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1.
Vedad Delic Crupa Kurien Josean Cruz Sandra Zivkovic Jennifer Barretta Avery Thomson Daniel Hennessey Jaheem Joseph Jared Ehrhart Alison E. Willing Patrick Bradshaw Svitlana Garbuzova‐Davis 《Journal of neuroscience research》2018,96(8):1353-1366
Amyotrophic lateral sclerosis (ALS) is an adult onset neurodegenerative disease characterized by progressive motor neuron degeneration in the brain and spinal cord leading to muscle atrophy, paralysis, and death. Mitochondrial dysfunction is a major contributor to motor neuron degeneration associated with ALS progression. Mitochondrial abnormalities have been determined in spinal cords of animal disease models and ALS patients. However, molecular mechanisms leading to mitochondrial dysfunction in sporadic ALS (sALS) patients remain unclear. Also, segmental or regional variation in mitochondrial activity in the spinal cord has not been extensively examined in ALS. In our study, the activity of mitochondrial electron transport chain complex IV was examined in post‐mortem gray and white matter of the cervical and lumbar spinal cords from male and female sALS patients and controls. Mitochondrial distribution and density in spinal cord motor neurons, lateral funiculus, and capillaries in gray and white matter were analyzed by immunohistochemistry. Results showed that complex IV activity was significantly decreased only in gray matter in both cervical and lumbar spinal cords from ALS patients. In ALS cervical and lumbar spinal cords, significantly increased mitochondrial density and altered distribution were observed in motor neurons, lateral funiculus, and cervical white matter capillaries. Discrete decreased complex IV activity in addition to changes in mitochondria distribution and density determined in the spinal cord in sALS patients are novel findings. These explicit mitochondrial defects in the spinal cord may contribute to ALS pathogenesis and should be considered in development of therapeutic approaches for this disease. 相似文献
2.
The diagnostic hallmarks of amyotrophic lateral sclerosis (ALS) are degeneration of upper and lower motor neurons and of corticospinal tracts. Here, we demonstrate the suitability of the gliosis marker [3H]PK11195 for quantitative evaluation of tract degeneration in ALS in vitro. Binding of [3H]PK11195 was increased in lateral and ventral white matter of ALS spinal cords but not in the anterior horn, in spite of a dramatic loss in muscarinic binding sites and a high level of oxidatively modified protein. Labeling of activated microglia with [11C]PK11195 may also allow tract degeneration in ALS to be visualized in vivo. 相似文献
3.
Morphological evidence for lipid peroxidation and protein glycoxidation in spinal cords from sporadic amyotrophic lateral sclerosis patients 总被引:5,自引:0,他引:5
Shibata N Nagai R Uchida K Horiuchi S Yamada S Hirano A Kawaguchi M Yamamoto T Sasaki S Kobayashi M 《Brain research》2001,917(1):97-104
For determining whether both the spinal cord motor neurons and glial cells are exposed to increased oxidative stress in amyotrophic lateral sclerosis (ALS), we performed an immunohistochemical investigation of end products of lipid peroxidation and protein glycoxidation in spinal cords from seven sporadic ALS patients and seven age-matched control individuals. In the ALS spinal cords, immunoreactivities for adducts of 4-hydroxy-2-nonenal-histidine and crotonaldehyde-lysine as markers of lipid peroxidation, N(epsilon)-(carboxymethyl)lysine as a marker of lipid peroxidation or protein glycoxidation, and pentosidine as a marker of protein glycoxidation were localized in the gray matter neuropil and almost all of the motor neurons, reactive astrocytes and microglia/macrophages, whereas none of the immunoreactivities for N(epsilon)-(carboxyethyl)lysine or argpyrimidine as markers of protein glycoxidation or enzymatic glycolysis, or pyrraline or imidazolone as markers of nonoxidative protein glycation were detectable. The control spinal cords displayed no significant immunoreactivities for any of these examined products. Our results indicate that in sporadic ALS, both lipid peroxidation and protein glycoxidation are enhanced in the spinal cord motor neurons and glial cells, and suggest that the formation of certain products in these abnormal reactions is implicated in motor neuron degeneration. 相似文献
4.
