The relative and interactive impact of multiple risk factors in schizophrenia spectrum disorders: a combined register-based and clinical twin study.

BACKGROUND: Research has yielded evidence for genetic and environmental factors influencing the risk of schizophrenia. Numerous environmental factors have been identified; however, the individual effects are small. The additive and interactive effects of multiple risk factors are not well elucidated. Twin pairs discordant for schizophrenia offer a unique opportunity to identify factors that differ between patients and unaffected co-twins, who are perfectly matched for age, sex and genetic background. METHODS: Register data were combined with clinical data for 216 twins including monozygotic (MZ) and dizygotic (DZ) proband pairs (one or both twins having a schizophrenia spectrum diagnosis) and MZ/DZ healthy control (HC) pairs. Logistic regression models were applied to predict (1) illness vulnerability (being a proband v. HC pair) and (2) illness status (being the patient v. unaffected co-twin). Risk factors included: A polygenic risk score (PRS) for schizophrenia, birth complications, birth weight, Apgar scores, paternal age, maternal smoking, season of birth, parental socioeconomic status, urbanicity, childhood trauma, estimated premorbid intelligence and cannabis. RESULTS: The PRS [odds ratio (OR) 1.6 (1.1-2.3)], childhood trauma [OR 4.5 (2.3-8.8)], and regular cannabis use [OR 8.3 (2.1-32.7)] independently predicted illness vulnerability as did an interaction between childhood trauma and cannabis use [OR 0.17 (0.03-0.9)]. Only regular cannabis use predicted having a schizophrenia spectrum diagnosis between patients and unaffected co-twins [OR 3.3 (1.1-10.4)]. CONCLUSION: The findings suggest that several risk factors contribute to increasing schizophrenia spectrum vulnerability. Moreover, cannabis, a potentially completely avoidable environmental risk factor, seems to play a substantial role in schizophrenia pathology.

Frontal FDG-PET activity correlates with cognitive outcome after STN-DBS in Parkinson disease.

BACKGROUND: Inconsistent changes of cognitive functioning have been reported in patients with Parkinson disease (PD) with deep brain stimulation (DBS) of the subthalamic nucleus (STN). To investigate the underlying pathomechanisms, we correlated alterations of cognitive test performance and changes of neuronal energy metabolism in frontal basal ganglia projection areas under bilateral STN stimulation. METHODS: We conducted verbal fluency, learning, and memory tests and 18-fluorodeoxyglucose (FDG) PET in nine patients with PD with STN-DBS before and 6 months after surgery. Using coregistered MRI, postoperative changes of the normalized cerebral metabolic rates of glucose (nCMRGlc) in the dorsolateral prefrontal cortex (DLPFC), lateral orbitofrontal cortex (LOFC), ventral and dorsal cingulum (v/dACC), and in Broca area were determined and correlated with alterations of neuropsychological test results. RESULTS: After surgery, highly variable changes of both cognitive test performance and frontal nCMRGlc values were found with significant correlations between verbal fluency and FDG uptake in the left DLPFC (Brodmann area [BA] 9, 46), left Broca area (BA 44/45), and the right dACC (BA 32). A decrease of nCMRGlc in the left OFC (BA 11/47) and dACC (BA 32) correlated with a decline of verbal learning. All patients showed reduced metabolic activity in the right anterior cingulate cortex after DBS. Baseline cognitive abilities did not predict verbal learning or fluency changes after surgery. CONCLUSIONS: These data show a significant linear relationship between changes in frontal 18-fluorodeoxyglucose PET activity and changes in cognitive outcome after deep brain stimulation of the subthalamic nucleus (STN) in advanced Parkinson disease. The best correlations were found in the left frontal lobe (dorsolateral prefrontal cortex and Broca area). Baseline performance on cognitive tests did not predict cognitive or metabolic changes after STN electrode implantation.

STN-DBS activates the target area in Parkinson disease: an FDG-PET study.

