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PubMed1998

Complex regional pain syndrome I (CRPS I): prospective study and laboratory evaluation.

OBJECTIVE: To relate clinical features to autonomic laboratory indices used in the diagnosis of Complex Regional Pain Syndrome type I (CRPS I) (reflex sympathetic dystrophy) to generate improved diagnostic criteria. DESCRIPTION: CRPS I is a chronic pain syndrome, characterized by diffuse limb pain with allodynia and prominent vasomotor and sudomotor dysfunction. METHODS: We conducted a prospective study on 102 patients referred for possible CRPS I. These patients completed a structured questionnaire and underwent neurologic examination, with special attention to the evaluation of clinical features of vasomotor, sudomotor, motor, and sensory, including pain, dysfunction. All patients were tested using a standard autonomic protocol that compared side-to-side skin temperature, resting sweat output, and quantitative sudomotor axon reflex test (QSART) measurements. Composite autonomic clinical (CRPS-Sx) and laboratory (CRPS-LAB) scores were defined. The clinical (subjective and objective) and the laboratory data were analyzed using Pearson's correlation analysis and Bonferroni's probability value to assess concordance and their value in correctly diagnosing CRPS I. RESULTS: All cases occurred after limb injury. One-third of cases did not fulfill our criteria of CRPS I. Highly significant correlations (p<.001) were found among certain clusters of symptoms and signs that shared unifying pathophysiologies. CRPS-Sx correlated with CRPS-LAB (p = .035). The indices that correlated most reliably with clinical data and with each other were RSO, QSART, and skin temperature reductions. CONCLUSION: Clinical and autonomic laboratory probability scores correlate in an internally consistent manner. Both CRPS-Sx and CRPS-LAB are sensitive and reliable tools to formulate a correct diagnosis of CRPS I and can be combined to provide an improved set of diagnostic criteria for CRPS I.

Adult↗
PubMed1991

Changes in glial fibrillary acidic protein mRNA expression after corticospinal axotomy in the adult hamster.

We examined changes in the expression of glial fibrillary acidic protein (GFAP) mRNA during Wallerian degeneration in the corticospinal system of the adult Golden hamster following axotomy. GFAP is the product of a type III intermediate filament (IF) gene that is expressed specifically in mature astrocytes. A well-studied component of a complex response termed reactive astrogliosis that occurs after various types of CNS injury is the increased production of astrocytic processes filled with GFAP-containing IFs. While increased expression of GFAP during reactive astrogliosis has been well established at the protein level, little is known about whether or not changes in GFAP mRNA levels occur after CNS injury. In the present study we used in situ hybridization methods to examine this issue. A 35S-labeled mouse GFAP cDNA probe was used for in situ hybridizations of sections of the brain stem obtained 2, 7, and 14 days after unilateral transections of the corticospinal tract in the caudal medulla. Film as well as emulsion autoradiography showed a dramatic increase in GFAP mRNA labeling associated with the degenerating corticospinal tract. GFAP mRNA levels were already dramatically increased in the injured corticospinal tract by 2 days post axotomy and remained elevated at 14 days. Interestingly, in addition to the robust increase in GFAP mRNA levels specifically associated with the degenerating tract, a diffuse increase in GFAP mRNA labeling was observed throughout the grey matter of the brain stem at 2 days post-axotomy, but not after this time. Immunoblotting and immunocytochemical experiments verified that the increased GFAP mRNA levels in the degenerating corticospinal system were accompanied by an increased expression of the protein. These results demonstrate that an increase in GFAP mRNA levels occurs during Wallerian degeneration in the CNS and suggest that increased expression of the GFAP gene is a major contributor to CNS scarring that results after direct traumatic injury.

Animals↗
PubMed2001

Inactivation of the glial fibrillary acidic protein gene, but not that of vimentin, improves neuronal survival and neurite growth by modifying adhesion molecule expression.

