Moderate Neuronal Loss Research Articles

Early loss of neurons and axon terminals in scrapie-affected mice revealed by morphometry and immunocytochemistry.

This study demonstrates that an unsuspected and dramatic neuronal loss occurs in the dLGN of mice intraocularly infected with ME7 scrapie, up to 100 d before clinical signs are apparent. The onset of detectable neuronal loss has a close correlation with the onset of vacuolation. Since a similar loss has been shown in cattle affected with BSE, it suggests that neuronal loss is a consistent feature of the pathology of these and other spongiform encephalopathies. The extent of vacuolar pathology is well recognized in these diseases, and although an associated “slight neuronal loss” is often quoted, we have shown that the degree of neuronal loss cannot be estimated by subjective analysis, except in extremely severe cases. The genesis and progression of the vacuolation is not known, nor is the extent to which this lesion compromises neuronal function. Several clinical cases of various spongiform encephalopathies have been reported that show little or no vacuolation (Taylor, 1991). It is possible, therefore, that moderate neuronal loss has a closer correlation with clinical diseases than has been recognized. Ultrastructural studies on primary transmissions of spongiform encephalopathy to mice have revealed conspicuous neuronal autophagy (Jeffrey et al., 1992c), which, together with the recognized absence of inflammatory changes with this disease, suggests an apoptotic rather than necrotic mechanism of neuronal loss.

Degree of hippocampal neuron loss determines severity of verbal memory decrease after left anteromesiotemporal lobectomy.

Fifty-eight left speech dominant adults with medically refractory epilepsy originating from the temporal lobe (28 left, 30 right) were examined using the verbal Selective Reminding Test before and after anteromesiotemporal lobectomy. After neuron density in the excised hippocampal tissue was established, a median split procedure was performed to distinguish patients with severe neuron loss (13 left, 16 right) from those with only mild or moderate neuron loss (15 left, 14 right). The memory of patients with severe left hippocampal neuron loss did not decrease significantly postoperatively. Patients with mild or moderate left hippocampal neuron loss experienced significant verbal memory decrease postoperatively. The magnitude of the verbal memory decrease was not related to recurrence of seizures after operation. Patients undergoing right anteromesiotemporal lobectomy exhibited significant improvements in verbal memory, regardless of the condition of the excised hippocampal tissue. The degree of hippocampal neuron loss determines to a great extent the severity of the verbal memory decrease that follows dominant anteromesiotemporal lobectomy.

Medullary catecholaminergic neurons in the normal human brain and in Parkinson's disease

Parkinson's disease is thought to cause degeneration of melanin-pigmented catecholaminergic neurons throughout the brainstem, but little quantitative information is available on the fate of catecholaminergic neurons associated with the dorsal vagal complex or medullary reticular formation. We therefore examined these neurons in the normal human medulla and in the brains of patients with Parkinson's disease, using both a melanin stain and immunohistochemical methods with an antiserum against tyrosine hydroxylase. The greatest numbers of catecholaminergic neurons in the ventrolateral reticular formation (A1/C1 group) were located in the far rostral medulla, whereas the largest populations of catecholaminergic cells in the dorsal vagal complex (A2/C2 group) were found at the level of the area postrema. No loss of cells was observed in the A1/C1 group in the parkinsonian brains. In contrast, the A2/C2 group showed moderate loss of neurons, most marked at the level of the area postrema. This difference was entirely due to the loss of neurons in the medial component of the A2 group, a population that normally is only lightly pigmented, while the heavily pigmented neurons in the ventral and intermediate components of the A2 complex were unaffected. Parkinson's disease causes degeneration only of selected populations of medullary catecholaminergic neurons, without apparent relationship to the extent of melanin pigmentation.

Paraneoplastic degeneration of the substantia nigra with dystonia and parkinsonism

A 42-year-old woman suffered unexplained weight loss followed by action tremor and difficulty initiating gait. Three months after onset of symptoms, infiltrating ductal carcinoma of the breast, metastatic to liver and lymph nodes, was diagnosed and treated briefly with cyclophosphamide, methotrexate, and 5-flourouracil (5FU). Severe symmetric action and postural tremor with a myoclonic component developed, with minimal rest tremor, severe dysarthria and dysphagia, small-stepped and slightly ataxic gait progressing to a bedbound state, and severe widespread dystonic posturing. The latter began as a typical parkinsonian posture of trunk and upper extremities and progressed to a fixed and painful flexion of the elbows and wrists and extension of fingers and neck. Sinemet, anticholinergics, baclofen, diazepam, and plasmapheresis gave no benefit. The patient died of complications of immobility 5 months after neurologic symptom onset. Autopsy revealed many pigment-laden macrophages in substantia nigra and moderate loss of pigmented neurons. Inflammation, Lewy bodies, and tumor were absent. Cerebellar Purkinje cells were moderately depleted. Mild neuronal loss and gliosis were present in globus pallidus and cerebellar cortex. Stains for anti-human IgG, IgM, kappa, and lambda were negative. This, to our knowledge, is the first report of paraneoplastic degeneration of substantia nigra or paraneoplastic parkinsonism.

