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Biomedical subjects

Andrew J Dwork

Publications and source records attributed to Andrew J Dwork.

10 recordsLinked to original sources
PubMed2026

Dysregulated adult hippocampal neurogenesis in major depressive disorder.

Major depressive disorder (MDD) is associated with reduced hippocampal volume, altered connectivity and negative memory bias, suggesting disrupted hippocampal plasticity. Dysregulated adult hippocampal neurogenesis is a potential contributor, but its relevance in humans and role in MDD remain unclear. Here we investigated the molecular basis of hippocampal dysfunction in nonmedicated individuals with MDD by integrating analyses of neurogenic trajectories, cell-type- and subfield-specific gene expression, chromatin accessibility and protein expression. We identify a neurogenic lineage in the adult human hippocampal subgranular zone and provide evidence for a stalled neurogenic process in MDD, associated with transcriptional regulation, stress-related reprogramming and interferon signaling across developmental stages. Excitatory and inhibitory neurons show dysregulation of transcription factor networks affecting cell states. Cellular stress, excitatory-inhibitory imbalance, impaired synaptic plasticity, reduced metabolic capacity and immune activation, underlie impaired neurogenesis and reduced hippocampus circuit plasticity. Findings indicate genetic and epigenetic regulation of gene expression in MDD, and overlapping pathogenetic mechanisms with autoimmune, neurodevelopmental and neurodegenerative diseases. This work provides a new understanding of the pathogenesis of hippocampus-dependent cognitive symptoms in MDD and suggests potential therapeutic targets.

Journal Article↗
PubMed2007

Lifelong course of positive and negative symptoms in chronically institutionalized patients with schizophrenia.

BACKGROUND: Despite widespread policies of deinstitutionalization, a substantial number of patients with schizophrenia require continuous custodial care. The hospital records of such patients provide contemporaneous documentation of symptoms throughout the illness, permitting a longitudinal study of the course of symptoms. We sought to describe this course, and to determine the influences of sex, age of onset, and treatment on its evolution. METHODS: Using the modified Diagnostic Evaluation After Death, we performed standardized chart reviews of 99 chronic inpatients who remained in state institutions through the 1960's and 1970's and subsequently died in those institutions. Data were available from the onset of illness until death. RESULTS: We found significant decreases in positive symptoms and increases in negative symptoms over the course of the illness. Symptom patterns were analyzed by repeated measures ANOVA. Onset before age 25 was associated with greater numbers of negative symptoms at a given age (p = 0.05). Female sex was associated with greater numbers of positive symptoms (p=0.04). The widespread introduction of neuroleptic drugs in the mid-1950's did not affect the trends in symptom patterns. CONCLUSIONS: The lifetime course of schizophrenia in chronically institutionalized individuals is characterized by a decrease in positive symptoms and an increase in negative symptoms. Schizophrenia with earlier onset is associated with greater numbers of negative symptoms throughout life. In this sample of patients, chronically hospitalized until death, neuroleptic drugs failed to effect a persistent decrease in positive symptoms.

Activities of Daily Living↗
PubMed2005

Hippocampal complexin proteins and cognitive dysfunction in schizophrenia.

