Atypical dopa responsive parkinsonism in a patient with megalencephaly, midbrain Lewy body disease, and some pathological features of Hallervorden-Spatz disease.

A 38 year old patient with megalencephaly, mental retardation, and lifelong tremor developed levodopa responsive parkinsonism in his mid-30s followed by the appearance of dyskinesiae, motor fluctuations, hallucinations, and dementia. Brain MRI showed, as well as other changes, iron deposition in the globus pallidus, substantia nigra, and the pulvinar of the thalamus. Postmortem examination disclosed depigmentation of the substantia nigra pars compacta with neuronal loss, gliosis, and Lewy body formation. Axonal dystrophic spheroids, neuronal loss, calcification, and iron deposition were found in the substantia nigra pars reticulata. Less severe changes without neuronal loss were seen in the globus pallidus. This combination of megalencephaly with neuroaxonal changes predominantly in the pars reticulata and Lewy body degeneration isolated to the substantia nigra pars compacta has not been previously reported.     

Subthalamic nucleus lesion regularizes firing patterns in globus pallidus and substantia nigra pars reticulata neurons in rats

Subthalamic nucleus lesion altered the statistical properties of the firing patterns of globus pallidus and substantia nigra pars reticulata neurons recorded in urethane anesthetized rats by increasing the proportion of cells in both structures that fired with a very highly regular pattern (from 25%to 50%). In all cases, the most regularly firing neurons fired at a higher mean rate than did more slowly firing neurons. In contrast, globus pallidus lesion shifted the pattern of substantia nigra neurons towards more irregular firing and induced a bursty pattern in two neurons.     

5-HT1D receptors in the guinea pig brain: pre- and postsynaptic localizations in the striatonigral pathway

The caudate-putamen, globus pallidus and substantia nigra pars reticulata of the guinea pig contain high densities of the 5-HT1D receptor subtype. The cellular localization of these sites in the striatonigral pathway was investigated using receptor autoradiography and selective neurotoxin lesions. In guinea pigs with unilateral 6-hydroxydopamine lesions of the nigral dopaminergic cells, no significant decrease was observed in any of the components of the striatonigral pathway. In contrast, when quinolinic acid was injected in the caudate-putamen, marked reductions in [3H]5-HT binding were seen in the caudate-putamen, the globus pallidus and the substantia nigra pars reticulata, on the side ipsilateral to the lesion. These data, which are comparable to previous results in human pathologies where similar cell populations are known to degenerate (Parkinson disease and Huntington's chorea), indicate a presynaptic localization of 5-HT1D receptors on the terminals of the striatal neurons projecting to the pars reticulata of the substantia nigra. In addition, these receptors could be located on the cell bodies or dendrites of these neurons in the striatum, postsynaptically to serotoninergic fibers.     

Demonstration of a pallido-nigral projection innervating dopaminergic neurons.

Afferents to the substantia nigra from the neostriatum and globus pallidus were studied in the rat by means of the autoradiographic tracing technique. 3H-leucine was injected stereotaxically into either the globus pallidus or neostriatum. Twenty-four hours later the axoplasmic transport of labelled proteins to the substantia nigra was studied by light and electron microscopic autoradiography. In animals used for electron microscopy, degeneration of dopaminergic cells in the substantia nigra was induced by intraventricular injection of 6-hydroxydopamine 72 hours before sacrifice. After neostriatal injections, light microscopic analysis revealed heavy labelling of the globus pallidus and entopeduncular nucleus, but only background labelling of the subthalamic nucleus. There was preferential labelling of the zone reticulata of the substantia nigra, with significantly less labelling of the zone compacta. After pallidal injections, light microscopic analysis showed very light labelling of those parts of the caudate-putamen in the vicinity of the injection site. There was intense labelling of the subthalamic nucleus and heavy labelling of the entopeduncular nucleus. The zona compacta of the substantia nigra was also heavily labelled. There was considerably less labelling of the zona reticulata. The electron microscopic analyses showed that after neostriatal injections, autoradiographic grains in the substantia nigra were located preferentially over boutons which terminated on normal dendritic processes. After pallidal injections, however, grains were preferentially located over boutons synapsing with degenerating dendritic processes. The degeneration produced in these dopaminergic processes by 6-hydroxydopamine was invariably of the dark type. Except for the different association with degenerating vs. non-degenerating dendrites, the subcellular distribution of autoradiographic grains in the substantia nigra was the same after injection into either the globus pallidue or caudate-putamen. Approximately 80 percent of the grains were over axons or boutons which invariably made symmetrical synaptic contacts. These observations demonstrate the existence of a pallido-nigral projection which terminates preferentially on dopaminergic cells in the pars compacta of the substantia nigra. They also confirm previous studies indicating that the strionigral projection terminates mainly in the pars reticulata. These terminations appear to be principally to non-dopaminergic cells.     

