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Biomedical subjects

W G Honer

Publications and source records attributed to W G Honer.

At least 37 records · Page 2Linked to original sources
PubMed2001

Dementia as a complication of schizophrenia.

OBJECTIVES: Cognitive impairment is known to occur in schizophrenia, and may be marked in institutionalised patients. The aim of this study was to determine whether it ever warrants an additional diagnosis of dementia. METHODS: A population of chronic schizophrenic patients who were aged 65 or younger and showed no organic risk factors for dementia were screened for presence of disorientation. Any showing this underwent neuropsychological testing, physical investigations, and structural and functional neuroimaging. Information about day to day cognitive function was also obtained from carers. RESULTS: Eight patients aged 28 to 64 were identified who showed disorientation; in all cases this was accompanied by general intellectual impairment and objective evidence of a dementia syndrome. The patients' schizophrenic symptoms were unexceptional and did not seem sufficient to account for their cognitive impairment. Neuropsychological testing disclosed relative sparing of visual and visuospatial function and language syntax, but pervasive deficits in memory and executive function. Brain CT demonstrated only minor abnormalities but most of the patients showed frontal or temporal hypoperfusion on SPECT. CONCLUSIONS: Dementia in schizophrenia seems to be a real entity with a neuropsychological signature similar to that of frontotemporal dementia. Functional but not structural imaging abnormalities may also be characteristic.

Adult↗
PubMed2001

Right frontal hypergyria differentiation in affected and unaffected siblings from families multiply affected with schizophrenia: a morphometric mri study.

OBJECTIVE: The authors used magnetic resonance imaging to corroborate the postmortem finding of right frontal hypergyria associated with schizophrenia. METHOD: Twelve affected-unaffected sibling pairs from families multiply affected with schizophrenia were studied. Bilateral measurement of the gyrification index, the ratio of the inner and outer surface contours, was performed on three different slices of the prefrontal region. RESULTS: The mean gyrification index on the right side was significantly higher in siblings with schizophrenia or schizoaffective disorder than in the unaffected siblings. CONCLUSIONS: In this family cohort study, the postmortem finding of right-sided hypergyria in subjects with schizophrenia was replicated in vivo with magnetic resonance imaging. This observation provides further support for a neurodevelopmental mechanism in the pathogenesis of schizophrenia.

Adult↗
PubMed2001

An MRI study of basal ganglia volumes in first-episode schizophrenia patients treated with risperidone.

OBJECTIVE: The basal ganglia may contribute to extrapyramidal movement disorders, affective disturbances, and cognitive deficits in schizophrenia. Basal ganglia volumes are putatively affected by antipsychotic medications. The purpose of this study was to determine the long-term effects of risperidone treatment in a cohort of first-episode patients with schizophrenia. METHOD: The subjects were 30 patients with first-episode schizophrenia, 12 patients chronically treated with typical antipsychotics, and 23 healthy comparison subjects. They were scanned by magnetic resonance imaging at baseline. The first-episode patients received 1 year of continuous risperidone treatment, after which they and the comparison subjects were rescanned. Caudate, putamen, and globus pallidus volumes were determined from coronal images. RESULTS: The baseline caudate, putamen, and globus pallidus volumes were significantly larger in the chronically treated patients than in the untreated first-episode subjects and comparison subjects. These volumes did not differ between the first-episode patients and healthy comparison subjects. Basal ganglia volumes were unchanged after 1 year of exposure to risperidone in the first-episode subjects. Extrapyramidal movement disorders were present in the majority of chronically treated patients and more than one-third of the never-medicated first-episode patients at baseline. CONCLUSIONS: This group of first-episode patients did not exhibit abnormalities of basal ganglia volumes, nor were basal ganglia volumes affected by exposure to risperidone. Movement disorders were observed in both first-episode and chronically treated patients, suggesting effects of both illness and medications.

Adult↗
PubMed2001

Impaired olfactory identification in relatives of patients with familial schizophrenia.

OBJECTIVE: Impaired olfactory identification ability has previously been demonstrated in patients with schizophrenia. This study assessed olfactory function in psychotic and nonpsychotic members of multigenerational families with familial schizophrenia to determine whether deficits were present in both groups. METHOD: The University of Pennsylvania Smell Identification Test was administered birhinally to three groups of subjects aged less than 65 years: 19 psychotic and 27 nonpsychotic members of families with familial schizophrenia and 43 age- and sex-matched healthy volunteers. RESULTS: Nonpsychotic family members had significantly higher mean University of Pennsylvania Smell Identification Test scores than psychotic family members but were impaired relative to the healthy volunteer group. These group differences could not be accounted for by age, sex, or smoking habit. Fifty-eight percent of the psychotic and 34% of the nonpsychotic family members performed in the microsmic (impaired) range, compared to 9% of the healthy volunteers. CONCLUSIONS: Impaired olfactory deficits may aggregate in families with schizophrenia and may be indicative of a genetic predisposition to psychosis.

