PubMed Health⌕ Search

Biomedical subjects

Steven E Arnold

Publications and source records attributed to Steven E Arnold.

36 records · Page 2Linked to original sources
PubMed2004

alpha-Internexin aggregates are abundant in neuronal intermediate filament inclusion disease (NIFID) but rare in other neurodegenerative diseases.

Abnormal neuronal aggregates of alpha-internexin and the three neurofilament (NF) subunits, NF-L, NF-M, and NF-H have recently been identified as the pathological hallmarks of neuronal intermediate filament (IF) inclusion disease (NIFID), a novel neurological disease of early onset with a variable clinical phenotype including frontotemporal dementia, pyramidal and extrapyramidal signs. alpha-Internexin, a class IV IF protein, a major component of inclusions in NIFID, has not previously been identified as a component of the pathological protein aggregates of any other neurodegenerative disease. Therefore, to determine the specificity of this protein, alpha-internexin immunohistochemistry was undertaken on cases of NIFID, non-tau frontotemporal dementias, motor neuron disease, alpha-synucleinopathies, tauopathies, and normal aged control brains. Our results indicate that class IV IF proteins are present within the pleomorphic inclusions of all cases of NIFID. Small subsets of abnormal neuronal inclusions in Alzheimer's disease, Lewy body diseases, and motor neuron disease also contain epitopes of alpha-internexin. Thus, alpha-internexin is a major component of the neuronal inclusions in NIFID and a relatively minor component of inclusions in other neurodegenerative diseases. The discovery of alpha-internexin in neuronal cytoplasmic inclusions implicates novel mechanisms of pathogenesis in NIFID and other neurological diseases with pathological filamentous neuronal inclusions.

Adult↗
PubMed2004

A comparison of classification methods for differentiating fronto-temporal dementia from Alzheimer's disease using FDG-PET imaging.

Flurodeoxyglucose positron emission tomography (FDG-PET) is being explored to determine its ability to differentiate between a diagnosis of Alzheimer's disease (AD) and fronto-temporal dementia (FTD). We have examined statistical discrimination procedures to help achieve this purpose and compared the results to visual ratings of FDG-PET images. The methods are applied to a data set of 48 subjects with autopsy confirmed diagnoses of AD or FTD (these subjects come from a multi-centre collaborative study funded by the National Alzheimer's Coordinating Center). FDG-PET images are composed of thousands of voxels (volume elements) so one is left with a situation where there are vastly more variables than subjects. Therefore, it is necessary to perform a data reduction before a statistical procedure can be applied. Approaches using both the entire image and summary statistics calculated on a number of volumes of interest (VOI) are examined. We performed the data reduction techniques of principal components analysis (PCA) and partial least-squares (PLS) on the entire image and then used linear discriminant analysis (LDA), quadratic (QDA) or logistic regression (LR) to classify subjects as having AD or FTD. Some of these methods achieve diagnostic accuracy (as assessed by leave-one-out cross-validation) that is similar to visual ratings by expert raters. Methods using PLS appear to be more successful. Averaging or using VOI data may also be helpful.

Alzheimer Disease↗
PubMed2004

Neurofibrillary tangles mediate the association of amyloid load with clinical Alzheimer disease and level of cognitive function.

OBJECTIVE: To test the hypothesis that the association of amyloid load with clinical Alzheimer disease (AD) and cognitive impairment is mediated through neurofibrillary tangles. DESIGN: Longitudinal clinicopathologic cohort study. PARTICIPANTS AND SETTING: Forty-four individuals with clinically diagnosed AD and 53 without dementia who participated in the Religious Orders Study underwent a uniform structured clinical evaluation for AD and cognitive testing about 8 months prior to death, and brain autopsy at death. METHODS: The percent area occupied by amyloid-beta and the density of neurofibrillary tangles were quantified from 6 brain regions and averaged to yield summary measures of amyloid load and neurofibrillary tangles. Multivariate regression analyses were used to simultaneously examine the effects of amyloid load and neurofibrillary tangles on clinically diagnosed AD and level of cognition. MAIN OUTCOME MEASURES: Clinically diagnosed AD and level of global cognitive function proximate to death. RESULTS: In separate logistic regression analyses, each 1% increase in amyloid load was associated with about a 50% increase in the odds of clinical AD (P =.002), and each neurofibrillary tangle was associated with a greater than 20% increase in the odds of clinical AD (P<.001). When a term for tangles was added to the regression model with amyloid, the association of amyloid load with clinical disease was reduced by more than 60% and was no longer significant, whereas the association of tangles with clinical disease was essentially unchanged. Similar results were found in analyses of global cognitive function. CONCLUSION: These findings are consistent with a sequence of pathologic events whereby the effect of amyloid deposition on clinical disease is mediated by neurofibrillary tangles.