An immunohistochemical study using a monoclonal antibody against macrophage (Ki-M1p) was performed to examine which fiber tracts are affected in the spinal cords and brainstems of ALS patients. In 21 out of 30 ALS patients, various degrees of macrophage infiltration were observed diffusely in the anterolateral columns beyond the corticospinal tracts. On the other hand, a few macrophages were scattered in 20 non-ALS patients in the anterolateral columns outside the corticospinal tracts. In ALS brainstems, the macrophages were mainly localized in the corticospinal tracts. The result suggests that the diffuse myelin pallor in the anterolateral columns beyond the corticospinal tracts may be derived from intrinsic spinal cord lesions. Quantitative investigation using a monoclonal antibody against phosphorylated neurofilaments (SMI-31) revealed that the decrease in the numbers of small fibers would induce the diffuse myelin pallor in anterolateral columns of ALS patients. From these findings, we propose that the propriospinal bundles are candidates for the degenerating fibers in the anterolateral columns of ALS. 相似文献
5.
Our earlier studies indicate that the KDI tripeptide of gamma1 laminin reverts paralysis and protects adult rat CNS from excitotoxicity of glutamate and from oxidative stress. Here we show that gamma1 laminin is selectively overexpressed in reactive astrocytes of the amyotrophic lateral sclerosis (ALS) spinal cord, with both gray and white matter astrocytes overexpressing gamma1 laminin. Intensely gamma1 laminin-positive, aggressive-looking reactive astrocytes of the lateral columns of both cervical and thoracic spinal cord surround the lateral ventral horns and roots and extend into the area of the lateral corticospinal tract. In the cervical ALS spinal cord, large numbers of strongly gamma1 laminin-immunoreactive astrocytes are also present in the dorsal columns of the ascending sensory pathways. No other laminin or any other ALS-associated protein localizes in this manner. This unique distribution of gamma1 laminin-immunoreactive astrocytes in the ALS white matter together with our recent results on the efficacy of the KDI domain as a neuronal protector strongly suggest that gamma1 laminin may be expressed by astrocytes of the ALS spinal cord as a protective measure intended to aid neuronal survival. Further comparative studies on ALS spinal cord tissues and those of the animal models of ALS are needed to clarify the specific role of gamma1 laminin and its KDI domain in ALS and its putative interactions with the additional ALS-associated factors, such as excitotoxicity, oxidative stress, and neurofilament accumulation. Most importantly, further studies are urgently needed to test the potential of the KDI tripeptide as a therapeutic treatment for ALS. 相似文献
6.
Lymphocytic infiltration in the spinal cord of patients with amyotrophic lateral sclerosis 总被引:6,自引:0,他引:6
Amyotrophic lateral sclerosis (ALS) is a devastating systemic atrophy affecting the upper and lower motor neurons. The etiology is unknown, but one theory of pathogenesis supposes that the motor system is affected by abnormal immune responses. We have studied the prevalence and extent of lymphocytic infiltration, previously reported as a rare finding in the ALS spinal cord. Application of monoclonal antibodies against macrophages, T- and B-cells to spinal cords from 48 ALS patients disclosed a cellular mononuclear infiltrate in 38 specimens (79%), intense enough to be revealed by routine neuropathological techniques in 6 of them (12.5%); the remaining 10 cords (21%) exhibited no infiltrates. Since duration and clinical signs of the preceeding illness were the same in cases with and without infiltrates, we consider it unlikely that such infiltrates are entirely secondary to atrophy of the cord. As Wallerian degeneration is not accompanied by infiltrates of lymphocytes, their presence in the cord tracts of our material throws doubt on the conventional view that tract degeneration in ALS is exclusively Wallerian. 相似文献
7.
