K.L. Davis

Dissociation of neuropathology from severity of dementia in late-onset Alzheimer disease

Background: Little is known about Alzheimer disease at advanced ages, although its incidence continues to increase at least through the ninth decade of life. Objective: To examine the effects of age on the relationship between clinical dementia severity and neuropathologic hallmarks in a large sample spanning the full age range. Methods: The authors assessed 81 subjects during life for dementia severity, and examined their brains. They analyzed plaque and tangle burden, as well as the activities of the cholinergic marker enzymes acetylcholinesterase (AChE) and choline acetyltransferase (ChAT), in relation to age at death and the clinical severity of dementia. Results: Dementia severity was strongly related to plaque and tangle burden in relatively young patients (aged <75 years), but this correlation diminished with age and disappeared in the ninth decade of life. Among the oldest patients studied, there was no difference in plaque and tangle load between the mild and severe dementia cases. This interaction (p < 0.0001 for plaque density) was not observed for the cholinergic markers ChAT and AChE. Conclusion: The nature or expression of Alzheimer disease may be different in severely demented older patients, who have equal cholinergic deficits but significantly lower plaque and tangle burden. If confirmed in a prospective study, these findings have diagnostic and therapeutic implications.

Variations in differential gene expression patterns across multiple brain regions in schizophrenia.

Large-scale gene expression studies in schizophrenia (SZ) have generally focused on the dorsolateral prefrontal cortex. Despite a wealth of evidence implicating multiple other brain regions in the disease, studies of other brain regions have been less frequent and have rarely been performed in the same subjects. We analyzed postmortem gene expression in the frontal, cingulate, temporal, parietal and occipital cortices (Brodmann areas 8, 10, 44, 46, 23/31, 24/32, 20, 21, 22, 36/28, 7 and 17, respectively) as well as in the hippocampus, caudate nucleus and putamen of persons with schizophrenia and control subjects (Ns = 13) using Affymetrix GeneChip microarrays. Under identical data filtering conditions, the superior temporal cortex (BA22) of schizophrenia subjects showed the maximal number of altered transcripts (approximately 1200) compared to controls. Anterior and posterior cingulate cortices (BA23/31, 24/32) and the hippocampus followed the superior temporal cortex with two-times lower numbers of altered transcripts. The dorsolateral prefrontal cortex (BA46), a frequent target of SZ-associated studies, showed substantially fewer altered transcripts (approximately 33). These regional differences in differentially expressed genes could not be accounted for by factors such as total numbers of genes expressed or the filtering conditions and criteria used for identification of differentially expressed genes. These findings suggest that the temporal and cingulate cortices and the hippocampal formation represent brain regions of particular abnormality in SZ and may be more susceptible to the disease process(es) than other regions thus far studied.

Cortical cholinergic markers in schizophrenia

Cortical cholinergic deficits have been implicated in the cognitive deficits produced by a variety of neurodegenerative diseases including Alzheimers disease (AD). Recent studies have suggested that many of the chronically institutionalized geriatric schizophrenic patients are also cognitively impaired. In this postmortem study we compared cholinergic marker activity in six different cortical regions derived from elderly controls, chronically institutionalized geriatric schizophrenic patients, and AD patients. All of the Alzheimers disease cases met neuropathological criteria for AD, while none of the schizophrenic cases met criteria for AD. Cholinergic marker activity (choline acetyltransferase and acetylcholinesterase) was significantly diminished in the AD cohort but not in the schizophrenic cohort. Additionally, cortical choline acetyltransferase activity was significantly and negatively correlated with Clinical Dementia Rating scores (CDR), whereas no such correlations were evident in the schizophrenic cohort. These results suggest that cognitive deficits in geriatric schizophrenics are not due to diminished cortical cholinergic activity.

