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The regional expression of immune-mediated and neurotoxic events in the human immunodeficiency virus (HIV)-infected brain in relationship to the acquired immunodeficiency syndrome (AIDS) dementia complex (ADC) and brain pathology remains uncertain. The extent of gp41, inducible nitric oxide synthase (iNOS), and HLA-DR expression was examined in the frontal lobe and basal ganglia of 25 patients at varying stages of ADC. The expression of gp41 and iNOS was present predominantly in perivascular cells and most often in the basal ganglia. Staining for gp41 correlated significantly with iNOS in the basal ganglia, whereas the severity of staining for gp41 and iNOS in the basal ganglia and white matter was significantly greater in subjects with moderate to severe dementia compared with those with milder impairment. The degree of macrophage staining in the white matter and basal ganglia also correlated significantly with ADC severity and was more abundant than gp41 or iNOS staining, particularly in the white matter. Logistic regression analysis revealed that staining for iNOS and gp41 increased linearly with ADC severity and was significantly more abundant in the basal ganglia compared with the white matter. Double-immunolabeling studies colocalized iNOS predominantly to macrophage/microglia and to gp41-positive cells. The expression of iNOS and gp41 in the basal ganglia combined with immune activation contributes to the development and progression of the clinical syndrome.

In contrast to the well-established dopaminergic innervation of the neostriatum, the existence of dopaminergic innervation of the subthalamic nucleus and globus pallidus is controversial. In the present study, tyrosine hydroxylase (TH)-immunoreactive elements were observed by light microscopy after antigen retrieval in the subthalamic nucleus and in the internal and external segments of the globus pallidus in postmortem human brain. Small islands of apparent neostriatal tissue with abundant arborization of fine, TH-immunoreactive axons in the vicinity of calbindin-positive small neurons resembling neostriatal medium spiny neurons were present in the external segment of the globus pallidus. Large numbers of medium-large, TH-immunoreactive axons were observed passing above and through the subthalamic nucleus and through both pallidal segments; these are presumed to be axons of passage on their way to the neostriatum. In addition, fine, TH-immunoreactive axons with meandering courses, occasional branches, and irregular outlines, morphologically suggestive of terminal axon arborizations with varicosities, were seen in both pallidal segments, including the ventral pallidum, and the subthalamic nucleus, consistent with a catecholaminergic (probably dopaminergic) innervation of these nuclei. This finding suggests that, in Parkinson's disease and in animal models of this disorder, loss of dopaminergic innervation might contribute to abnormal neuronal activation in these three nuclei.

We present a case of an 80-year-old man who developed a seizure disorder at age 66 and was treated with chronic phenytoin. In the last 3 years of his life, he developed multiple neurological deficits, including bilateral chorea, ataxic gait, sensory neuropathy, and progressive dementia. After death from pneumonia, autopsy examination of the patient's brain was most remarkable for a selective loss of neurons from both subthalamic nuclei and Purkinje cell loss in the cerebellum. This pattern of injury is consistent with a toxic process and does not fit previously characterized pathological syndromes known to be associated with movement disorders or dementia or both. Phenytoin has been shown to cause choreiform movements, peripheral neuropathy, and cognitive decline in some patients, but the pathological basis for these changes has not been elucidated. The patient's chorea was very likely the result of neuronal loss in the subthalamic nuclei, but causes for his dementia and neuropathy were not found. The pathological findings may represent either an unusual form of chronic phenytoin toxicity or a previously undescribed primary degenerative brain syndrome.

The topographic organization of neostriatal connections was investigated by axonal transport of horseradish peroxidase, tritiated amino acids, or mixtures of both injected into the neostriatum of macaque monkeys. Striatal projections to pallidum and substantia nigra and the origin of projections to striatum from cerebral cortex and substantia nigra were examined. All striatal injections gave rise to projections to external and internal pallidum and to substantia nigra. Injections in caudate nucleus and in putamen both gave rise to substantial projections to pallidum and to substantia nigra, and the ratio of pallidal and nigral projections was generally similar. The striatopallidal projection showed prominent arborizations at right angles to the striatofugal pathway traversing the pallidum, forming in this manner terminal fields consisting of multiple bands or discs within a broad segment of the pallidum. Thus separate but neighboring regions of striatum appeared to have overlapping pallidal projection territories. In broad terms, rostral striatum projects to rostral pallidum, caudal striatum to caudal pallidum, and dorsal and ventral striatum, respectively, to dorsal and ventral pallidum. Inner (medial) and outer (lateral) putamen showed only subtle differences in pallidal projection patterns. The striatonigral projection from each injected area of striatum formed a longitudinal band extending over the entire length of the substantia nigra, with scattered, dense terminal fields occupying portions of pars compacta as well as pars reticularis. Rostral striatum projected to medial nigra and caudal striatum to lateral nigra. Terminal fields from ventral striatum were located somewhat more dorsally in the substantia nigra than those from dorsal striatum. Neighboring but separate regions of striatum appeared to have overlapping nigral projection territories, especially in caudal nigra. The nigrostriatal neurons projecting to an injected area of striatum generally were located in the same longitudinal band of the substantia nigra as the corresponding striatonigral projection. Labeled pars compacta neurons were often surrounded by a dense, labeled striatonigral terminal field, suggesting the existence of a striato-nigrostriatal loop. The rostromedial pars compacta contained labeled neuronal cell bodies in most cases, suggesting a widely divergent projection to striatum from this cell group. A slight tendency for preferential cell labeling rostrally in nigra with rostral striatal injection and caudally in nigra with caudal injections was noted. The preferred relationship of lateral nigra with caudal striatum and medial nigra with rostral striatum has implications for clinical expression of Parkinson's disease, which may vary with differential involvement of different nigral cell groups along the medial to lateral axis.(ABSTRACT TRUNCATED AT 400 WORDS)