Calbindin-D28k in the basal ganglia of patients with parkinsonism.

An immunohistochemical study was carried out to investigate the topographic distribution of calbindin-D28k in the human basal ganglia and substantia nigra and its alterations in patients with idiopathic Parkinson's disease (PD), parkinsonism-dementia complex on Guam, progressive supranuclear palsy, and striatonigral degeneration. In normal control subjects, calbindin-D28k immunoreactivity was identified in the medium-sized neurons and neuropil of the matrix compartment of the striatum, the woolly fiber arrangements of the globus pallidus, and the fiber structures of the pars reticulata of the substantia nigra. Calbindin-D28k expression in the basal ganglia of patients with PD and parkinsonism-dementia on Guam was not different from that of control subjects, suggesting that the matrical output pathway is spared in these disorders. In contrast, its disruption is inferred from the observed disorganization of woolly fibers in the globus pallidus of patients with progressive supranuclear palsy and the reduced calbindin-D28k reactivity in the putaminal matrix and the pars reticulata of the substantia nigra of subjects with striatal degeneration. Thus, our results indicate that calbindin-D28k is a useful marker for the projection system from the matrix compartment and that its expression is modified in patients with progressive supranuclear palsy and striatal degeneration.     

Alterations in local cerebral glucose utilization during electrical stimulation of the striatum and globus pallidus in rats

Alterations in local cerebral glucose utilization (LCGU) in conscious rats during electrical stimulation of the striatum and the globus pallidus were investigated using the [14C]deoxyglucose method. Stimulation of the globus pallidus produced a marked contraversive circling behavior, while stimulation of the striatum led only to contraversive head turning. Unilateral stimulation of the striatum increased LCGU bilaterally in the globus pallidus and substantia nigra pars compacta, but only ipsilaterally in the entopeduncular nucleus, substantia nigra pars reticulata and subthalamic nucleus. Similar stimulation of the globus pallidus increased LGCU in the globus pallidus, substantia nigra pars reticulata and compacta, entopeduncular nucleus, subthalamic nucleus, lateral habenular nucleus, parafascicular nucleus of the thalamus, deep layers of the superior colliculus and pedunculopontine nucleus, exclusively on the ipsilateral side. These results indicate that the electrical stimulation induces LCGU changes in the respective structures having both monosynaptic and transsynaptic neuronal inputs. Some changes may also be mediated by antidromic activation. They also suggest that activation of a synaptic process whether excitatory or inhibitory results in increases in LCGU. The bilateral modulatory effects of striatal stimulation may cancel out the circling behavior seen during pallidal stimulation, and cause only head turning.     

