Src kinase as a mediator of convergent molecular abnormalities leading to NMDAR hypoactivity in schizophrenia.

Numerous investigations support decreased glutamatergic signaling as a pathogenic mechanism of schizophrenia, yet the molecular underpinnings for such dysregulation are largely unknown. In the post-mortem dorsolateral prefrontal cortex (DLPFC), we found striking decreases in tyrosine phosphorylation of N-methyl-D aspartate (NMDA) receptor subunit 2 (GluN2) that is critical for neuroplasticity. The decreased GluN2 activity in schizophrenia may not be because of downregulation of NMDA receptors as MK-801 binding and NMDA receptor complexes in postsynaptic density (PSD) were in fact increased in schizophrenia cases. At the postreceptor level, however, we found striking reductions in the protein kinase C, Pyk 2 and Src kinase activity that in tandem can decrease GluN2 activation. Given that Src serves as a hub of various signaling mechanisms affecting GluN2 phosphorylation, we postulated that Src hypoactivity may result from convergent alterations of various schizophrenia susceptibility pathways and thus mediate their effects on NMDA receptor signaling. Indeed, the DLPFC of schizophrenia cases exhibit increased PSD-95 and erbB4 and decreased receptor-type tyrosine-protein phosphatase-α (RPTPα) and dysbindin-1, each of which reduces Src activity via protein interaction with Src. To test genomic underpinnings for Src hypoactivity, we examined genome-wide association study results, incorporating 13 394 cases and 34 676 controls. We found no significant association of individual variants of Src and its direct regulators with schizophrenia. However, a protein-protein interaction-based network centered on Src showed significant enrichment of gene-level associations with schizophrenia compared with other psychiatric illnesses. Our results together demonstrate striking decreases in NMDA receptor signaling at the postreceptor level and propose Src as a nodal point of convergent dysregulations affecting NMDA receptor pathway via protein-protein associations.

Responses to colour and host odour cues in three cereal pest species, in the context of ecology and control.

Many insects show a greater attraction to multimodal cues, e.g. odour and colour combined, than to either cue alone. Despite the potential to apply the knowledge to improve control strategies, studies of multiple stimuli have not been undertaken for stored product pest insects. We tested orientation towards a food odour (crushed white maize) in combination with a colour cue (coloured paper with different surface spectral reflectance properties) in three storage pest beetle species, using motion tracking to monitor their behaviour. While the maize weevil, Sitophilus zeamais (Motsch.), showed attraction to both odour and colour stimuli, particularly to both cues in combination, this was not observed in the bostrichid pests Rhyzopertha dominica (F.) (lesser grain borer) or Prostephanus truncatus (Horn) (larger grain borer). The yellow stimulus was particularly attractive to S. zeamais, and control experiments showed that this was neither a result of the insects moving towards darker-coloured areas of the arena, nor their being repelled by optical brighteners in white paper. Visual stimuli may play a role in location of host material by S. zeamais, and can be used to inform trap design for the control or monitoring of maize weevils. The lack of visual responses by the two grain borers is likely to relate to their different host-seeking behaviours and ecological background, which should be taken into account when devising control methods.

Who Benefited Most from the Internet-Based Conversational Engagement RCT (I-CONECT)? Application of the Personalized Medicine Approach to a Behavioral Intervention Study.

