The neuropathology of kernicterus in the premature neonate: diagnostic problems.

Yellow staining of central nervous system (CNS) nuclei occurs in the brains of some neonates, despite low levels of serum bilirubin. Two conditions appear to be important in the evolution of this form of kernicterus: prematurity and asphyxia. In a seven year retrospective study of a large neonatal autopsy population, 102 cases had kernicterus as indicated by selective macroscopic yellow staining and microscopic damage within specific CNS nuclei. Neuropathological study disclosed minor variations and numerous similarities in the manifestations of kernicterus in the asphyctic premature neonate with low levels of serum bilirubin, as compared to kernicterus in the full-term neonate with high levels of serum bilirubin. Acidosis, hypoxia, hyperoxia, hypothermia and sepsis have been considered significant risk factors, but recent comparative clinical studies have not defined predictive indices. Analysis of this disorder is difficult because of the concurrence of other complications of asphyxia and its pathological correlates in premature infants. Diagnostic difficulties are also compounded by variations in the definitions of kernicterus as used by different investigators.

31P nuclear magnetic resonance study of the brain in Alzheimer's disease.

The histopathological hallmarks of Alzheimer's disease have long been considered to be neurofibrillary tangles (NFT) and neuritic (senile) plaques (SP). Neither of these structures, however, are unique to Alzheimer's disease, and both probably represent end-stage markers of the disorder. NFT have been demonstrated in many disorders; SP occur in small numbers with normal aging. Evidence is presented for elevation of phosphomonoesters (PME) in Alzheimer's brain compared to non-Alzheimer's diseased controls and normal controls. The PME detected by 31P nuclear magnetic resonance (NMR) spectroscopy of autopsy brain are predominantly anabolic precursors of membrane phospholipids. Elevated PME could be secondary to a metabolic block at the rate-limiting enzyme in membrane phospholipid synthesis, which is cytidine triphosphate (CTP): phosphocholine (or phosphoethanolamine) cytidyltransferase (EC 2.7.7.15). Elevated PME could also be secondary to decreased breakdown of PME by phospholipase D activity. Since CTP: phosphocholine cytidyltransferase is inactivated by phosphorylation and since there is independent evidence for hyperphosphorylation of tau and MAP-2 proteins in AD brain, enhanced protein kinase activity could be a common factor. Preliminary evidence suggests that PME could interact with N-methyl-D-aspartate receptors and potentially act as false neurotransmitters. Further studies will be needed to investigate these possibilities.

Amplification of epidermal growth factor receptor gene in gliomas: histopathology and prognosis.

In order to evaluate the incidence and prognostic significance of gene amplification in primary brain neoplasms we measured the number of gene copies per cell of three oncogenes (epidermal growth factor receptor [EGFR] gene, N-myc, C-myc) and syntenic control genes in 40 specimens using quantitative DNA dot blots. We observed EGFR gene amplification in astrocytomas and anaplastic astrocytomas with approximately the same incidence as in glioblastoma multiforme (33%), although large amplifications were only seen in glioblastoma multiforme. Fourteen patients had a supratentorial glioblastoma multiforme; six had EGFR gene amplification and eight had either normal EGFR gene copy number or elevated EGFR copy number attributable to extra copies of chromosome 7. Patients with gene amplification had shorter survival than patients without gene amplification (p = 0.01). The observed difference in survival was not likely to be due to group differences in age, sex, treatment, or histopathology.

Hydrocephalus in weanling mice induced by a temperature-sensitive mutant of vesicular stomatitis virus.

Hydrocephalus developed in weanling Swiss-Webster mice after intracerebral (IC) inoculation of a naturally selected temperature-sensitive (ts) mutant of vesicular stomatitis virus (VSV). This spontaneous ts mutant was isolated from a persistent infection (pi) of mouse L cells with VSV, and named VSV-tspi 364 (complementation Group I). High doses of the mutant virus induced hydrocephalus in 87% of the mice. Infected mice were clinically asymptomatic, except for a few with transient hind-limb paralysis and proximal muscle weakness. After inoculation, mice were killed every other day for the first two weeks, and weekly thereafter for two months. Virological studies showed replication in the brain in the first nine days post-inoculation (DPI). Neutralizing antibody titers increased rapidly after 15 DPI, and elevated titers were measured at 30 DPI. Pathologically, there was patchy ependymal cell necrosis in the aqueduct and lateral ventricles, as early as the second DPI. Mild meningoencephalitis and severe ependymal cell necrosis with focal aqueductal stenosis were present iun the first two weeks of infection. Hydrocephalus began as early as 10 DPI and became severe at 28 DPI. This represents the first animal model for hydrocephalus following IC inoculation of a spontaneous ts mutant of a rhabdovirus. In our study, inoculation of mice with wild-type VSV and with other spontaneous and chemical ts mutants of VSV IC as well as with tspi 364 by other routes did not cause hydrocephalus.