Erratum

Tritiated tracer was injected into the head of the caudate nucleus in cats. Following such injections, labeling is present within extensive regions of both the globus pallidus and entopeduncular nucleus, where it presents a mottled or meshlike appearance. These projections are topographically organized in that there is simple correspondence between the mediolateral, dorsoventral, and rostrocaudal origin of the caudate projection and its input to the globus pallidus and entopeduncular nucleus. Transported tracer is also present within the substantia nigra, where it is most abundant within the pars reticularis. However, distinct labeling also overlies cells of the pars corapacta, and lesser amounts of labeling are present within the pars lateralis and within the retrorubral area. Following injections of horseradish peroxidase into the caudate nucleus, and subsequent tissue processing by the tetramethylbenzidine (TMB) method of Mesulam (1978), labeled anterograde fibers are present in abundance within the globus pallidus, entopeduncular nucleus, and all subdivisions of the substantia nigra, thus confirming the autoradiographic findings. Also, it is especially obvious in this HRP material that, contrary to previous degeneration studied, both the rostromedial and caudolateral parts of the pars reticularis of the substantia nigra contain numerous anterogradely labeled fibers. Retrogradely labeled neurons are also present within the substantia nigra of these same tissue sections, where they are most abundant within the pars compacta, but lesser numbers of labeled neurons are also present within the pars reticularis, pars lateralis, retrorubral area, and ventral tegmental area on the ipsilateral side, and all of these same subdivisions of the substantia nigra on the contralateral side. Also, within the subthalamic nucleus in these experiments, there are anterogradely labeled fibers, as well as retrogradely labeled neurons, which are interpreted to represent a reciprocal connection between the subthalamic nucleus and the striatum. In a separate series of experiments, horseradish peroxidase was injected into the motor cortex–specifically into the anterior sigmoidal gyrus. Following such injections, labeled neurons representing afferents to the motor cortex are found in all subcortical nuclei commonly known as the “basal ganglia,” including the caudate nucleus, putamen, globus pallidus, entopeduncular nucleus, substantia innominata, nucleus of the diagonal band of Broca, medial septal nucleus, claustrum, and basolateral amygdaloid nucleus.     

Efferent connections of the caudate nucleus, including cortical projections of the striatum and other basal ganglia: an autoradiographic and horseradish peroxidase investigation in the cat

Tritiated tracer was injected into the head of the caudate nucleus in cats. Following such injections, labeling is present within extensive regions of both the globus pallidus and entopeduncular nucleus, where it presents a mottled or meshlike appearance. These projections are topographically organized in that there is simple correspondence between the mediolateral, dorsoventral, and rostrocaudal origin of the caudate projection and its input to the globus pallidus and entopeduncular nucleus. Transported tracer is also present within the substantia nigra, where it is most abundant within the pars reticularis. However, distinct labeling also overlies cells of the pars compacta, and lesser amounts of labeling are present within the pars lateralis and within the retrorubral area. Following injections of horseradish peroxidase into the caudate nucleus, and subsequent tissue processing by the tetramethylbenzidine (TMB) method of Mesulam ('78), labeled anterograde fibers are present in abundance within the globus pallidus, entopeduncular nucleus, and all subdivisions of the substantia nigra, thus confirming the autoradiographic findings. Also, it is especially obvious in this HRP material that, contrary to previous degeneration studies, both the rostromedial and caudolateral parts of the pars lateralis of the substantia nigra contain numerous anterogradely labeled fibers. Retrogradely labeled neurons are also present within the substantia nigra of these same tissue sections, where they are most abundant within the pars compacta, but lesser numbers of labeled neurons are also present within the pars reticularis, pars lateralis, retrorubral area, and ventral tegmental area on the ipsilateral side, and all of these same subdivisions of the substantia nigra on the contralateral side. Also, within the subthalamic nucleus in these experiments, there are anterogradely labeled fibers, as well as retrogradely labeled neurons, which are interpreted to represent a reciprocal connection between the subthalamic nucleus and the striatum. In a separate series of experiments, horseradish peroxidase was injected into the motor cortex-specifically into the anterior sigmoidal gyrus. Following such injections, labeled neurons representing afferents to the motor cortex are found in all subcortical nuclei commonly known as the "basal ganglia," including the caudate nucleus, putamen, globus pallidus, entopeduncular nucleus, substantia innominata, nucleus of the diagonal band of Broca, medial septal nucleus, claustrum, and basolateral amygdaloid nucleus.     

The course and distribution of efferents from the tail of the caudate nucleus in the monkey

Small electrolytic lesions were placed at various sites in the tail of the caudate nucleus of monkeys to study the topographical distribution of its efferents. The degenerating fibers were impregnated with the Nauta or the Fink-Heimer techniques, or both. Fibers from all parts studied follow a similar dorsomedial course along the ventral border of the lentiform nucleus. Fibers originating rostrally run in a caudal direction, while the posterior ones turn anteriorly, both meeting fibers of intermediate origin in a narrow region of the peduncle above the lateral geniculate body. After traversing the peduncle they distribute topographically in posterior and ventrolateral regions of the substantia nigra pars reticulata, leaving the posterior tip free of degeneration. A ventromedial strip of the globus pallidus also receives afferents. Lesions placed lateral to the tail of the caudate nucleus did not cause degeneration in the globus pallidus or in the substantia nigra.     