Intermediate filaments (IFs) are a major component of the cytoskeleton in astrocytes. Their role is far from being completely understood. Immature astrocytes play a major role in neuronal migration and neuritogenesis, and their IFs are mainly composed of vimentin. In mature differentiated astrocytes, vimentin is replaced by the IF protein glial fibrillary acidic protein (GFAP). In response to injury of the CNS in the adult, astrocytes become reactive, upregulate the expression of GFAP, and reexpress vimentin. These modifications contribute to the formation of a glial scar that is obstructive to axonal regeneration. Nevertheless, astrocytes in vitro are considered to be the ideal substratum for the growth of embryonic CNS axons. In the present study, we have examined the potential role of these two major IF proteins in both neuronal survival and neurite growth. For this purpose, we cocultured wild-type neurons on astrocytes from three types of knock-out (KO) mice for GFAP or/and vimentin in a neuron-astrocyte coculture model. We show that the double KO astrocytes present many features of immaturity and greatly improve survival and neurite growth of cocultured neurons by increasing cell-cell contact and secreting diffusible factors. Moreover, our data suggest that the absence of vimentin is not a key element in the permissivity of the mutant astrocytes. Finally, we show that only the absence of GFAP is associated with an increased expression of some extracellular matrix and adhesion molecules. To conclude, our results suggest that GFAP expression is able to modulate key biochemical properties of astrocytes that are implicated in their permissivity.

Animals↗
PubMed1999

Functional reconnection of severed mammalian spinal cord axons with polyethylene glycol.

We describe a technique using the water-soluble polymer polyethylene glycol (PEG) to reconnect the two segments of completely transected mammalian spinal axons within minutes. This was accomplished by fusing completely severed strips of isolated guinea pig thoracic white matter maintained in vitro in a double sucrose gap recording chamber. The faces of the severed segments were pressed together, and PEG (MW 1,400-3,500 d; approximately 50% by weight in distilled water) was applied directly to this region through a micropipette and removed by aspiration within 2 min. Successful fusion was documented by the immediate restored conduction of compound action potentials through the original transection and by the variable numbers of fused axons in which anatomical continuity was shown to be restored by high-resolution light microscopy and by the diffusion of intracellular fluorescent dyes through fused axons. These data support the conclusion that some severed and subsequently PEG-fused spinal axons both demonstrate restored anatomical continuity and also are physiologically competent to conduct action potentials. This work adds to our previous demonstration that PEG application can immediately repair severely crushed, rather than cut, spinal cord white matter, and may lead to novel treatments for acute trauma to the central and peripheral nervous systems.

Action Potentials↗
PubMed1990

Human immunodeficiency virus (HIV) leukoencephalopathy and the microcirculation.

We studied the brains of three patients with acquired immune deficiency syndrome (AIDS), all of whom developed subacutely progressive dementia unassociated with opportunistic infection or neoplasm in the central nervous system. Computed tomographic (CT) scans of the head revealed cortical atrophy, ventricular dilation, and diffuse hypodensity of the centrum semiovale. On microscopic examination, the cerebral and cerebellar white matter in all cases showed diffuse and focal, angiocentric regions of myelin pallor, focal vacuolization, and extensive gliosis. Variable axonal loss and axonal spheroids were evident. The microvasculature showed striking changes, including mural thickening, increased cellularity, and enlargement and pleomorphism of endothelial cells with variable numbers of macrophages and multinucleated giant cells (MNGC), which often contained hemosiderin pigment. Human immunodeficiency virus type 1 (HIV-1) antigens were identified immunocytochemically within perivascular macrophages and MNGC and in some microglial cells. We suggest that the morphologic abnormalities of the microcirculation may be associated with an alteration of the blood-brain barrier. The increased vascular permeability could contribute to damage and loss of the white matter including both myelin and axons, and result in subcortical cerebral atrophy. The HIV-1 infected cells present in relation to the microvasculature may play a role in mediating the vascular injury.

Acquired Immunodeficiency Syndrome↗
PubMed1989

Neuroglial response to neuron injury. A study using intraneural injection of ricinus communis agglutinin-60.