Adult↗
PubMed2000

Decreased frontal lobe ratio of N-acetyl aspartate to choline in familial schizophrenia: a proton magnetic resonance spectroscopy study.

Neuropathological and neuroimaging studies suggest neuronal dysfunction in schizophrenia. N-acetyl aspartate (NAA) is a useful marker of neuronal dysfunction that can be measured with magnetic resonance spectroscopy (MRS). In the present study NAA, choline (Cho), phospho-creatine ((P)Cr), inositol containing compounds and glutamine/glutamate (Glx) were assessed in the left frontal lobe and basal ganglia of subjects with familial schizophrenia, family members with mixed psychiatric diagnoses, unaffected family members, and community controls. Concentrations of metabolites were analyzed and expressed as ratios. NAA/Cho, NAA/(P)Cr and Glx containing compounds showed a negative correlation with age in the frontal lobe. After covarying for age, subjects with schizophrenia had a significant reduction in the left frontal lobe NAA/Cho ratio compared with unaffected family members (P=0.018) as well as with community non-familial (P=0.037) controls. These MRS observations support the hypothesis of a disease-related neuronal deficit in the frontal lobe of schizophrenic patients, and relatively normal basal ganglia.

Adult↗
PubMed2000

Entorhinal cortex pre-alpha cell clusters in schizophrenia: quantitative evidence of a developmental abnormality.

BACKGROUND: Previous studies using semiquantitative or qualitative techniques demonstrated abnormalities of positioning of clusters of neurons (pre-alpha cells) in the entorhinal cortex in schizophrenia, suggesting a developmental mechanism could contribute to the illness. Recent quantitative studies of laminar thickness and laminar cell counts have been less consistent, and several failed to replicate the finding. However, none of the quantitative studies focused on the position of the pre-alpha cell clusters. METHODS: To study pre-alpha cell position in detail, we examined the entorhinal cortex in serial sections from 21 control and 19 schizophrenic brains. Cluster position relative to the gray-white matter junction and cluster size were measured. RESULTS: Quantitative assessment of 1991 clusters indicated clusters were positioned relatively closer to the gray-white matter junction in the anterior half of schizophrenic entorhinal cortices. In addition, the size of clusters in males with schizophrenia was reduced. CONCLUSIONS: These results support the model of schizophrenia as an illness in which brain development is impaired. The findings in males with schizophrenia may indicate the presence of more severe pathology, or an additional pathogenic mechanism.

Adult↗
PubMed2000

Location of a major susceptibility locus for familial schizophrenia on chromosome 1q21-q22.

Schizophrenia is a complex disorder, and there is substantial evidence supporting a genetic etiology. Despite this, prior attempts to localize susceptibility loci have produced predominantly suggestive findings. A genome-wide scan for schizophrenia susceptibility loci in 22 extended families with high rates of schizophrenia provided highly significant evidence of linkage to chromosome 1 (1q21-q22), with a maximum heterogeneity logarithm of the likelihood of linkage (lod) score of 6.50. This linkage result should provide sufficient power to allow the positional cloning of the underlying susceptibility gene.

Chromosome Mapping↗
PubMed2000

Staging of cytoskeletal and beta-amyloid changes in human isocortex reveals biphasic synaptic protein response during progression of Alzheimer's disease.

We have examined the relationships between dementia, loss of synaptic proteins, changes in the cytoskeleton, and deposition of beta-amyloid plaques in the neocortex in a clinicopathologically staged epidemiological cohort using a combination of biochemical and morphometric techniques. We report that loss of synaptic proteins is a late-stage phenomenon, occurring only at Braak stages 5 and 6, or at moderate to severe clinical grades of dementia. Loss of synaptic proteins was seen only after the emergence of the full spectrum of tau and beta-amyloid pathology in the neocortex at stage 4, but not in the presence of beta-amyloid plaques alone. Contrary to previous studies, we report increases in the levels of synaptophysin, syntaxin, and SNAP-25 at stage 3 and of alpha-synuclein and MAP2 at stage 4. Minimal and mild clinical grades of dementia were associated with either unchanged or elevated levels of synaptic proteins in the neocortex. Progressive aggregation of paired helical filament (PHF)-tau protein could be detected biochemically from stage 2 onwards, and this was earliest change relative to the normal aging background defined by Braak stage 1 that we were able to detect in the neocortex. These results are consistent with the possibility that failure of axonal transport associated with early aggregation of tau protein elicits a transient adaptive synaptic response to partial de-afferentation that may be mediated by trophic factors. This early abnormality in cytoskeletal function may contribute directly to the earliest clinically detectable stages of dementia.