Aged↗
PubMed2004

Dysbindin-1 is reduced in intrinsic, glutamatergic terminals of the hippocampal formation in schizophrenia.

Eleven studies now report significant associations between schizophrenia and certain haplotypes of single-nucleotide polymorphisms in the gene encoding dysbindin-1 at 6p22.3. Dysbindin-1 is best known as dystrobrevin-binding protein 1 (DTNBP1) and may thus be associated with the dystrophin glycoprotein complex found at certain postsynaptic sites in the brain. Contrary to expectations, however, we found that when compared to matched, nonpsychiatric controls, 73-93% of cases in two schizophrenia populations displayed presynaptic dysbindin-1 reductions averaging 18-42% (P = 0.027-0.0001) at hippocampal formation sites lacking neuronal dystrobrevin (i.e., beta-dystrobrevin). The reductions, which were not observed in the anterior cingulate of the same schizophrenia cases, occurred specifically in terminal fields of intrinsic, glutamatergic afferents of the subiculum, the hippocampus proper, and especially the inner molecular layer of the dentate gyrus (DGiml). An inversely correlated increase in vesicular glutamate transporter-1 (VGluT-1) occurred in DGiml of the same schizophrenia cases. Those changes occurred without evidence of axon terminal loss or neuroleptic effects on dysbindin-1 or VGluT-1. Our findings indicate that presynaptic dysbindin-1 reductions independent of the dystrophin glycoprotein complex are frequent in schizophrenia and are related to glutamatergic alterations in intrinsic hippocampal formation connections. Such changes may contribute to the cognitive deficits common in schizophrenia.

Adult↗
PubMed2003

Decrements in volume of anterior ventromedial temporal lobe and olfactory dysfunction in schizophrenia.

CONTEXT: Patients with schizophrenia exhibit olfactory deficits, but it is unclear whether these represent a specific abnormality. The link between olfactory impairments and regional brain abnormalities has yet to be established. OBJECTIVES: To determine whether patients with schizophrenia exhibit volumetric deficits in the anterior ventromedial temporal lobe, the target for neuronal inputs from the olfactory bulb, and whether these are related to olfactory performance deficits. DESIGN: A cohort study of patients and healthy control subjects who underwent both 1-mm spoiled-gradient echo magnetic resonance imaging and behavioral tests of olfaction and memory. SETTING: Schizophrenia Research Center at the University of Pennsylvania, Philadelphia. PARTICIPANTS: Fifty-two patients with a DSM-IV diagnosis of schizophrenia and 38 healthy control subjects. Individuals were excluded for history of head trauma, significant substance abuse, and medical conditions affecting brain function or olfactory capacity. MAIN OUTCOME MEASURES: Gray matter volumes of the left and right temporal poles and the perirhinal and entorhinal cortexes; olfactory threshold detection sensitivity and identification test scores; composite indexes of verbal and spatial memory ability. RESULTS: Patients had reduced volumes, relative to cranial size, in left (P =.003) and right (P =.01) perirhinal and left (P =.002) and right (P =.002) entorhinal cortexes, but not in the temporal pole. Perirhinal, but not entorhinal, cortical volume decrement was associated with decreased olfactory threshold sensitivity. Neither region was associated with impaired memory performance. CONCLUSIONS: Patients with schizophrenia have reduced cortical volumes in brain regions that receive afferents directly from the olfactory bulb. Behavioral olfactory deficits are related to structural brain abnormalities in these regions.

Adolescent↗
PubMed2003

Subicular dendritic arborization in Alzheimer's disease correlates with neurofibrillary tangle density.