The present study has shown the selective destruction of large ventral horn neurons in the lumbosacral cord segments following a single injection of RCA-60 into the sciatic nerve. The neurons appeared to undergo structural alteration beginning 3 days after the RCA application. In the postoperative period extending from 1 to 60 days, degeneration of neurons was progressive and irreversible and this elicited a rapid increase in the number of microglial cells. They were most numerous in the 7 days postoperative animals. The massive microglial cells penetrated the neuropil and appeared to strip off the axon terminals from the postsynaptic somata. Occasional axon terminals were phagocytosed by microglia. The numerous microglial cells often formed a multilayered 'barrier' encircling the somata of the RCA-poisoned neurons which eventually became totally disorganised. It is postulated that in the course of neuronal degeneration induced by RCA, microglial cells serve to prevent the leakage or diffusion of the toxic lectin from the neuronal somata into the neighbouring neuropil. They also function as scavenger cells in the removal of degenerating myelinated axons in the longer surviving rats. Oligodendrocytes do not appear to react actively to the degeneration process. However, astrocytes showed a significant increase in the 7 and 15 day postoperative rats and this coincided with the presence of mitotic astrocytes in the same period.

Animals↗
PubMed1996

Microglial responses to focal lesions of the rabbit retina: correlation with neural and macroglial reactions.

There is a very wide spread Müller glial response to focal laser photocoagulation lesions in the rabbit retina. In this study we have described the microglial response to similar lesions and compared this with the Müller and retinal ganglion cell responses. Microglia were labelled using nucleoside di-phosphatase histochemistry in adult rabbit retinal wholemounts and compared with axonal and Müller cell responses as shown respectively by neurofilament and GFAP immunohistochemistry. In the normal retina, microglia were located in the nerve fibre layer (NFL), inner plexiform layer (IPL), and sparsely in the outer plexiform layer (OPL). Following laser photocoagulation each layer reacted differently. The NFL reaction was exclusively associated with axonal degeneration, as shown by abnormal neurofilament label, and therefore only started several days after injury. In the IPL, neighbouring microglial cells directed their processes towards the lesion by 2 h and had migrated into the lesion by 6 h, but the reaction did not extend more than 2-3 cell diameters from the lesion and was over by 7 days. In the OPL the cell density increased by 1-2 days over a few millimeters from the lesion. The Müller cells expressed GFAP for several millimeters from the lesion starting at 24 h and persisting for over one month and therefore the correlation with the microglial reaction was poor. The different reaction in each retinal layer is evidence that microglial responses are modulated by local factors, probably mainly by contact with injured retinal elements as well as diffusable factors.

Acid Anhydride Hydrolases↗
PubMed2002

Transplants and neurotrophic factors increase regeneration and recovery of function after spinal cord injury.