BACKGROUND: Many Alzheimer's Disease (AD) clinical trials have failed to demonstrate treatment efficacy on cognition. It is conceivable that a complex disease like AD may not have the same treatment effect due to many heterogeneities of disease processes and individual traits. OBJECTIVES: We employed an individual-level treatment response (ITR) approach to determine the characteristics of treatment responders and estimated time saved in cognitive decline using the Internet-based Conversational Engagement Clinical Trial (I-CONECT) behavioral intervention study as a model. DESIGN AND SETTING: I-CONECT is a multi-site, single-blind, randomized controlled trial aimed to improve cognitive functions through frequent conversational interactions via internet/webcam. The experimental group engaged in video chats with study staff 4 times/week for 6 months; the control group received weekly 10-minute check-in phone calls. PARTICIPANTS: Out of 186 randomized participants, current study used 139 participants with complete information on both baseline and 6-month follow-up (73 with mild cognitive impairment (MCI), 66 with normal cognition; 64 in the experimental group, and 75 in the control group). MEASUREMENTS: ITR scores were generated for the Montreal Cognitive Assessment (MoCA) (global cognition, primary outcome) and Category Fluency Animals (CFA) (semantic fluency, secondary outcome) that showed significant efficacy in the trial. ITR scores were generated through 300 iterations of 3-fold cross-validated random forest models. The average treatment difference (ATD) curve and the area between the curves (ABC) were estimated to measure the heterogeneity of treatment responses. Responder traits were identified using SHapley Additive exPlanations (SHAP) and decision tree models. The time saved in cognitive decline was explored to gauge clinical meaningfulness. RESULTS: ABC statistics showed substantial heterogeneity in treatment response with MoCA but modest heterogeneity in treatment response with CFA. Age, cognitive status, time spent with family and friends, education, and personality were important characteristics that influenced treatment responses. Intervention group participants in the upper 30% of ITR scores demonstrated potential delays of 3 months in semantic fluency (CFA) and 6 months in global cognition (MoCA), assuming a 5-fold faster natural cognitive decline compared to the control group during the post-treatment period. CONCLUSIONS: ITR-based analyses are valuable in profiling treatment responders for features that can inform future trial design and clinical practice. Reliably measuring time saved in cognitive decline is an area of ongoing research to gain insight into the clinical meaningfulness of treatment.

Sex differences in regional cerebral glucose metabolism during a resting state.

Positron emission tomography was used to evaluate the regional distribution of cerebral glucose metabolism in 61 healthy adults at rest. Although the profile of metabolic activity was similar for men and women, some sex differences and hemispheric asymmetries were detectable. Men had relatively higher metabolism than women in temporal-limbic regions and cerebellum and relatively lower metabolism in cingulate regions. In both sexes, metabolism was relatively higher in left association cortices and the cingulate region and in right ventro-temporal limbic regions and their projections. These results are consistent with the hypothesis that differences in cognitive and emotional processing have biological substrates.

Factors associated with survival probability in autopsy-proven frontotemporal lobar degeneration.

OBJECTIVE: To examine the clinical and pathological factors associated with survival in autopsy-confirmed frontotemporal lobar degeneration (FTLD). METHODS: The final analysis cohort included 71 patients with pathologically proven FTLD, excluding patients with clinical motor neuron disease (MND), evaluated at the University of Pennsylvania or at the University of California, San Francisco. We assessed clinical and demographic features; cognitive functioning at presentation; genetic markers of disease; and graded anatomical distribution of tau, ubiquitin and amyloid pathology. RESULTS: The tau-negative group (n = 35) had a median survival time of 96 months (95% CI: 72-114 months), whereas the tau-positive group (n = 36) had a median survival time of 72 months (95% CI: 60-84 months). Patients with tau-positive pathology across all brain regions had shorter survival than those with tau-negative pathology in univariate Cox regression analyses (Hazard ratio of dying = 2.003, 95% CI = 1.209-3.318, p = 0.007). CONCLUSIONS: Tau-positive pathology represents a significant risk to survival in FTLD, whereas tau-negative pathology is associated with a longer survival time when clinical MND is excluded.

The relationship between cerebral Alzheimer's disease pathology and odour identification in old age.