Intracellular accumulation of PHFtau in Alzheimer's disease (AD) disrupts the neuronal cytoskeleton and other neuronal machinery and contributes to axonal and dendritic degeneration, and neuronal death. Furthermore, amyloid-beta (Abeta) has been reported to be toxic to neurons and neurites. While loss of presynaptic elements is an established feature of AD, the nature and extent of dendritic degeneration has been infrequently studied. We investigated MAP2-immunoreactive dendrites using a novel method of high-throughput quantification and also measured cortical thickness and the densities of NeuN-immunoreactive neurons, PHFtau neurofibrillary tangles (NFTs), and Abeta plaque burden in the subiculum in AD and elderly controls. Corrected for atrophy, the "dendritic arborization index" was significantly reduced by up to 66% in all three layers of the subiculum. Laminar thickness was reduced by an average 33% and there was a marked reduction in neuron density of approximately 50%. As expected, NFTs and Abeta plaques were significantly increased in AD. Dendritic arborization indices negatively correlated with NFT densities while no significant correlations were found with Abeta plaque densities. The pattern of dendritic loss in the subiculum and the correlations with NFT densities respectively suggest that deafferentation and intrinsic neurofibrillary degeneration both may contribute to dendritic loss in AD.

Aged↗
PubMed2003

Distribution of microtubule-associated protein MAP2-immunoreactive interstitial neurons in the parahippocampal white matter in subjects with schizophrenia.

OBJECTIVE: Evidence suggests that schizophrenia is a neurodevelopmental disorder that may involve abnormal connectivity between various cortical and subcortical brain areas. The parahippocampal gyrus is an area important for higher cognition in which a variety of cytoarchitectural, neuronal morphometric, and innervation abnormalities in schizophrenia have been reported. Previous studies have reported abnormal distributions of interstitial white matter neurons in prefrontal, parietal, and temporal neocortices, which suggests that schizophrenia may be related to prenatal disturbances in the cortical subplate, a transitory structure involved in the formation of connections in the developing cortex from which the interstitial white matter neurons derive. Abnormalities in the distribution of interstitial white matter neurons in the parahippocampal gyrus in schizophrenia may indicate an alteration in the migration of subplate neurons or in the pattern of programmed cell death that could lead to defective cortical circuitry and impaired cognition. METHOD: The authors used a monoclonal antibody against the microtubule-associated protein MAP2 to label interstitial white matter neurons in the anterior region of the parahippocampal gyrus from 41 individuals with schizophrenia and 15 comparison subjects. The distribution of MAP2-labeled neurons in relation to the gray matter/white matter boundary was determined by computer-assisted microscopy. RESULTS: The number of interstitial white matter neurons decreased with increasing white matter depth in both groups, but significantly more slowly in the schizophrenia group, with interstitial white matter neurons located deeper in white matter in schizophrenia subjects. CONCLUSIONS: These findings indicate there is an abnormality in the residua of the cortical subplate in the anterior region of the adult parahippocampal gyrus in schizophrenia subjects.

Adult↗
PubMed2003

Impairment of odor hedonics in men with schizophrenia.

OBJECTIVE: Olfactory deficits in patients with schizophrenia, including those of odor identification, detection threshold sensitivity, discrimination, and memory, have been well described. Deficits in emotional perception, processing, and experience have also been reported, with anhedonia being one of the core features. While anatomical connections testify to the relationship between olfaction and emotion, there has been little investigation of the hedonic properties of odors in schizophrenia. This study examined intensity and hedonic judgments in patients with schizophrenia to determine whether these functions were differentially impaired. METHOD: Suprathreshold scaling of odor intensity and pleasantness was acquired by using the Suprathreshold Amyl Acetate Odor Intensity and Odor Pleasantness Rating Test given to 30 patients (15 men and 15 women) with a DSM-IV diagnosis of schizophrenia and 30 age- and sex-matched healthy comparison subjects. RESULTS: Despite virtually identical ratings of odor intensity, male patients were impaired in the assignment of odor pleasantness to amyl acetate. This gender-specific diagnostic group difference was not explained by variability in symptom severity or negative/positive symptoms. The impact of smoking status and general cognitive impairment on this deficit was also insignificant. CONCLUSIONS: Findings reveal a gender-specific disruption in the ability to attribute appropriate hedonic valence to odors in male patients with schizophrenia. This difficulty in identifying the hedonic valence of odors, despite intact intensity ratings, is consistent with clinical observations of anhedonia and points to a neural substrate that might contribute to the emotional disturbances seen in patients with schizophrenia.

