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Biomedical subjects

Brian Kirkpatrick

Publications and source records attributed to Brian Kirkpatrick.

At least 19 recordsLinked to original sources
PubMed2006

Lack of association between COMT gene and deficit/nondeficit schizophrenia.

BACKGROUND: The dopamine dysregulation hypothesis of schizophrenia posits that positive, negative and cognitive symptoms correlate with cortical/subcortical imbalances in dopaminergic transmission. A functional polymorphism (Val158Met) in the catechol-O-methyltransferase (COMT) gene is implicated in the pathophysiology of schizophrenia by its effect on prefrontal dopamine transmission, and its unique impact on prefrontal cognitive and behavioral phenotypes. Cognitive impairments and negative symptoms in schizophrenia have been hypothesized to be associated with hypodopaminergic states. Schizophrenia patients with the deficit syndrome are characterized by primary enduring negative symptoms, impairment on neurocognitive tasks sensitive to frontal and parietal cortical functioning, and poorer functional outcome compared to non-deficit patients. METHODS: Eighty-six schizophrenia cases that met DSM-IV criteria for schizophrenia were recruited. Additional categorization into deficit and nondeficit syndrome was performed using the Schedule for the Deficit Syndrome (SDS). A healthy comparison group (n = 50) matched to cases on age and ethnicity was recruited. Allele and genotype frequencies of the Val158Met polymorphism were compared among healthy controls, and schizophrenia cases with the deficit (n = 21), and nondeficit syndrome (n = 65). RESULTS: There was a significant difference in Val/Val genotype frequencies between schizophrenia cases (combined deficit/nondeficit) and healthy controls (p = 0.004). No significant differences in allele or genotype frequencies were observed between deficit and nondeficit cases. CONCLUSION: Results from this preliminary analysis failed to show an effect of COMT gene on deficit schizophrenia.

Journal Article↗
PubMed2006

Neuropsychology of the deficit syndrome: new data and meta-analysis of findings to date.

The deficit syndrome is thought to characterize a pathophysiologically distinct subgroup of patients with schizophrenia. Supporting this notion, prior research examining the neuropsychological correlates of the deficit syndrome has suggested the presence of a differential impairment in frontal and parietal functions. This article reports findings from 2 studies attempting to replicate and extend previous reports of a differential neuropsychological impairment in deficit schizophrenia. In the first study, we administered a comprehensive neuropsychological battery to 20 deficit and 25 nondeficit patients with schizophrenia and 25 normal healthy controls. In the second study, a meta-analysis was conducted of 13 separate studies examining the neuropsychology of the deficit syndrome. There was little evidence from either of the present studies that the deficit syndrome is associated with a selective impairment in frontal and parietal lobe functions. The first study failed to find significant differences in frontal or parietal abilities for deficit vs nondeficit patients. The meta-analytic findings revealed that deficit patients were globally more neuropsychologically impaired than nondeficit patients (effect size [ES] = 0.41). Relative to nondeficit patients, deficit patients performed poorest on tests of olfaction (ES = 1.11), social cognition (ES = 0.56), global cognition (ES = 0.52), and language (ES = 0.51). The neuropsychological impairments associated with the deficit form of schizophrenia do not follow an obvious anatomically defined pattern of impairment. The question of whether deficit patients exhibit a unique cognitive impairment profile will require a more sophisticated and rigorous examination of the neuropsychology of the deficit syndrome.

Adult↗
PubMed2006

DISC1 immunoreactivity at the light and ultrastructural level in the human neocortex.

Disrupted-In-Schizophrenia 1 (DISC1) is one of two genes that straddle the chromosome 1 breakpoint of a translocation associated with an increased risk of schizophrenia. DISC1 has been identified in the brain of various mammalian species, but no previous immunocytochemical studies have been conducted in human neocortex. We examined DISC1 immunoreactivity in frontal and parietal cortex (BA 4, 9, 39, and 46) in normal human brain. At the light microscopic level, immunolabeling was prominent in the neuropil, in multiple populations of cells, and in the white matter. At the ultrastructural level, staining was prominent in structures associated with synaptic function. Immunolabeled axon terminals comprised 8% of all terminals and formed both asymmetric and symmetric synapses. Labeled axon terminals formed synapses with labeled spines and dendrites; in some, only the postsynaptic density (PSD) of the postsynaptic structure was labeled. The most common configuration, however, was an unlabeled axon terminal forming an asymmetric synapse with a spine that had immunoreactivity deposited on the PSD and throughout the spine. The presence of DISC1 in multiple types of synapses suggests the involvement of DISC1 in corticocortical as well as thalamocortical connections. Staining was also present in ribosomes, parts of the chromatin, in dendritic shafts, and on some microtubules. Labeling was absent from the Golgi apparatus and multivesicular bodies, which are associated with protein excretion. These anatomical localization data suggest that DISC1 participates in synaptic activity and microtubule function, and are consistent with the limited data on its adult function.