BACKGROUND: Olfactory dysfunction is common in old age, but its basis is uncertain. OBJECTIVE: To test the hypothesis that difficulty in identifying odours in old age is related to the accumulation of Alzheimer's disease pathology. METHODS: As part of the Rush Memory and Aging Project, participants completed the 12-item Brief Smell Identification Test, a standard measure of odour identification. During a mean (standard deviation (SD)) of 2.2 (1.2) years of follow-up (range 0.2-4.9), 166 people died, with brain autopsies performed on 129 (77.7%) people and neuropathological examinations completed on 77 (mean (SD) age at death 87.5 (5.9) years; median postmortem interval 6.1 h). From a uniform postmortem examination of multiple brain regions, summary measures of plaque and tangle pathology were derived on the basis of silver staining, and those of amyloid beta burden, tangle density and Lewy bodies on the basis of immunohistochemistry. RESULTS: Odour identification performance ranged from 0 to 12 correct (mean (SD) 8.0 (2.6)). In analyses adjusted for age, sex and education, a composite measure of plaques and tangles accounted for >12% of the variation in odour identification. The association remained after controlling for dementia or semantic memory. Density of tau tangles was inversely related to odour identification. A similar effect for amyloid burden was attenuated after controlling for tangles. The association with odour identification was robust for tangles in the entorhinal cortex and CA1/subiculum area of the hippocampus, but not for tangles in other cortical sites. Lewy bodies, identified in 12.5%, were not related to odour identification, probably partly due to to their relative infrequency. CONCLUSION: The results suggest that difficulty in identifying familiar odours in old age is partly due to the accumulation of neurofibrillar pathology in central olfactory regions.

AMPA receptor subunit and splice variant expression in the DLPFC of schizophrenic subjects and rhesus monkeys chronically administered antipsychotic drugs.

Disturbances in glutamate neurotransmission are thought to be one of the major contributing factors to the pathophysiology of schizophrenia. In the dorsolateral prefrontal cortex (DLPFC), glutamate neurotransmission is largely mediated by AMPA receptors. Data regarding alterations of subunit expression in the brains of patients with schizophrenia remain equivocal. This may be due to differences in technique sensitivity, endogenous control selection for normalization of data, or effect of antipsychotic drug treatment in different cohorts of schizophrenia. This study attempted to address these issues by examining the expression of AMPA receptor subunits and splice variants in the DLPFC of two schizophrenia cohorts using quantitative PCR (qPCR) with normalization to the geometric mean of multiple endogenous controls. In addition, a non-human primate model of chronic antipsychotic drug administration was used to determine the extent to which the transcript expression may be altered by antipsychotic drug treatment in the primate DLPFC. AMPA receptor subunits and flip and/or flop splice variants were not significantly different in the DLPFC of schizophrenia subjects versus controls in either of the two cohorts. However, in rhesus monkeys chronically treated with antipsychotic drugs, clozapine treatment significantly decreased GRIA1 and increased GRIA3 mRNA expression, while both clozapine and haloperidol increased the expression of GRIA2 subunit mRNA. Expression of AMPA receptor splice variants was not significantly altered by antipsychotic drug administration. This is the first study to show that AMPA receptor subunit mRNAs in the primate DLPFC are altered by antipsychotic drug administration. Antipsychotic drug-induced alterations may help explain differences in human post-mortem studies regarding AMPA receptor subunit expression and provide some insight into the mechanism of action of antipsychotic drugs.

Inositol 1,4,5-trisphosphate receptor expression in odontoblast cells.

The cellular distribution of inositol 1,4,5-trisphosphate receptors was examined in rodent maxillary incisor teeth. In situ hybridization studies with a transmembrane probe of type I inositol 1,4,5-trisphosphate receptor indicated that this receptor/channel was highly expressed in odontoblast cells of incisor teeth. In contrast, very low labeling was observed in dental pulp. Northern analysis showed a message size of approximately 9.5 kilobases for this receptor, and demonstrated that type III inositol 1,4,5-trisphosphate receptor was expressed in incisor teeth. Immunocytochemical studies confirmed that types I and III inositol 1,4,5-trisphosphate receptors were both highly expressed in odontoblasts while very low expression was detected in dental pulp. Finally, antibodies that recognized alpha subunits of the Gq class of GTP binding proteins also stained odontoblasts. These results indicate that receptor-mediated regulation of calcium release through inositol 1,4,5-trisphosphate receptors may occur in odontoblasts of rat incisor teeth. These findings also suggest that inositol 1,4,5-trisphosphate receptor/channels regulate calcium flux in odontoblasts during mineralization of dentin, or in growth and differentiation of incisor tissue.

Mesolimbic dopamine D3 receptors and use of antipsychotics in patients with schizophrenia. A postmortem study.