Adult↗
PubMed2003

Low olfactory bulb volume in first-degree relatives of patients with schizophrenia.

OBJECTIVE: There is a substantial genetic contribution to schizophrenia but no way to readily identify individuals at risk. Biological abnormalities reflecting greater genetic vulnerability may be discovered by examining healthy family members of patients with schizophrenia. There is evidence that olfactory impairments are common in patients. The authors previously reported that patients have abnormal olfactory bulbs, assessed by magnetic resonance imaging (MRI). This study examined olfactory bulbs in patients' relatives to determine whether low bulb volume represents an endophenotypic marker of genetic vulnerability. METHOD: Olfactory psychophysical measures and MRI scans of olfactory bulbs were acquired from 19 healthy first-degree relatives, 20 healthy comparison subjects with similar age and gender distributions, and the 11 patient probands of these relatives. Olfactory bulb volumes were measured by using a reliable region-of-interest procedure. RESULTS: The patients had impaired ability to detect odors and had lower olfactory bulb volumes than the comparison subjects. Although the family members had normal olfactory ability, they exhibited low right bulb volume. The patients had smaller left, but not right, olfactory bulbs than their own healthy relatives. CONCLUSIONS: The findings in family members suggest that structural abnormalities of the olfactory system in schizophrenia may partly reflect preexisting genetic vulnerability to illness. Preliminary analyses suggest that right olfactory bulb volume may serve as an endophenotypic marker of genetic vulnerability, while left bulb volume may reflect overt disease among individuals who share genetic vulnerability. Bulb abnormalities in patients are consistent with reports of cellular abnormalities affecting peripheral olfactory receptor neurons.

Adolescent↗
PubMed2002

Mutations in Rab3a alter circadian period and homeostatic response to sleep loss in the mouse.

Rab3a is the most abundant Rab (ras-associated binding) protein in the brain and has a regulatory role in synaptic vesicle trafficking. Mice with a targeted loss-of-function mutation in Rab3a have defects in Ca(2+)-dependent synaptic transmission: the number of vesicles released in response to an action potential is greater than in wildtype mice, resulting in greater synaptic depression and the abolishment of CA3 mossy-fiber long term potentiation. The effect of these changes on behavior is unknown. In a screen for mouse mutants with abnormal rest-activity and sleep patterns, we identified a semidominant mutation, called earlybird, that shortens the circadian period of locomotor activity. Sequence analysis of Rab3a identified a point mutation in the conserved amino acid (Asp77Gly) within the GTP-binding domain of this protein in earlybird mutants, resulting in significantly reduced levels of Rab3a protein. Phenotypic assessment of earlybird mice and a null allele of Rab3a revealed anomalies in circadian period and sleep homeostasis, providing evidence that Rab3a-mediated synaptic transmission is involved in these behaviors.

Alleles↗
PubMed2002

Neuropsychological functioning in elderly patients with schizophrenia and Alzheimer's disease.

Cognitive functioning was compared in elderly patients with schizophrenia, elderly patients with probable Alzheimer's disease (AD), and matched healthy controls using a brief neuropsychological battery. Both schizophrenia and AD patients demonstrated marked impairment as compared to controls, with the profile of neuropsychological deficits in both disorders appearing remarkably similar. Only visual confrontation naming, verbal delayed recall, and rate of forgetting (i.e. savings score) significantly differentiated between the two patient groups, with AD patients showing poorer overall recall and more rapid forgetting of verbal information over delay. In addition, schizophrenia subjects showed a significantly greater deficit in visual confrontation naming than the AD group. The relationship of neuropsychological function and clinical symptoms of schizophrenia subjects was also examined. Results showed that word list learning, delayed recall, and rate of forgetting correlated most strongly with positive and negative symptoms. Recent neuropathological studies have indicated abnormalities in specific subfields of the hippocampal formation in schizophrenia that are also severely affected in AD. Though the specific histopathology of the two disorders differs, abnormalities in the common sites may underlie the common neuropsychological profile.