Computer measurements of axis cylinder diameters of radial fibers and “comb” bundle fibers

In electron micrographs of the squirrel monkey (Saimiri sciureus) brain the striatal efferents were observed at two different levels in their course: (1) in cross-sectioned radial fiber bundles just before they enter the globus pallidus; (2) in cross-sectioned “comb” bundle fibers just before they enter the substantia nigra. In the radial bundles nearly all of the fibers are myelinated; in the “comb” bundle most are unmyelinated. The polarity of all the “comb” bundle fibers is descending. None of them degenerate following a large lesion in the substantia nigra but they do degenerate following a large lesion in the striatum. Also following this latter lesion the endings with large synaptic vesicles, which make up most of the endings in the globus pallidus and the substantia nigra, degenerate. For computer measurements, electron micrographs of the radial bundle were enlarged photographically to a final magnification of 20,000; those of the “comb” bundle to × 50,000. Measurements of 1309 radial fibers revealed a mean axis-cylinder diameter of 0.68 microns, and measurements of 749 unmyelinated “comb” bundle fibers gave a mean axis-cylinder diameter of 0.21 microns. Myelinated fibers were not included in the “comb” bundle measurements because it contains myelinated fibers of pallidal origin in addition to myelinated fibers of striatal origin. The results here indicate that the striatal efferents undergo a decided decrease in axis-cylinder diameter during their transit through the globus pallidus. It is suggested that the large non-spine bearing neurons in the striatum are the source of the striatal efferents and that they send their axons into the substantia nigra and enroute spend a great quantity of their axoplasm by extending extensive collaterals in both segments of the globus pallidus. This could account for the decreased caliber of the striatal efferents in the “comb” bundle and other findings in the striatum, globus pallidus and substantia nigra.     

Comparative cellular distribution of GABAA and GABAB receptors in the human basal ganglia: immunohistochemical colocalization of the alpha 1 subunit of the GABAA receptor, and the GABABR1 and GABABR2 receptor subunits

The GABA(B) receptor is a G-protein linked metabotropic receptor that is comprised of two major subunits, GABA(B)R1 and GABA(B)R2. In this study, the cellular distribution of the GABA(B)R1 and GABA(B)R2 subunits was investigated in the normal human basal ganglia using single and double immunohistochemical labeling techniques on fixed human brain tissue. The results showed that the GABA(B) receptor subunits GABA(B)R1 and GABA(B)R2 were both found on the same neurons and followed the same distribution patterns. In the striatum, these subunits were found on the five major types of interneurons based on morphology and neurochemical labeling (types 1, 2, 3, 5, 6) and showed weak labeling on the projection neurons (type 4). In the globus pallidus, intense GABA(B)R1 and GABA(B)R2 subunit labeling was found in large pallidal neurons, and in the substantia nigra, both pars compacta and pars reticulata neurons were labeled for both receptor subunits. Studies investigating the colocalization of the GABA(A) alpha(1) subunit and GABA(B) receptor subunits showed that the GABA(A) receptor alpha(1) subunit and the GABA(B)R1 subunit were found together on GABAergic striatal interneurons (type 1 parvalbumin, type 2 calretinin, and type 3 GAD neurons) and on neurons in the globus pallidus and substantia nigra pars reticulata. GABA(B)R1 and GABA(B)R2 were found on substantia nigra pars compacta neurons but the GABA(A) receptor alpha(1) subunit was absent from these neurons. The results of this study provide the morphological basis for GABAergic transmission within the human basal ganglia and provides evidence that GABA acts through both GABA(A) and GABA(B) receptors. That is, GABA acts through GABA(B) receptors, which are located on most of the cell types of the striatum, globus pallidus, and substantia nigra. GABA also acts through GABA(A) receptors containing the alpha(1) subunit on specific striatal GABAergic interneurons and on output neurons of the globus pallidus and substantia nigra pars reticulata.     