Adult↗
PubMed2006

Three dimensions of clinical symptoms in elderly patients with schizophrenia: prediction of six-year cognitive and functional status.

BACKGROUND: A three-syndrome categorization of schizophrenia has been recently proposed [Arndt, S., Alliger R.J., Andreasen, N.C., 1991. The distinction of positive and negative symptoms: the failure of a two-dimensional model. Br. J. Psychiatry 158, 317-322; Miller, D.D., Arndt, S., Andreasen, N.C., 1993. Alogia, attentional impairment, and inappropriate affect: their status in the dimensions of schizophrenia. Comp. Psychiatry 34, 221-226; Gur, R.E., Mozley, D., Resnick, S.M., Levick, S., Erwin, R., Saykin, A.J., Gur, R.C., 1991. Relations among clinical scales in schizophrenia. Am. J. Psychiatry 148, 472-478. Brown, K.W., White, T., 1992. Syndromes of chronic schizophrenia and some clinical correlates. Br. J. Psychiatry 161, pp. 317-322]. METHODS: Chronic, elderly, schizophrenia patients with deficit (N = 111), nondeficit with High reality distortion/Low conceptual disorganization (nondeficit-delusional) (N = 40) and nondeficit with Low reality distortion/High conceptual disorganization (nondeficit-disorganized) (N = 56) were followed-up for 6 years. Assessment included the Positive and Negative Syndrome Scale (PANSS), the Mini-mental Status Examination (MMSE) and the Alzheimer's Disease Assessment-Late Stage Cognitive and Non-Cognitive Subscale (ADAS-L Cog and ADAS-L Self care). RESULTS: At initial assessment, MMSE scores were significantly lower, while the ADAS-L Cog and Negative symptoms were significantly higher in the deficit and nondeficit-disorganized groups compared with the nondeficit-delusional group (all p values <0.05). Positive symptoms were significantly lower in the deficit group than in both nondeficit syndrome groups (p < 0.05). On the ADAS-L Self Care scale the nondeficit-delusional group was the most impaired while the nondeficit-disorganized was the least impaired. There was a significant decline over time in MMSE scores in the deficit and the nondeficit-delusional groups (p < 0.01), but no change in the nondeficit-disorganized group. ADAS-L Cog and ADAS-L Self Care functions worsened over time in all three groups (p < 0.0001). Severity of negative symptoms was stable over time in deficit patients and in nondeficit-disorganized patients but worsened in nondeficit-delusional patients (p < 0.001). There was also a significant worsening of positive symptoms over time in deficit patients (p = 0.04). CONCLUSION: Deficit, nondeficit-delusional and nondeficit-disorganized patients with schizophrenia may represent distinct subgroups discriminated by different courses in negative and positive symptoms and cognitive status.

Age of Onset↗
PubMed2006

Season of birth and schizophrenia in Northeast Brazil: relationship to rainfall.

Although the association of schizophrenia and winter birth has been replicated many times in the Northern hemisphere, studies in the Southern hemisphere have been less consistent in their findings. A study from NE Brazil indicated the period between May and July, 3 months after the peak in rainfall, as a risk period for schizophrenia birth. We report findings from a random selection of charts (N = 1789) from the only public inpatient psychiatric facility in Ceará, Brazil (2 degrees to 5 degrees S). We compared the seasonality of birth in the schizophrenia group (N = 406) to multiple control groups: (1) psychosis not otherwise specified (N = 868), (2) other psychiatric diagnoses (N = 515), and (3) the average monthly birth rate in the general population. Patients with schizophrenia had a significantly greater risk of being born in the risk period compared with any of the control groups. There is a significant association between rainfall in a month and schizophrenia births 3 (p = 0.03) and 4 months (p = 0.01) later. This study corroborates findings of a significant seasonality in schizophrenia births in northeast Brazil.

Birth Rate↗
PubMed2005

Deficit schizophrenia: association with serum antibodies to cytomegalovirus.

