Primary dystonias: a review of the pathology and suggestions for new directions of study.
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Basal Ganglia↗
Biomedical subjects
D L Price
Publications and source records attributed to D L Price.
A historical perspective on the neuropathology of dementia with emphasis on the senile plaque.
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Dementia↗
Corticotropin-releasing hormone (CRH) is decreased in the basal ganglia in Huntington's disease.
Corticotropin-releasing hormone-like immunoreactivity (CRH-IR) was measured in control and Huntington's disease brain tissues obtained postmortem. The concentration of CRH-IR was markedly decreased in the caudate/putamen in Huntington's disease; the concentration of somatostatin-like immunoreactivity measured in the same extracts was significantly increased in the caudate/putamen in Huntington's disease compared with the control group. In contrast to previously reported decreases in CRH-IR in the cerebral cortex in Alzheimer's disease, Parkinson's disease and progressive supranuclear palsy, no significant differences were observed in the concentrations of CRH-IR between controls and Huntington's disease in frontal, parietal, temporal, occipital and cingulate cortex and in globus pallidus.
Adult↗
Muscarinic and nicotinic cholinergic binding sites in Alzheimer's disease cerebral cortex.
The total population of muscarinic receptors and a subpopulation of muscarinic receptors with high affinity for agonists were measured with [3H]quinuclidinyl benzilate and [3H]acetylcholine, respectively, in homogenates of cerebral cortex from control and Alzheimer's disease brains. No significant differences between control and Alzheimer's diseased cortex were found in either the total population of receptors or the subpopulation with high affinity for agonists in either the frontal or temporal poles. Nicotinic cholinergic receptors labeled by [3H]acetylcholine were measured in homogenates and by autoradiography in the same brain areas. In contrast to muscarinic sites, binding to nicotinic sites was markedly decreased in Alzheimer's disease cortex. Autoradiography of [3H]acetylcholine binding to nicotinic sites indicated that in control cortex these sites are more concentrated in laminae IV-VI than in the superficial laminae, and that in Alzheimer's disease there is loss of these sites in all cortical laminae.
Acetylcholine↗
Corticotropin-releasing factor as a transmitter in the human olivocerebellar pathway.
This study demonstrates that the neuropeptide, corticotropin-releasing factor (CRF), is present in neurons of the human inferior olivary complex (IOC). The medulla (including the inferior olive) and the anterior vermis of the cerebellum of 6 human controls obtained at autopsy were immunostained with an antibody directed against CRF. CRF receptors in cerebellum were localized with labeled CRF using in vitro receptor autoradiography. The great majority of neurons in all divisions of the IOC expressed CRF immunoreactivity, and CRF-immunoreactive fibers were demonstrated in the hilus of the olive and in the molecular layer of the cerebellum, where they closely resembled climbing fibers as visualized with other methods. CRF receptors were enriched in the cerebellum, with the highest density in inner portions of the molecular layer. These findings in human brain, consistent with studies in tissues from rat, cat, and monkey, demonstrate that CRF may be a peptidergic transmitter in the IOC climbing fiber system and that CRF receptors are expressed by cellular targets in the cerebellum.
Adult↗
Fiber pathways of basal forebrain cholinergic neurons in monkeys.
In rhesus monkeys, autoradiographic tracing methods, complemented by immunocytochemical and histochemical techniques, were used to delineate pathways by which cholinergic neurons of the nucleus basalis of Meynert (nbM) and nucleus of the diagonal band of Broca (ndbB) project to forebrain targets. Following injections of [3H]amino acids into these nuclei, 5 major fiber pathways were identified: axons of the nbM and ndbB project medially, principally within the cingulum bundle, to dorsomedial portions of the hemispheres; nbM and ndbB fibers exit laterally beneath the pallidum and striatum, enter the external and extreme capsules, and pass within the corona radiata to terminate in lateral and caudal regions of neocortex; axons coursing ventrally from the nbM project to portions of the temporal lobe, including the amygdala; some fibers pass through the fibrae pass orbitofrontales to the orbitofrontal cortex; and, finally axons of the nbM/ndbB project via the fimbria/rornix and a ventral pathway to the hippocampus. The presence of these 5 radiolabeled pathways arising from basal forebrain cholinergic neurons was confirmed by acetylcholinesterase histochemistry and choline acetyltransferase immunocytochemistry.
Acetylcholinesterase↗
Neuromelanin: a role in MPTP-induced neurotoxicity.
