Spinal cord injuries, human neuropathology and neurophysiology.

A correlative approach to human spinal cord injuries (SCI) through the combination of neuropathology and neurophysiology provides a much better understanding of the condition than with either alone. Among the benefits so derived is the wide range of interventions applicable to the restorative neurology (RN) of SCI so that the neurological status of the SCI patient is thereby much improved. The neurophysiological and neuropathological elements underlying these advances are described.

The neuropathological foundations for the restorative neurology of spinal cord injury.

An appreciation of the neuropathology of human spinal cord injury (SCI) is a basic requirement for all concerned with the medical treatment of patients with SCI as well as for the many neuroscientists devoted to finding a "cure". An understanding of the neuropathology of SCI is a necessary guide to those concerned at all levels of treatment, whether they are doctors or other health professionals. The underlying changes in the spinal cord are especially relevant to the restorative neurology (RN) of SCI. The new discipline of RN seeks to enhance the function of residual spinal cord elements which have survived the injury and so improve the patient's rehabilitative status. This is in contrast to the conventional approach in rehabilitation which works around the clinical neurological deficiencies. Following the injury a series of changes take place in the spinal cord and surrounding tissues which continue to evolve throughout the life of the patient. In flexion and extension injuries resulting from motor vehicle trauma, diving and sporting accidents the spinal cord is compressed and disrupted but usually with some continuity remaining in the white matter columns. The brunt of the injury is usually centrally placed where there is bleeding into the disrupted grey matter involving one two segments, usually cervical. The loss of central grey matter is nowhere near as important as is the tearing apart of the white matter tracts in determining the patient's clinical state. The central grey matter supplies one two overlapping segmental myotomes and sensory fields. In contrast loss of continuity in the long white matter tracts is catastrophic because all functions below the level of injury are affected, autonomic or voluntary either by paralysis or anaesthesia, usually both. It is important to determine the exact nature of the injury in every patient as a preliminary to treatment by RN. This assessment is both clinical and neurophysiological with special attention given to any part of the long white matter tracts which may have escaped the initial injury. It is these residual nerve fibres which provide the opportunity to improve the patient's neurological state by being re-activated, modulated and enhanced by stimulation or by other RN methods. The conversion of a clinically complete SCI patient to being incomplete and ambulant is a tremendous improvement in the patient's status. It is the purpose of this article to provide the reader with the essential neuropathology of SCI as a beginning point in planning treatment whether it is medical or ancillary, as well as to inform the neuroscientist about the condition being addressed in his or her research.

Restorative neurology: consideration of the new anatomy and physiology of the injured nervous system.

The adult human nervous system is an incredibly complex set of thousands to tens of thousands of connections between a hundred billion neurons that develops via an intricate spatial-temporal process and is shaped by experience. In addition, any one anatomical arrangement of neural circuits is usually capable of multiple physiological states. Following neurological injury, a new anatomy, and consequently a new spectrum of physiology, emerges within this nervous system with its mix of both injured and uninjured parts. It is this new combination of neural components that determines the extent to which natural functional recovery can occur and the extent to which clinical interventions can further that recovery. Detecting the new anatomy and physiology of the injured human nervous system is difficult but not impossible and some methods can track over time changes in neural structure or, more often, functions that correlate with neurological improvement. The goal of restorative neurology is to make best use of this new anatomy and physiology to facilitate neurological recovery. While we are still learning about how neurorehabilitation interventions generate functional recovery, we can begin to test hypothesis regarding the underlying mechanisms of neural plasticity and attempt to augment those processes.

NG2 and phosphacan are present in the astroglial scar after human traumatic spinal cord injury.

BACKGROUND: A major class of axon growth-repulsive molecules associated with CNS scar tissue is the family of chondroitin sulphate proteoglycans (CSPGs). Experimental spinal cord injury (SCI) has demonstrated rapid re-expression of CSPGs at and around the lesion site. The pharmacological digestion of CSPGs in such lesion models results in substantially enhanced axonal regeneration and a significant functional recovery. The potential therapeutic relevance of interfering with CSPG expression or function following experimental injuries seems clear, however, the spatio-temporal pattern of expression of individual members of the CSPG family following human spinal cord injury is only poorly defined. In the present correlative investigation, the expression pattern of CSPG family members NG2, neurocan, versican and phosphacan was studied in the human spinal cord. METHODS: An immunohistochemical investigation in post mortem samples of control and lesioned human spinal cords was performed. All patients with traumatic SCI had been clinically diagnosed as having "complete" injuries and presented lesions of the maceration type. RESULTS: In sections from control spinal cord, NG2 immunoreactivity was restricted to stellate-shaped cells corresponding to oligodendrocyte precursor cells. The distribution patterns of phosphacan, neurocan and versican in control human spinal cord parenchyma were similar, with a fine reticular pattern being observed in white matter (but also located in gray matter for phosphacan). Neurocan staining was also associated with blood vessel walls. Furthermore, phosphacan, neurocan and versican were present in the myelin sheaths of ventral and dorsal nerve roots axons. After human SCI, NG2 and phosphacan were both detected in the evolving astroglial scar. Neurocan and versican were detected exclusively in the lesion epicentre, being associated with infiltrating Schwann cells in the myelin sheaths of invading peripheral nerve fibres from lesioned dorsal roots. CONCLUSION: NG2 and phosphacan were both present in the evolving astroglial scar and, therefore, might play an important role in the blockade of successful CNS regeneration. Neurocan and versican, however, were located at the lesion epicentre, associated with Schwann cell myelin on regenerating peripheral nerve fibres, a distribution that was unlikely to contribute to failed CNS axon regeneration. The present data points to the importance of such correlative investigations for demonstrating the clinical relevance of experimental data.