BACKGROUND: Converging neuroimaging and postmortem evidence indicates synaptic terminals are abnormal in schizophrenia. A putative molecular mechanism implicates abnormalities of proteins involved in the presynaptic secretory machinery, including the modulator proteins complexin I and complexin II. OBJECTIVES: To determine the amount and distribution of complexin proteins in the hippocampus of subjects with schizophrenia, in parallel with markers for excitatory and inhibitory nerve terminals. The functional implications were also investigated. DESIGN: We used immunocytochemistry to study complexin I and complexin II proteins in hippocampus, as well as the vesicular transporters for gamma-aminobutyric acid (GABA) and for glutamate. Immunocytochemical findings were correlated with cognitive function assessed through medical record review. To further explore the implications of the human findings, we studied rats exposed to haloperidol, amphetamine, and ketamine as well as rats trained in memory tasks. SUBJECTS: We studied hippocampal sections from 12 subjects with schizophrenia and 12 subjects with no known neuropsychiatric disorder. RESULTS: The absolute values and ratio of the hippocampal presynaptic proteins complexin II-complexin I were lower in subjects with schizophrenia. Disturbances in the complexin proteins in subjects with schizophrenia were greater than those observed for vesicular gamma-aminobutyric acid or vesicular glutamate transporters. The lower complexin II-complexin I ratio in several hippocampal subfields in subjects with schizophrenia was inversely correlated with the severity of antemortem cognitive impairment. In contrast, the hippocampal complexin II-complexin I ratio was higher in rats trained in a memory task compared with untrained rats. Treatment of rats with antipsychotic drugs or with the psychotomimetic drugs amphetamine or ketamine did not alter the complexin II-complexin I ratio. CONCLUSIONS: The pathology of hippocampal complexin proteins might play an important role in schizophrenia, especially concerning cognitive disturbances.

Adaptor Proteins, Vesicular Transport↗
PubMed2005

Altered subicular MAP2 immunoreactivity in schizophrenia.

We wished to test independently a previously reported loss of subicular microtubule-associated protein 2 (MAP2) in the brains of deceased individuals who had suffered from schizophrenia, and to determine whether there were any clinical characteristics attached to such a loss. Immunohistochemistry for MAP2 was examined in the hippocampal region from 94 psychiatric patients: 64 with a primary diagnosis of schizophrenia or schizoaffective disorder, 12 with a primary diagnosis of major depressive or bipolar disorders, and 18 with a primary diagnosis of dementia; and from 17 individuals without psychiatric disease. Lifelong symptomatology was evaluated with the modified Diagnostic Evaluation After Death. Subicular MAP2 immunoreactivity was prominently depressed in 20% of schizophrenia cases, 8% of mood disorder cases, 22% of dementia cases, and in no nonpsychiatric cases. Among dementia cases, those with loss of subicular MAP2 immunoreactivity displayed more subicular gliosis, while among the schizophrenia cases, there was no such association. Among schizophrenia subjects, loss of subicular MAP2 immunoreactivity was associated with fewer positive and negative symptoms over the course of the illness. Subicular MAP2 immunoreactivity is markedly diminished in a significant proportion of individuals chronically institutionalized for schizophrenia, and this does not represent a generalized destruction of subicular neurons. In contrast, among individuals institutionalized for dementia, loss of subicular MAP2 immunoreactivity is accompanied by gliosis. The loss of MAP2 immunoreactivity is associated with fewer clinical symptoms, suggesting that it may represent an adaptive response to schizophrenia. The chemical or structural abnormalities underlying decreased MAP2 immunoreactivity in schizophrenia remain to be determined.

Aged↗
PubMed2004

Absence of histological lesions in primate models of ECT and magnetic seizure therapy.

OBJECTIVE: The authors present preliminary findings from the first nonhuman primate neuropathological study of ECT to use perfusion fixation and adequate controls and the first to compare ECT with magnetic seizure therapy, to their knowledge. METHOD: Twelve Macaca mullata received 6 weeks of daily ECT, magnetic seizure therapy, or anesthesia alone. After perfusion fixation, their brains were examined while masked to intervention. RESULTS: No identified lesions were attributable to the interventions. Cortical and hippocampal immunoreactivity for glial fibrillary acidic protein (an astrocytic marker) was most intense in the group that received ECT. CONCLUSIONS: This small but rigorous primate study supports the view that ECT does not produce histological lesions in the brain and provides the first comparable safety data on magnetic seizure therapy.

Amygdala↗
PubMed2003

Optimization of Golgi methods for impregnation of brain tissue from humans and monkeys.