Methylphenyltetrahydropyridine (MPTP) selectively destroys melanin-containing neurons in the substantia nigra of humans and other primates. Methylphenylpyridine (MPP+), an active metabolite of MPTP, which is accumulated intraneuronally by the catecholamine uptake system, binds with high affinity to neuromelanin. MPP+ bound intracellularly to neuromelanin may be released gradually, resulting in damage to the neurons of the substantia nigra. Chloroquine, a drug which blocks MPP+ binding to neuromelanin, can protect monkeys from MPTP neurotoxicity.
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
Conservation of brain amyloid proteins in aged mammals and humans with Alzheimer's disease.
The formation of clusters of altered axons and dendrites surrounding extracellular deposits of amyloid filaments (neuritic plaques) is a major feature of the human brain in both aging and Alzheimer's disease. A panel of antibodies against amyloid filaments and their constituent proteins from humans with Alzheimer's disease cross-reacted with neuritic plaque and cerebrovascular amyloid deposits in five other species of aged mammals, including monkey, orangutan, polar bear, and dog. Antibodies to a 28-amino acid peptide representing the partial protein sequence of the human amyloid filaments recognized the cortical and microvascular amyloid of all of the aged mammals examined. Plaque amyloid, plaque neurites, and neuronal cell bodies in the aged animals showed no reaction with antibodies to human paired helical filaments. Thus, with age, the amyloid proteins associated with progressive cortical degeneration in Alzheimer's disease are also deposited in the brains of other mammals. Aged primates can provide biochemically relevant models for principal features of Alzheimer's disease: cerebrovascular amyloidosis and neuritic plaque formation.
Aging↗
Dysfunction and death of neurons in human degenerative neurological diseases and in animal models.
The human neurological disorders--amyotrophic lateral sclerosis (ALS), Parkinson's disease (PD), and Alzheimer's disease (AD)--share certain features: they occur in later stages of adult life; are slowly progressive; and involve specific groups of nerve cells. Different clinical syndromes result from dysfunction and death of these specific groups of neurons. In ALS, patients are weak due to disease of motor neurons in the spinal cord. The clinical features of PD, e.g. slow movements, tremor and rigidity, are attributed, in part, to degeneration of dopaminergic neurons of the substantia nigra. Impairments of cognition and memory in AD result from disease of neurons in a number of regions, including brainstem, basal forebrain, amygdala, hippocampus, and neocortex. In each of these diseases, affected neurons exhibit abnormalities of the neuronal cytoskeleton: in ALS, neurofilaments accumulate and distend proximal motor axons; in PD, nigral perikarya show Lewy bodies-intracytoplasmic inclusions containing neurofilament antigens; in AD, neurons develop neurofibrillary tangles, Hirano bodies, granulovacuolar degeneration and filament-filled neurites in plaques. Certain features of ALS, PD and AD are recapitulated in animal models, three of which are described in this review. Hereditary canine spinal muscular atrophy (HCSMA), a dominantly inherited motor neuron disease, shows many clinical and pathological features in common with ALS, including weakness, muscle atrophy, neurofilamentous swellings of proximal axons, impaired transport of neurofilament proteins, and degeneration of motor neurons. In primates, intoxication with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) produces a parkinsonian syndrome due to injury of nigral dopaminergic neurons and associated denervation of the striatum. Finally, aged macaques exhibit memory deficits, and their cerebral cortices show senile plaques and filament-filled neurites derived from a variety of transmitter-specific populations of nerve cells. In human diseases, the causes and mechanisms leading to dysfunction and death of nerve cells are unknown. Investigators have begun using a variety of techniques derived from neurobiology to study animal models in an effort to clarify the mechanisms, evolutions, and consequences of structural-chemical abnormalities occurring in different neuronal systems implicated in human disease. Understanding such processes in these models should provide important new insights into the pathogeneses of similar processes occurring in ALS, PD and AD.
Animals↗
Loss of pedunculopontine neurons in progressive supranuclear palsy.