Methamphetamine increases basal ganglia iron to levels observed in aging

Increases in basal ganglia iron are well documented for neurodegenerative diseases but have not been associated with methamphetamine (METH). In this study, vervet monkeys that received two doses of METH (2 mg/kg, intramuscularly, 6 h apart) showed at 1 month, iron increases in substantia nigra pars reticulata and globus pallidus, with concurrent increases of ferritin-immunoreactivity and decreases of tyrosine hydroxylase-immunoreactivity in substantia nigra. At 1.5 years, substantia nigra tyrosine hydroxylase-immunoreactivity had recovered while iron and ferritin-immunoreactivity increases persisted. Globus pallidus and substantia nigra iron levels of the adult METH-exposed animals (age 5-9 years) were now comparable with those of drug-naive, aged animals (19-22 years), suggesting an aging-related condition that might render those regions more vulnerable to oxidative stress.     

A novel grading scale for striatonigral degeneration (multiple system atrophy)

Summary. Striatonigral degeneration (SND) is commonly thought to represent the neuropathological substrate of L-Dopa unresponsive parkinsonism in patients with multiple system atrophy (MSA). Other neuropathological hallmarks of MSA include olivopontocerebellar atrophy (OPCA) and preganglionic sympathetic spinal cord lesions. Clinicopathological evaluation of MSA patients recruited into ongoing natural history studies or neuroprotective intervention trials will require standardized grading of MSA pathology. Based on 25 autopsy cases of MSA, we propose a novel SND grading scale which allows semiquantitative assessment of lesion severity based on neuronal loss, astrogliosis and presence of α-synuclein positive glial cytoplasmic inclusions (GCIs) in substantia nigra, putamen, caudate nucleus, and globus pallidus. SND grade I is defined as degeneration of the substantia nigra pars compacta (SNC) with relative preservation of the striatum except for minimal gliosis and GCIs in the posterior putamen ("minimal change MSA"). SND grade II is characterized by neuronal loss, astrogliosis and presence of GCIs in SNC and posterior/dorsolateral putamen. Caudate nucleus and external globus pallidus may exhibit slight gliosis. Striatal pathology is severe and extends to anterior ventromedial subregions in SND grade III. There is neuronal loss in caudate nucleus and globus pallidus. GCIs are more abundant in grade II than grade III SNC and putamen. Preliminary clinicopathologic correlation studies suggest milder parkinsonian disability and better initial L-Dopa responsiveness in SND grade I and II cases compared to grade III cases. Prospective clinicopathologic studies are required to validate the proposed SND grading scale and may result in further subdivisions, particularly of SND grade III. Received April 11, 2001; accepted July 11, 2001     

Corticobasal degeneration with primary progressive aphasia and accentuated cortical lesion in superior temporal gyrus: case report and review

A 57-year-old woman showed progressive sensory aphasia as an initial symptom, and then developed total aphasia within 6 years and, finally, severe dementia. Neuropathologically, the cerebral cortex was most severely affected in the superior and transverse temporal gyri, and subsequently in the inferior frontal gyrus, especially in the pars opercularis. The degeneration in the subcortical grey matter was most severe in the substantia nigra, and it was moderate to mild in the ventral part of thalamus, globus pallidus and striatum. Cytopathologically, in addition to achromatic ballooned neurons, massive tau-positive types of cytosekeletal abnormalities were observed both in neurons and glia, mainly in the degenerating region. This cytoskeletal pathology coincided with that reported in corticobasal degeneration (CBD). On Bodian staining, only a few neurofibrillary tangles were found in the entorhinal pre-alpha layer and substantia nigra. Pick’s bodies and senile plaques could not be found. This case is thought to represent a type of CBD, but with its cortical lesion focus located in the speech area instead of the frontoparietal region. A survey of 28 pathologically evaluated cases of CBD revealed two similar cases, both of which began with progressive aphasia and presented cortical degeneration in the superior temporal gyrus. An overview of CBD cases clarified the features in another group of cases, in which the cerebral accentuated focus was shifted forward from the central region, clinically resembling Pick’s disease. The clinical manifestations in CBD seem to be the expression of these diverse cortical lesions. Primary progressive aphasia may include cases of CBD with involvement of the language center. Received: 5 February 1996 / Revised, accepted: 13 May 1996     