Cortical organization after treatment of a peripheral nerve with ricin: an evaluation of the relationship between sensory neuron death and cortical adjustments after nerve injury.

The present study was designed to assess whether cortical changes after peripheral nerve damage are related to the degree of death of primary sensory neurons in the damaged nerve. The cytotoxin ricin was injected into the sciatic nerves of adult rats to kill primary sensory neurons with axons through the injection site. Following periods of 6-101 days, the S-I hindpaw map was evaluated with neurophysiological techniques and compared with the hindpaw maps of previously studied normal adult rats and adult rats that had undergone adult or neonatal sciatic section at a comparable level of the nerve. These comparisons allowed evaluation of cortical functional organization following different degrees of sensory neuron loss after sciatic nerve injury. There were three main results. 1) The comparison of ricin-treated and normal adult rats indicated that ricin treatment interrupted inputs from the sciatic skin territory on the hindpaw and caused a limited increase in the size of the cortical area that was activated by stimulation of hindpaw skin innervated by the remaining saphenous nerve. 2) The cortical maps of rats that had undergone adult ricin treatment (relatively large primary neuron loss) or section during adulthood (small to moderate primary neuron loss) were similar. In both groups, only the saphenous hindpaw skin was represented in cortex, and the cortical area that was activated by stimulation of the saphenous hindpaw skin had undergone a comparable limited enlargement. 3) The comparison of ricin-treated adult rats (relatively large primary neuron loss) and adult rats that had undergone neonatal section (relatively large primary neuron loss) indicated that cortical organization differed after these treatments. In particular, after ricin treatment the cortical area that was activated by stimulation of the saphenous hindpaw skin was larger than the comparable area in neonatal denervates, and the topographical progressions between the hindpaw and adjacent body representations were not as variable as after neonatal section. These findings indicate that cortical maps are altered after injection of ricin into a nerve. The similarity in cortical organization after ricin treatment (relatively large sensory neuron loss) and nerve section in adults (relatively small sensory neuron loss) and the differences in cortical organization after ricin treatment and nerve section in neonates (both relatively large sensory neuron loss) indicate cortical changes do not covary as a simple function of the degree of peripheral neuron death.

Effects of retrograde axonal transport ofRicinus communis agglutinin I on neuroma formation

The lectin Ricinus communis agglutinin I (RCAI) was topically applied to transected mouse sciatic nerve or to neuromas formed 2 months after a nerve transection. Fluorochrome-labelled ricin was transferred to the corresponding dorsal root ganglia where it accumulated selectively in the nerve cells, apparently as a consequence of retrograde axonal transport. The ricin caused an almost total loss of the dorsal root ganglionic neurons and, consequently, could prevent formation of neuromas or eliminate an already existing neuroma. The hybrid toxin wheat germ agglutinin (WGA)-ricin-A chain caused no apparent increased sensitivity for neuronal destruction. The drugs doxorubicin and ethidium bromide, similarly applied, labelled satellite and other cells in addition to neurons in the ganglia, and caused only a moderate neuronal loss. The presented method to eliminate neuromas by selectively destroying sensory neurons may provide a means to study pain mechanisms in neuromas.

Variations in the Axon Reaction after Different Types of Nerve Lesion

The retrograde nerve cell reaction was studied after evulsion, transection and crush lesion of the facial nerve in rats. Crush lesion caused barely discernible light and electron microscopic changes. The Nissl bodies became slightly smaller than normal and the arrangement of the granular endoplasmic reticulum (rER) somewhat more irregular. The crush lesions were followed by complete functional and morphologic recovery. After nerve evulsion, the cells showed severe chromatolysis, nuclear caps, nuclear eccentricity, and folding of the nuclear membrane. Ultrastructurally there was a dispersion of the rER and formation of laminated dense bodies. Lager, the rER was partly degranulated and some of the polyribosomes dissociated. These neurons ultimately disappeared. Transection of the nerve caused an intermediate axon reaction and a moderate loss of neurons. It is concluded that certain neurons may regenerate after axotomy in spite of minimal light and electron microscopic changes in the nerve cell bodies, and that the same neurons may show the typical axon reaction after more severe nerve injuries. Mechanisms which may be involved in the regulation of the retrograde nerve cell reaction after axotomy are briefly discussed.