Alteration in amino acids in motor neurons of the spinal cord in amyotrophic lateral sclerosis. 总被引:1,自引:0,他引:1
S Ono T Imai K Takahashi K Jinnai F Kanda Y Fukuoka K Hashimoto N Shimizu K Nagao 《Journal of the neurological sciences》1999,167(2):121-126
Little is known concerning the changes of amino acid composition in different regions of the spinal cord in patients with amyotrophic lateral sclerosis (ALS). We performed quantitative amino acid analyses in the posterior funiculus, the lateral corticospinal tract, and the anterior horn of cervical enlargement of the spinal cord from seven ALS patients, and the results were compared with those of seven patients with other neurologic diseases (control A) and seven patients without neurologic diseases (control B). The levels of collagen-associated amino acids, hydroxyproline, proline, glycine, and hydroxylysine, were markedly lower in the lateral corticospinal tract and the anterior horn of ALS patients than in controls A and B. The contents of the acidic amino acids glutamate and aspartate were also significantly decreased in the lateral corticospinal tract and the anterior horn of ALS patients as compared with those of controls A and B. These data suggest that decreased contents of collagen-associated amino acids and excitatory amino acids are related to the degeneration of the upper and lower motor neurons in the spinal cord in ALS. 相似文献
8.
9.
A case of amyotrophic lateral sclerosis (ALS) and cerebral glioblastoma multiforme is presented in which bizarre astrocytes were found in the degenerating lateral corticospinal tracts, along with Rosenthal fibers, which were present in the corticospinal tracts of the lower medulla and spinal cord, and in anterior horns. These bizarre astrocytes did not result from direct infiltration of tumor from the cerebrum. "Malignant transformation" and/or an exceptionally intense glial response to the corticospinal tract degeneration are discussed as possibilities for the development of these bizarre astrocytes. Rosenthal fiber formation is described, to our knowledge, for the first time in ALS. 相似文献
10.
Volumetric analysis reveals corticospinal tract degeneration and extramotor involvement in ALS. 总被引:5,自引:0,他引:5
C M Ellis J Suckling E Amaro E T Bullmore A Simmons S C Williams P N Leigh 《Neurology》2001,57(9):1571-1578
BACKGROUND: Pathologic changes in the motor cortex and corticospinal tracts in ALS may be reflected by abnormal signal intensities on conventional MRI. The sensitivity of these changes in detecting underlying pathology remains unclear. METHOD: The authors used automated image analysis to quantify volumes of cerebral gray and white matter in 16 patients with ALS (eight limb onset, eight bulbar onset) and eight normal controls. Previously they had demonstrated a reduction in N-acetyl aspartate/creatine + phosphocreatine (NAA/[Cr + PCr]) measured by (1)H-MRS in the subcortical white matter in the motor cortex region in the patients with bulbar-onset ALS. To determine whether this resulted from axonal degeneration, they also compared gray and white matter volumes in the patients with limb- and bulbar-onset ALS. RESULTS: There were no differences in the total brain volumes of gray or white matter for the three subject groups (p > 0.23). Comparison of the total ALS group and controls revealed localized deficits in gray matter volume centered on Brodmann areas 8, 9, and 10 bilaterally. Comparison of the patients with limb- and bulbar-onset ALS revealed deficits in the white matter volume in the bulbar-onset group, extending bilaterally from the precentral gyrus into the internal capsule and brainstem, consistent with the course of the corticospinal tract. There was no loss in gray matter volume in the precentral gyri. CONCLUSIONS: The loss of gray matter in the frontal regions (total ALS group) provides further support that ALS is a multisystem disorder. In addition, there is in vivo evidence of axonal degeneration in the subcortical white matter in the motor region in patients with bulbar-onset ALS. This is consistent with a "dying back" process affecting cortical motoneurons in bulbar-onset ALS. 相似文献
11.
Xiaojun Mu Jin He David W. Anderson Joe E. Springer John Q. Trojanowski 《Annals of neurology》1996,40(3):379-386
One of the primary neurodegenerative events occurring in amyotrophic lateral sclerosis (ALS) is the selective loss of spinal cord α motor neurons. To study the potential role of apoptosis in the degeneration of these motor neurons, in situ hybridization was used to measure the expression of two apoptotic cell death genes, bcl-2 and bax, in control and ALS lumbar spinal cord sections. The strongest hybridization signal for bcl-2 mRNA in neurological and nonneurological control spinal cords was found primarily in lamina IX α motor neurons, while a weaker hybridization signal was found in neurons of Clarke's nucleus and the proper sensory nucleus of the dorsal horn. Surviving lamina IX motor neurons in ALS spinal cord sections also expressed bcl-2 mRNA, but at levels that were significantly and selectively decreased (4.7-fold) compared with control. bax mRNA hybridization signal was detected in several cells throughout the gray matter in control and ALS lumbar spinal cord, but was significantly and selectively increased (2.8-fold) in ALS motor neurons. Given the proposed interactive roles of these genes in apoptosis, the present findings favor a scenario in which this mode of cell death would contribute to spinal cord motor neuron degeneration in ALS. 相似文献
12.