Golgi impregnation is unique in its ability to display the dendritic trees of large numbers of individual neurons. However, its reputation for inconsistency leaves many investigators reluctant to embrace this methodology, particularly for the study of formalin-fixed human brain tissue. After reviewing the literature, testing a variety of technical variations, and discussing the procedure with experienced practitioners, we have concluded that much of the unpredictability can be removed by matching the Golgi technique to the conditions that were used for fixation of the tissue. Briefly fixed tissues worked best with the rapid Golgi technique, which includes osmium during the initial chromation step, and with the Golgi-Cox method, which includes mercuric chloride during chromation. For tissues that have been fixed for several years or even for several decades, superior results are obtained with the Golgi-Kopsch technique, using multiple changes of a chromation solution that contains paraformaldehyde. In the Golgi-Kopsch technique, pH should be used to monitor the reduction of Cr6+ to Cr3+, which is a crucial determinant of successful chromation. With any Golgi technique, agitation throughout the impregnation helps to avoid precipitates and to improve the quality of impregnation. When the appropriate method is chosen, Golgi impregnation is a useful technique for the neuropathologist.

Animals↗
PubMed2002

Altered editing of serotonin 2C receptor pre-mRNA in the prefrontal cortex of depressed suicide victims.

Five adenosines within the coding sequence of the serotonin 2C receptor (5-HT2C) pre-mRNA are converted to inosines by RNA editing (named A, B, C' (E), C, and D sites). In human prefrontal cortex (PFC), the most abundant 5-HT2C mRNA sequences result from editing at the A site, or from the editing combinations AC'C, ABCD, and ABD. In suicide victims with a history of major depression, C' site editing is significantly increased, D site editing is significantly decreased, and the C site shows a trend toward increased editing. Treatment of mice with the antidepressant drug fluoxetine (Prozac) causes changes in C', C, and D site editing that are exactly opposite to those seen in suicide victims. Thus, one outcome of fluoxetine treatment may be to reverse the abnormalities in 5-HT2C pre-mRNA editing seen in depressed suicide victims.

Adult↗
PubMed2002

Abnormalities of SNARE mechanism proteins in anterior frontal cortex in severe mental illness.

A fundamental molecular component of neural connectivity is the SNARE (SNAP receptor) protein complex, which consists of three proteins, syntaxin, SNAP-25 and VAMP. Under appropriate conditions, the SNARE complex can be formed in vitro. To investigate the hypothesis that dysregulation of SNARE proteins or their interactions could be abnormal in severe mental disorders, the three SNARE proteins and the complex were studied in post-mortem anterior frontal cortex homogenates. An ELISA was used to quantify SNARE protein immunoreactivities in cortical homogenates from four groups: patients with schizophrenia who died of causes other than suicide (n = 6), patients with schizophrenia and suicide (n = 7), patients with depression and suicide (n = 11), and controls (n = 11). Differences between groups in patterns of SNARE protein immuno-reactivities were demonstrated [Wilks' Lambda F(9,68) = 3.57, P = 0.001]. Protein-by-protein analyses indicated a significant reduction in SNAP-25 immunoreactivity in the schizophrenia non-suicide group [28% decrease relative to controls, F(3,31) = 6.45, P = 0.002, Student-Newman-Keuls test, P < 0.01]. The intercorrelations between SNARE protein and synaptophysin immunoreactivities were high in controls, but lower in the other groups, further indicating disturbances in relationships between these proteins. The extent of SNARE complex formation in vitro was studied using immuno-blotting. Significant differences related to group membership were observed for the SNARE complexes identified by SNAP-25 [Wilks' Lambda F(3,31) = 4.76, P = 0.008] and by syntaxin immunostaining [Wilks' Lambda F(3,31) = 9.16, P = 0.0002]. In both groups with suicide as a cause of death, relatively more SNAP-25 and syntaxin was present in the heterotrimeric SNARE complex than in other molecular forms. These abnormalities in the SNARE complex could represent a molecular substrate for abnormalities of neural connectivity in severe mental disorders.

Adult↗