Alzheimer Disease↗
PubMed2000

Alpha-synuclein inclusions in Alzheimer and Lewy body diseases.

Alpha-synuclein has assumed particular neuropathological interest in the light both of its identification as a non-beta-amyloid plaque constituent in Alzheimer disease (AD), and the recent association between dominant inheritance of Parkinson disease (PD) and 2 missense mutations at positions 30 and 53 of the synuclein protein. We report a systematic study of alpha-synuclein, tau, and ubiquitin immunoreactivity in representative neurodegenerative disorders of late life. The alpha-synuclein association with Lewy bodies is variable, peripheral, and is not stable with respect to proteases or acid treatment, whereas there is no association with Pick bodies. Stable patterns of immunoreactivity included neurites and a novel inclusion body. Although there is an overlap between the presence of Lewy bodies and stable alpha-synuclein immunoreactivity, this is seen only in the presence of concomitant neuropathological features of AD. The novel alpha-synuclein inclusion body identified in pyramidal cells of the medial temporal lobe in particular was found in AD and in the Lewy body variant of AD, and was associated neither with ubiquitin nor tau protein. The inclusion is therefore neither a Lewy body nor a PHF-core body, but may be confused with the Lewy body, particularly in the Lewy body variant of AD. Abnormal processing of alpha-synuclein leading to its deposition in the form of proteolytically stable deposits is a particular feature of the intermediate stages of AD.

Aged↗
PubMed2000

A qualitative and quantitative study of grumose degeneration in progressive supranuclear palsy.

Grumose degeneration (GD) of the dentate nucleus is a common feature in progressive supranuclear palsy (PSP), but its pathogenesis has not been well studied, and its clinical significance remains unknown. This report describes a quantitative study of GD in 9 cases of PSP using image analysis with single- and double-immunolabeling, as well as histochemical stains for myelin and axons. GD was associated with demyelination, axonal loss, glial tau pathology, and microgliosis in regions juxtaposed to the dentate nucleus (DN). Specifically, demyelination and microgliosis were prominent in the superior cerebellar peduncle (SCP), dentate hilus, and cerebellar hemispheric white matter. Tau pathology and microgliosis were less prominent in the DN itself. The degree of myelin loss correlated with the tau burden in the SCP. GAP-43, which is a phosphoprotein known to be involved in axonal growth and sprouting, was decreased in the DN of PSP, and the degree of GAP-43 loss correlated with severity of GD. These results suggest that GD may be related to progressive pathology in the dentatorubrothalamic tract as well as the cerebellar hemispheric white matter, and that GD may be a consequence of concurrent degeneration in both output from and input to the DN. The results further suggest a possible role for oligodendroglial and myelin pathology in the pathogenesis of PSP.

Aged↗
PubMed2000

Cortical cholinergic denervation elicits vascular A beta deposition.

Selective destruction of the cholinergic nucleus basalis magnocellularis (nbm) in the rabbit by the p75 neurotrophin receptor (NTR) immunoglobulin G (IgG) complexed to the toxin saporin leads to the deposition of amyloid-beta (A beta) in and around cerebral blood vessels. In some instances, the perivascular A beta resemble the diffuse deposits observed in Alzheimer's disease (AD). We propose that cortical cholinergic deprivation results, among other perturbations, in the loss of vasodilation mediated by acetylcholine. In addition to a dysfunctional cerebral blood flow, alterations in vascular chemistry affecting endothelial and smooth muscle cells may result in cerebral hypoperfusion and a breached blood-brain barrier (BBB). The selective removal of the rabbit nbm and A beta accumulation may serve as an important nontransgenic, and more physiological, model for the testing of pharmacological and immunological agents designed to control the deposition and the deleterious effects of A beta in AD.

Acetylcholine↗
PubMed2000

Disturbed gyrification of the prefrontal region in male schizophrenic patients: A morphometric postmortem study.

OBJECTIVE: The goal was to test the hypothesis that abnormalities of gyrification are present in the prefrontal region of postmortem brains from schizophrenic patients. METHOD: The authors compared the prefrontal regions in brains from 24 schizophrenic patients and 24 normal comparison subjects. The gyrification index, the ratio of inner and outer surface contours, was measured bilaterally in three different slices from each brain. Area measurements of gray and white matter were studied separately by planimetric analysis in the same sections. In addition, a gray-to-white-matter ratio and an asymmetry coefficient were computed. RESULTS: The mean gyrification index on the right side was significantly higher in the male schizophrenic patients than in the comparison men. The gyrification index of the female patients was not significantly different from that of the female comparison subjects. Analysis of area measurements revealed no significant differences. CONCLUSIONS: As gyrification is an ontogenetic stable feature unaffected by atrophic processes during aging, the gyrification abnormalities of the prefrontal region provide further evidence of the importance of a neurodevelopmental mechanism in the etiology of schizophrenia, at least in males.