BACKGROUND: The pharmacological properties and distribution of a recently cloned member of the dopamine D2 receptor subfamily, the D3 receptor, has led directly to the hypothesis that it may be the target of antipsychotic action. METHODS: To quantify D3 receptors, we characterized the conditions for selective binding of the radioligand iodine 125-labeled (R)-trans-7-hydroxy-2-[N-propyl-N-(3'-iodo-2'-propenyl)-amino] tetralin ([125I]trans-7-OH-PIPAT) to the human D3 receptor. We then measured by quantitative autoradiography in postmortem tissue the concentration of D3 receptors in the caudal and rostral basal ganglia regions in patients with schizophrenia and control subjects. RESULTS: We found about 2-fold elevations in the number of D3 receptors in the basal ganglia and ventral forebrain of long-term hospitalized patients with schizophrenia who received no antipsychotic drugs for at least a month before death (n = 7) compared with matched control subjects (n = 15). Patients with schizophrenia receiving antipsychotic drugs less than 72 hours before death (n = 8) had levels similar to those of control subjects. There were no differences in the binding characteristics or affinity of [125I]trans-7-OH-PIPAT binding to D3 receptors between control subjects and patients with schizophrenia. CONCLUSION: In contrast to the previously detected elevation of D2 and D4 receptor levels in schizophrenia, elevation of D3 receptor levels in limbic striatum and its efferents observed in patients with schizophrenia may be reduced by antipsychotic drugs.

Some cytoarchitectural abnormalities of the entorhinal cortex in schizophrenia.

The cytoarchitecture of the entorhinal cortex was examined in the brains of six patients with a diagnosis of schizophrenia and in 16 controls. All six brains of schizophrenic patients showed abnormalities of the rostral and intermediate portions of the entorhinal cortex. The abnormalities included aberrant invaginations of the surface, disruption of cortical layers, heterotopic displacement of neurons, and paucity of neurons in superficial layers. These changes suggest disturbed development. Because the entorhinal cortex is pivotal for neural systems that mediate corticohippocampal interactions, early disruption of its structure could lead to important neuropsychological changes during development and in adult life and could contribute to the symptomatology of schizophrenia.

Absence of neurodegeneration and neural injury in the cerebral cortex in a sample of elderly patients with schizophrenia.

BACKGROUND: The cognitive and functional deterioration that is observed in many "poor-outcome" patients with schizophrenia suggests a neurodegenerative process extending into late life. Previous diagnostic studies have excluded known neurodegenerative diseases as explanations for this dementia. However, we hypothesized that relatively small accumulations of age- or disease-related neurodegenerative lesions occurring in an otherwise abnormal brain could result in deterioration in schizophrenia. METHODS: Postmortem studies were conducted using 23 prospectively accrued elderly persons with chronic schizophrenia for whom clinical ratings had been determined before death, 14 elderly control patients with no neuropsychiatric disease, and 10 control patients with Alzheimer disease. Immunohistochemistry and unbiased stereological counting methods were used to quantify common neurodegenerative lesions (ie, neurofibrillary tangles, amyloid plaques, and Lewy bodies) and cellular reactions to a variety of noxious stimuli (ubiquitinated dystrophic neurites, astrocytosis, and microglial infiltrates) in the ventromedial temporal lobe and the frontal and the calcarine (primary visual) cortices. RESULTS: No statistically significant differences were found between the patients with schizophrenia and the control patients without neuropsychiatric disease for the densities of any of the markers, while both groups exhibited fewer lesions than did the control group with Alzheimer disease. Correlation analyses in the schizophrenia sample failed to identify significant correlations between cognitive and psychiatric ratings and densities of any of the neuropathologic markers. CONCLUSIONS: No significant evidence of neurodegeneration or ongoing neural injury in the cerebral cortex was found in this sample of elderly persons with schizophrenia. Furthermore, the behavioral and cognitive deterioration observed in late life did not correlate with age-related degenerative phenomena.

Dysregulation of olfactory receptor neuron lineage in schizophrenia.