OBJECTIVE: The immediate effects of deep brain stimulation (DBS) on subcortical neurons of its target region are controversial. METHODS: We measured the regional normalized resting cerebral metabolic rate of glucose (nCMRGlc) with 18-fluorodeoxyglucose (FDG) and PET in 12 patients with Parkinson disease (PD) and bilateral DBS of the subthalamic nucleus (STN) compared to 10 age-matched controls. PET was performed before surgery and 6 months after electrode implantation in DBS off- and on-conditions. Stereotactic coordinates of active STN electrode poles were determined with intraoperative skull x-ray and transferred to preoperative MR images. Subsequently, volumes of interest (VOIs) were placed around active electrode contacts, in the STN and in the globus pallidus. DBS induced changes of nCMRGlc values were determined in each VOI after PET and MRI coregistration. RESULTS: Electrode placement without stimulation led to significant FDG uptake reduction in the electrode region and in the STN (microlesional effect). Under active DBS, the local nCMRGlc significantly increased in all VOIs under investigation. CONCLUSIONS: The data demonstrate that deep brain stimulation (DBS) induced metabolic activation of the subthalamic region and the directly connected globus pallidus which is in line with local and remote excitation of neurons by high frequency stimulation. These PET findings most likely reflect tonic driving of the DBS target area and its projection sites via ortho- and antidromic fiber conduction. We conclude that subthalamic nucleus DBS has predominant excitatory properties and does, therefore, fundamentally differ from lesional neurosurgery.

Role of in vivo imaging of the central nervous system for developing novel drugs.

Over the past decade imaging technologies employed in clinical neurosciences have significantly advanced. Imaging is not only used for the diagnostic work-up of neurological disorders but also crucial to follow up on therapeutic efforts. Using disease-specific imaging parameters, as read-outs for the efficiency of individual therapies, has facilitated the development of various novel treatments for neurological disease. Here, we review various imaging technologies, such as cranial computed tomography (CT), magnetic resonance imaging (MRI) and spectroscopy (MRS), positron emission tomography (PET) and single-photon emission computed tomography (SPECT), with respect to their current applications in non-invasive disease phenotyping and the measurement of therapeutic outcomes in neurology. In particular, applications in neuro-oncology, Parkinson's disease, Alzheimer's disease, and cerebral ischemia are discussed. Non-invasive imaging provides further insights into the molecular pathophysiology of human diseases and facilitates the design and implementation of improved therapies.

Disease progression continues in patients with advanced Parkinson's disease and effective subthalamic nucleus stimulation.

OBJECTIVES: Glutamate mediated excitotoxicity of the hyperactive subthalamic nucleus (STN) has been reported to contribute to nigral degeneration in Parkinson's disease (PD). Deep brain stimulation of the STN (STN DBS), in its role as a highly effective treatment of severe PD motor complications, has been thought to inhibit STN hyperactivity and therefore decrease progression of PD. METHODS: In a prospective two centre study, disease progression was determined by means of serial (18)F-fluorodopa (F-dopa) positron emission tomography (PET) in 30 patients with successful STN DBS over the first 16 (SD 6) months after surgery. RESULTS: Depending on the method of PET data analysis used in the two centres, annual progression rates relative to baseline were 9.5-12.4% in the caudate and 10.7-12.9% in the putamen. CONCLUSIONS: This functional imaging study is the first to demonstrate a continuous decline of dopaminergic function in patients with advanced PD under clinically effective bilateral STN stimulation. The rates of progression in patients with STN DBS were within the range of previously reported data from longitudinal imaging studies in PD. Therefore this study could not confirm the neuroprotective properties of DBS in the STN target.

Variability in infectivity of primary cell cultures of human brain tumors with HSV-1 amplicon vectors.

We investigated the variability in infectivity of cells in primary brain tumor samples from different patients using an HSV-1 amplicon vector. We studied the infectivity of HSV-1 amplicon vectors in tumor samples derived from neurosurgical resections of 20 patients. Cells were infected with a definite amount of HSV-1 amplicon vector HSV-GFP. Transduction efficiency in primary tumor cell cultures was compared to an established human glioma line. Moreover, duration of transgene expression was monitored in different tumor cell types. All primary cell cultures were infectable with HSV-GFP with variable transduction efficiencies ranging between 3.0 and 42.4% from reference human Gli36 Delta EGFR glioma cells. Transduction efficiency was significantly greater in anaplastic gliomas and meningiomas (26.7+/-17.4%) compared to more malignant tumor types (glioblastomas, metastases; 11.2+/-8.5%; P=0.05). To further investigate the possible underlying mechanism of this variability, nectin-1/HevC expression was analyzed and was found to contribute, at least in part, to this variability in infectability. The tumor cells expressed the exogenous gene for 7 to 61 days with significant shorter expression in glioblastomas (18+/-13 d) compared to anaplastic gliomas (42+/-24 d; P<0.05). Interindividual variability of infectivity by HSV-1 virions might explain, at least in part, why some patients enrolled in gene therapy for glioblastoma in the past exhibited a sustained response to HSV-1-based gene- and virus therapy. Infectivity of primary tumor samples from respective patients should be tested to enable the development of efficient and safe herpes vector-based gene and virus therapy for clinical application.