This report concerns the demonstration and distribution of neurofibrillary tangles (NFTs), immunoreactive neuropil thread-like structures and dots in the spinal cord gray and white matter of six patients with parkinsonism-dementia complex on Guam and five patients with Guamanian amyotrophic lateral sclerosis (ALS). A monoclonal antibody to Alzheimer NFTs was used. NFTs were found in the spinal cord gray matter and white matter and all patients had immunoreactive neuropil thread-like structures and dots in the gray matter as well as in the white matter. They were particularly numerous in the lateral funiculus of patients with Guamanian ALS.Supported in part by a grant of the Amyotrophic Lateral Sclerosis Associaton 相似文献
13.
Insulin-like growth factor-1 receptors in human spinal cord: changes in amyotrophic lateral sclerosis 总被引:2,自引:0,他引:2
A. Adem J. Ekblom P. G. Gillberg S. S. Jossan A. Höög B. Winblad S. M. Aquilonius L. H. Wang V. Sara 《Journal of neural transmission (Vienna, Austria : 1996)》1994,97(1):73-84
Summary Neurotrophic factors are important for neuronal survival and maintenance in the adult nervous system. The regional distribution of insulin-like growth factor-1 (IGF-1) receptors in human spinal cords from controls and amyotrophic lateral sclerosis (ALS) patients was studied by immunohistochemistry and quantitative autoradiography. When comparing125I-IGF-1 binding in the different spinal levels of normal spinal cord the same distribution pattern was found in which the binding was highest in the central canal > dorsal horn > ventral horn > white matter. In the ALS cases although a general upregulation of IGF-1 receptors was observed throughout the spinal cord, significant increases were observed in the cervical and sacral segments compared to controls. IGF-1 receptor immunoreactivity showed a similar pattern to that for125I-IGF-1 binding, with immunoreactivity being found in the gray matter of the spinal cord and enhanced immunoreactivity occuring in ALS patients compared to controls. In agreement with the distribution of IGF-1 receptors, IGF-1 immunoreactivity was found within the gray matter of the spinal cord. The cartography of IGF-1 receptors in the normal spinal cord as well as the change of these receptors in diseased spinal cord may be of importance in future treatment strategies of ALS. 相似文献
14.
Shintaro Hayashi Masakuni Amari Masamitsu Takatama Koichi Okamoto 《Neuropathology》2007,27(2):121-126
Little attention has been paid to the degeneration of small neurons in ALS spinal gray matter. The purpose of the present paper was to undertake morphometric and quantitative analysis of the spinal gray matter of 15 ALS patients and compare findings to those of five controls. A significant reduction of small neurons in the anteromedial and intermediate parts of the gray matter were detected in ALS spinal cords with diffuse myelin pallor in the ventral aspects of the anterolateral columns outside the corticospinal tracts, and the number of small neurons in these areas was decreased significantly depending on the intensity of the myelin pallor. There were no significant alterations in the number of small neurons in the corresponding areas of ALS spinal cords without diffuse myelin pallor or in those of controls. In the posterior parts of the gray matter, there were no significant differences in the number of small neurons among ALS patients and controls. These findings strongly suggest that diffuse myelin pallor in the ventral aspects of anterolateral columns in ALS spinal cords is derived from the degeneration of small neurons in the anteromedial and intermediate parts of the gray matter. 相似文献
15.