Age Factors↗
PubMed2002

Gene expression profile for schizophrenia: discrete neuron transcription patterns in the entorhinal cortex.

BACKGROUND: Several lines of evidence indicate the altered function of the temporal lobe, including the hippocampus and entorhinal cortex (EC), is associated with schizophrenia. We used single-cell gene expression technologies to assess coordinate changes in the expression of multiple genes, including neuronal signaling and synaptic-related markers in EC layer II stellate neurons. METHODS: We used a single-neuron microdissection technique coupled with linear antisense RNA amplification and high density/candidate gene arrays to assess coordinate changes in gene expression. The expression and relative abundance of more than 18,000 messenger RNAs were assessed from EC layer II stellate neurons from postmortem samples of schizophrenic and age-matched control brains. Results of this initial screen were used to perform a more specific secondary messenger RNA screen for each subject. RESULTS: Data disclosed marked differences in expression of various G-protein-coupled receptor-signaling transcripts, glutamate receptor subunits, synaptic proteins, and other transcripts. Results of secondary screening showed significant decreases in levels of G-protein subunit i(alpha)1, glutamate receptor 3, N-methyl-D-aspartate receptor 1, synaptophysin, and sensory nerve action potentials 23 and 25 in the stellate neurons of schizophrenic patients. We observed down-regulation of phospholemman (a phosphoprotein associated with anion channel formation) messenger RNA and protein levels in layer II/III stellate neurons in the population with schizophrenia. CONCLUSIONS: These results provide a preliminary expression profile of schizophrenia in defined neuronal populations. Understanding the coordinated involvement of multiple genes in human disease provides insight into the molecular basis of the disease and offers new targets for pharmacotherapeutic intervention.

Aged↗
PubMed2002

Parahippocampal tau pathology in healthy aging, mild cognitive impairment, and early Alzheimer's disease.

Abnormally phosphorylated tau accumulates as neurofibrillary tangles and neuropil threads in older persons with and without Alzheimer's disease. The relationship between neurofibrillary tangles and neuropil threads and how they relate to cognitive function is unknown. This study investigated the relationship between phosphorylated tau lesions and cognitive function in 31 persons participating in the Religious Orders Study, a prospective, longitudinal clinicopathological study of aging and Alzheimer's disease. All subjects underwent detailed neuropsychological performance testing within a year of death and evidenced a spectrum of cognitive performance ranging from normal abilities to mild dementia. Measures of neurofibrillary tangle density and phosphorylated tau immunoreactive structures (predominantly neuropil threads) in the entorhinal and perirhinal cortices by quantitative image analysis were significantly correlated (r = 0.5). In multiple linear regression analyses controlling for age, sex, and education, parahippocampal neurofibrillary tangles and neuropil threads were significantly lower in persons without cognitive impairment compared to those with mild cognitive impairment and/or Alzheimer's disease. Further, neurofibrillary tangles were significantly correlated to measures of episodic memory but not other cognitive abilities; neuropil tangles were not significantly related to memory or other cognitive functions. These data indicate that phosphorylated tau pathology in the ventromedial temporal lobe develop prior to the onset of clinical dementia and their presence is associated with cognitive impairment, particularly impairment of episodic memory.

Aged↗
PubMedDate not supplied

Harm avoidance and disability in old age.

The relation of personality to disability in old age is not well understood. The authors examined the relation of harm avoidance, a trait indicating a tendency to worry, fear uncertainty, be shy, and tire easily, to disability in a group of 474 older persons without dementia. Participants completed the 35-item Harm Avoidance scale. Disability was assessed with the Rosow-Breslau scale, a self-report measure of physical mobility. Performance-based tests of lower limb functions were also administered from which composite measures of gait, balance, and strength were derived. In a logistic regression model controlled for age, sex, education, and lower limb function, persons with high levels of harm avoidance were nearly three times as likely to report mobility limitations as persons with low levels, and these effects largely reflected fatigability and fear of uncertainty. The association of harm avoidance with disability was not explained or modified by frailty, physical activity, depressive symptoms, neuroticism, extraversion, or cognition. The results suggest that harm avoidance is associated with disability in old age.