Age Factors↗
PubMed1999

Organization of the secretory machinery in the rodent brain: distribution of the t-SNAREs, SNAP-25 and SNAP-23.

Vesicular transport events appear to be facilitated by the VAMP/synaptobrevin family of membrane proteins in the vesicle (v-SNAREs) and a heterodimeric complex of syntaxin and SNAP-23/25 family members in the target membrane (t-SNAREs). In this manuscript we examine the tissue distribution and composition of the heterodimeric t-SNARE complexes in adult rodent brain. Analysis of protein extracts from brain regions shows that SNAP-25, syntaxin 1, and 4 are broadly distributed, while SNAP-23, syntaxin 3, and 7 show distinct patterns of expression. Further immunohistochemistry and fractionation studies show that while SNAP-25 is enriched in axons and nerve terminals, SNAP-23 is concentrated in cell bodies. Both SNAP-23 and SNAP-25 associate with the plasma membrane and can be metabolically labeled with [(3)H] palmitate in AtT-20 cells. Anti-SNAP-25 antibodies co-immunoprecipitate t-SNARE heterodimers from brain extracts that predominantly contain syntaxin 1 and 2. Contrary to results from in vitro binding assays, SNAP-23 was found predominantly associated with syntaxin 3. These observations suggest that t-SNARE, heterodimer composition is governed more by SNARE expression and localization than by simple protein-protein affinity.

Acylation↗
PubMed1999

Olfactory identification and psychosis.

BACKGROUND: Olfactory identification performance has been investigated in several psychiatric populations, with deficits most commonly reported in patients with schizophrenia. In this study, olfactory identification performance was investigated in a more homogenous group of treatment-refractory patients with schizophrenia (T-RS) and in two additional psychiatric groups who demonstrate some similarities to the patients with schizophrenia in terms of symptomotology and medication regime. METHODS: The olfactory identification performance of 16 T-RS patients was assessed using the University of Pennsylvania Smell Identification Test (UPSIT) and compared to that of 16 normal control subjects and two other psychiatric patient groups: 19 affective disorder patients requiring maintenance antipsychotic medication and 20 affective disorder patients not receiving antipsychotic medication. RESULTS: The olfactory identification performance of T-RS patients was significantly lower than that of normal controls but not significantly different from either affective disorder group. The olfactory identification performance of affective disorder patients receiving antipsychotic medication was significantly lower than that of affective disorder patients not receiving antipsychotic medication. DISCUSSION: Results are discussed in the context of a possible link between psychotic symptomotology and olfactory identification performance.

Adult↗
PubMed1999

Synaptic and plasticity-associated proteins in anterior frontal cortex in severe mental illness.

Abnormalities of proteins involved in neurotransmission and neural plasticity at synapses are reported in schizophrenia, and may be markers of dysregulated neural connectivity in this illness. Studies of brain development and neural regeneration indicate a dynamic interplay between neural and oligodendroglial mechanisms in regulating synaptic plasticity and axonal sprouting. In the present study, markers of synapses (synaptophysin), plasticity (growth-associated protein-43) and oligodendrocytes (myelin basic protein) were investigated in anterior frontal cortex homogenates from individuals with schizophrenia and depression. Synaptophysin immunoreactivity was reduced in schizophrenics who died of natural causes relative to controls. Myelin basic protein immunoreactivity was decreased in both schizophrenics and depressed individuals who died by suicide. Overall, no changes were observed in growth-associated protein-43 immunoreactivity. However, a slight increase in immunoreactivity in depressed suicides relative to control was observed. These findings support the hypothesis that synaptic abnormalities are a substrate for disordered connectivity in severe mental illness, and suggest that synaptic-oligodendroglial interactions may contribute to the mechanism of dysregulation in certain cases.

Adult↗
PubMed1999

No evidence for astrogliosis in brains of schizophrenic patients. A post-mortem study.

Schizophrenia is clinically and neuropsychologically characterized by severe cognitive and functional impairment suggesting the presence of a neurodegenerative process in the brains of affected individuals. A variety of neuroanatomical changes have been described such as loss and disorientation of neurons in grey and white matter and cortical atrophy. However, the neuropathological basis for schizophrenia is still unclear. In the present study we monitored the density of GFAP-positive astrocytes in brains of 33 schizophrenic patients and 26 healthy controls. Both grey matter (entorhinal cortex and subiculum) and white matter (premotor cortex, subventricular zone of the third ventricle and next to inferior horn) structures were measured bilaterally. The overall finding was that there is no evidence for increased astrogliosis in brains of schizophrenic patients vs healthy controls. Therefore, degeneration is unlikely to be the main neuropathological mechanism in schizophrenic brains.

Astrocytes↗