Attenuation of nucleus basalis of Meynert lesion-induced cholinergic deficits by nerve growth factor

Nerve growth factor (NGF) was administered into either the lateral ventricle or into the basal forebrain of n. basalis of Meynert (nbM) lesioned rats. Rats received either continuous infusion of 5 micrograms of 7S NGF per day for 28 days, or 5 micrograms of 7S NGF on 4 occasions distributed evenly during the first two post-lesion weeks. The administration of NGF reduced lesion-induced cortical cholinergic marker deficits by approximately 50%, irrespective of the locus or mode of NGF administration. Thus NGF is able to attenuate lesion-induced cholinergic deficits across a range of treatment and lesion conditions.

Interactions of forebrain cholinergic and somatostinergic systems in the rat

The neurochemical, behavioral and pharmacological effects of forebrain cholinergic and somatostatinergic deficits were assessed in adult rats. Brain somatostatinergic activity was manipulated by the systemic administration of different doses of cysteamine. Forebrain cholinergic systems were lesioned by the infusion of ibotenic acid into the nucleus basalis of Meynert (nbM). Forebrain cholinergic lesions did not affect forebrain somatostatin-like-immunoreactivity (SLI). Depletion of forebrain SLI by cysteamine did not significantly affect forebrain cholinergic marker activity. The combination of forebrain cholinergic deficits with forebrain somatostatinergic deficits did not lead to any greater impairment of mnemonic function than that produced by lesions alone, nor did SLI deficits hamper the efficacy of physostigmine to enhance memory in sham operated or nbM-lesioned rats. These results suggest that although forebrain cholinergic and somatostatinergic systems do interact at some levels, this interaction is a minor one with respect to neurochemical, behavioral or pharmacological variables.

Kraepelinian schizophrenia: A replication in an independent sample

Chronic, unremitting schizophrenic patients, who for the past 5 years had been either continuously hospitalized or completely dependent on others for their survival are designated Kraepelinians according to Emil Kraepelin’s description of dementia praecox. Previous studies from our center have demonstrated that Kraepelinian patients more consistently received a diagnosis of schizophrenia across a variety of cross-sectional and longitudinal diagnostic criteria and had more severe negative symptoms and formal thought disorder compared to a group of age-matched non-Kraepelinian chronic schizophrenic patients. In addition, Kraepelinian schizophrenics had a greater morbid risk for schizophrenia spectrum disorders in their first-degree relatives, had a greater left-to-right asymmetry of their lateral cerebral ventricles, and had less of a prospective response to a standard dose of haloperidol. On the other hand, the severity of positive symptoms did not distinguish Kraepelinian schizophrenics from other chronic schizophrenic patients. This study presents data on a completely independent sample of 22 Kraepelinian and 86 non-Kraepelinian schizophrenic patients. Initial data analyses suggest a replication of the findings reported on the original cohort. Kraepelinian patients had more severe negative symptoms (p < 0.002) and formal thought disorder (p c 0.001) than non-Kraepelinian chronic schizophrenic patients. The first degree relatives of Kraepelinian patients had a greater morbid risk for schizophrenia spectrum disorders than the relatives of other chronic schizophrenic patients (z = 3.3 1, p < 0.001). CT ventricular measures indicated a left frontal horn enlargement in Kraepelinian patients relative to nonKraepelinians (p < 0.05). These analyses provide independent confirmation that Kraepelinian schizophrenic patients, who require institutionalization or institution-like care, differ from other schizophrenic patients on measures of clinical presentation and family history, suggesting that these patients are a relatively homogenous subgroup of schizophrenics with very severe symptoms and uniformly poor outcomes.