Hyperoxia produces neuronal necrosis in the rat.

Widespread cerebral neuronal necrosis occurred in newborn Sprague-Dawley rats submitted to three hours of pure oxygen (100% O2) at normal atmospheric pressure. Neuronal necrosis (NN) was most severe in the immediate newborn period and less marked with advanced maturation. It was minimal and different in its morphological characteristics in rats 10, 15 and 20 days old, and in adults breathing pure oxygen at normal atmospheric pressure for three hours. In the newborn rat, hyperoxemic NN was different in topography and cytopathology from that induced by hypoxia in the same animals. Hyperoxemic NN was similar to the NN described in human premature infants submitted to episodic hyperoxemia. Neuronal damage with karyorrhexis was most prominent in the subiculum of the hippocampus, thalamus, reticular nuclei of the brain stem and the granular cells of the cerebellum. Ultrastructural studies demonstrated nuclear and cytoplasmic membrane damage in neurons and the cellular accumulation of electron-dense lipid droplets. The pathogenesis of NN produced by hyperoxia in the human premature newborn infant may be related to lipid peroxidation of cell membranes such as that induced by oxygen-free radicals in other experimental and in vitro studies, when the anti-oxidant cellular defenses (mainly enzymes such as superoxide dismutase) are overwhelmed.

Brain regional analysis of NADH-cytochrome C reductase activity in Alzheimer's disease.

The specific activity of antimycin A-insensitive nicotinamide adenine dinucleotide (NADH)-dependent cytochrome C reductase, an enzyme associated with endoplasmic reticulum, was determined in the superior temporal, entorhinal, and cerebellar cortex of 16 patients who died with Alzheimer's disease and eight nondemented controls. The specific activity of choline acetyltransferase was also measured to provide an index of presynaptic cholinergic dysfunction. Our results revealed reciprocal changes in these activities that were of similar magnitude across the three regions examined. Furthermore, cytochrome C reductase activity was positively correlated with the density of neurofibrillary tangles, especially in the superior temporal cortex. These results support the hypothesis that Alzheimer's disease may be associated with an alteration of endoplasmic reticulum and the functions related to this intracellular membrane system, including the post-translational modification and localization of essential proteins.

Further studies on the effects of lesions in the rostral hypothalamus on gonadotropin secretion in the female rhesus monkey (Macaca mulatta).

Bilateral radiofrequency lesions were stereotaxically placed in the rostral hypothalamus of four adult female rhesus monkeys. These lesions resulted in extensive destruction of the ventromedial preoptic-anterior hypothalamic area (POA-AHA) and included the suprachiasmatic nucleus as well as, with the exception of one animal, the organum vasculosum of the lamina terminalis. In three of these four animals, gonadotropin surges similar to those observed before surgery were elicited in response to either a spontaneous increment in serum estrogen concentration or an estradiol benzoate injection. This stimulatory action of estradiol on LH and FSH release was not demonstratable in the remaining lesioned animal, but estradiol benzoate injections also failed to elicit a gonadotropin discharge in one of a series of five normal control animals. These findings fail to support the view that destruction of the ventromedial POA-AHA in this species compromises the ability of the hypothalamicohypophysial apparatus to respond to the positive feedback action of estradiol. The diurnal variation in serum cortisol concentration was not interrupted by placement of the lesions in the ventromedial POA-AHA.

The arcuate nucleus and the control of gonadotropin and prolactin secretion in the female rhesus monkey (Macaca mulatta).