DJ-1 (PARK7) mutations are less frequent than Parkin (PARK2) mutations in early-onset Parkinson disease.

BACKGROUND: Mutations in the Parkin gene (PARK2) are the most commonly identified cause of recessively inherited early-onset Parkinson disease (EOPD) but account for only a portion of cases. DJ-1 (PARK7) was recently reported as a second gene associated with recessively inherited PD with a homozygous exon deletion and a homozygous point mutation in two families. METHODS: To investigate the frequency of DJ-1 mutations, the authors performed mutational analysis of all six coding exons of DJ-1 in 100 EOPD patients. For the detection of exon rearrangements, the authors developed a quantitative duplex PCR assay. Denaturing high performance liquid chromatography analysis was used to screen for point mutations and small deletions. Further, Parkin analysis was performed as previously described. RESULTS: The authors identified two carriers of single heterozygous loss-of-function DJ-1 mutations, including a heterozygous deletion of exons 5 to 7 and an 11-base pair deletion, removing the invariant donor splice site in intron 5. Interestingly, both DJ-1 mutations identified in this study were found in the heterozygous state only. The authors also detected a polymorphism (R98Q) in 1.5% of the chromosomes in both the patient and control group. In the same patient sample, 17 cases were detected with mutations in the Parkin gene. CONCLUSIONS: Mutations in DJ-1 are less frequent than mutations in Parkin in EOPD patients but should be considered as a possible cause of EOPD. The effect of single heterozygous mutations in DJ-1 on the nigrostriatal system, as described for heterozygous changes in Parkin and PARK6, remains to be elucidated.

Acute demyelination: diagnostic difficulties and the need for brain biopsy.

BACKGROUND: Despite the rapid development in neuro-imaging over the past two decades, ring like contrast-enhancing lesions on CCT or MRI still may pose a diagnostic challenge. The main differential diagnoses of these lesions include metastatic carcinoma, high-grade glioma and brain abscess. Acute demyelination seldom turns out to be the underlying pathology. METHOD: Retrospective analysis was done on six patients with acute demyelination treated at our neurosurgical department between 1990 and 2001. Clinical, radiological, PET, intra-operative and histological findings were evaluated. FINDINGS: In five patients, the diagnosis of acute demyelination was established by histopathological evaluation of stereotactic biopsy specimen, in the sixth patient following microsurgical extirpation of the lesion. Neuropathology revealed demyelination with the presence of myelin-phagocytosing macrophages. In addition, lymphocytic infiltrates were present. Symptoms and signs improved significantly after high-dose steroid therapy. CONCLUSIONS: Despite CNS tissue destruction, necrosis and cyst formation are not usually found in demyelinating disease, being rather more common in young patients with ring-like contrast-enhancing lesions on CCT and MRI. Though an incorrect diagnosis can lead to a potentially fatal therapeutic intervention, histological diagnosis should be made in all cases. Due to minimum morbidity, stereotactic biopsy is the method of choice to obtain representative specimens for histological diagnosis. Open microsurgery of these lesions is not indicated since conservative medical treatment with steroids results in a favourable outcome in most cases.

PET-based molecular imaging in neuroscience.