A brief history of muscular dystrophy research: a personal perspective.

The field of myology has undergone remarkable changes. From the period of early clinical descriptions and clinical classifications, new knowledge of these disorders has come from the developments of histopathology, enzyme histochemistry and later, immunocytochemistry and electron microscopy. These techniques have enhanced the understanding of the pathophysiology of myopathies at the cellular level. The parallel evolution of molecular genetics has taken the science further not only by way of understanding and accuracy of diagnosis, but has opened up exciting possibilities of modulation of these chronic debilitating diseases. This review gives a personal perspective of the developments in the field of myology.

Matrix metalloproteinases and their inhibitors in human traumatic spinal cord injury.

BACKGROUND: Matrix metalloproteinases (MMPs) are a family of extracellular endopeptidases that degrade the extracellular matrix and other extracellular proteins. Studies in experimental animals demonstrate that MMPs play a number of roles in the detrimental as well as in the beneficial events after spinal cord injury (SCI). In the present correlative investigation, the expression pattern of several MMPs and their inhibitors has been investigated in the human spinal cord. METHODS: An immunohistochemical investigation in post mortem samples of control and lesioned human spinal cords was performed. All patients with traumatic SCI had been clinically diagnosed as having "complete" injuries and presented lesions of the maceration type. RESULTS: In the unlesioned human spinal cord, MMP and TIMP immunoreactivity was scarce. After traumatic SCI, a lesion-induced bi-phasic pattern of raised MMP-1 levels could be found with an early up-regulation in macrophages within the lesion epicentre and a later induction in peri-lesional activated astrocytes. There was an early and brief induction of MMP-2 at the lesion core in macrophages. MMP-9 and -12 expression peaked at 24 days after injury and both molecules were mostly expressed in macrophages at the lesion epicentre. Whereas MMP-9 levels rose progressively from 1 week to 3 weeks, there was an isolated peak of MMP-12 expression at 24 days. The post-traumatic distribution of the MMP inhibitors TIMP-1, -2 and -3 was limited. Only occasional TIMP immuno-positive macrophages could be detected at short survival times. The only clear induction was detected for TIMP-3 at survival times of 8 months and 1 year in peri-lesional activated astrocytes. CONCLUSION: The involvement of MMP-1, -2, -9 and -12 has been demonstrated in the post-traumatic events after human SCI. With an expression pattern corresponding largely to prior experimental studies, they were mainly expressed during the first weeks after injury and were most likely involved in the destructive inflammatory events of protein breakdown and phagocytosis carried out by infiltrating neutrophils and macrophages, as well as being involved in enhanced permeability of the blood spinal cord barrier. Similar to animal investigations, the strong induction of MMPs was not accompanied by an expression of their inhibitors, allowing these proteins to exert their effects in the lesioned spinal cord.

Growth-modulating molecules are associated with invading Schwann cells and not astrocytes in human traumatic spinal cord injury.

Despite considerable progress in recent years, the underlying mechanisms responsible for the failure of axonal regeneration after spinal cord injury (SCI) remain only partially understood. Experimental data have demonstrated that a major impediment to the outgrowth of severed axons is the scar tissue that finally dominates the lesion site and, in severe injuries, is comprised of connective tissue and fluid-filled cysts, surrounded by a dense astroglial scar. Reactive astrocytes and infiltrating cells, such as fibroblasts, produce a dense extracellular matrix (ECM) that represents a physical and molecular barrier to axon regeneration. In the human situation, correlative data on the molecular composition of the scar tissue that forms following traumatic SCI is scarce. A detailed investigation on the expression of putative growth-inhibitory and growth-promoting molecules was therefore performed in samples of post-mortem human spinal cord, taken from patients who died following severe traumatic SCI. The lesion-induced scar could be subdivided into a Schwann cell dominated domain which contained large neuromas and a surrounding dense ECM, and a well delineated astroglial scar that isolated the Schwann cell/ECM rich territories from the intact spinal parenchyma. The axon growth-modulating molecules collagen IV, laminin and fibronectin were all present in the post-traumatic scar tissue. These molecules were almost exclusively found in the Schwann cell-rich domain which had an apparent growth-promoting effect on PNS axons. In the astrocytic domain, these molecules were restricted to blood vessel walls without a co-localization with the few regenerating CNS neurites located in this region. Taken together, these results favour the notion that it is the astroglial compartment that plays a dominant role in preventing CNS axon regeneration. The failure to demonstrate any collagen IV, laminin or fibronectin upregulation associated with the astroglial scar suggests that other molecules may play a more significant role in preventing axon regeneration following human SCI.