Echaniz-Laguna A Degos B Mohr M Kessler R Urban-Kraemer E Tranchant C 《Muscle & nerve》2006,33(3):356-362
We report three patients with a syndrome that fulfilled clinical and laboratory criteria for definite chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) who failed immunosuppressive treatment and eventually developed progressive amyotrophic lateral sclerosis (ALS). Mean disease duration was 23 months (13-38) before death. Two patients had a family history of ALS without mutations of the SOD1 gene. Postmortem examination in one patient showed an endoneurial infiltration of mononuclear cells in lumbar roots and distal and proximal peripheral nerves, mainly around myelinated fibers, with demyelination and axonal loss, consistent with CIDP. The spinal cord revealed severe neuronal loss in the anterior horn, axonal loss in the corticospinal tract, and large numbers of phagocytes in the anterior and lateral tracts, indicative of ALS. Whether demyelinating polyneuropathy was coincident with ALS or was a cause or consequence of motor neuron degeneration in these patients remains to be elucidated. This unusual combination may provide an important clue in elucidating the pathogenesis of ALS in some patients. 相似文献
16.
The origin and distribution of corticospinal fibers in the slow loris (Nycticebus coucang) were studied with the aid of the Nauta-Gygax technique following selected ablations of portions of the left cerebral cortex. Reconstruction of the cortical area which contributes to the corticospinal tract reveals a “motor” area which approximates that of Perodicticus, another lorisiform lemur, mapped by electrophysiological methods. Degenerated corticospinal fibers found in the contralateral lateral funiculus were traced caudally to sacral segments. A small number of degenerated fibers were also found in the ipsilateral lateral funiculus as far caudally as the lumbar cord. Preterminal fiber degeneration was most abundant in the contralateral dorsal horn and zona intermedia. Similar, but less abundant, degeneration was found in the contralateral ventral horn. Some degenerating fibers re-crossed through the dorsal and ventral gray commissures to the ipsilateral gray matter where preterminal fiber degeneration was most abundant in the medial portions of the ventral horn. Degenerating corticospinal fibers could be seen among the large, laterally-placed cells of the contralateral ventral horn. 相似文献
17.
Distinct patterns of progressive gray and white matter degeneration in amyotrophic lateral sclerosis
Abdullah Ishaque Daniel Ta Muhammad Khan Lorne Zinman Lawrence Korngut Angela Genge Annie Dionne Hannah Briemberg Collin Luk YeeHong Yang Christian Beaulieu Derek Emery Dean T. Eurich Richard Frayne Simon Graham Alan Wilman Nicolas Dupr Sanjay Kalra 《Human brain mapping》2022,43(5):1519
Progressive cerebral degeneration in amyotrophic lateral sclerosis (ALS) remains poorly understood. Here, three‐dimensional (3D) texture analysis was used to study longitudinal gray and white matter cerebral degeneration in ALS from routine T1‐weighted magnetic resonance imaging (MRI). Participants were included from the Canadian ALS Neuroimaging Consortium (CALSNIC) who underwent up to three clinical assessments and MRI at four‐month intervals, up to 8 months after baseline (T 0). Three‐dimensional maps of the texture feature autocorrelation were computed from T1‐weighted images. One hundred and nineteen controls and 137 ALS patients were included, with 81 controls and 84 ALS patients returning for at least one follow‐up. At baseline, texture changes in ALS patients were detected in the motor cortex, corticospinal tract, insular cortex, and bilateral frontal and temporal white matter compared to controls. Longitudinal comparison of texture maps between T 0 and T max (last follow‐up visit) within ALS patients showed progressive texture alterations in the temporal white matter, insula, and internal capsule. Additionally, when compared to controls, ALS patients had greater texture changes in the frontal and temporal structures at T max than at T 0. In subgroup analysis, slow progressing ALS patients had greater progressive texture change in the internal capsule than the fast progressing patients. Contrastingly, fast progressing patients had greater progressive texture changes in the precentral gyrus. These findings suggest that the characteristic longitudinal gray matter pathology in ALS is the progressive involvement of frontotemporal regions rather than a worsening pathology within the motor cortex, and that phenotypic variability is associated with distinct progressive spatial pathology.In this study, we use MRI texture analysis to detect progressive cerebral degeneration in amyotrophic lateral sclerosis (ALS). Here, we demonstrate distinct spatiotemporal patterns of degeneration related to clinical phenotypes in patients with ALS. 相似文献
18.