BACKGROUND: Growing evidence implicates abnormal neurodevelopment in schizophrenia. While neuron birth and differentiation is largely completed by the end of gestation, the olfactory epithelium (OE) is a unique part of the central nervous system that undergoes regeneration throughout life, thus offering an opportunity to investigate cellular and molecular events of neurogenesis and development postmortem. We hypothesized that OE neurons exhibit deviant progress through neurodevelopment in schizophrenia characterized by an increase in immature neurons. METHODS: Olfactory epithelium was removed at autopsy from 13 prospectively assessed elderly subjects who had schizophrenia and 10 nonpsychiatric control subjects. Sections were immunolabeled with antibodies that distinguish OE neurons in different stages of development, including basal cells (low-affinity nerve growth factor receptor, p75NGFR), postmitotic immature neurons (growth-associated protein 43 [GAP43]), and mature olfactory receptor neurons (olfactory marker protein). Absolute and relative densities of each cell type were determined. RESULTS: We observed a significantly lower density of p75NGFR basal cells (37%) in schizophrenia and increases in GAP43 + postmitotic immature neurons (316%) and ratios of GAP43 + postmitotic immature neurons to p75NGFR + cells (665%) and olfactory marker protein + mature neurons to p75NGFR + basal cells (328%). Neuroleptic-free schizophrenia subjects exhibited the highest GAP43 + postmitotic immature neuron values. CONCLUSIONS: Abnormal densities and ratios of OE neurons at different stages of development indicate dysregulation of OE neuronal lineage in schizophrenia. This could be because of intrinsic factors controlling differentiation or an inability to gain trophic support from axonal targets in the olfactory bulb. While caution is necessary in extrapolating developmental findings in mature OE to early brain development, similarities in molecular events suggest that such studies may be instructive.

Reduced dorsal and orbital prefrontal gray matter volumes in schizophrenia.

BACKGROUND: Converging neuroanatomic, neurophysiological, and neurobehavioral evidence implicate prefrontal subregions in schizophrenia. Neuroanatomic studies with magnetic resonance (MR) imaging enable regional volume parcellation. Inconsistent reports may relate to variable methods and small samples. We attempted to resolve volume differences within sectors of the prefrontal lobe in a large sample, relating volumes to clinical and neurocognitive features. METHODS: Magnetic resonance imaging was performed in 70 patients with schizophrenia (40 men and 30 women; 29 neuroleptic naive and 41 previously treated) and 81 healthy controls (34 men and 47 women). Gray and white matter volumes of the dorsolateral, dorsomedial, orbitolateral, and orbitomedial prefrontal cortex were quantified. Symptoms, functioning, and neurocognition were assessed concurrently. RESULTS: Reduced prefrontal gray matter volume was observed in patients. The reduction was evident for the dorsolateral area in men (9%) and women (11%), for the dorsomedial area only in men (9%), and for orbital regions only in women (23% and 10% for lateral and medial, respectively). The reduction of orbital volume in women was associated with poorer premorbid functioning, more severe negative symptoms, and depression. Volume of dorsal cortex was positively associated with better performance on abstraction and attention tasks across all groups. CONCLUSIONS: Schizophrenia is associated with reduced gray matter volume in prefrontal cortex, which affects men and women in the dorsolateral sector. The effects are moderated by sex for dorsomedial and orbital regions and are related to symptom severity and cognitive function. This is not a by-product of treatment, since the differences are evident in neuroleptic-naive patients.

Temporolimbic volume reductions in schizophrenia.

BACKGROUND: Neuroanatomic studies of schizophrenia have reported temporolimbic abnormalities. Most magnetic resonance imaging studies have evaluated small samples of primarily men with chronic schizophrenia. Our goal was to evaluate sex differences in segmented temporal lobe subregions with reliable parcellation methods, relating volume with clinical and neurocognitive parameters. METHODS: Magnetic resonance imaging was performed in 100 patients with schizophrenia (58 men, 42 women; 39 neuroleptic naive, 61 previously treated) and 110 healthy controls (51 men, 59 women). Gray and white matter volumes of temporolimbic (hippocampus and amygdala) and neocortical regions (superior temporal gyrus and temporal pole) were examined. Symptoms, functioning, and neurocognition were assessed concurrently. RESULTS: Hippocampal gray matter volume was reduced in men (7%) and women (8.5%) with schizophrenia. In the amygdala, however, decreased volume was evident for men (8%) whereas women (10.5%) had increased volume. Magnetic resonance imaging of the temporal pole showed decreased gray matter in men (10%) and women (8.5%). For the superior temporal gyrus, the decrease exceeded that of whole-brain only in men (11.5%). Volumes were largely uncorrelated with clinical measures, but higher hippocampal volumes were associated with better memory performance for all groups. Cortical volumes were associated with better memory performance in healthy women. CONCLUSIONS: Schizophrenia is associated with reduced gray matter volume in temporolimbic structures. In men, reduction was manifested in all regions, whereas women showed decreased hippocampal volumes but increased amygdala volumes. The abnormalities are evident in patients with first-episode schizophrenia and correlate more strongly with cognitive performance than with symptom severity.