Demented patients with Parkinson disease share certain neuropathological and neurochemical features with patients suffering from Alzheimer disease. Recently, loss of cholinergic neurons in the basal forebrain, particularly the nucleus basalis of Meynert, has been implicated in the pathophysiology of Alzheimer disease. The present investigations of 12 patients with Parkinson disease demonstrates that the demented patients with this disease also show a selective loss of cells in the nucleus basalis of Meynert, thus providing an important link between the dementias of Alzheimer disease and Parkinson disease.

We have examined callosal-axon neurons giving rise to homotopic and heterotopic callosal projections to caudal inferior parietal lobule (area PG) in Macaca mulatta, identifying these neurons by means of retrograde axonal transport of horseradish peroxidase. The labeled neurons in the homotopic region occur predominantly in layers IIIB and V.A moderate number are also seen in layer VI, a smaller number of layer IV, and rare cells occur in layer II. These neurons occupy a region very similar in outline to the injection area, and though variable in density in the horizontal plane, are continuously distributed in this plane. The heterotopic neurons are seen in the contralateral cingulate gyrus, continuing caudally into medial parietal cortex, in the cortex of the superior temporal and occipitotemporal sulci, in the caudal superior temporal gyrus, and in the caudal inferior parietal lobule, behind the homotopic area. These same regions on the ipsilateral side contain labeled neurons of origin of ipsilateral association projections to area PG. For other ipsilateral labeling was found. A review of the literature on heterotopic callosal connections of a particular generalization of this conclusion: The callosal heterotopic connections of a particular cortical area are made with regions which on the ipsilateral side have associated connections with that area, though usually not with all of such regions.

Immunocytochemistry with antibodies to human erythrocyte acetylcholinesterase (AChE) was used to demonstrate axons containing this enzyme in the visual cortex (area 17) of macaques. AChE-positive fibers were most dense in layers I, IIIB, IV, and VIB of Hassler and Wagner (I, IVA, IVC, and VIB of Brodmann) with three strata of more sparsely distributed fibers (layers II-IIIA, IIIC, and V-VIA of Hassler and Wagner [II-III, IVB, and V-VIA of Brodmann]). Layer I contained the most dense plexus of AChE-positive axons, oriented horizontally. Horizontally oriented axons were also located in layers IIIB, IIIC, IV, and V of Hassler and Wagner (IVA, IVB, IVC, and V of Brodmann). Layer VIB contained axons of variable orientation, apparently afferent to cortex. Moderately stained neuronal perikarya were occasionally encountered in layer VIB and superficial white matter, but no intensely stained neurons were seen.

In order to comprehensively evaluate pathological involvement of the locus coeruleus (LC) and cortically projecting raphe nuclei in Alzheimer's disease (AD), we have recently completed a study (Zweig, et al., 1988) in which numbers of neurons containing neuromelanin within the LC and large nucleolus-containing neurons within the dorsal raphe nucleus (DR) and the central superior (raphe) nucleus (CSN) were determined in 25 cases of AD and 12 age-matched controls. Numbers of neurofibrillary tangles (NFTs) within these regions were also counted. Pathological results were compared with clinical data, including psychiatric evaluations, available for 21 of the AD cases. Neuronal loss in AD cases was most severe within LC at mid level (p less than .01) and within DR, caudally (p less than .05). Counts of NFTs within LC were also highest at mid level (p less than .05) in comparison with caudal level). Neuronal loss was not demonstrated within CSN, although NFTs were abundant within this nucleus. At individual levels, neuronal and NFT counts did not correlate. Relative severity of neuronal loss or NFTs was usually consistent from level to level within nuclei; internuclear correlations were weaker. Cases of AD complicated by depression had significantly fewer neurons at mid LC and rostral CSN levels than nondepressed cases (p less than .05). There was also a trend (nonsignificant) suggesting increased neuronal loss at all levels of LC and DR in depressed cases. Neuronal loss correlated negatively with age, particularly within LC. NFT counts correlated negatively with duration of illness, particularly within DR. As all but 3 individuals had severe dementia, NFT counts may reflect rate of progression of disease. Neuronal loss and NFTs frequently occur in the LC and cortically projecting raphe nuclei in AD (Curcio and Kemper, 1984, Hirano and Zimmermann, 1962, Ishii, 1966, Marcynuik et al., 1986, Yamamoto and Hirano, 1985, Bondareff and Mountjoy, 1986, Iverson et al., 1983, Mann et al., 1985, Tabaton et al., 1986). We have recently completed a comprehensive evaluation of pathological involvement of the LC, the DR, and the CSN in a series of aged controls and AD patients for whom detailed clinical information, including psychiatric evaluations, were available (Zweig et al., 1988). This report summarizes the findings of that study.

