John Moossy

The Consortium to Establish a Registry for Alzheimer's Disease (CERAD). Part II. Standardization of the neuropathologic assessment of Alzheimer's disease

The Neuropathology Task Force of the Consortium to Establish a Registry for Alzheimers Disease (CERAD) has developed a practical and standardized neuropathology protocol for the postmortem assessment of dementia and control subjects. The protocol provides neuropathologic definitions of such terms as “definite Alzheimers disease” (AD), “probable AD,” “possible AD,” and “normal brain” to indicate levels of diagnostic certainty, reduce subjective interpretation, and assure common language. To pretest the protocol, neuropathologists from 15 participating centers entered information on autopsy brains from 142 demented patients clinically diagnosed as probable AD and on eight nondemented patients. Eighty-four percent of the dementia cases fulfilled CERAD neuropathologic criteria for definite AD. As increasingly large numbers of prospectively studied dementia and control subjects are autopsied, the CERAD neuropathology protocol will help to refine diagnostic criteria, assess overlapping pathology, and lead to a better understanding of early subclinical changes of AD and normal aging.

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.

Thiopental Amelioration of Brain Damage after Global Ischemia in Monkeys

The authors studied the effect of thiopental in ameliorating permanent brain damage in monkeys after 16 min of global ischemia of the brain produced by a high-pressure neck tourniquet and systemic arterial hypotension. Intensive care and life support, including monitoring of physiologic variables, w

N‐acetyl‐L‐aspartate and other amino acid metabolites in Alzheimer's disease brain: A preliminary proton nuclear magnetic resonance study

We used proton nuclear magnetic resonance spectroscopy in this preliminary study of perchloric acid extracts of 12 Alzheimers disease (AD) and five control brain samples to measure the relative levels of taurine, aspartate, glutamine, glutamate, γ-aminobutyric acid (GABA), and the putative neuronal marker, N-acetyl-L-aspartate (NAA). We found no significant changes in taurine, aspartate, or glutamine. NAA was lower in AD compared with control, and this decrease correlated with the number of senile plaques and neurofibrillary tangles in adjacent tissue sections. GABA levels also were lower in AD brain. Glutamate levels were greater in AD than control and showed a close, inverse correlation with NAA levels. These findings suggest that the decrease in NAA reflects neuronal loss and that remaining neurons could be exposed to a relative excess of glutamate and a relative lack of GABA. If present in the neurotransmitter pool, this imbalance could result in neurotoxic cell damage. This hypothesis is further supported by in vitro and in vivo phosphorus 31 nuclear magnetic resonance findings.

Amelioration of brain damage by lidoflazine after prolonged ventricular fibrillation cardiac arrest in dogs

Calcium entry blockers can ameliorate postischemic cerebral hypoperfusion, protect the myocardium against ischemia, and may protect against early postischemic neurologic deficit. This study documents that a calcium entry blocker, given after cardiac arrest, can ameliorate late postischemic neurologic deficit (ND). Thirty-four dogs received 10 min of ventricular fibrillation, restoration of spontaneous circulation by external cardiopulmonary resuscitation, and standard postarrest intensive care. Eleven of these dogs were given lidoflazine, 1 mg/kg body weight, within 10 min postarrest and again at 8 h and 16 h. Pupillary light reflexes, EEG activity, arterial-cerebrovenous oxygen gradients (O2 demand/supply ratios) and intracranial pressure were the same in both groups. After weaning from controlled ventilation at 24 h, ND scores improved consistently through the 96-h observation period in the lidoflazine-treated dogs. In the control group, ND scores were significantly higher than in the lidoflazine-treated dogs. In the lidoflazine-treated group, 5/11 dogs achieved normal overall performance and none remained comatose, whereas all control dogs had some deficit and 4/11 remained comatose. Delayed neurologic deterioration occurred in 6/ 11 control and 0/11 lidoflazine-treated dogs. Total mean cerebral histopathologic damage (HD) scores at 96 h were not significantly different between the two groups; however, individual HD scores and maximum cerebrospinal fluid (brain-specific) creatine-phosphokinase activity—which increases after brain insults—correlated well with 96-h ND scores. In the lidoflazine group, life-threatening dysrhythmias were less frequent and the norepinephrine requirement for blood pressure maintenance was the same as in the control group. Cardiac output remained at prearrest levels in the lidoflazinetreated dogs, but decreased in the control group, particularly during the first 4 h postarrest.

Global brain ischemia: a reproducible monkey model.

We developed a monkey model of 16 minutes global brain ischemia (GBI) resulting in reproducible, severe, permanent functional neurologic deficit with long term (7 days) postischemic (PI) survival made possible by standardized intensive care with 24 hour coverage by trained personnel. Quantitated neurologic deficit (ND) and brain histopathological examinations were developed. Fifteen minutes GBI resulted in rapid recovery within12--24 hours PI without residual neurologic sequelae. Twenty minutes GBI caused severe neurologic deficit and within 4 days PI, a delayed Cushing response eventually leading to cardiac arrest. Sixteen minutes GBI resulted in severe neurologic deficit (monkeys unable to sit, stand, walk, or feed themselves), but with long term survival. Brain histopathological analyses revealed a combination of cortical and brainstem lesions. Severest changes were observed in the occipital (calcarine) cortex with less severe damage in the frontal and temporal regions. Oculomotor nuclei and medial longitudinal fasciculus in the midbrain were regularly affected. With this model we can test the efficacy of promising therapies in terms of clinically relevant variables.

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

The histopathological hallmarks of Alzheimers disease have long been considered to be neurofibrillary tangles (NFT) and neuritic (senile) plaques (SP). Neither of these structures, however, are unique to Alzheimers 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 Alzheimers brain compared to non-Alzheimers 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.

Diagnosis of dementia: Clinicopathologic correlations

Based on 54 demented patients consecutively autopsied at the University of Pittsburgh, we studied the accuracy of clinicians in predicting the pathologic diagnosis. Thirty-nine patients (72.2%) had Alzheimers disease, while 15 (27.7%) had other CNS diseases (four multi-infarct dementia; three Creutzfeldt-Jakob disease; two thalamic and subcortical gliosis; three Parkinsons disease; one progressive supranuclear palsy; one Huntingtons disease; and one unclassified). Two neurologists independently reviewed the clinical records of each patient without knowledge of the patients identity or clinical or pathologic diagnoses; each clinician reached a clinical diagnosis based on criteria derived from those of the NINCDS/ADRDA. In 34 (63%) cases both clinicians were correct, in nine (17%) one was correct, and in 11 (20%) neither was correct. These results show that in patients with a clinical diagnosis of dementia, the etiology cannot be accurately predicted during life.

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 kernicteurs: 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.

The dissolution of language in Pick's disease with neurofibrillary tangles: A case study

This paper is a detailed retrospective history of a patient who began to have difficulty with speaking and comprehension in 1967, and whose neuropathological examination at time of death 12 1/2 years later was consistent with a diagnosis of Picks disease, complicated by neurofibrillary tangles. It follows the deteriorating course of his language abilities in the context of relatively less-impaired general cognitive abilities, using two sources of information. The first is his own written record of his deteriorating abilities, shown in letters and notes he wrote over this period. The second is through an oral history obtained from the patients family. The purpose of this report is to illustrate in detail the course of a degenerative condition and to suggest the utility of such descriptional records in increasing understanding of language deterioration in dementia.