Activities of Daily Living↗
PubMedDate not supplied

Relationship between clock-drawing and neuropsychological and functional status in elderly institutionalized patients with schizophrenia.

OBJECTIVE: The authors sought to examine the usefulness of the clock-drawing test (CDT) as a measure of general cognitive and adaptive functioning in elderly patients with schizophrenia. METHODS: CDT performance of elderly institutionalized patients with schizophrenia were contrasted with a comparison group, similar in age. Cognitive and functional status was examined using an expanded battery from the Consortium to Establish a Registry for Alzheimer's disease and the Psychogeriatric Dependency Rating Scale. RESULTS: Patients (N=21) performed more poorly overall on the CDT than the comparison group (N=21), with greater clock number and hand errors. Production of the clock's gestalt did not differ between groups. In patients, overall CDT performance and clock hand placement were significantly correlated with general cognitive functioning, memory, visuoconstruction, and word-list generation. CDT global and hand placement performances corresponded to patients' general orientation. CONCLUSIONS: Impaired CDT performance in elderly patients with schizophrenia is not attributable to normal aging. Also, the CDT uniquely relates to an array of cognitive abilities in this population, validating its multicognitive character and implicating multiple brain regions. The CDT's tolerability and brevity make it attractive for use in geriatric schizophrenia.

Adaptation, Psychological↗
PubMedDate not supplied

Evidence for oxidative DNA damage in the hippocampus of elderly patients with chronic schizophrenia.

OBJECTIVE: The authors investigated the idea that some patients with schizophrenia exhibit a chronic, deteriorating course without showing frank neurodegeneration at postmortem examination. Oxidative damage is one form of cellular injury that may cause cellular dysfunction without necessarily leading to neuron death. METHODS: Authors obtained postmortem hippocampi from 13 elderly non-psychiatric comparison cases and 10 patients with "poor-outcome" schizophrenia. The groups were compared for the presence of neuronal 8-hydroxy, 2' deoxyguanosine (8-OHdG), a robust marker of oxidized DNA, and neuronal Ki-67, a marker of cell-cycle activation, as well as neurofibrillary tangles, amyloid-beta senile plaques, and astrocytosis. RESULTS: The mean proportion of neurons exhibiting 8-OHdG immunoreactivity was 10 times higher in schizophrenia than in comparison cases. Ki-67 was similarly elevated and was correlated with 8-OHdG in the schizophrenia group. There were no significant between-group differences for densities of neurofibrillary tangles, amyloid-beta plaques, or astrocytes. CONCLUSIONS: Our data provide evidence for oxidative DNA damage and coordinated cell-cycle activation in elderly "poor-outcome" schizophrenia. These findings could have important implications for cellular metabolism, gene expression, and membrane functioning in schizophrenia.

Adenosine Triphosphate↗
PubMedDate not supplied

Cerebral infarctions and the relationship of depression symptoms to level of cognitive functioning in older persons.

OBJECTIVE: Recent studies report an association between depressive symptoms and cognitive impairment in old age. The neurobiologic basis of this association is unknown. The authors examined whether cerebral infarcts (present in 55 persons) accounted for the association of depressive symptoms with cognitive impairment in a group of 153 older Catholic nuns, priests, and brothers (67 with dementia and 86 without dementia). METHODS: Subjects underwent detailed clinical evaluations and brain autopsy at death. RESULTS: Mean values for depressive symptoms during the time of participation were associated with level of cognitive functioning proximate to death in analyses that controlled for age, sex, education, and Alzheimer disease (AD) pathology. The association of depressive symptoms with cognitive functioning was essentially unchanged after controlling for cerebral infarctions, which suggests that depressive symptoms, cerebral infarctions, and AD pathology were independently related to cognitive function. Similar results were found in analyses with episodic memory, semantic memory, working memory, perceptual speed, and visual-spatial ability. The results did not change in analyses examining the volume or location of cerebral infarctions. CONCLUSIONS: These data suggest that cerebral infarctions do not account for the association of depressive symptoms with level of cognitive functioning. The neurobiologic basis for this association remains to be elucidated.

Aged↗