Bilateral morphological changes in the substantia nigra of the rat following unilateral damage of the striatum

The effects of damage of the striatum and globus pallidus of one side on the size of cells in the pars reticulata and pars compacta of the substantia nigra on both sides and in the contralateral globus pallidus have been examined. Cellular cross-sectional areas have been compared with those for neurons in the same nuclei in normal age and sex matched littermate control animals. One week after removal of the left striatum and globus pallidus and overlying cortex, the cells in the ipsilateral pars compacta are significantly shrunken (15%). This decrease in size gets progressively more marked with longer survival times reaching 50% 112 days after operation, the longest survival time examined. The shrinkage is accompanied by marked cell loss. Neurons in the contralateral pars compacta show an initial significant hypertrophy of their cell bodies (20%) in the first week after the operation, and later show a shrinkage of 20% at 35 days. The degree of this contralateral shrinkage gradually declines to 12% at 112 days. The changes in the pars compacta are accompanied by a significant enlargement (33%) of the cells in the pars reticulata of the substantia nigra on the side of the damage. This hypertrophy is present by 35 days after operation and persists at least until 112 days. Similar hypertrophy occurs in the ipsilateral globus pallidus in the one case where this could be examined. There are no significant changes in the contralateral pars reticulata, but there is significant enlargement (23%) of the neurons in the contralateral globus pallidus.     

Origin and distribution of glutamate decarboxylase in substantia nigra of the cat

The topographical distribution of glutamate decar?ylase (GAD) in substantia nigra in unoperated and operated cats was studied in samples microdissected from freeze-dried tissue sections.The concentration of GAD, the enzyme synthesizing γ-aminobutyric acid (GABA), was highest in the medial part of pars reticulata, and decreased in the mediolateral direction. In pars compacta, on the other hand, the highest enzyme activity was found in the lateral part which merges with pars reticulata, and it decreased gradually in the latero-medial direction. The activity of GAD was always lower in the medial part of pars compacta, which contains the highest concentration of cell bodies. GAD in substantia nigra decreased after lesions in putamen, nucleus caudatus, globus pallidus and nucleus entopeduncularis. The loss of enzyme activity was strictly localized and was related to the site of termination of the degenerating striato-nigral fibers. The reduction of GAD in substantia nigra following lesions of globus pallidus or nucleus entopeduncularis may be ascribed to the interruption of striato-nigral fibers passing through these regions. The results thus indicate that the fibers of the GAD-containing axon terminals in substantia nigra of the cat originate in putamen and nucleus caudatus.Subcellular fractionation showed that about 85% of GAD and about 25% of lactate dehydrogenase were present in particles (probably synaptosomes) from substantia nigra in unoperated animals. Electron microscopic examination revealed that 11.5% of the tissue volume of pars reticulata was occupied by boutons compared to 5.9% for pars compacta. The concentration of GABA in pars reticulata was found to be 9 mM. From these data the intraterminal concentration of GABA was estimated to be at least 60 mM, probably over 100 mM.DOPA decar?ylase was mainly found in pars compacta. Acetylcholin-esterase showed a very high activity in substantia nigra, the highest concentration being found in the medial part of pars reticulata. In contrast, the concentration of choline acetyltransferase was very low. The ratio of acetylcholinesterase activity to choline acetyltransferase activity was 1000. DOPA decar?ylase and the cholinergic enzymes were little affected by the above described lesions.     

Efferent connections of the subthalamic region in the rat. I. The subthalamic nucleus of luys

The efferent connections of the subthalamic nucleus of Luys (STN) in the rat were investigated with the aid of the anterograde autoradiographic and the retrograde horseradish peroxidase (HRP) tracer techniques.A small microelectrophoretic injection of tritiated proline and leucine centered in the STN (case RST-4) was found to label fibers directed mainly at 3 ipsilateral structures: the substantia nigra (chiefly the ventral portions of this pars reticulata), the entopeduncular nucleus and the globus pallidus (including the ventral pallidum). In addition to this major labeling pattern, much sparser labeling was seen in striatal, thalamic, hypothalamic, pretectal, tectal and reticular territories. In another series of experiments, microelectrophoretic HRP injections confined to the substantia nigra or the globus pallidus consistently resulted in retrograde labeling of neurons in the ipsilateral STN. On the other hand, HRP injections of the vontromedial portion of the midbrain tegmentum (including the red nucleus), the superior colliculus, the pretectal area or a midbrain region at the lateral border of the central gray substance resulted in retrograde labeling of cells in the zona incerta, but no labeled cells appeared in these cases in the ventrally adjacent STN. These HRP results, together with autoradiographic data obtained in control cases, suggest that the minor projections to territories other than the substantia nigra and the pallidal complex originate in the zona incerta or the cerebral cortex rather than in STN.     