Intranigral kainic acid: Evidence for nigral non-dopaminergic neurons controlling posture and behavior in a manner opposite to the dopaminergic ones

The unilateral, intranigral administration of kainic acid (k.a.) produced a syndrome characterized by early sequelae of contra- and ipsilateral circling and by a chronic contralateral turning associated with moderate loss of neurons in the pars reticulata. The acute contralateral circling seems to be related to dopaminergic nigro-neostriatal neuron stimulation, since it was prevented by previous intranigral injections of 6-OHDA. The acute ipsilateral circling and the chronic contralateral turning, on the other hand, seem to be independent of the integrity of the dopaminergic system and may be due to an initial stimulation, followed by destruction, of a nigral neuronal system which mediates turning behavior in a manner opposite to that of nogro-striatal dopamine. Treatment with D-amphetamine or apomorphine changed the contralateral into ipsilateral turining, while haliperidol potentiated the contralateral turning. Bilateral injection of k.a. into the nigra resulted in chronic stereotyped sniffing and gnawing, which were not inhibited by haloperidol. Moreover, haloperidol did not produce catalepsy in these animals. It is suggested that the intranigral k.a. injection destroyed a neuronal system antagonistic to dopamine and resulted in a reduction of the response to DA-receptor stimulation of the c. striatum.

Autosomal dominant striatonigral degeneration

An autosomal dominant striatonigral degeneration is present in a family of Portuguese ancestry numbering in excess of 329 persons in eight generations. The illness begins in the second, third, or fourth decade, and progresses for about 15 years with parkinsonian rigidity, spasticity, spastic dysarthria, and abnormalities of eye movement. Neuropathologic findings are severe neuronal loss and astrocytic gliosis in the corpus striatum and substantia nigra, with a moderate neuronal loss in the dentate nucleus of the cerebellum and nucleus ruber of the midbrain. This is a new genetic entity, distinct from other autosomal dominant neurologic disorders such as nigrospinodentatal degeneration, olivopontocerebellar degeneration, dystonia musculorum deformans, Machado's disease, and Huntington's disease.

Experimental kuru in the spider monkey. Histopathological and ultrastructural studies of the brain during early stages of incubation.

The brains of 10 spider monkeys inoculated intracerebrally with brain suspension from kuru patients have been studied histologically and ultrastructurally. The animals were killed by perfusion of fixative from four to forty-one weeks after inoculation, when healthy and free of neurological signs. Definite histopathological changes had occurred as early as four weeks after inoculation, when moderate numbers of bi-nucleated neurons were found within the limbic cortex, striatum, the hypothalamus and amongst the Purkinje cells of the cerebellum. At later stages of incubation a moderate loss of neurons in the cerebral and cerebellar cortex and a mild to moderate proliferation of fibrous astrocytes here and also in the hypothalamus were the most striking features. None of our cases showed either status spongiosus or the generalized astrocytic proliferation and hypertrophy, characteristic of fully developed experimental kuru, in any region of the brain. The principal ultrastructural abnormalities consisted of the formation of membrane-bound intracytoplasmic vacuoles, predominantly within dendrites, and of concentric laminar arrays derived from the endoplasmic reticulum. The former were seen in all regions of the brain examined and at all stages of incubation. Concentric laminar arrays were confined to the cerebellar nodulus, where they were most numerous in dendrites and neuronal perikarya four weeks after inoculation. Both changes are interpreted as an indication that the kuru agent acts upon the plasma membrane from an early stage onwards and, by stimulating its growth, leads to the formation of complex, membrane-bounded vacuoles and to hyperplasia of the endoplasmic reticulum. The formation of vacuoles is further regarded as the first sign of status spongiosus on an ultrastructural level. Attention is drawn to the great similarities between the changes observed in the present material and those described in the brains of patients dying from kuru and of primates with fully developed experimental kuru. The significance of the relatively rapid spread of the kuru agent throughout the brain is discussed in relation to the concept of "slow virus" diseases.

FAMILIAL NONHEMOLYTIC JAUNDICE: BILIRUBINOSIS AND ENCEPHALOPATHY

The unique pathological findings of a case of congenital familial hyperbilirubinemia are presented. The patient (Case 3 of Crigler and Najjar's original report), although severely jaundiced, had developed normally without evidence of neurological disease until 15½ years of age. He then developed a progressive neurological deterioration which was clinically similar to infantile kernicterus. At autopsy most of his organs showed extensive intra- and extracellular deposition of bile pigment, particularly the renal papillae, atrial endocardium, intestinal mucosa, Kupffer cells of the liver, and the perivascular adventitia. Although no pigment was found in the central nervous system, there was striking neuronal loss and gliosis of the thalamus. Moderate neuronal loss was found in the putamen, caudate nucleus, dentate nucleus, and red nuclei. No histopathological changes were found in the hippocampus or cerebral cortex. It is suggested that the patient suffered from a late onset of "kernicterus" with involvement, in this older patient, of regions of the nervous system somewhat different from those in infantile kernicterus.