Earlier studies suggested that while after spinal cord lesions and transplants at birth, the transplants serve both as a bridge and as a relay to restore supraspinal input caudal to the injury (Bregman, 1994), after injury in the adult the spinal cord transplants serve as a relay, but not as a bridge. We show here, that after complete spinal cord transection in adult rats, delayed spinal cord transplants and exogenous neurotrophic factors, the transplants can also serve as a bridge to restore supraspinal input (Fig. 9). We demonstrate here that when the delivery of transplants and neurotrophins are delayed until 2 weeks after spinal cord transection, the amount of axonal growth and the amount of recovery of function are dramatically increased. Under these conditions, both supraspinal and propriospinal projections to the host spinal cord caudal to the transection are reestablished. The growth of supraspinal axons across the transplant and back into the host spinal cord caudal to the lesion was dependent upon the presence of exogenous neurotrophic support. Without the neurotrophins, only propriospinal axons were able to re-establish connections across the transplant. Studies using peripheral nerve or Schwann cell grafts have shown that some anatomical connectivity can be restored across the injury site, particularly under the influence of neurotrophins (Xu et al., 1995a,b; Cheng et al., 1996; Ye and Houle, 1997). Without neurotrophin treatment, brainstem axons do not enter [figure: see text] the graft (Xu et al., 1995a,b; Cheng et al., 1996; Ye and Houle, 1997). Similarly, cells genetically modified to secrete neurotrophins and transplanted into the spinal cord influence the axonal growth of specific populations of spinally projecting neurons (Tuszynski et al., 1996, 1997; Grill et al., 1997; Blesch and Tuszynski, 1997). Taken together, these studies support a role for neurotrophic factors in the repair of the mature CNS. The regrowth of supraspinal and propriospinal input across the transection site was associated with consistent improvements in hindlimb locomotor function. Animals performed alternating and reciprocal hindlimb stepping with plantar foot contact to the treadmill or stair during ascension. Furthermore, they acquired hindlimb weight support and demonstrated appropriate postural control for balance and equilibrium of all four limbs. After spinal cord injury in the adult, the circuitry underlying rhythmic alternating stepping movements is still present within the spinal cord caudal to the lesion, but is now devoid of supraspinal control. We show here that restoring even relatively small amounts of input allows supraspinal neurons to access the spinal cord circuitry. Removing the re-established supraspinal input after recovery (by retransection rostral to the transplant) abolished the recovery and abolished the serotonergic fibers within the transplant and spinal cord caudal to the transplant. This suggests that at least some of the recovery observed is due to re-establishing supraspinal input across the transplant, rather than a diffuse influence of the transplant on motor recovery. It is unlikely, however, that the greater recovery of function in animals that received delayed transplant and neurotrophins is due solely to the restoration of supraspinal input. Recent work by Ribotta et al. (2000) suggests that segmental plasticity within the spinal cord contributes to weight support and bilateral foot placement after spinal cord transection. This recovery of function occurs after transplants of fetal raphe cells into the adult spinal cord transected at T11. Recovery of function appears to require innervation of the L1-L2 segments with serotonergic fibers, and importantly, animals require external stimulation (tail pinch) to elicit the behavior. In the current study, animals with transection only did not develop stepping overground or on the treadmill without tail pinch, although the transplant and neurotrophin-treated groups did so without external stimuli. Therefore both reorganization of the segmental circuitry and partial restoration of supraspinal input presumably interact to yield the improvements in motor function observed. It is unlikely that the recovery of skilled forelimb movement observed can be mediated solely by reorganization of segmental spinal cord circuitry. We suggest that the restoration of supraspinal input contributes to the recovery observed. It is likely that after CNS injury, reorganization occurs both within the spinal cord and at supraspinal levels, and together contribute to the recovery of automatic and skilled forelimb function and of locomotion. In summary, the therapeutic intervention of tissue transplantation and exogenous neurotrophin support leads to improvements in supraspinal and propriospinal input across the transplant into the host caudal cord and a concomitant improvement in locomotor function. Paradoxically, delaying these interventions for several weeks after a spinal cord transection leads to dramatic improvements in recovery of function and a concomitant restoration of supraspinal input into the host caudal spinal cord. These findings suggest that opportunity for intervention after spinal cord injury may be far greater than originally envisioned, and that CNS neurons with long-standing injuries may be able to re-initiate growth leading to improvement in motor function.

Animals↗
PubMed2002

Differences in peripheral nerve degeneration/regeneration between wild-type and neuronal nitric oxide synthase knockout mice.

Nitric oxide (NO), a unique biological messenger molecule, is synthesized by three isoforms of the enzyme NO synthase (NOS) and diffuses from the site of production across cellular membranes. A postulated role for NO in degeneration and regeneration of peripheral nerves has been explored in a sciatic nerve model comparing wild-type mice and mice lacking neuronal NOS after transection and microsurgical repair. In NOS knockout mice, regenerative delay was observed, preceded by a decelerated Wallerian degeneration (WD). In the regenerated nerve, pruning of uncontrolled sprouts was disturbed, leading to an enhanced number of axons, whereas remyelination seemed to be less affected. Delayed regeneration was associated with a delayed recovery of sensor and motor function. In such a context, possible NO targets are neurofilaments and myelin sheaths of the interrupted axon, filopodia of the growth cone, newly formed neuromuscular endplates, and Schwann cells in the distal nerve stump. The results presented suggest that 1) local release of NO following peripheral nerve injury is a crucial factor in degeneration/regeneration, 2) success of fiber regeneration in the peripheral nervous system depends on a regular WD, and 3) manipulation of NO supply may offer interesting therapeutic options for treatment of peripheral nerve lesions.

