比较,波幅和面积下降程度均小于20%,时限增宽小于15%;(2)在MND患者,常规节段测定共有76个节段(5.57%)波幅下降超过20%,45个节段(3.30%)面积下降超过20%,76个节段(5.57%)时限延长超过15%。仅有4例(2.5%)患者4条神经的4个常规节段(0.29%)达到运动神经部分性传导阻滞标准,但采用位移技术测定时均未达到短节段传导阻滞的诊断标准。结论在大部分MND患者常规节段运动神经传导测定正常,在部分患者也可以出现“传导阻滞样”的电生理表现,但其发生率极低,进一步采用位移技术测定有助于鉴别。     

British motor neuron disease twin study.

OBJECTIVES: To investigate the cause of sporadic motor neuron disease (MND) by twin study, so allowing (1) estimation of the genetic contribution, and (2) collection of matched pairs for a case-control study of possible environmental factors. METHODS: 10872 death certificates bearing the diagnosis MND were collected from 1979 to 1989 inclusive. Inspection of individual birth entries allowed identification of potential twins. The status of each co-twin was determined and contact made through the National Health Service Central Register (NHS-CR) and their general practitioner (GP). The diagnosis of MND was verified via the co-twin and relatives, and medical records where available. Zygosity was assessed using a recognised questionnaire. Details concerning environmental exposures and health were gathered by interview of cotwin and relatives using a semistructured questionnaire. Heritability (h2) of MND was estimated, and the environmental information was analysed by conditional logistic regression modelling. RESULTS: Seventy seven probands were identified, of whom 26 were monozygotic and 51 dizygotic. Four monozygotic probands were concordant, but two probands came from a family known to have familial MND. The estimated heritability was between 0.38 and 0.85. Most environmental risk factors were not significant. Regular vehicle maintenance (odds ratio (OR) = 7.0; 95% confidence interval (95% CI) 1.3-89.9) and occupational paint usage (OR = 3.75; 95% CI 1.0-17.1), however, occurred significantly more often in the affected cases. CONCLUSIONS: This "death discordant" method for twin collection has proved to be viable, and has allowed the ascertainment of a large population sample in a rare disease. The genetic role in sporadic MND is substantial, and higher than expected. Exposure to industrial chemicals, particularly constituents of petrochemicals and paints, may contribute to the aetiology of MND.     

Ultrastructural evidence of neurofilament involvement in immune-mediated motor neuron injury

Abstract

Amyotrophic lateral sclerosis (ALS) is a progressive neurological disorder. A pathologic hallmark of ALS is accumulation of neurofilaments in proximal axons of affected motor neurones. As the neurofilaments involved in immune-mediated spinal cord ventral horn motor neuron degeneration and loss, we developed immune-mediated motor neuron injury animal model by inoculating Lewis rats with swine spinal cord homogenate and investigated the ultrastructural features of neurofilament accumulation using transmission electron microscopy. Our results showed that there was aberrant accumulation of neurofilaments in perikarya and processes of remaining motor neurons in recipient animals, which is similar to those observed in ALS patients. These findings suggest that immune-mediated motor neuron injury may share a common pathogenesis with ALS.     

Ultrastructural evidence of neurofilament involvement in immune-mediated motor neuron injury

Amyotrophic lateral sclerosis (ALS) is a progressive neurological disorder. A pathologic hallmark of ALS is accumulation of neurofilaments in proximal axons of affected motor neurones. As the neurofilaments involved in immune-mediated spinal cord ventral horn motor neuron degeneration and loss, we developed immune-mediated motor neuron injury animal model by inoculating Lewis rats with swine spinal cord homogenate and investigated the ultrastructural features of neurofilament accumulation using transmission electron microscopy. Our results showed that there was aberrant accumulation of neurofilaments in perikarya and processes of remaining motor neurons in recipient animals, which is similar to those observed in ALS patients. These findings suggest that immune-mediated motor neuron injury may share a common pathogenesis with ALS.     

A clinicopathological study on 13 cases of motor neuron disease with dementia]

Thirteen patients suffering from motor neuron disease with dementia were studied to analyze the clinicopathological spectrum. The diagnosis of the disease was made on the basis of a clinical history of progressive dementia and motor neuron involvement. The mean age at onset of 11 sporadic cases was 54.9 years (range, 43 to 69 years), with a mean duration of disease of 25 months (range, 11 to 47 months). The initial symptoms were dementia in 7 cases, motor neuron involvement in 2 cases, and both dementia and motor neuron involvement in 2 cases. The clinical picture of motor neuron disturbance in sporadic cases represented bulbar-type of amyotrophic lateral sclerosis (ALS). Bulbar palsy was the initial symptom in 7 sporadic cases and all 11 patients developed bulbar palsy with advancing course of illness. Muscular wasting and fasciculation were more predominant in the upper limbs, shoulder girdle and anterior chest. Fasciculation was more extensively and frequently observed in those portions than that of classical ALS. In contrast, muscle strength in the lower limbs was well preserved so that all patients could walk even when respiratory failure developed. Hyperreflexia including jaw jerk was found in all cases and positive Babinski sign in 7 cases. Parkinsonism appeared in the initial stage in one sporadic case and in two familial cases. The type of dementia with uninhibited behavior and personality change closely mimicked that of Pick's disease. The degree of dementia was mild or moderate in 8 cases and severe in 3 cases. Language disorder was characterized by progressive reduction of speech output, leading finally to mutism in 5 cases. Perseveration was observed in 10 cases. Visuospatial disorder was absent even in the advanced stage. Mild memory disturbance was noted in the early stage in 10 cases. Pathological examination was performed in 7 cases including one familial case, revealing frontal atrophy in 3 cases, frontotemporal atrophy in 2 cases and temporal atrophy in 2 cases. On microscopic examination there were mild neuronal loss, gliosis, mild spongy state of the cortical superficial layers and fibrous gliosis in the frontotemporal white matter. The scattered senile plaques in one case did not justify a diagnosis of Alzheimer's type dementia. Neither circumscribed atrophy nor Pick body was found in any case. The nucleus basalis of Meynert showed no neuronal loss. The substantia nigra showed a mild to severe loss of nerve cells without Lewy bodies in all cases.(ABSTRACT TRUNCATED AT 400 WORDS)     