Attempts were made to destroy selectively the arcuate nucleus with radiofrequency current in adult female rhesus monkeys as a first step in identifying the areas of the mediobasal hypothalamus (MBH) that are responsible for the neural control of gonadotropin secretion in this species. Extensive or complete destruction of the arcuate region was produced in three animals and in two of these the lesion was confined primarily to the arcuate region and the dorsal aspect of the posterior median eminence. These lesions resulted in the cessation of LH and FSH secretion and blocked the positive feedback action of estradiol on gonadotropin release but did not appear to influence grossly basal thyroid and adrenocortical function, or to abolish GH discharge in response to insulin hypoglycemia. Adenohypophysial infarcts were not observed and exogenous LHRH and TRH induced marked discharges of the appropriate anterior pituitary hormones. In two additional animals with large hypothalamic lesions, destruction of the arcuate region was incomplete. In this group only partial inhibition of gonadotropin secretion was observed. LH and FSH secretion did not appear to be influenced in one animal bearing a large MBH lesion that entirely spared the arcuate region. Although serum prolactin remained at pre-lesion control levels after placement of the two relatively discrete lesions confined to the arcuate region, unambiguous increases in the secretion of this hormone were observed when the area of destruction encompassed tissue anterior and/or dorsal to the arcuate region. These observations suggest that the arcuate region is the primary structure mediating the hypothalamic control of gonadotropin secretion in the rhesus monkey. They also suggest that, in this species, the regions of the MBH involved with the regulation of gonadotropin release and those which control prolactin secretion are anatomically distinct.

Estrogen-induced gonadotropin surges in decerebrated female rhesus monkeys with medial basal hypothalamic peninsulae.

Hypothalamic peninsulae, posteriorly continuous with the brain stem, were produced in ovariectomized rhesus monkeys by aspiration of the cerebral hemispheres and all brain structures anterior and dorsal to the optic chiasm. These preparations were sustained for 52 to 60 h postoperatively by maintaining blood gases and pH within physiological limits and by supporting arterial blood pressure, when necessary, with infusions of rhesus monkey blood and norepinephrine. The sc injection of estradiol benzoate (EB) to such animals upon completion of the ablation procedure was followed 18-24 h later by unambiguous surges of serum LH and FSH with durations in the excess of 24 h. These findings are consonant with the view that the central components of the control system that initiates the preovulatory gonadotropin surge in the rhesus monkey are resident within the medial basal hypothalamic-hypophysial apparatus.

Brain enzyme levels in CSF after cardiac arrest and resuscitation in dogs: markers of damage and predictors of outcome.

Levels of brain creatine kinase (CK), aspartate aminotransferase (ASAT), and lactate dehydrogenase (LD) in CSF after cardiac arrest were studied in dog models. Ventricular fibrillation cardiac arrest lasting 10 min or asphyxiation cardiac arrest lasting 0-10 min was followed by cardiopulmonary resuscitation and 96-h intensive care. Outcome was scored as neurologic deficit (0% = normal, 100% = brain death) and overall performance category (1 = normal, 5 = death). Both measures correlated with EEG return time after asphyxiation cardiac arrest, but not after ventricular fibrillation cardiac arrest. Peak activity of enzymes in CSF at 48-72 h post arrest correlated with outcome, and CK was the best predictor. Brain histopathologic damage score at autopsy 96 h post arrest correlated with CK level in CSF (r = 0.79, n = 39) and neurologic deficit (r = 0.70, n = 50). Ischemic neuronal changes occurred after ventricular fibrillation cardiac arrest of 10 min, and neuronal changes plus microinfarcts occurred after asphyxiation cardiac arrest of 1.5-10 min. Brain enzymes were decreased at 6 h post arrest in regions with worst histologic damage (gray matter of neocortex, hippocampus, caudate nucleus, cerebellum). Brain CK decreased further, ASAT remained low, and LD increased at 72 h after arrest. The temporal changes in CK level paralleled the temporal ischemic neuronal changes in the brain, and time to peak activity was unaffected by the severity of the ischemic insult. Peak activity of individual enzymes in CSF was determined predominantly by the brain concentration, but was also influenced by rate of decomposition. This "chemical brain biopsy method" represents a useful adjunctive tool to predict permanent, severe brain damage during comatose states after cardiac arrest and resuscitation.

Prospective study of increased platelet membrane fluidity as a risk factor for Alzheimer's disease: results at 5 years.

OBJECTIVE: The primary goal of this study was to evaluate increased platelet membrane fluidity as a putative risk factor for Alzheimer's disease. METHOD: This report describes the initial results of a prospective, longitudinal study of 330 initially asymptomatic, first-degree relatives of probands with Alzheimer's disease. RESULTS: Five incident cases of Alzheimer's disease were detected during the first 1,582 subject-years of the follow-up period. The age-specific incidence of Alzheimer's disease was several-fold higher than corresponding figures that were obtained in two prospective community studies. Most important, both age and increased platelet membrane fluidity made significant independent contributions to the risk of developing Alzheimer's disease. CONCLUSIONS: These results validate age and a family history of Alzheimer's disease as risk factors for this disorder and provide the first prospective evidence of increased platelet membrane fluidity as a biological risk factor for Alzheimer's disease.