BACKGROUND: Patients with deficit schizophrenia differ from nondeficit patients with schizophrenia relative to several neurobiological correlates and relative to the risk factors of family history and season of birth. Exposure to human herpesviruses is a possible risk factor for schizophrenia. We hypothesized that there would be deficit/nondeficit difference in the prevalence of serum antibodies to human herpesviruses. METHODS: In deficit (N = 88) and nondeficit (N = 235) schizophrenia patients, we measured IgG class antibodies to the 6 known human herpesviruses: herpes simplex virus type 1, herpes simplex virus type 2, cytomegalovirus, Epstein-Barr virus, human herpes virus 6, and varicella-zoster virus. RESULTS: Deficit categorization was associated with the presence of serum antibodies to cytomegalovirus (odds ratio = 2.01, p = .006). This association remained significant after covarying for positive psychotic symptoms and demographic features known to be associated with cytomegalovirus seropositivity and after correcting for multiple comparisons. An association between herpes simplex virus type 1 and deficit status was not significant after covarying for potentially confounding variables. No other human herpesvirus was significantly associated with deficit versus nondeficit categorization. CONCLUSIONS: The association between deficit schizophrenia and cytomegalovirus antibody seropositivity provides further evidence for differences in etiopathophysiology between deficit and nondeficit schizophrenia.

Adult↗
PubMed2005

Catechol-O-methyltransferase Val158Met polymorphism in schizophrenia: associations with cognitive and motor impairment.

Cognitive and motor deficits have been proposed as markers of abnormal neurodevelopment in schizophrenia and have been associated with genetic liability. In a multicenter study involving 106 subjects, 56 with deficit schizophrenia and 50 with nondeficit schizophrenia, we tested the hypothesis that the catechol-O-methyltransferase (COMT) Val(158)Met polymorphism is associated with cognitive and motor deficits either in schizophrenia as a whole or in its deficit subtype. The COMT Val(158)Met polymorphism shared 6.6% of the executive/attention dysfunction variance in patients with schizophrenia and 15.6% of the motor impairment variance in patients with deficit schizophrenia. These results support the hypothesis that the COMT Val(158)Met polymorphism influences executive functions in schizophrenia and the neuromotor performance in the deficit subtype only.

Adolescent↗
PubMed2005

Ultrastructural localization of reelin in the cortex in post-mortem human brain.

Reelin is a glycoprotein that plays a critical role in brain development, including proper cortical lamination. In adult animals, reelin continues to be expressed in different neuronal populations in many brain regions. We performed labeling for reelin immunoreactivity (-i) in post-mortem cerebral cortex from five adults and two fetuses with three different antibodies. The tissue was then processed for light and electron microscopy. In cell bodies, reelin-i was found in pyramidal and nonpyramidal neurons on the outer nuclear membrane, rough endoplasmic reticulum (rER), and ribosomes. In dendrites, labeling was found in the rER and ribosomes and was diffusely distributed in spines. In the neuropil, diffuse labeling was seen in small axon terminals and unmyelinated axons, and the postsynaptic density (PSD) frequently had discrete labeling. Reelin-i was also found in glial somata and in small astrocytic processes. With rare exceptions, reelin-i in the adult was conspicuously absent from both the extracellular matrix (ECM) and the subcellular organelles, where secreted proteins are modified and taken back into the cell. Labeling in fetal cortex was similar to that in the adult except for prominent labeling in the ECM. The presence of reelin in adult spines, PSD, and terminals suggests that in the adult human reelin has a role in synaptic remodeling, which is consistent with the evidence for its role in long-term potentiation in the adult brain.

Adult↗
PubMed2005

COMT Val(158)Met and BDNF C(270)T polymorphisms in schizophrenia: a case-control study.

In a multicenter study involving 217 subjects of European ancestry [106 patients with schizophrenia and 111 healthy subjects], we tested the hypothesis that the catechol-O-methyl transferase (COMT) Val(158)Met and/or the brain-derived neurotrophic factor (BDNF) C(270)T gene polymorphisms are associated with schizophrenia. The COMT and BDNF genotype and their allele distribution did not differ between patients with schizophrenia and healthy comparison subjects. These results do not support the hypothesis that the COMT Val(158)Met or BDNF C(270)T gene polymorphisms are associated with liability to schizophrenia.

Alleles↗
PubMed2005

Developmental changes in rat cardiac titin/connectin: transitions in normal animals and in mutants with a delayed pattern of isoform transition.

Rat cardiac titin undergoes developmental changes in isoform expression during the period from late embryonic through the first 20-25 days of life. At least five size classes of titin isoforms have been identified using SDS agarose gel electrophoresis. The longest normal isoform is expressed in the embryonic stages, and it is progressively replaced with increasingly smaller versions. The isoform switching is consistent with changes in resting tension from lower values in one-day neonates to higher levels in adult myocytes. Considerable micro-heterogeneity in alternative splicing patterns also was found, particularly in the N2BA PEVK region of human, rat, and dog ventricle. A rat mutation has been identified in which the embryonic-neonatal titin isoform transitions are markedly delayed. These mutant animals may prove useful for examining the role of titin in stretch-activated signal transduction and in the Frank-Starling relationship.