Anterograde and transsynaptic degeneration ‘en cascade’ in basal ganglia induced by intrastriatal injection of kainic acid: an animal analogue of huntington''s disease

Damage of striatal neurons by kainic acid (KA) induces an anterograde and transsynaptic degeneration 'en cascade' in the globus pallidus (GP) and substantia nigra (SN). By causing only degeneration of projections arising from KA-sensitive striatal neurons while sparing the connections of KA-resistant striatal neurons, the lesion-induced alterations of the basal ganglia show a characteristic pattern which bears a close resemblance with the neuropathological changes occurring in Huntington's disease: (1) severe degeneration of small and medium-sized striatal neurons, of pallidal neurons and the neurons of the pars reticulata of the SN, and (2) sparing of large striatal neurons, 'peripallidal' (nucleus basalis) neurons and neurons of the pars compacta of the SN. The probable interconnections of both the degenerated and the spared neuronal groups are discussed with respect to the present concept of the neuronal organization and biochemical neuroanatomy of the basal ganglia.     

Neurotensin receptor binding levels in basal ganglia are not altered in Huntington's chorea or schizophrenia.

Autoradiographic techniques were used to examine the distribution and levels of neurotensin receptor binding sites in the basal ganglia and related regions of the human brain. Monoiodo ([125I]-Tyr3)neurotensin was used as a ligand. High amounts of neurotensin receptor binding sites were found in the substantia nigra pars compacta. Lower but significant quantities of neurotensin receptor binding sites characterized the caudate, putamen, and nucleus accumbens, while very low quantities were seen in both medial and lateral segments of the globus pallidus. In Huntington's chorea, the levels of neurotensin receptor binding sites were found to be comparable to those of control cases. Only slight but not statistically significant decreases in amounts of receptor binding sites were detected in the dorsal part of the head and in the body of caudate nucleus. No alterations in the levels of neurotensin receptor binding sites were observed in the substantia nigra pars compacta and reticulata. These results suggest that a large proportion of neurotensin receptor binding sites in the basal ganglia are located on intrinsic neurons and on extrinsic afferent fibers that do not degenerate in Huntington's disease.     

Immunocytochemical studies of substance P and leucine-enkephalin in Huntington's disease

The distribution of substance P and leucine-enkephalin in selected regions of brain obtained postmortem from patients with Huntington's disease and from neurologically normal persons has been studied with immunocytochemical techniques. In the normal brain, substance P immunoreactivity was identified in medium-sized neurons in the neostriatum, in neurons of the external segment of the globus pallidus, and in fine fibers in teh neostriatum, inner segment of the globus pallidus, and in the pars reticulata of the substantia nigra. Huntington's disease brains all exhibited a marked decrease in substance P fiber density in the substantia nigra and globus pallidus. A few medium-sized neurons with substance P immunoreactivity remained in the neostriatal remnant. Leucine-enkephalin immunoreactive processes were present throughout the neostriatum of normal brain, and were densely packed in the external segment of the globus pallidus and in the substantia nigra. A uniform population of medium-sized neurons containing immunoreactive leucine-enkephalin was present in the caudate and putamen. By contrast, in the Huntington's disease brains there was a marked diminution of fiber staining in the globus pallidus and substantia nigra. A few medium-size neurons and sparse fibers with leucine-enkephalin immunoreactivity persisted in the atrophic neostriatum. These observations are consistent with previous reports of regional peptide concentrations in both normal and Huntington's disease brain. Cells containing substance P and leucine-enkephalin immunoreactivity persist in the basal ganglia in brains from patients with Huntington's disease, and we have no evidence that cellular content of one or the other peptide is associated with disproportionate cell death or survival.