Animals↗
PubMed2001

Immunohistochemical expression of the alpha5 integrin subunit in the normal adult rat central nervous system.

We investigated the distribution of the alpha5 integrin subunit in the normal adult rat CNS using immunohistochemical methods. Results indicated that the alpha5 integrin subunit was expressed on the vast majority of neurons throughout the brain and spinal cord. In general, neurons showed diffuse cytoplasmic labelling, although many cortical neurons in layers 4 and 5 did show punctate labelling on the cell surface. In addition, axons within the white matter of the brainstem and caudal CNS areas were labelled, with the most intense labelling seen within the white matter of the spinal cord. In addition, labelling of astrocytes was seen throughout white matter, with particularly heavy astrocyte labelling in the spinal cord. The widespread distribution of the alpha5 subunit suggests a general function for the alpha5beta1 integrin receptor (the only integrin receptor that includes the alpha5 subunit) in the adult CNS. The increased expression of fibronectin, the only known ligand for the alpha5beta1 integrin receptor, known to occur around the site of a CNS lesion suggests a possible role for the alpha5beta1 receptor in the response of neurons in the vicinity of a CNS injury.

Animals↗
PubMed2000

Engineering strategies for peripheral nerve repair.

Tissue engineering in the peripheral nervous system unites efforts by physicians, engineers, and biologists to create either natural or synthetic tubular nerve guidance channels as alternatives to nerve autografts for the repair of peripheral nerve defects. Guidance channels help direct axons sprouting from the regenerating nerve end, provide a conduit for diffusion of neurotropic and neurotrophic factors secreted by the damaged nerve stumps, and minimize infiltration of fibrous tissue. In addition to efforts to control these physical characteristics of nerve guidance channels, researchers are optimizing the incorporation of biologic factors and engineering interactive biomaterial that can specifically stimulate the regeneration process. Current and future research will ultimately result in biologically active and interactive nerve guidance channels that can support and enhance peripheral nerve regeneration over longer, more clinically relevant defect lengths.

Animals↗
PubMed1999

Dementia following treatment of brain tumors with radiotherapy administered alone or in combination with nitrosourea-based chemotherapy: a clinical and pathological study.

A retrospective clinical and pathological study of 4 patients who developed the syndrome of radiation induced dementia was performed. All patients fulfilled the following criteria: (1) a history of supratentorial irradiation; (2) no evidence of symptomatic recurrent tumor; (3) no other cause of progressive cerebral dysfunction and dementia. The clinical picture consisted of a progressive "subcortical" dementia occurring 3-12 months after a course of cerebral radiotherapy. Examination revealed early bilateral corticospinal tract involvement in all patients and dopa-resistant Parkinsonian syndrome in two. On CT scan and MRI of the brain, the main features consisted of progressive enlargement of the ventricles associated with a diffuse hypodensity/hyperintensity of the white matter best seen on T2 weighted images on MRI. The course was progressive over 8-48 months in 3 patients while one patient had stabilization of his condition for about 28 years. Treatment with corticosteroids or shunting did not produce sustained improvement and all patients eventually died. Pathological examination revealed diffuse white matter pallor with sparing of the arcuate fibers in all patients. Despite a common pattern on gross examination, microscopic studies revealed a variety of lesions that took two basic forms: (1) a diffuse axonal and myelin loss in the white matter associated with tissue necrosis, particularly multiple small foci of necrosis disseminated in the white matter which appeared different from the usual "radionecrosis"; (2) diffuse spongiosis of the white matter characterized by the presence of vacuoles that displaced the normally-stained myelin sheets and axons. Despite a rather stereotyped clinical and radiological course, the pathological substratum of radiation-induced dementia is not uniform. Whether the different types of white matter lesions represent the spectrum of a single pathological process or indicate that the pathogenesis of this syndrome is multifactorial with different target cells, remains to be seen.