Resting cerebral glucose metabolism in first-episode and previously treated patients with schizophrenia relates to clinical features.

BACKGROUND: Functional neuroimaging can elucidate brain dysfunction in schizophrenia. The frontal, temporolimbic, and diencephalic regions have been implicated. There is a lack of prospective samples of first-episode and previously treated patients followed up longitudinally. METHODS: Patients and controls (42 per group) were studied. Positron emission tomography with flurodeoxyglucose, cross-registered with magnetic resonance imaging, measured metabolism. Scales assessed clinical features, premorbid adjustment, and outcome. RESULTS: There were no differences between groups in whole-brain metabolism or regional ratios or in anterior-posterior gradients, but left midtemporal metabolism was relatively higher in patients. This was pronounced in the negative and Schneiderian and absent in the paranoid subtypes. Higher metabolism and lower relative left hemispheric values were associated with better premorbid adjustment and outcome. A higher subcortical-cortical gradient was noted in first-episode patients. CONCLUSIONS: There are no resting metabolic abnormalities in any brain region, but abnormal gradients are evident. These vary in subtypes, and laterality is associated with functioning. The results support the hypothesis of temporolimbic disturbance in schizophrenia that is all ready present at the onset of illness.

Further evidence of abnormal cytoarchitecture of the entorhinal cortex in schizophrenia using spatial point pattern analyses.

Previous studies have reported cytoarchitectural abnormalities in superficial laminae of rostral portions of the entorhinal cortex in schizophrenia, including decreased densities of neurons, poorly formed layer II neuron islands, and apparent displacement of layer II-type neurons deep into layer III; however, findings have been controversial, given the qualitative nature of the descriptions and the normal heterogeneity of cytoarchitecture of the region. The x, y coordinates of Nissl-stained neurons were mapped in layers II, III, and V of entorhinal subdivision ER in 8 prospectively accrued patients with schizophrenia and 8 nonneuropsychiatric controls. Indices of neuron dispersion, nearest neighbor distances, and effective radius were determined. An abnormally clustered dispersion of neurons in layer III was present in schizophrenics compared to controls along with a reduced neuron effective radius, whereas the mean nearest-neighbor distance was normal. In layer II, there was a significantly increased effective radius, whereas other indices were normal. No between-group differences were noted in layer V for any variable. These data provide further evidence for subtle aberrant cytoarchitecture in superficial laminae of the entorhinal cortex in schizophrenia and are consistent with neurodevelopmental models of abnormal neuronal pruning, "miswiring," and/or migration in the illness.

Physostigmine reversal of scopolamine-induced hypofrontality.

The muscarinic receptor antagonist scopolamine produces a transient memory deficit in healthy humans. This deficit has been offered as a model of the cholinergic deficit of Alzheimer's disease (AD). However, we have previously shown that scopolamine produces a deficit of cortical perfusion maximal in the frontal lobe, dissimilar to the parietal cortex deficit characteristic of AD. The current experiment was aimed at replicating and extending this observation by critically testing the central cholinergic origin of both cognitive and perfusion deficits. Nine healthy subjects participated in regional cerebral blood flow (rCBF) measurements at baseline, after scopolamine (7.2 micrograms/kg i.v.), and after both physostigmine (22 micrograms/kg i.v.) and neostigmine (7 or 11 micrograms/kg i.v.). rCBF was quantified by the xenon 133 inhalation method. As expected, scopolamine reduced cortical perfusion, mainly in the frontal cortex, and produced a memory deficit. Physostigmine, but not neostigmine, reversed all three variables partially or completely. These results support the hypothesis that all three consequences of scopolamine, namely, reduction of mean flow, frontal deficit, and memory impairment, are cholinergically mediated. Furthermore, because neostigmine poorly crosses the blood-brain barrier, these findings confirm that the effect is centrally mediated and cannot be explained by peripheral effects. However, they also confirm the frontal cortex locus of action for both scopolamine and its reversal by physostigmine and therefore suggest a major dissimilarity to the characteristic rCBF appearance of AD. This study extends our previous preliminary findings with tacrine and strengthens the suggestion that only nicotinic receptors are associated with the characteristic parietal deficit of AD.

