William G. Honer

Regional synaptic pathology in Alzheimer's disease

Synaptic pathology in Alzheimers disease (AD) may occur diffusely or may have regional predilections. A new antibody called EP10 which detects synaptophysin-like immunoreactivity was used to study synapses in postmortem brain tissue. Four brain regions from cases of AD and controls were studied. Controls with a wide range of ages were used to investigate the possibility of age-related changes in synaptophysin-like immunoreactivity. A significant reduction in the EP10 antigen was observed to occur with age in the control caudate but not in the hippocampus or temporal or occipital cortices. Antigen levels were significantly reduced in the hippocampus (77%) and the temporal cortex (54%) in AD. The expected abnormal pallor of the outer two-thirds of the dentate gyrus molecular layer was observed with immunocytochemistry. In the temporal cortex, the reduction in synaptophysin-like immunoreactivity was inversely correlated with the neurofibrillary tangle count. No such relationship existed in the hippocampus. These results suggest that at least certain components of the synaptic loss in AD occur regionally and are disproportionately large in the hippocampus.

Scopolamine Reduces Frontal Cortex Perfusion

While the cognitive deficits of Alzheimers disease are considered related to a cholinergic deficit, no attempt has yet been made to test the hypothesis that the characteristic regional cerebral blood flow (rCBF) pattern of Alzheimers disease may also relate to such a deficit. We therefore measured rCBF using the [133Xe] inhalation technique in 15 young normal subjects before and after induction of reversible cholinergic blockade with scopolamine at doses of 6.1 and 7.3 μg/kg i.v. Significant cognitive impairment was observed at both doses, while rCBF changes occurred only at the higher dose. Global CBF was significantly reduced 25 min after scopolamine. The pattern of regional change in CBF was not similar to Alzheimers disease. Rather than a focal parietotemporal deficit as seen in Alzheimers disease, we observed a predominantly frontal reduction in flow of about 20%. These results suggest that the frontal but not the parietotemporal deficits seen in several dementing conditions may be related to cholinergic dysfunction.

Characterization of a synaptic antigen of interest in neuropsychiatric illness

Monoclonal antibodies exhibiting relative differences in binding to brain homogenates from diseased versus control brains may be useful probes into the molecular pathology of neuropsychiatric illness. To be of value, the antibodies must be useful in characterization of the antigens putatively involved in the illness. An antibody called EP10 showed some differences in binding to homogenates from a small sample of schizophrenia brains compared with controls. In the present study, the antigen for this antibody was characterized in control brains using quantitative, immunocytochemical, and biochemical techniques. The antigen is a 38,000 dalton synaptic vesicle protein, which is identical to synaptophysin by immunological criteria. However, the EP10 epitope is of interest, as this binding site does not appear to be present in rat or bovine synaptophysin. Brain regional studies using EP10 indicate that the antigen may be present in only a subset of synaptic terminals. Further studies are required to fully characterize the epitope, and to determine the significance of the earlier findings related to schizophrenia.

Monoclonal antibodies to study the brain in schizophrenia.

Twelve monoclonal antibodies were developed which show selective reactivity with brain tissue homogenates from 4 patients with schizophrenia compared to 4 normal controls. Certain antibodies were more reactive with tissue from cases with schizophrenia, others with control tissue. Patterns of reactivity also depended on brain region tested. Differences in reactivity generally ranged from 2- to as much as 8-fold. This panel of monoclonal antibodies may be useful to investigate the pathophysiology of schizophrenia.

Developmental abnormalities and cortical sulcal enlargement in psychosis

Neurodevelopmental abnormalities and cortical sulcal enlargement both occur in schizophrenia. To test the hypothesis that these abnormalities were related, CT scans from 164 psychotic patients (80 with schizophrenia) were reviewed. Neurodevelopmental abnormalities were observed in 11%. Abnormalities were equally prevalent in schizophrenia and other psychotic disorders. Cortical sulcal enlargement was observed in 39% of patients with schizophrenia, and was not associated with developmental abnormalities. Different mechanisms may contribute to distinct structural abnormalities.

PERSONALITY FEATURES AND DISORDER IN THE SUBJECTS IN THE NEW YORK HIGH-RISK PROJECT.

One hundred and seventy-five offspring of parents in two psychiatrically ill groups and of normal controls in the New York High-Risk Project (NYHRP) were assessed for Axis II personality traits and disorders as defined by the Diagnostic and Statistical Manual of Mental Disorders, Third Edition, Revised (DSM-III-R). These offspring include: subjects at high risk for schizophrenia (HRSz, n = 48), all of whom have a parent with schizophrenic disorder; subjects at high risk for affective disorder (HRAff, n = 40), all of whom have a parent with affective disorder; and subjects at no increased risk for psychiatric illness (NC, n = 87), whose parents are psychiatrically normal. The trained interviewers, who administered a standardized direct interview, were blind to parental clinical status and to previous clinical status of the offspring.The rates for any personality disorder (PD) ranged from 7% to 20%. Comorbidity between Axis I and Axis II disorders was high for all groups.

A genotype-phenotype research strategy for schizophrenia

A research strategy which integrates known biological aspects of schizophrenia is proposed. The strategy includes genotype and phenotype components and emphasizes interactions. Its central feature is the comprehensive diagnostic assessment of patients with schizophrenia. Clinical and laboratory based methodologies are applied within the genotype and phenotype components of the strategy. Examples of research from each area and the potential interactions with other aspects of the strategy are presented. The expectation is that a greater understanding of the pathophysiology of schizophrenia will result from the application of the genotype-phenotype strategy and that consequently more efficacious treatments will ultimately be developed.

Organic affective disorder and vascular dysregulation in systemic lupus erythematosus.

A case is reported in which an exacerbation of systemic lupus erythematosus presented as an organic depressive disorder with psychotic features. Brain imaging using regional cerebral blood flow techniques demonstrated vascular dysregulation in the left frontal lobe of this patient. The implications for understanding the pathogenesis of psychiatric disorders in lupus are discussed.