Positron emission tomography (PET) allows non-invasive assessment of physiological, metabolic and molecular processes in humans and animals in vivo. Advances in detector technology have led to a considerable improvement in the spatial resolution of PET (1-2 mm), enabling for the first time investigations in small experimental animals such as mice. With the developments in radiochemistry and tracer technology, a variety of endogenously expressed and exogenously introduced genes can be analysed by PET. This opens up the exciting and rapidly evolving field of molecular imaging, aiming at the non-invasive localisation of a biological process of interest in normal and diseased cells in animal models and humans in vivo. The main and most intriguing advantage of molecular imaging is the kinetic analysis of a given molecular event in the same experimental subject over time. This will allow non-invasive characterisation and "phenotyping" of animal models of human disease at various disease stages, under certain pathophysiological stimuli and after therapeutic intervention. The potential broad applications of imaging molecular events in vivo lie in the study of cell biology, biochemistry, gene/protein function and regulation, signal transduction, transcriptional regulation and characterisation of transgenic animals. Most importantly, molecular imaging will have great implications for the identification of potential molecular therapeutic targets, in the development of new treatment strategies, and in their successful implementation into clinical application. Here, the potential impact of molecular imaging by PET in applications in neuroscience research with a special focus on neurodegeneration and neuro-oncology is reviewed.

Molecular and functional imaging technology for the development of efficient treatment strategies for gliomas.

Gliomas are the most common types of brain tumors, which invariably lead to death over months or years. Before new and potentially more effective treatment strategies, such as gene therapy, can be effectively introduced into clinical application the following goals must be reached: (1) the determination of localization, extent and metabolic activity of the glioma; (2) the assessment of functional changes within the surrounding brain tissue; (3) the identification of genetic changes on the molecular level leading to disease; and in addition (4) a detailed non-invasive analysis of both endogenous and exogenous gene expression in animal models and in the clinical setting. Non-invasive imaging of endogenous gene expression by means of positron emission tomography (PET) may reveal insight into the molecular basis of pathogenesis and metabolic activity of the glioma and the extent of treatment response. When exogenous genes are introduced to serve for a therapeutic function, PET imaging techniques may reveal the assessment of the location, magnitude and duration of therapeutic gene expression and its relation to the therapeutic effect. Here, we review the main principles of PET imaging and its key roles in neurooncology research.

[Mixed tumors of the pineal area. Diagnosis and therapy consisting of secreting germ cell tumor]. / Mischtumoren der Pinealisregion. Diagnostik und Therapie bei Vorliegen sezernierender Keimzelltumoranteile.

Primary intracranial germ cell tumors are rare neurological diseases. Secreting germ cell tumors that predominantly appear in the pineal region are characterized by elevated levels of beta-HCG and AFP in CSF. Adequate diagnostic and therapeutic regimens of these tumors are still under debate. We present the case of a patient suffering from spinal metastasis of a secreting germ cell tumor with raised levels of beta-HCG in CSF. Six years before, a pineocytoma of intermediate differentiation had been diagnosed by stereotaxic biopsy. This demonstrates the importance of an early detection of a germ cell neoplasm in case of midline-sized brain-tumors by evaluation of beta-HCG and AFP in CSF and serum. Today, different therapeutic strategies depending on the histological diagnosis are available and justify a high priority of a surgical tumor biopsy. However, the value of stereotaxic procedures remains controversial. Recently published data gave evidence of a definite improved prognosis of secreting CNS germ cell tumors following combined treatment with high-dose polychemotherapy, surgical resection and radiation of the tumor area. beta-HCG and AFP may serve as useful markers to enable follow-up of the disease.

A hypertension control program based on the workplace. Report on the Chicago Center.

In several large Chicago companies and institutions, workplace screening of 7,151 persons yielded 833 suspect hypertensives. Of these, 91% attended a follow-up verification visit, where for 513 persons high diastolic pressure was confirmed. One-half of these persons were referred to their physicians for treatment and one-half were randomly assigned to be treated directly by HDFP, in a step-wise pharmacologic regimen to normalize diastolic pressure. Of the 257 persons assigned to program treatment, 94% accepted such treatment, and over 90% of these still living in the community were active participants at one year. Average diastolic pressure of these active participants was 83.1 mm Hg at one year, compared to 102.6 at first screen and 98.8 at the second confirmatory screening. A strenuous effort has been made to reduce or eliminate obstacles to treatment, including lack of understanding of the need for long-term therapy, cost barriers and barriers of inconvenience of treatment. The medical team conducting the program combined physicians with nonphysician therapist-health counselors, plus "outreach" staff, to maximize program adherence. Preliminary experiences in the Chicago Center of the Hypertension Detection and Follow-Up Program (HDFP) give encouraging evidence that the workplace is a useful base for successful hypertension control efforts.