Elderly patients with schizophrenia exhibit infrequent neurodegenerative lesions.

Immunohistochemistry and conventional stains were used to examine the brains of 10 elderly patients with both schizophrenia and dementia to characterize the neuropathology of their cognitive deterioration. Control cases included five nondemented elderly patients with schizophrenia, five age-compatible Alzheimer's disease (AD) patients, and five neurologically normal elderly patients. Only one of the patients with schizophrenia and dementia had AD, another was diagnosed with adult polyglucosan body disease, and the others were devoid of neuropathology that could account for dementia. Quantitation of immunohistochemically detected neurofibrillary tangles and senile plaques revealed similarly low counts for the normal control group and both schizophrenia groups. Typically, the neuropathological causes of dementia can be identified in up to 95% of cases, with AD accounting for 50-60%. The unexpected lack of neuropathological findings to explain the cognitive deterioration in this group of elderly patients with schizophrenia prompts speculation about alternative etiologies.

Strategies for improving the postmortem neuropathological diagnosis of Alzheimer's disease.

Despite recognition that Alzheimer's disease (AD) is a polygenic and heterogeneous dementing neurodegenerative disorder, there is continued merit in defining the AD phenotype by the presence of progressive cognitive impairments and the pathological brain lesions (senile plaques, neurofibrillary tangles) as originally formulated by Alois Alzheimer. This position paper discusses the rationale for emphasizing the detection of both beta amyloid-rich plaques and tau-rich tangles in the next iteration of the neuropathological criteria for the postmortem diagnosis of AD that has been recommended by the Working Group on Consensus Criteria for the Postmortem Diagnosis of AD. Further, it also underlines the need to exploit continuing advances in understanding the pathobiology of plaques and tangles in subsequent iterations of these criteria. It is expected that such efforts, now and in the future, will hasten the development of strategies for the early and accurate antemortem diagnosis of AD as well as the discovery of effective treatments for this common dementing illness of the elderly.

Quantitative neurohistological features of frontotemporal degeneration.

Frontotemporal degeneration (FTD) is a neurodegenerative condition that has been principally associated with frontal lobe dementia. In this study, we compared neuropathological abnormalities in frontal, hippocampal, and calcarine cortices from patients assigned a diagnosis of FTD, normal elderly and Alzheimer's disease (AD). Densities of Nissl-stained neurons and lesions which were immunolabeled for tau, beta-amyloid (Abeta), alpha- and beta-synuclein, ubiquitin, glial fibrillary acidic protein (GFAP) and CD68 antigen were determined using computer-assisted, non-biased quantitative microscopy. We found that FTD frontal and hippocampal regions exhibited marked neuron loss, abundant ubiquitin-immunoreactive (ir) dystrophic neurites, GFAP-ir astrocytes, and CD68-ir microglia, while calcarine cortex was spared. No alpha- or beta-synuclein-ir lesions were observed, and neither the density of tau-ir neurofibrillary tangles nor that of Abeta-ir plaques in FTD exceeded normal controls. In addition, there were no neuropathological differences between FTD subjects who presented clinically with a frontal lobe dementia versus an AD-like dementia. These findings indicate that FTD is a category of neurodegnerative dementias with varying clinical presentations that is characterized by the progressive degeneration of select populations of cortical neurons. The molecular neurodegenerative mechanisms that lead to FTD remain to be elucidated.