Adolescent↗
PubMed2004

The neurophysiology of brain injury.

OBJECTIVE: This article reviews the mechanisms and pathophysiology of traumatic brain injury (TBI). METHODS: Research on the pathophysiology of diffuse and focal TBI is reviewed with an emphasis on damage that occurs at the cellular level. The mechanisms of injury are discussed in detail including the factors and time course associated with mild to severe diffuse injury as well as the pathophysiology of focal injuries. Examples of electrophysiologic procedures consistent with recent theory and research evidence are presented. RESULTS: Acceleration/deceleration (A/D) forces rarely cause shearing of nervous tissue, but instead, initiate a pathophysiologic process with a well defined temporal progression. The injury foci are considered to be diffuse trauma to white matter with damage occurring at the superficial layers of the brain, and extending inward as A/D forces increase. Focal injuries result in primary injuries to neurons and the surrounding cerebrovasculature, with secondary damage occurring due to ischemia and a cytotoxic cascade. A subset of electrophysiologic procedures consistent with current TBI research is briefly reviewed. CONCLUSIONS: The pathophysiology of TBI occurs over time, in a pattern consistent with the physics of injury. The development of electrophysiologic procedures designed to detect specific patterns of change related to TBI may be of most use to the neurophysiologist. SIGNIFICANCE: This article provides an up-to-date review of the mechanisms and pathophysiology of TBI and attempts to address misconceptions in the existing literature.

Animals↗
PubMed1992

Schwann cell endocytosis: a role in nerve regeneration?

Schwann cell plasma membrane vesicles have been shown to increase in numerical density after nerve injury but their function is unclear. In this study, ultrastructural tracers were micro-injected in vivo into crushed rat sciatic nerves after various time intervals to ascertain whether plasma membrane vesicles of Schwann cells are involved in the uptake and utilization of molecules from the endoneurium during axonal regeneration and remyelination. Horseradish peroxidase (HRP), a tracer of fluid-phase endocytosis, was taken up by macrophages and fibroblasts but remained external to Schwann cells throughout the study. After 14-16 days of crush injury, HRP was present within vessel lumina and in cytoplasmic vesicles of pericytes and vascular endothelia. Low-density lipoprotein-gold, which is primarily internalized by receptor-mediated endocytosis, and bovine serum albumin-gold, proposed as a tracer for fluid-phase endocytosis, were internalized by macrophages and fibroblasts but were not taken up by Schwann cells. Although Schwann cells formed pits in the plasma membrane and vesicles were evident in the cytoplasm, none of the tracers used were internalized by Schwann cells. It is suggested that Schwann cell plasmalemmal and cytoplasmic vesicles have a cellular role unrelated to endocytosis or alternatively the Schwann cell basal lamina may function as a diffusion barrier to the tracers employed.

Animals↗
PubMed2004

Keeping promises: translating basic research into new spinal cord injury therapies.

Centuries of medical wisdom-namely that spinal cord injury (SCI) treatment was limited to caretaking until the patients inevitably succumbed to complications-has given way to tremendous medical and research advancements. The prognosis for survival after SCI improved significantly after World War II, leading to the largest population of people aging with chronic SCI in history. Despite the general lack of optimism for functional recovery after SCI, the spinal cord has proven to be one of the most attractive systems for studying central nervous system plasticity. Predictions of clinical applications derived from basic findings now routinely accompany reports of evidence for spinal axon regeneration. This has led to great debate in the SCI research community about the level and quality of evidence needed to select truly promising candidate therapies. This article reviews the basis for optimism in the new understanding of the processes of degeneration after SCI and the mechanisms of regeneration. The emphasis is on neuroprotective and reparative strategies emerging from the animal literature, and on the steps remaining to be taken to translate these into effective clinical trials of new therapies. Examples of the translational process in related areas of brain injury and stroke are cited, as well as the specific issues relating to the needs of individuals with SCI.

Animals↗
PubMed1999

Engineering strategies for peripheral nerve repair.

