Axonal degeneration in motor neuron disease

Growing evidence from animal models and patients with amyotrophic lateral sclerosis (ALS) suggests that distal axonal degeneration begins very early in this disease, long before symptom onset and motor neuron death. The cause of axonal degeneration is unknown, and may involve local axonal damage, withdrawal of trophic support from a diseased cell body, or both. It is increasingly clear that axons are not passive extensions of their parent cell bodies, and may die by mechanisms independent of cell death. This is supported by studies in which protection of motor neurons in models of ALS did not significantly improve symptoms or prolong lifespan, likely due to a failure to protect axons. Here, we will review the evidence for early axonal degeneration in ALS, and discuss possible mechanisms by which it might occur, with a focus on oxidative stress. We contend that axonal degeneration may be a primary feature in the pathogenesis of motor neuron disease, and that preventing axonal degeneration represents an important therapeutic target that deserves increased attention.     

Lower motor neuron disease with spinocerebellar degeneration

A patient with polymyositis responded initially to steroid therapy. A muscle biopsy disclosed features of primary myopathy and group atrophy. The patient became refractory to therapy and died with relentlessly progressive weakness. The autopsy disclosed lower motor neuron involvement and degeneration of the spinocerebellar tracts. There was loss of Purkinje cells, which may have occurred secondary to an anoxic episode prior to death. The case is unique because of the limited involvement of the lower motor and spinocerebellar systems.     

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.     

Sensory neuron diseases

Sensory neuron diseases (SND) are a distinct subgroup of peripheral-nervous-system diseases, first acknowledged in 1948. Acquired SND have a subacute or chronic course and are associated with systemic immune-mediated diseases, vitamin intoxication or deficiency, neurotoxic drugs, and life-threatening diseases such as cancer. SND are commonly idiopathic but can be genetic diseases; the latter tend to involve subtypes of sensory neurons and are associated with certain clinical pictures. The loss of sensory neurons in dorsal root ganglia causes the degeneration of short and long peripheral axons and central sensory projections in the posterior columns. This pathological process leads to a pattern of sensory nerve degeneration that is not length dependent and explains distinct clinical and neurophysiological abnormalities. Here we propose a comprehensive approach to the diagnosis of acquired and hereditary SND and discuss clinical, genetic, neurophysiological, neuroradiological, and neuropathological assessments.     

Association of cardiomyopathy with Kugelberg-Welander disease

A case of Kugelberg-Welander disease with echocardiographic evidence of mitral and tricuspid valve prolapse, in the contest of a cardiomyopathy that might be pathogenically related to the neurologic disease is reported.

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Sommario Viene presentato un caso di malattia di K-W reperti ecocardiografici di prolasso delle valvole mitrale e tricuspide nell'ambito di una cardiomiopatia che potrebbe essere patogeneticamente correlata alla malattia neurologica.

     

Lower motor neuron degeneration and familial predisposition to colonic neoplasia in two adult siblings.

A previously unreported association between a familial predisposition to colonic neoplasia and familial adult onset lower motor neuron (LMN) degeneration is reported. Two brothers presented at the ages of 53 and 44 years with multiple colonic adenomata and invasive colonic carcinoma respectively. Subsequently both developed a virtually identical pattern of motor neuron disease of progressive muscular atrophy type. At presentation both had LMN weakness affecting predominantly the upper limb and neck muscles. The disease progressed rapidly to involve the lower limb and bulbar musculature and both brothers died after a 15 month course. Necropsy was performed on one brother and showed pathological changes confined to the LMNs with no evidence of involvement of the pyramidal tracts or motor cortex. The combination of these diseases in two brothers may be of importance in the search for genes responsible for familial motor neuron disorders. It is suggested that a genomic search should be directed initially to the vicinity of known colon neoplasia genes, particularly 5q, 17q and 18q.     

TDP-43 A315T mutation in familial motor neuron disease

To identify novel causes of familial neurodegenerative diseases, we extended our previous studies of TAR DNA-binding protein 43 (TDP-43) proteinopathies to investigate TDP-43 as a candidate gene in familial cases of motor neuron disease. Sequencing of the TDP-43 gene led to the identification of a novel missense mutation, Ala-315-Thr, which segregates with all affected members of an autosomal dominant motor neuron disease family. The mutation was not found in 1,505 healthy control subjects. The discovery of a missense mutation in TDP-43 in a family with dominantly inherited motor neuron disease provides evidence of a direct link between altered TDP-43 function and neurodegeneration.     