In the present study, the number of neurons (greater than 20 microns in diameter) within the lateral part of the pedunculopontine nucleus pars compacta (PPNc) was determined at six rostrocaudal levels in 3 subjects with progressive supranuclear palsy (PSP), in 9 subjects with Alzheimer's disease, and in 6 age-matched control subjects. At each level examined, significantly fewer neurons were present in patients with PSP than in control subjects (49 to 69% reduction). Significant differences in numbers of neurons were not demonstrated between control subjects and patients with Alzheimer's disease. The extent of pathological changes, particularly neurofibrillary tangles, was examined within the PPNc of subjects in these three groups. The average number of neurofibrillary tangles in a 12-microns-thick midlevel section of the lateral PPNc was 68.7 in subjects with PSP, 18.3 in those with Alzheimer's disease, and 3.0 in aged control subjects. These abnormalities of PPNc neurons in PSP may play important roles in some of the clinical features characteristic of this disease.
Aged↗
Aminergic systems in Alzheimer's disease and Parkinson's disease.
Biochemical markers for serotoninergic and catecholaminergic neurons in frontal and temporal poles were examined post mortem in brains of patients with Alzheimer's disease, Parkinson's disease, and the two combined. Binding of [3H] citalopram to serotoninergic uptake sites and levels of serotonin were decreased by 40 to 50% in brains of persons in each disease category. In contrast, significant reductions of catecholaminergic markers were not detected. In all three disease groups, the choline acetyltransferase activity was reduced by 50 to 60%. Binding sites for adenosine (A1), muscarinic cholinergic, phencyclidine, beta-adrenergic, and calcium antagonist receptors were unchanged. We conclude that substantial damage to serotoninergic neurons occurs in persons with Parkinson's and Alzheimer's diseases.
Alzheimer Disease↗
Immunohistochemical study of neurons containing corticotropin-releasing factor in Alzheimer's disease.
In the brains of controls and individuals with Alzheimer's disease (AD), antisera to corticotropin-releasing factor (CRF) were used to immunostain neurons and their processes. In AD, we identified abnormal CRF-immunoreactive axons as well as neurites associated with deposits of amyloid in brain regions showing senile plaques. The number of immunoreactive fibers was decreased in individuals with AD. In contrast, CRF immunoreactivity was markedly increased in some neurons located within the paraventricular nucleus (PVN) of the hypothalamus. These findings support previous neurochemical studies indicating that certain CRF systems are affected in AD.
Adult↗
Effects of scopolamine and physostigmine on recognition memory in monkeys with ibotenic-acid lesions of the nucleus basalis of Meynert.
Monkeys with bilateral ibotenic-acid lesions of the nucleus basalis of Meynert, an area rich in cholinergic neurons that innervate the cerebral cortex, were compared with unoperated control monkeys on a recognition memory task. Although animals with large lesions had substantial reductions of cortical choline acetyltransferase activity, none showed impairment in the task. Lesion effects were observed, however, when performance was assessed following administration of a muscarinic receptor blocker (scopolamine) or a cholinesterase inhibitor (physostigmine). Although scopolamine produced dose-related impairments in both groups, this effect was greater in the experimental animals. Conversely, whereas physostigmine produced modest improvement in performance in the control group, no such improvement was observed in the experimental animals. The altered sensitivity to the mnemonic effects of cholinergic agents in the experimental group suggests that the cholinergic neurons of the nucleus basalis of Meynert contribute to recognition memory.
Acetylcholinesterase↗
An autoradiographic study of the development of [3H]hemicholinium-3 binding sites in human and baboon basal ganglia: a marker for the sodium-dependent high affinity choline uptake system.
The developmental distribution of the sodium-dependent high affinity choline uptake (SDHACU) system has been studied in the caudate and putamen of the baboon and of the human by in vitro autoradiography with the ligand, [3H]hemicholinium-3 [( 3H]HCh3). Our results show that [3H]HCh3 binding sites in the newborn baboon and fetal human neostriatum are localized to patches, and then adopt a 'striosome-like' distribution in the juvenile baboon brain. These findings indicate a reorganization of [3H]HCh3 binding site distribution during the ontogeny of the primate neostriatum.
Acetylcholinesterase↗
beta-Amyloid gene is not present in three copies in autopsy-validated Alzheimer's disease.