Alternative Splicing↗
PubMed2005

Olanzapine treatment of residual positive and negative symptoms.

OBJECTIVE: Olanzapine has been hypothesized to have superior efficacy in patients with treatment-resistant schizophrenia. The authors examined the comparative efficacy and safety of olanzapine and haloperidol in outpatients with partially responsive schizophrenia. METHOD: Sixty-three outpatients with schizophrenia who met retrospective and prospective criteria for either residual positive or residual negative symptoms entered a 16-week double-blind, parallel-groups comparison of olanzapine and haloperidol. RESULTS: There were no significant differences between the two drugs in their effect on positive or negative symptoms. There were no significant differences between the two treatment groups on measures of social and functional outcome. Olanzapine-treated patients had a significant reduction in extrapyramidal symptoms and subjective measures of stiffness and dry mouth, but the increases in systolic blood pressure and weight in olanzapine-treated patients were significantly greater than they were in haloperidol-treated patients. CONCLUSIONS: Olanzapine has limited differential benefit for either positive or negative symptoms in patients with treatment-resistant schizophrenia. Although olanzapine is associated with fewer extrapyramidal symptoms, other side effects may offset this benefit.

Adult↗
PubMed2004

Summer birth and deficit schizophrenia: a pooled analysis from 6 countries.

BACKGROUND: In some reports, summer birth has been associated with deficit schizophrenia. Deficit schizophrenia and nondeficit schizophrenia also differ in several other ways. OBJECTIVE: To conduct a combined analysis of the published and unpublished data sets from the northern hemisphere that relate deficit and nondeficit schizophrenia to month of birth. DATA SOURCES: Studies of season of birth in which it was possible to make a deficit/nondeficit categorization. STUDY SELECTION: Published studies with samples of convenience and all known population-based studies with the deficit/nondeficit categorization were included. The studies came from 6 countries. DATA EXTRACTION: Three published studies of samples of convenience, 2 population-based prevalence studies, and 5 population-based studies that approximated incident samples were included. Month of birth was compared for deficit and nondeficit schizophrenia, using meta-analytic fixed-effects models. DATA SYNTHESIS: A group x month goodness-of-fit chi2 showed a significant difference between deficit and nondeficit subjects in season of birth (P < .001) in the studies that approximated incidence. This difference was largely due to an increase in deficit schizophrenia births in June and July (odds ratio, 1.9; 95% confidence interval, 1.3-2.9). Similar results were found in the prevalence studies. A similar pattern was found in 2 of the 3 samples of convenience, but when combined, these 3 samples did not show a significant deficit/nondeficit difference. CONCLUSIONS: Deficit schizophrenia has a season of birth pattern that differs from that of nondeficit schizophrenia. This analysis supports the notion of a separate disease within schizophrenia.

Cohort Studies↗
PubMed2004

The deficit syndrome in schizophrenia: implications for the treatment of negative symptoms.

Schizophrenia psychopathology clusters around several symptom domains. One of these domains is negative symptomatology. We have defined the deficit syndrome as a disease entity characterized by the presence of primary enduring negative symptoms. A focus on primary negative symptoms demonstrates that deficit and nondeficit schizophrenia subgroups differ on clinical features, associated neuroimaging findings, neuropsychological and neurological measures, pattern of risk factors, and pharmacological response profiles. In the present article we focus on the importance of the distinction between primary and secondary negative symptoms for pathophysiology research. The development and mechanistic understanding of anti-negative symptom drugs may be informative regarding pathophysiology of primary negative symptoms. Although new antipsychotics are effective for secondary negative symptoms they have shown no efficacy for the deficit syndrome and new mechanisms of drug action appear to be required to address this aspect of the disease syndrome. The loss of precious human experiences and the association with poor long-term functional outcome justifies a focused and dedicated effort to discover the causes and treatments of this distinctive aspect of schizophrenia.

Affect↗
PubMed2004

Sexual dimorphism and the NMDA receptor in alloparental behavior in juvenile prairie voles (Microtus ochrogaster).

The prairie vole (Microtus ochrogaster) exhibits parental behavior in both males and females and extensive alloparenting in juveniles. The authors studied the effects on juvenile alloparenting of antagonists for the PCP, glycine, and glutamate sites on the N-methyl-D-aspartate (NMDA) receptor. In male voles, all 3 drugs had an inverted-U dose-response curve. This change could not be attributed to fear of the pup or a nonspecific impairment of cognition, level of locomotor activity, or motor coordination. The PCP site antagonist had a U-shaped dose-response curve in females, the opposite of that in males, but neither of the other drugs changed female alloparental behavior. Both male and female voles exhibit alloparental behavior, but its neurobiological underpinnings are sexually dimorphic in juveniles.

Analysis of Variance↗