Major depression in primary dementia. Clinical and neuropathologic correlates.

Cytopathologic features were quantified in seven brain regions in the brains of 37 demented patients, with or without major depression, and in those of seven controls with no history of dementia or depression. The middle frontal and superior temporal cortex, prosubiculum and entorhinal cortex of the hippocampus, nucleus basalis of Meynert, locus ceruleus, and substantia nigra were the areas evaluated. Patients with major depression had significantly more degenerative findings in the locus ceruleus and substantia nigra than demented patients who were not depressed. In contrast, these groups were similar with respect to other clinical features and indexes of global severity of dementia. A logistic regression model that included the degenerative features of both the locus ceruleus and the substantia nigra was significantly better at predicting the presence of major depression than those employing the characteristics of either pigmented nucleus alone. Our results indicate that the development of major depression in patients with primary dementia is associated with the degeneration of the locus ceruleus and substantia nigra.

Neurochemical correlates of major depression in primary dementia.

Biogenic amine neurotransmitters and metabolites as well as choline acetyltransferase activity were quantified in eight brain regions from 37 demented patients, with or without major depression, and 10 controls with no history of dementia or depression. The middle frontal and temporal cortex, prosubiculum and entorhinal cortex of the hippocampus, substantia nigra, thalamus, amygdala, and caudate were examined. Demented patients with major depression exhibited a 10-fold to 20-fold reduction in the level of norepinephrine in the cortex, along with relative preservation of choline acetyltransferase activity in subcortical regions, compared with demented patients who were not depressed. Serotonin levels were reduced in all eight brain regions, but the reduction did not reach statistical significance in any region examined. A para-doxical increase in dopamine levels was observed in the entorhinal cortex of depressed, demented patients, although no consistent pattern of change in the level of this neurotransmitter emerged across brain regions. Our results indicate that the development of major depression in primary dementia is associated with a profile of concurrent neurochemical changes that is largely consistent with existing neurochemical hypotheses of idiopathic affective disorders, and qualitatively distinct from that associated with primary dementia.

Bilateral symmetry of morphologic lesions in Alzheimer's disease.

We studied 16 brains of patients with Alzheimer's disease for left-right differences, or similarities, in the density of senile plaques (SPs) or neurofibrillary tangles (NFTs). Counts were made of SPs and NFTs on the left and right side of five different brain areas, which included middle frontal, superior temporal, the prosubiculum of the hippocampus (HPR), the entorhinal cortex of the hippocampus (HEN), and the basal nucleus of Meynert. The density of SPs was bilaterally symmetrical in all regions except the basal nucleus of Meynert in which technical problems may have occurred in sampling. In contrast to SPs, the density of NFTs was bilaterally symmetrical in both neocortical regions (middle frontal, superior temporal), but not in either hippocampal region (HPR, HEN). The absence of bilateral symmetry for the density of NFTs in the hippocampus, where the density of SPs was highly symmetrical, suggests that there may be a different pathogenesis for these lesions in Alzheimer's disease. The lack of a significant correlation between SP and NFT density within four of five regions, including HPR and HEN, also supports this suggestion.

Correlative angiographic and pathologic findings in the diagnosis of ulcerated plaques in the carotid artery.

We determined the accuracy of angiography in the diagnosis of internal carotid ulcers by comparing the angiographic reports with the pathologic findings in 36 endarterectomy specimens. Eighteen of these specimens had microscopic ulcerations, and the observer with the highest accuracy rate read 12, of which ten were ulcerated. These results revealed a sensitivity of 56%, a specificity of 89%, and an overall accuracy of 61% for angiography. The ulcers were classified into types A, B, and C to assess the interobserver agreement rate among three readers. This resulted in a 4% interobserver agreement among a total of 75 ulcers. Because of the high interobserver disagreement and the poor correlation between angiographic and pathologic findings in the surgical specimens, we conclude that the diagnosis of carotid artery ulceration by angiography is not reliable.

Thalamic and subcortical gliosis with dementia.

We describe two cases of patients with "primary dementia" in whom autopsy showed marked astrocytosis in several subcortical nuclei, but chiefly in those of the thalamus. One patient had the onset of symptoms at 31 years of age and a subacute course. The second patient was an elderly man with a strong familial history of dementia. These cases offer further evidence that subcortical lesions, especially in the thalamus, may produce a dementia that is not always clinically distinguishable from Alzheimer's disease and other "cortical" dementias.