108. Neurocognitive predictors of functional decline in poor-outcome schizophrenia

Although cognitive abilities have been shown to be directly related to social, occupational, and adaptive functioning in patients with schizophrenia, there is no evidence indicating that a specific neuropsychological index can predict decline in functional status. Impairments in verbal learning and memory, verbal skills, and executive functions correlate with functional impairments, and are predictive of functional ability over time. Yet, there is no evidence that impairment on a specific neurocognitive index is associated with functional decline, or whether these measures are all associated with functional impairments due to a global or specific cognitive deficit. In order to test whether any of these neuropsychological measures (Verbal Learning and Memory, Praxis, and Confrontational Naming) is most associated with functional decline, 68 subjects were chosen from a long-term study of the effects of aging in schizophrenia. Subjects were chosen specifically because they declined functionally from a mildly impaired level of functioning to a moderate or severely impaired level of functioning across two assessments (mean interval 5 1.89 years, sd 5 1.42 years), based on a global rating of functioning on the Clinical Dementia Rating Scale (CDR). Age and education corrected z-scores were derived for measures of verbal learning, delayed memory, praxic ability, and confrontational naming, based on performance of healthy controls on these measures as part of the Consortium to Establish a Registry of Alzheimer’s Disease (CERAD). Change in performance on these neuropsychological measures was calculated by subtracting the standardized z-score of each measure at the follow-up assessment from the standardized score obtained on each measure at the initial assessment. A repeated measures ANOVA was used to determine if any of these measures were specifically associated with functional decline. Whereas the overall ANOVA was significant (F(1, 67) 5 14.49, p , .001), no specific measure of neurocognitive functioning was able to account for the decline in functional ability (Rao’s R (3, 65) 5 1.19, p , .321). These data suggest that the cognitive decline seen in these patients is generalized, rather than selective. It may be that this functional decline is related to low levels of cortical decline in patients with poor premorbid functioning and a chronic clinical course of illness.

Longitudinal classification in schizophrenia: The relationship between kraepelinian and deficit syndrome subtypologies

Kraepelinian schizophrenics are defined as a subgroup of schizophrenic patients who display at least five continuous years of complete dependence on others for food, shelter, and clothing. These patients have been empirically distinguished from nonkmepelinian schizophrenics in several areas of diagnostic validation. Kraepelinians demonstrate an absence of treatment response, greater CT vencicular abnormalities, more severe formal thought disorder and negative symptoms, less severe symptoms of mood disorder, and greater morbid risk for schizophrenia spectrum disorders in their first degree relatives. The deficit syndrome, as described by Carpenter et al (1987), is defined as the presence of enduring negative symptoms considered to be primary (ie., not secondary to such factors as depression, medication, etc.) and stable (i.e., present both during and between exacerbations of positive symptomatology for at least one year), it was the aim of the present study to assess the relationship between Kraepelinian status and the deficit syndrome, two longitudinal subtypologies of schizophrenia. The Schedule for the Deficit Syndrome was completed by 16 Kraepelinian and 31 nonkmepelinian schizophrenic patients, similar in terms of age, education, and duration of illness. Kraepelinian patients were significantly more likely to present with the deficit syndrome than were nonkraepelinian patients (chi-square 18.0, dfi, p -.0001). Every Kraepelinian patient met criteria for the deficit syndrome while only 35% of the nonkraepelinian patients (I I out of 31) exhibited the deficit syndrome. Of 27 total deficit patients, only 16 were Kraepelinian. Thus, there is substantial overlap between the Kraepelinian and the deficit syndrome subtypes, with the Kraepelinian subtype identifying a more restricted group of patients. 290. EMPIRICAL EVALUATION OF THE FACTORIAL STRUCTURE OF CLINICAL SYMPTOMS IN SCHIZOPHRENIA: IS THE PANSS A VALID SCALE?

Acute administration of alprazolam has no effect on plasma homovanillic acid concentration in normal subjects

Alprazolam has been suggested as an adjuvant to neuroleptic drugs in the treatment of schizophrenic patients. In an attempt to investigate whether alprazolam has an effect on dopaminergic neurotransmission, plasma homovanillic acid concentrations were measured for 24 h following a challenge with 3 mg of alprazolam or placebo in eight healthy subjects. Alprazolam had no effect on plasma homovanillic acid which may suggest that this agent is devoid of activity at the dopaminergic system in normal subjects.