Disease Prediction in the At-Risk Mental State for Psychosis Using Neuroanatomical Biomarkers: Results From the FePsy Study

Background: Reliable prognostic biomarkers are needed for the early recognition of psychosis. Recently, multivariate machine learning methods have demonstrated the feasibility to predict illness onset in clinically defined at-risk individuals using structural magnetic resonance imaging (MRI) data. However, it remains unclear whether these findings could be replicated in independent populations. Methods: We evaluated the performance of an MRI-based classification system in predicting disease conversion in at-risk individuals recruited within the prospective FePsy (Früherkennung von Psychosen) study at the University of Basel, Switzerland. Pairwise and multigroup biomarkers were constructed using the MRI data of 22 healthy volunteers, 16/21 at-risk subjects with/without a subsequent disease conversion. Diagnostic performance was measured in unseen test cases using repeated nested cross-validation. Results: The classification accuracies in the “healthy controls (HCs) vs converters,” “HCs vs nonconverters,” and “converters vs nonconverters” analyses were 92.3%, 66.9%, and 84.2%, respectively. A positive likelihood ratio of 6.5 in the converters vs nonconverters analysis indicated a 40% increase in diagnostic certainty by applying the biomarker to an at-risk population with a transition rate of 43%. The neuroanatomical decision functions underlying these results particularly involved the prefrontal perisylvian and subcortical brain structures. Conclusions: Our findings suggest that the early prediction of psychosis may be reliably enhanced using neuroanatomical pattern recognition operating at the single-subject level. These MRI-based biomarkers may have the potential to identify individuals at the highest risk of developing psychosis, and thus may promote informed clinical strategies aiming at preventing the full manifestation of the disease.     

The importance of intraoperative angiographic findings for predicting long-term patency in coronary artery bypass operations

BACKGROUND: The quality of anastomosis is the cornerstone in coronary artery bypass operations. Intraoperative coronary angiography confirms graft patency with the possibility to revise graft failure. The aim of this study was to describe the lesions found at "on-table" angiography, and to evaluate the significance of these immediate angiographic findings for the long-term patency. METHODS: A total of 57 grafts (42 left internal mammary artery grafts and 15 saphenous vein grafts) in 45 patients who underwent off-pump coronary artery bypass operations were included. On-table angiography was carried out with fixed angiographic equipment installed in the operating room. Follow-up angiographies were performed at 3 months and at 12 months. RESULTS: The most frequent finding in an on-table angiogram was spasm, which was not present at follow-up. Out of nine kinks, only one developed into a significant stenosis at follow-up. Of 44 grafts that were normal on-table, 37 (84%) were normal at the follow-up. Of 11 grafts with significant lesions on-table, eight (73%) were normal at the follow-up. Five percent of the grafts were revised because of the on-table angiography. CONCLUSIONS: On-table angiograms can be occasionally difficult to interpret because not all findings are important for later patency. Optimal results on-table predict good long-term results with a negative predictive value of 0.84, whereas significant lesions on-table have less impact on the follow-up results because the positive predictive value was only 0.38.     

Human immunodeficiency virus dementia: evidence of a subcortical process from studies of fine finger movements

HIV-1 associated dementia is the major manifestation of HIV-1 within the central nervous system and a devastating disease which is characterized by cognitive, motor, and emotional deficits. HIV-1 associated minor motor deficits can manifest as psychomotor slowing and predict the later development of HIV-1 associated dementia, AIDS, and death. These minor motor deficits can be described, e.g., by electrophysiological assessment of basal ganglia motor function (frequency of most rapid alternating finger movements, reaction and contraction times of most rapid index finger extensions). Minor motor deficits quantified by contraction times can be subdivided into a more incipient and a more sustained type of deficit. Parallel examination of motor function and positron emission tomography, magnetic resonance spectroscopy of the basal ganglia, or SPECT helps to point to the basal ganglia as a pivotal point of HIV-1 associated CNS pathology.     

Primary stenting as emergency therapy in acute basilar artery occlusion

In three patients with acute occlusion of the basilar artery intra-arterial fibrinolysis resulted in only partial recanalization and revealed severe stenosis as the underlying cause. Application of micro-stents without previous dilatation resulted in vessel re-opening. Two patients had an excellent clinical outcome. One patient died 10 days after the stroke due to brainstem infarction. Emergency primary stent application may improve the outcome in acute basilar artery occlusion, if intra-arterial thrombolysis fails to re-establish a sufficient flow.     