TDP-43 proteinopathy: the neuropathology underlying major forms of sporadic and familial frontotemporal lobar degeneration and motor neuron disease

The rapid confirmation of the initial report by Neumann et al. (Science 314:130–133, 2006) that transactive response (TAR)-DNA-binding protein 43 (TDP-43) is the major disease protein linking frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTLD-U) with and without motor neuron disease (MND) as well as amyotrophic lateral sclerosis (ALS) implies that TDP-43 proteinopathy underlies major forms of sporadic as well as familial FTLD and ALS. Not only was the identity of the ubiquitinated proteins that accumulate in neurons and glia of these disorders finally resolved, but it also was shown that pathologic TDP-43 was hyperphosphorylated, ubiquitinated and cleaved to generate C-terminal fragments in affected brain and spinal cord of FTLD-U and ALS. This review summarizes the growing evidence that TDP-43 proteinopathy is the common pathologic substrate linking FTLD and ALS, and it considers the implications of these findings for developing better strategies to diagnose and treat these neurodegenerative disorders.     

Laminar distribution of neuron degeneration in posterior cingulate cortex in Alzheimer's disease

Summary The laminar distribution of neuron losses in posterior cingulate cortex were evaluated in 25 clinically and neuropathologically diagnosed cases of dementia of the Alzheimer type (DAT). The layer of maximal neuron loss in area 23a for each DAT case was determined by comparison with mean neuron densities for each layer of 17 neurologically intact control cases. The DAT cases were separated into five classes: class 1, 12% of all DAT cases, no or less than 40% neuron loss in any layer; class 2, 24%, maximal neuron losses in layers II or III; class 3, 28%, losses mainly in layer IV; class 4, 12%, losses mainly in layers V or VI; class 5, 24%, severe losses in all layers. An analysis of large and small neurons showed that in class 2 there was an equal loss of both in layer IIIa–b, in class 3 mostly small neurons were lost in layer IV, in class 4 mostly large neurons were lost in layers III, IV and V, while in class 5 there was no selectivity. The age of disease onset and length of the disease were the same for all classes, although classes 4 and 5 tended to have an earlier onset. No measures of thioflavin S-stained neuritic plaque (NP) or neurofibrillary tangle (NFT) density discriminated among these classes. In 64% of all DAT cases there was a progressive shift in NFT from ventral area 30 where most were in layer II to areas 23a–b where there was a balance between those in superficial and deep layers to dorsal area 23c where most were in layers V and VI. There were four cases with massive numbers of NFT in area 23a (1802±477 versus 261±44 for all other cases). Since one of these cases was in each of classes 1, 2, 3 and 5, it is unlikely that this form of amyloid deposition is related to laminar specificities in neuron degeneration. Finally, neuron and NFT densities in the hippocampal formation were the same for each class. In conclusion, differential laminar changes in neuron density provide a basis for neuropathological subtyping of DAT which is more sensitive than measures of thioflavin S-stained NP and NFT densities either in neocortex or the hippocampus.Supported by NIH-NINDS grants, NS18745, NS14944 and PONS19632     

Functional motor unit failure precedes neuromuscular degeneration in canine motor neuron disease

Hereditary canine spinal muscular atrophy (HCSMA) features rapidly progressive muscle weakness that affects muscles in an apparent proximal-to-distal gradient. In the medial gastrocnemius (MG) muscle of homozygous HCSMA animals, motor unit tetanic failure is apparent before the appearance of muscle weakness and appears to be presynaptic in origin. We determined whether structural changes in neuromuscular junctions or muscle fibers were apparent at times when tetanic failure is prevalent. We were surprised to observe that, at ages when motor unit tetanic failure is common, the structure of neuromuscular junctions and the appearance of muscle fibers in the MG muscle were indistinguishable from those of symptom-free animals. In contrast, in more proximal muscles, many neuromuscular junctions were disassembled, with some postsynaptic specializations only partially occupied by motor nerve terminals, and muscle fiber atrophy and degeneration were also apparent. These observations suggest that the motor unit tetanic failure observed in the MG muscle in homozygous animals is not due to synaptic degeneration or to pathological processes that affect muscle fibers directly. Together with previous physiological analyses, our results suggest that motor unit failure is due to failure of neuromuscular synaptic transmission that precedes nerve or muscle degeneration.     