Tissue engineering in the peripheral nervous system unites efforts by physicians, engineers, and biologists toward a common goal to create either natural or synthetic tubular nerve guidance channels as alternatives to nerve autografts for the repair of peripheral nerve defects. Guidance channels help direct axons sprouting from the regenerating nerve end, provide a conduit for diffusion of neurotropic and neurotrophic factors secreted by the damaged nerve stumps, and minimize infiltration of fibrous tissue. In addition to efforts to control these physical characteristics of nerve guidance channels, researchers are optimizing the incorporation of biologic factors and engineering interactive biomaterial that can specifically stimulate the regeneration process. It is believed that current and future research will ultimately result in biologically active and interactive nerve guidance channels that can support and enhance peripheral nerve regeneration over longer, more clinically relevant defect lengths.

Animals↗
PubMed2000

Complete and long-term rescue of lesioned adult motoneurons by lentiviral-mediated expression of glial cell line-derived neurotrophic factor in the facial nucleus.

To date, delivery of neurotrophic factors has only allowed to transiently protect axotomized facial motoneurons against cell death. In the present report, long-term protection of these neurons was evaluated by continuously expressing the neurotrophic factor glial cell line-derived neurotrophic factor (GDNF) within the facial nucleus using a lentiviral vector system. The viral vector was injected unilaterally into the facial nucleus of 4-month-old Balb/C mice. In contrast to axotomy in other adult rodents, facial nerve lesion in these animals leads to a progressive and sustained loss and/or atrophy of >50% of the motoneurons. This model thus represents an attractive model to evaluate potential protective effects of neurotrophic factors for adult-onset motoneuron diseases, such as amyotrophic lateral sclerosis. One month after unilateral lentiviral vector injection, the facial nerve was sectioned, and the animals were killed 3 months later. Viral delivery of the GDNF gene led to long-term expression and extensive diffusion of GDNF within the brainstem. In addition, axotomized motoneurons were completely protected against cell death, because 95% of the motoneurons were present as demonstrated by both Nissl staining and choline acetyltransferase immunoreactivity. Furthermore, GDNF prevented lesion-induced neuronal atrophy and maintained proximal motoneuron axons, despite the absence of target cell reinnervation. This is the first evidence that viral-mediated delivery of GDNF close to the motoneuron cell bodies of the facial nucleus of adult mice can lead to complete and long-term protection against lesion-induced cell death.

Age Factors↗
PubMed2005

Brain damage after heat stroke.

Cerebellar syndromes and radiologic cerebellar atrophy after hyperpyrexia have occasionally been reported, mostly in neuroleptic malignant syndromes, but neuropathologic studies are extremely rare. We studied 3 patients (a 74-year-old woman, a 63-year-old man, and an 80-year-old man) who had heat stroke during heat waves in France. One patient had generalized seizures and died 28 hours after admission. The other patients survived one month and 2 months after admission; both had palatal myoclonus, and in one case, magnetic resonance imaging showed high signal intensity in the cerebral peduncles. The main neuropathology in the 3 cases was severe diffuse loss of Purkinje cells associated with heat shock protein 70 expression by Bergmann glia. In situ end labeling was negative in surviving Purkinje cells, suggesting that the mechanism of neuronal death was not apoptosis. Degeneration of Purkinje cells axons resulted in myelin pallor of the white matter of the folia and of the hilum of the dentate nuclei. DNA internucleosomal breakages were identified by in situ end labeling in the dentate nuclei and centromedian nuclei of the thalamus and were associated with degeneration of the cerebellar efferent pathways: superior cerebellar peduncles, decussation of the superior cerebellar peduncles (Wernekinck commissure), and dentatothalamic tract. These findings suggest that the mechanisms of neuronal death in the dentate nuclei and centromedian nuclei of the thalamus was different from that in Purkinje cells and more likely resulted from deafferentation. Ammon's horn and other areas susceptible to hypoxia were spared. These observations confirm the selective vulnerability of Purkinje cells to heat-induced injury and involvement of the cerebellar efferent pathways in palatal myoclonus.

Aged↗