Savoxepine versus haloperidol

Savoxepine, an atypical neuroleptic compound developed in the 1980s, was believed to act via selective limbic dopamine D₂-receptor blockade. The results of the presented double-blind, randomised, controlled clinical trial comparing savoxepine (n = 58) with haloperidol (n = 29) did not confirm the preclinical data suggesting that savoxepine would produce fewer extrapyramidal symptoms than the comparator. Animal data and PET-results obtained a posteriori suggested that this unfavourable outcome may have been due to the conventional, step-wise dose increase strategy used in the study leading to a high dopamine D₂-receptor occupancy in the striatum thus eliciting EPS. Using either a slower dose-titration or a high, single loading dose followed by a low maintenance dosing may have offered the possibility to obtain a good antipsychotic effect together with low incidence of EPS. In future clinical trials with new neuroleptics, the preclinical data should be carefully evaluated, and drug brain kinetic parameters taken into consideration. Received: 4 December 2001 / Accepted: 5 April 2002     

Progression of corpus callosum atrophy in Alzheimer disease

BACKGROUND: Atrophy of the corpus callosum in the absence of primary white matter degeneration reflects loss of intracortical projecting neocortical pyramidal neurons in Alzheimer disease (AD). OBJECTIVES: To determine individual rates of atrophy progression of the corpus callosum in patients with AD and to correlate rates of atrophy progression with clinical disease severity and subcortical disease. METHODS: Magnetic resonance imaging-derived measurements of corpus callosum size were studied longitudinally in 21 patients clinically diagnosed as having AD (mean observation time, 17.0 +/- 8.5 months) and 10 age- and sex-matched healthy controls (mean observation time, 24.1 +/- 6.8 months). RESULTS: Corpus callosum size was significantly reduced in AD patients at baseline. Annual rates of atrophy of total corpus callosum, splenium, and rostrum were significantly larger in AD patients (-7.7%, -12.1%, and -7.3%, respectively) than in controls (-0.9%, -1.5%, and 0.6%, respectively). Rates of atrophy of the corpus callosum splenium were correlated with progression of dementia severity in AD patients (rho = 0.52, P<.02). The load of subcortical lesions at baseline (P<.05) predicted rate of anterior corpus callosum atrophy in healthy controls. Rates of atrophy of corpus callosum areas were independent of white matter hyperintensity load in patients with AD. CONCLUSIONS: Measurement of corpus callosum size allows in vivo mapping of neocortical neurodegeneration in AD over a wide range of clinical dementia severities and may be used as a surrogate marker for evaluation of drug efficacy.     

Beneficial antipsychotic effects of celecoxib add-on therapy compared to risperidone alone in schizophrenia

OBJECTIVE: Abnormalities in the immune system in schizophrenia have been described. However, important findings such as high levels of activating cytokines in the CSF and signs of CNS inflammation have been controversial. The authors conducted a trial of the new selective cyclooxygenase-2 inhibitor celecoxib, an immunomodulatory drug, in schizophrenic patients to evaluate its therapeutic effects. METHOD: In a prospective, double-blind evaluation, 50 patients with an acute exacerbation of schizophrenia were randomly assigned to either risperidone plus celecoxib or risperidone plus placebo. After a washout period, 25 patients received 2-6 mg/day of risperidone plus placebo and 25 received risperidone plus 400 mg/day of celecoxib for 5 weeks. The treatment effect was calculated by analysis of covariance. There were no significant differences between groups in age, sex, duration or severity of disease or psychopathology, or risperidone dose or plasma level. RESULTS: Over 5 weeks, both groups of patients showed significant improvement in scores on the Positive and Negative Syndrome Scale and on all subscales. However, the celecoxib group showed significantly greater improvement in the total score. CONCLUSIONS: Additional treatment with celecoxib has significant positive effects on the therapeutic action of risperidone with regard to total schizophrenia psychopathology. Moreover, the fact that treatment with an immunomodulatory drug showed beneficial effects on schizophrenia symptoms indicates that immune dysfunction in schizophrenia is not just an epiphenomenon but is related to the pathomechanism of the disorder. However, a nonimmunological therapeutic effect of celecoxib mediated by the N-methyl-D-aspartic acid receptor has to be taken into account.     

Mediators of antigen-induced gastrin release: role of antigen-antibody complexes and the complement system

That orally administered antigen was shown to induce gastrin release in immunized animals was a new aspect of gastrointestinal physiology. The mediators responsible for this immunological effect are still unclear. In an attempt to discover more about the mechanisms regarding antigen-induced gastrin release, we developed an in vitro system where fragments of rat antral mucosa were challenged. This makes it possible to determine the role of antigen-antibody complexes and the complement system in the mechanism of antigen-induced gastrin release. Wistar rats were immunized in vivo with NIP-OVA and mucosal fragments were challenged in vitro with NIP-HGG. Gastrin was determined after a preincubation and a challenged incubation period without supernatants. After antigenic challenge, supernatants were used for in vitro challenge in order to rule out the presence of a soluble mediator and activation of complement. In a second group of experiments Wistar rats were used to study in vitro the release of specific antibodies after antigenic challenge. With this experimental design we were able to show increased gastrin secretion after antigenic challenge in vitro in the presence of intact tissue. It is shown that the increased gastrin release is most probably mediated by activation of the complement system in the presence of antigen-antibody complexes. These are built up by specific anti-NIP antibodies and NIP-HGG used for the challenge. The complement system might be the final pathway of the observed in-creased gastrin release.