Bilateral symmetry of cholinergic deficits in Alzheimer's disease.

The specific activities of the cholinergic enzymes, choline acetyltransferase and acetylcholinesterase, as well as the density of muscarinic binding sites, were determined in five corresponding left and right regions of 16 brains obtained at autopsy from patients with histologically confirmed Alzheimer's disease. While a significant proportion of the individual specimens exhibited left-right asymmetries in cholinergic deficits, bilateral symmetry was the rule for frontal and temporal cortex, basal nucleus, and the prosubiculum of the hippocampus. In contrast to these four regions, left-right asymmetries in choline acetyltransferase activity and muscarinic receptor density appeared to be typical in the entorhinal cortex of the hippocampus.

Neuropathologic and neurochemical correlates of psychosis in primary dementia.

Neuropathologic and neurochemical correlates of psychosis were determined using brain tissue from 27 autopsy-confirmed cases of Alzheimer's disease. The densities of senile plaques and neurofibrillary tangles were determined in the middle frontal and superior temporal cortex, the prosubiculum, and the entorhinal cortex of the hippocampus. The concentrations of norepinephrine, dopamine, and serotonin, the metabolites of these biogenic amines, and the specific activity of choline acetyltransferase were also determined in these four cortical regions as well as in the substantia nigra, thalamus, amygdala, and caudate nucleus. Psychosis was associated with significantly increased densities of senile plaques and neurofibrillary tangles in the prosubiculum and middle frontal cortex, respectively, with trends toward increased densities of these lesions in the other areas examined. This finding is consistent with the increased rate of cognitive decline that accompanies this behavioral disorder. Psychosis was also associated with the relative preservation of norepinephrine in the substantia nigra, with trends in this direction for five of the remaining seven brain regions examined, and a significant reduction of serotonin in the prosubiculum that was accompanied by trends toward reduced levels of serotonin and 5 hydroxyindoleacetic acid in the remaining regions. The profile of neuropathologic and neurochemical changes associated with psychosis is distinct from that previously reported for major depression in the context of primary dementia.

Lateralization of brain morphologic and cholinergic abnormalities in Alzheimer's disease.

The extent of left-right asymmetry in the densities of senile plaques and neurofibrillary tangles and the levels of the cholinergic enzymes choline acetyltransferase and acetylcholinesterase were quantified in the middle frontal and superior temporal cerebral cortex, entorhinal cortex, and prosubiculum of the hippocampus from 21 patients who died with Alzheimer's disease. Morphologic lesions were more asymmetrically distributed than deficits in the cholinergic enzymes. Neither cerebral hemisphere showed consistently higher densities of senile plaques and neurofibrillary tangles, or lower levels of choline acetyltransferase and acetylcholinesterase. Deficits in the cholinergic enzymes tended to colateralize, while asymmetries of senile plaques and neurofibrillary tangles did not. Finally, left-right asymmetry in the density of senile plaques diminished with increasing neuropathologic severity, while similar evidence for diminishing left-right asymmetry of neurofibrillary tangle density or cholinergic enzyme activity with increasing severity was not found.

A brain regional analysis of morphologic and cholinergic abnormalities in Alzheimer's disease.

In the brains of 21 patients with Alzheimer's disease (AD) and 10 nondemented controls, senile plaques (SPs), neurofibrillary tangles (NFTs), and three indexes of cholinergic function were quantified in the middle frontal (MF) and superior temporal (ST) cortex, the entorhinal cortex (HEN), and the prosubiculum (HPR) of the hippocampus. Control brains contained few SPs without preferential distribution in any of the brain regions examined, while NFTs were found almost exclusively in the HPR. In brains from patients with AD, an inverse relationship of SPs and NFTs was found in the brain regions examined; SPs were preferentially in the neocortex and NFTs preferentially in the hippocampus. The specific activities of choline acetyltransferase and acetylcholinesterase were reduced in all regions examined, while no significant change in the density of muscarinic binding sites was observed in any region. Numerous NFTs were associated with an earlier age at onset, while the presence of SPs was related to the cholinergic deficit in AD. Earlier-onset (less than 67 years) AD was also associated with a qualitative difference in the regional distribution of NFTs compared with cases with a later onset. In the latter group, most NFTs were observed in the hippocampus, a distribution pattern similar to that observed with normal aging. In AD cases with an earlier onset, NFTs were more globally distributed in the neocortex and allocortex.