免疫介导的脊髓前角运动神经元损伤过程中神经丝异常的观察

目的 研究免疫介导的脊髓前角运动神经元损伤过程中神经丝(NF)磷酸化及超微结构的特征,探讨免疫与肌萎缩侧索硬化发病之间的关系.方法 通过透射电镜技术及免疫组化方法,对免疫介导的脊髓前角运动神经元损伤过程中NF异常聚集的超微结构特征及异常磷酸化状态进行研究.结果 电镜观察发现免疫后动物脊髓前角运动神经元胞质及轴索近端有神经丝异常聚集;免疫组化证实抗非磷酸化神经丝(SMI-32)抗体阳性的脊髓前角运动神经元(个/张脊髓切片)数量(12.00±1.05)与对照组(18.00±1.83)相比,明显减少(P＜0.05),而抗磷酸化NF抗体(SMI-31)阳性的脊髓前角运动神经元数量(13.00±1.60)与对照相比(3.23±1.33)明显增加(P＜0.01).结论 在免疫介导的运动神经元损伤过程中存在类似于肌萎缩侧索硬化的神经丝结构及代谢异常特征,两者之间可能存在共同的发病机制.     

运动神经元病血清特异抗原成分的检测

目的检测运动神经元病（ＭＮＤ）病人血清中是否存在运动神经元特异抗原成分，并探索ＭＮＤ潜在的诊断标志物。方法制备５株抗运动神经元单克隆抗体，并证明其对大鼠脊髓前角运动神经元具有高度特异的免疫组织化学反应。应用抗运动神经元单克隆抗体２４Ｂ０－ＭｃＡｂ，用ＥＬＩＳＡ法对２５例运动神经元病病人血清中的特异抗原成分进行检测。根据临床表现将２５例病人分为肌萎缩侧索硬化（ＡＬＳ）、脊肌萎缩症（ＳＭＡ）及进行性球麻痹（ＰＢＰ）３组，再按年龄段分３个亚组（＜２０岁组、２０～３９岁组、＞４０岁组）。结果发现８５％（２２／２５）临床确诊的ＭＮＤ病人存在较高浓度的特异抗原成分，ＭＮＤ病人与正常对照组对２４Ｂ０－ＭｃＡｂ的反应性差异有显著性意义（Ｐ＜０．０５），ＡＬＳ、ＳＭＡ及ＰＢＰ亚型之间差异也有显著性意义（Ｐ＜０．０５），而年龄组之间差异虽有显著性意义，其临床意义尚需进一步研究。性别组之间的差异无显著性意义。结论ＭＮＤ病人血清中存在运动神经元特异抗原成分。用抗运动神经元单克隆抗体以ＥＬＩＳＡ法检测运动神经元特异抗原可以作为诊断ＭＮＤ的辅助检查。     

马德拉斯运动神经元病一例

目的探讨马德拉斯运动神经元病(MMND)的临床表现,以提高该病的诊断水平。方法分析1例MMND患者的病史资料。结果 43岁男性患者以咀嚼肌无力起病,出现多发的脑神经(Ⅴ、Ⅶ、Ⅸ、Ⅹ、Ⅺ、Ⅻ)损害,颈部、背部、上肢肌肉萎缩、无力,结合电生理检查结果,诊断为MMND。结论 MMND是运动神经元病的一个少见亚型,主要表现为多发的脑神经损害,广泛的肢体萎缩、无力,上、下运动神经元均受累,肌电图提示广泛神经源性损害,呈进展性但相对良性病程。     

Clinically undetected motor neuron disease in pathologically proven frontotemporal lobar degeneration with motor neuron disease

BACKGROUND: Frontotemporal lobar degeneration with motor neuron disease (FTLD-MND) is a pathological entity characterized by motor neuron degeneration and frontotemporal lobar degeneration. The ability to detect the clinical signs of dementia and motor neuron disease in pathologically confirmed FTLD-MND has not been assessed. OBJECTIVES: To determine if all cases of pathologically confirmed FTLD-MND have clinical evidence of frontotemporal dementia and motor neuron disease, and to determine the possible reasons for misdiagnosis. METHOD: Review of historical records and semiquantitative analysis of the motor and extramotor pathological findings of all cases of pathologically confirmed FTLD-MND. RESULTS: From a total of 17 cases of pathologically confirmed FTLD-MND, all had clinical evidence of frontotemporal dementia, while only 10 (59%) had clinical evidence of motor neuron disease. Semiquantitative analysis of motor and extramotor pathological findings revealed a spectrum of pathological changes underlying FTLD-MND. Hippocampal sclerosis, predominantly of the subiculum, was a significantly more frequent occurrence in the cases without clinical evidence of motor neuron disease (P<.01). In addition, neuronal loss, gliosis, and corticospinal tract degeneration were less severe in the other 3 cases without clinical evidence of motor neuron disease. CONCLUSIONS: Clinical diagnostic sensitivity for the elements of FTLD-MND is modest and may be affected by the fact that FTLD-MND represents a spectrum of pathological findings, rather than a single homogeneous entity. Detection of signs of clinical motor neuron disease is also difficult when motor neuron degeneration is mild and in patients with hippocampal sclerosis.