This report concerns a comparative immunocytochemical, ultrastructural and morphometric investigation on heterotopic neurons
in the white matter of the spinal cords of 19 patients with amyotrophic lateral sclerosis (ALS) and 18 age-matched neurologically
normal individuals. The study revealed that the heterotopic neurons were scattered in the white matter, often adjacent to
gray matter, that they immunoreacted with the antibody to synaptophysin, and that there were synaptic apparatuses on the surface
of their somata and their neuronal processes. Bunina bodies and ubiquitin-positive inclusions such as Lewy body-like inclusions
and skein-like inclusions, characteristic of anterior horn neurons of ALS, were present in the cytoplasm of the patients’
heterotopic neurons in the anterior or lateral column of the white matter. These findings suggest that heterotopic neurons
in the anterior or lateral column have the characteristics of alpha motor neurons. The average number of heterotopic neurons
observed in ALS patients was generally less than in normal subjects. This reduction was correlated with the severity of neuronal
loss. The heterotopic neurons in ALS were less susceptible to the degenerative process as compared with spinal cord anterior
horn cells. We assume that in this disease the heterotopic neurons may be degenerated and their number diminished after or
concomitantly with the depletion of anterior horn neurons.
Received: 18 August 1997 / Revised, accepted: 20 October 1997 相似文献
19.
Ciliary neurotrophic factor (CNTF), a potent survival factor in spinal motoneurons of embryonic chick and rat, is currently being investigated in humans as a treatment for amyotrophic lateral sclerosis (ALS). However, its physiological and pathological activities in ALS remain unclear. We measured CNTF contents in the cervical enlargement of the spinal cord from 9 ALS patients and 12 age-matched control subjects using a sensitive enzyme-linked immunoassay. CNTF genotypes were determined by the polymerase chain reaction-restriction fragment length polymorphism method. In control subjects, there were 8 homozygotes and 4 heterozygotes, while in ALS patients there were 6 and 3, respectively. In both homozygotes and heterozygotes, CNTF expression in the spinal cord from ALS patients tended to decrease compared to control subjects. In homozygotes, the decrease was significant (p < 0.05). Concerning the regional concentrations of CNTF, in homozygotes, CNTF contents in the lateral corticospinal tract were markedly lower (p < 0.001) in ALS patients than in controls. The decrease in CNTF expression in the lateral corticospinal tract of the spinal cord from ALS patients may be a feature of ALS and could be related to motor neuron loss. 相似文献
20.
Takefumi Kasai Hitoshi Ikeda Utano Tomaru Isao Yamashita Osamu Ohya Keisuke Morita Akemi Wakisaka Eiji Matsuoka Takashi Moritoyo Ken-ichiro Hashimoto Itsuro Higuchi Shyuji Izumo Mitsuhiro Osame T. Yoshiki 《Acta neuropathologica》1999,97(2):107-112
To investigate the pathogenetic role of human T lymphocyte virus type I (HTLV-I) in central nervous system disease, a rat
model for HTLV-I-associated myelopathy/tropical spastic paraparesis, designated as HAM rat disease, has been established.
Wistar-King-Aptekman-Hokudai strain rats with induced HTLV-I infection develop a chronic progressive myeloneuropathy with
paraparesis of hind limbs after an incubation period of 15 months. In the affected spinal cord in these rats, white matter
degeneration, demyelination and vacuolar change with microglia/macrophage infiltration are present as are the provirus DNA
and the virus mRNA. To identify infected cells in the affected lesions, we carried out in situ hybridization of amplified
fragments of the provirus DNA by polymerase chain reaction on thin sections, plus immunohistochemistry on the same sections.
The provirus DNA was localized in some microglia/macrophages in the spinal cord lesion. In addition, the HTLV-I provirus was
clearly evident not only in ED-1-negative lymphoid cells but also in ED-1-positive macrophages from lymph nodes. These observations
suggest that cells of microglia/macrophage lineage may be one of dominant viral reservoirs in the spinal cords and lymph nodes
in HAM rat disease. These infected microglia/macrophages may relate to cause the myeloneuropathy through neurotoxic cytokine
synthesis.
Received: 14 January 1998 / Revised, accepted: 30 July 1998 相似文献