Presenile non-Alzheimer dementia with motor neuron disease and laminar spongiform degeneration

We describe the clinicopathological findings in three autopsy cases of presenile dementia with motor neuron disease. These patients had a relatively rapid course involving dementia and muscle weakness with a distal pattern of atrophy in the upper extremities. Postmortem examination revealed features of motor neuron disease and spongiform cortical degeneration. The latter change was most marked in the second layer of the frontal or temporal cortex and included minimal to mild neuronal cell loss and mild to moderate gliosis. In this report we relate these patients' laminar spongiform degeneration to three other conditions; frontal lobe dementia, primary progressive aphasia and dementia lacking a distinctive histology. These three conditions and presenile dementia with motor neuron disease may fall within the spectrum of the non-Alzheimer type frontotemporal degenerative dementia.     

帕金森小鼠多巴胺能神经元轴突变性研究

目的建立1-甲基-4-苯基-1,2,3,6-四氢吡啶(MPTP)诱导的大龄(32～36 w)小鼠帕金森病慢性模型,探讨其多巴胺能神经元轴突变性在帕金森病发病机制中的作用。方法应用免疫组织化学染色、Fluoro-Jade C染色等方法,观察MPTP诱导的小鼠黑质多巴胺能神经元轴突变性与胞体凋亡的时效性关系。结果慢性MPTP腹腔注射大龄小鼠可诱导产生典型且稳定的帕金森病症状,并可引起黑质-纹状体多巴胺能神经元的凋亡与轴突变性,但轴突变性在发生时间上早于细胞凋亡。结论轴突变性在帕金森病发病机制中起着十分重要的作用,帕金森病可能与神经元-轴突-神经胶质细胞网络损伤密切相关。     

Comparison of sporadic and familial disease amongst 580 cases of motor neuron disease.

A review of 580 hospital case notes of patients with motor neuron disease (MND) revealed 20 families in which more than one case had been reported. For 27 of the cases in these families full medical records were available, and a history of a further 37 affected family members were obtained. The cases in these 20 families are termed familial and the remainder sporadic. Parent to child transmission occurred in 16 of the 20 families of the familial cases, suggesting autosomal dominant inheritance. In three families there was involvement of siblings only, and in one family two cousins were affected. The sex ratio for the documented familial case records seen was 0.8:1 (M/F = 12:15), for the total (documented and historical) it was 1.06:1 (33:31), but in sporadic cases it was 1.6:1 (341:212) and more frequent occurrence of sensory features at presentation was reported in the familial cases (15% in the familial cases and 5% in the sporadic cases). However, none of these differences reached statistical significance. Familial cases also differed from sporadic cases in having a younger age of onset (a mean of 52 years in the familial cases compared with 56 years in the sporadic) and in the shorter median reported duration of illness (1.1 year in the familial cases; 2.6 years in the sporadic). However, in only one fifth of sporadic cases was the age at onset and death known, although this was known for 22 of the 27 familial cases, so that the data on survival and age of onset are too incomplete to test formally.     

MRI findings in a patient with a familial form of motor neuron disease

The authors report the case of a 32-year-old woman who developed symptoms and signs possible manifestations of a familial motor neuron disease with left sided pyramidal signs and marked wasting and weakness in the ipsilateral upper girdle, progressively extended to the contralateral upper limb. The CT-scan showed only frontal cortical atrophy. MRI disclosed a restricted area of increased signal intensity in the centrum semiovale of the subcortical white matter of the right prefrontal cortex. This young woman did not disclose any risk factors for cerebrovascular diseases nor other disorders of the CNS; therefore the authors are of the opinion that the white matter changes observed on MRI are not occasional findings, but are related to the pathologic process occurring in consequence of her neurodegenerative disorder (possible ALS).