Correlation of postmortem 9.4 tesla magnetic resonance imaging and immunohistopathology of the human thoracic spinal cord 7 months after traumatic cervical spine injury.

OBJECTIVE: To correlate high-resolution magnetic resonance imaging (MRI) with immunohistopathology in the injured human spinal cord. METHODS: Postmortem MRI scans at a field strength of 9.4 T, as well as standard histology and immunohistochemistry, were performed on an excised specimen of human high thoracic spinal cord, obtained 7 months after the initial trauma, several segments below a severe spinal cord lesion (C5). RESULTS: A precise correlation is described between MRI and immunohistochemistry of the long white matter tracts undergoing Wallerian degeneration and of an extension of the cervical lesion into the high thoracic cord. CONCLUSION: MRI, the only imaging technique that currently provides useful information on the spinal cord parenchyma after trauma, is rapidly evolving. High-field scanners of up to 9.4 T are being clinically tested. The present postmortem investigation of an isolated spinal cord specimen demonstrates the precise correlation that can be achieved between imaging and pathology. In future investigations, this type of technique can lead to a more precise description of spinal cord injuries and their consequences in remote tissue. Translation into the clinical setting will improve diagnosis and follow-up of spinal cord injured patients.

Hippocampal and entorhinal cortex neurofibrillary tangle formation in Guamanian Chamorros free of overt neurologic dysfunction.

Since first described, amyotrophic lateral sclerosis/parkinsonism-dementia complex (ALS/PDC) of Guam has represented an important model of age-related neurodegenerative disease. ALS/PDC is characterized neuropathologically by severe widespread involvement by neurofibrillary tangles (NFTs). Over the past 30 years there has been a dramatic decrease in the incidence of ALS and a 10-year increase in the age of onset of ALS and PDC. In 1979, Anderson et al reported evidence of significant NFT involvement in Guam natives who had been free of evidence of neurologic dysfunction. Using the slides from this study, we re-examined the extent of hippocampus and entorhinal NFT involvement and compared it to brains recently obtained from neurologically intact Guam natives and age-matched controls from New York. The tendency towards hippocampal and entorhinal NFT formation continues to be encountered among the inhabitants of Guam, particularly among those over age 50. although severe involvement was less commonly noted in relatively young individuals (< 50 years). As noted by Anderson et al, the pattern of neuropathologic lesions seen in those with extensive NFT involvement suggests that such cases represent preclinical examples of ALS/PDC in individuals who have yet to accumulate a sufficient burden of pathology to attract clinical attention and diagnostic evaluation.

Prevalence of amyloid-beta deposition in the cerebral cortex in Parkinson's disease.

The pathological basis for the dementia which occurs in 20 to 40% of patients with idiopathic Parkinson's disease (PD) remains uncertain. In the present postmortem study, we compared the prevalence and severity of parenchymal and vascular amyloid-beta (Abeta) deposition in the cerebral cortex in a group of 57 PD brains, including 13 cases with dementia, and in 100 control brains. A higher proportion of PD brains had vascular Abeta deposition, whereas the proportions and severity of parenchymal Abeta were similar in the PD and control groups. There was a poor correlation between Abeta deposition and neurofibrillary tangles which were present in only small numbers in a minority of cases. Cortical Abeta deposition was present in only 6 of the 13 cases with dementia and only 3 fulfilled the Consortium to Establish a Registry for Alzheimer's Disease (CERAD) criteria for definite Alzheimer's disease. The present findings confirm that dementia in PD is only infrequently due to fully established Alzheimer's disease. However, vascular and parenchymal Abeta deposition could still contribute to dementia and cognitive decline when combined with other changes such as alpha-synuclein deposition in the cerebral cortex and cortical Lewy bodies.

Prevalence of stroke in Parkinson's disease: a postmortem study.

The results of previous epidemiological studies of the relationship between Parkinson's disease and stroke have been conflicting; some showing a reduced risk of ischaemic and haemorrhagic stroke during life, and others indicating an increased likelihood of stroke-related death. We compared the frequency of cerebral infarcts and haemorrhages at postmortem in 100 cases of pathologically verified idiopathic Parkinson's disease and 100 age-matched control brains. No significant differences were found in the numbers of infarcts or haemorrhages or stroke-related deaths between the two groups. Our findings do not indicate either a protective effect against stroke, or a greater susceptibility to death from stroke, in the population studied.