Neuronal loss and the presence of neurofibrillary tangles (NFTs) within aminergic nuclei were examined in a series of patients with Alzheimer's disease (AD). Neuromelanin-containing neurons within the locus ceruleus and large nucleolus-containing neurons within the dorsal raphe nucleus and the central superior (raphe) nucleus were counted in 25 patients with AD and in 12 age-matched control subjects. Numbers of NFTs were quantified in the same regions. Counts were compared with clinical data, including psychiatric evaluations, available for 21 of the patients with AD. Within the locus ceruleus in the patients with AD, abnormalities were more severe at mid level than at caudal or rostral levels (p less than 0.01). Within the dorsal raphe nucleus, neuronal loss was most severe caudally (p less than 0.05). NFTs, but not neuronal loss, were demonstrated within the central superior nucleus. Neuronal and NFT counts did not correlate at individual levels; the relative severity of both pathological processes was consistent from level to level within nuclei but was less consistent between nuclei. Neuronal loss correlated inversely with age, particularly within the locus ceruleus. Duration of disease correlated inversely with counts of NFTs, particularly within the dorsal raphe nucleus, implying a correlation between NFT counts and rate of progression of disease as all but 3 patients had severe dementia. Significantly, patients with AD complicated by major depression had fewer neurons at the mid level of the locus ceruleus and at the rostral level of the central superior nucleus in comparison with nondepressed patients. There was a trend suggesting greater loss of neurons at all levels of the locus ceruleus and dorsal raphe nucleus in depressed individuals.

The basal forebrain-cortex connections of the rat were topographically mapped by retrograde tracer methods; and their contribution to the cholinergic innervation of the cortex was assessed by excitotoxin lesions placed in the rostral and caudal aspects of the complex. Discrete injections of tracer into frontal cortex labeled the prominent multipolar acetylcholinesterase (AchE)-positive cells of the ventromedial globus pallidus. Injections of tracer into the parietal cortex labelled cells in the ventral globus pallidus, the underlying substantia innominata, and the lateral hypothalamus. Separate injections of Fast Blue and Nuclear Yellow in the frontal and in the parietal cortex resulted in double-labeled cells in the ventral globus pallidus, which indicates that at least some of these cells may possess collateralizing axons. The cingulate cortex is innervated predominantly by neurons in the nucleus of the horizontal limb of the diagonal band. The occipital cortex was also shown to receive a projection primarily from the nucleus of the horizontal limb of the diagonal band. The hippocampal formation is innervated primarily by cells located in the vertical limb of the diagonal band and in the medial septum. Consistent with the results of the retrograde tracing studies, excitotoxin lesions affecting the diagonal band and medial septum decreased choline acetyltransferase (CAT) activity up to 40% on the occipital cortex and by 64% in the hippocampus, but did not affect CAT activity in the rostral neocortex. In contrast, ibotenate lesions of the caudal ventral globus pallidus and substantia innominata caused decreases in CAT activity in the frontal cortex of up to 65% without affecting enzyme activity in the hippocampal formation. The results of the present study provide details on the topographic organization of the cortical projections originating in the basal forebrain complex and indicate that these neurons are the predominant source of cortical cholinergic innervation.

We used the anonymous DNA probe, D4S10 (G8), known to be linked to the Huntington's disease (HD) locus, to confirm inheritance at that locus in a family in whom most affected individuals had atypical clinical and pathological features. Their clinical features were similar to the Westphal variant (usually seen in juvenile-onset HD) but they had onset in adult life, and in contrast to juvenile-onset HD, their course of illness was prolonged. Most family members had been repeatedly misdiagnosed during life because of the absence of chorea and prominence of long-tract signs. In 2 patients who died, neuropathological examination at autopsy revealed prominent involvement of brainstem and spinal cord structures, and in 1, mild neostriatal atrophy relative to duration of the disease. The study demonstrates the usefulness of genetic linkage analysis as a diagnostic tool in families with atypical forms of HD. This method allows study of phenotypic variations that can be inherited at or near the HD locus and implies either multiple alleles at the locus gene, modifiers of a single allele, or another locus in the same region causing a dominantly inherited neurodegenerative disease.

This study demonstrated a significant loss of neurons within the lateral part of the pedunculopontine nucleus pars compacta in individuals with idiopathic Parkinson's disease and in individuals with combined Parkinson's and Alzheimer's disease. We also examined the extent of neuronal loss within the substantia nigra pars compacta, locus ceruleus, dorsal raphe nucleus, and nucleus basalis of Meynert. The number of pedunculopontine nucleus pars compacta neurons in the patients with Parkinson's or Parkinson's and Alzheimer's disease was reduced (average, 40%) in comparison with the number in control subjects or patients with Alzheimer's disease (p less than 0.01). This finding correlated significantly with the extent of loss of substantia nigra pars compacta neurons (p less than 0.01).