Recently, it has been suggested that Alzheimer's disease is associated with a duplication of the amyloid precursor protein gene localized to chromosome 21q21. In this study, a cloned DNA probe (B2.3), complementary to the sequence coding the beta-amyloid peptide, and DNA polymorphisms adjacent to this sequence were used to determine the number of copies of the beta-amyloid gene in DNA isolated from human blood and brain. Individuals with trisomy 21 (Down syndrome) who were heterozygous for the polymorphisms showed a gene-dosage effect, with one allele exhibiting twice the autoradiographic intensity as the other. Heterozygous individuals with Alzheimer's disease and controls showed equal intensities of the two allelic bands, suggesting that there are only two copies of the beta-amyloid gene in these individuals. In individuals with Alzheimer's disease and in controls who were homozygous for these polymorphisms, the number of copies of the beta-amyloid gene was determined by comparing the autoradiographic intensity of beta-amyloid alleles to that of DNA fragments detected by a reference probe. No difference was detected between these two groups.
Alzheimer Disease↗
Neurofilament gene expression: a major determinant of axonal caliber.
Within the wide spectrum of axonal diameters occurring in mammalian nerve fibers, each class of neurons has a relatively restricted range of axonal calibers. The control of caliber has functional significance because diameter is the principal determinant of conduction velocity in myelinated nerve fibers. Previous observations support the hypothesis that neurofilaments (NF) are major intrinsic determinants of axonal caliber in large myelinated nerve fibers. Following interruption of axons (axotomy) by crushing or cutting a peripheral nerve, caliber is reduced in the proximal axonal stumps, which extend from the cell bodies to the site of axotomy. (The distal axonal stumps, which are disconnected from the cell bodies, degenerate and are replaced by the outgrowth of regenerating axonal sprouts arising from the proximal stump). This reduction in axonal caliber in the proximal stumps is associated with a selective diminution in the amount of NF protein undergoing slow axonal transport in these axons, with a decrease in axonal NF content, and with reduced conduction velocity. The present report demonstrates that changes in axonal caliber after axotomy correlate with a selective alteration in NF gene expression. Hybridization with specific cDNAs was used to measure levels of mRNA encoding the 68-kDa neurofilament protein (NF68), beta-tubulin, and actin in lumbar sensory neurons of rat at various times after crushing the sciatic nerve. Between 4 and 42 days after axotomy by nerve crush, the levels of NF68 mRNA were reduced 2- to 3-fold. At the same times, the levels of tubulin and actin mRNAs were increased several-fold. These findings support the hypothesis that the expression of a single set of neuron-specific genes (encoding NF) directly determines axonal caliber, a feature of neuronal morphology with important consequences for physiology and behavior.
Animals↗
Distribution of neurofilament antigens after axonal injury.
Phosphorylated and nonphosphorylated epitopes of neurofilament (NF) proteins are distributed in different regions of individual neurons. Immunocytochemical methods, with monoclonal antibodies directed against phosphorylated and nonphosphorylated NF, demonstrated nonphosphorylated NF in perikarya and proximal axonal segments of neurons in dorsal root ganglia, while phosphorylated NF proteins were present in axons of these cells. The distribution of these epitopes of NF were examined at various times following injury of axons in the rat sciatic nerve. Between one and 21 days after crush of the proximal nerve, phosphorylated NF were present in neuronal perikarya. We have compared patterns of perikaryal immunoreactivity at one time point (three weeks) following a more distal crush or complete transection of the sciatic nerve. At this time period, following transection/ligation, phosphorylated NF immunoreactivity was not present in perikarya, but abnormal staining was observed after nerve crush. These altered distributions of phosphorylated epitopes of NF are of interest because several recent reports have indicated that similar, but not identical, abnormal staining patterns occur in human neurological diseases, including Alzheimer's disease and Parkinson's disease. In accord with previous studies, this investigation indicates that one response of neurons to injury, or to disease, is an abnormal distribution of phosphorylated epitopes of NF proteins.
Animals↗
Neuropeptidergic systems in plaques of Alzheimer's disease.
Polyclonal antibodies directed against substance P, somatostatin, neurotensin, cholecystokinin (CCK), leucine enkephalin, and vasoactive intestinal polypeptide (VIP) were employed to determine the immunoreactivities of neurites of senile plaques (SP) in Alzheimer's disease (AD). All of the antibodies labeled some neurites in some SP. The transmitter specificities of immunoreactive neurites tended to reflect the distribution of transmitter-associated fibers in normal tissue. This investigation also documented the presence of abnormal axons (as distinct from neurites within plaques) in the neuropil in brains of individuals with AD and in some aged controls. These findings suggest that a variety of transmitter systems are involved in the formation of neuropil abnormalities of SP. They also indicate that a greater number of neuronal systems are affected in AD than have been documented by neurochemical studies.
Adult↗