Project

cognition; structural MRI; functional MRI; schizophrenia; age of onset; biomarker; vulnerability; resilience; mitochondria; oxidative stress

Lead
Lay summary
It is being increasingly recognized that schizophrenia is a pleiotropic disorder. The past decade has witnessed an abundance of studies focussing on the broad spectrum of different psychopathology (including dysfunction in cognition, misinterpretations of perception or experiences, disorganised thinking and behaviour, affective disorders, and occupational dysfunction), abnormalities in mitochondrial function and oxidative stress levels as well as brain structure and function. The discrepancies in published data might be the result of investigating different tissues and/or different patient populations by using different methods. Although different schizophrenia types are similar in symptom presentation and many neurobiological aspects, there is evidence on different disease variations with diverse etiology and pathomechanisms as articulated in the endophenotype concept of schizophrenia. Furthermore, there is evidence that a more favourite outcome is associated, among others, with less vulnerability and greater resilience. In many cases investigated patient groups are not well defined with regard to e.g. type of schizophrenia, course of illness and medication, age of onset, impact of gender, and neurobiology. Therefore, the present project is designed with specific regard to cope with these limitations. That sets apart our study from all investigations, yet performed. We will include well defined and highly specific patient groups. The unique collaboration of the Dept. of Forensic Psychiatry at the Psychiatric Clinic of the Univ. of Basel, dealing with the most severe forms of schizophrenia and disastrous courses of illness, with the FEPSY Clinic (Basel early-detection-of-psychosis project) at the Psychiatric Polyclinic of the Univ. of Basel, engaged in characterizing subjects with a predisposition to schizophrenia and patients in the very early phase of schizophrenia as well as early clinical intervention, opens the great opportunity to study the broad range in course of illness of schizophrenia (from individuals with at-risk mental state/AMRS, patients with first episode/FE of schizophrenic symptoms adult age of onset or very early age of onset (< 18 years; EOS) up to patients with a chronic course of schizophrenia, paranoid type, with a very early (EOS) or adult age of onset as well as age-machted controls (only male subjects). This allows for the first time a direct comparison between distinct patients groups usually merged under the term "schizophrenia". The expertise of each of the participating research teams is complementary in the present multilevel approach: from neuropsychology and neurobiology to neuroimaging.

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Last update: 21.02.2013

Active participation

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It is being increasingly recognized that schizophrenia is a pleiotropic disorder. The past decade has witnessed an abundance of studies focussing on the broad spectrum of different psychopathology (including dysfunction in cognition, misinterpretations of perception or experiences, disorganised thinking and behaviour, affective disorders, and occupational dysfunction), abnormalities in mitochondrial function and oxidative stress levels as well as brain structure and function. The discrepancies in published data might be the result of investigating different tissues and/or different patient populations by using different methods. Although different schizophrenia types are similar in symptom presentation and many neurobiological aspects, there is evidence on different disease variations with diverse etiology and pathomechanisms as articulated in the endophenotype concept of schizophrenia. Furthermore, there is evidence that a more favourite outcome is associated, among others, with less vulnerability and greater resilience. In many cases investigated patient groups are not well defined with regard to e.g. type of schizophrenia, course of illness and medication, age of onset, impact of gender, and neurobiology. Therefore, the present project is designed with specific regard to cope with these limitations. That sets apart our study from all investigations, yet performed. We will include well defined and highly specific patient groups. The unique collaboration of the Dept. of Forensic Psychiatry at the Psychiatric Clinic of the Univ. of Basel, dealing with the most severe forms of schizophrenia and disastrous courses of illness, with the FEPSY Clinic (Basel early-detection-of-psychosis project) at the Psychiatric Polyclinic of the Univ. of Basel, engaged in characterizing subjects with a predisposition to schizophrenia and patients in the very early phase of schizophrenia as well as early clinical intervention, opens the great opportunity to study the broad range in course of illness of schizophrenia (from individuals with at-risk mental state/AMRS, n=15, patients with first episode/FE of schizophrenic symptoms adult age of onset, n=15, or very early age of onset (< 18 years; EOS), n=10, up to patients with a chronic course of schizophrenia, paranoid type, with a very early (EOS), n=15, or adult age of onset, n=15, as well as age-machted controls, n=30; only male subjects). This allows for the first time a direct comparison between distinct patients groups usually merged under the term “schizophrenia”. The expertise of each of the participating research teams is complementary in the present multilevel approach: from neuropsychology and neurobiology to neuroimaging. Objectives of the research projectThe distinct patient groups and the healthy controls will be investigated by using a multilevel approach addressing the following working hypotheses (1-3):Working hypothesis 1: Neurocognition and ResilienceIt is greatly accepted that most of the schizophrenia patients show lower cognitive performance than healthy controls. Our first hypothesis is that patients with early onset of schizophrenia (EOS) will have worse cognitive performance than patients with adult-onset schizophrenia. Second, we expect reduced cognitive functioning in individuals with an at-risk mental state (ARMS) compared to controls. Third, we expect that an increase of cognitive deficits is related to an increased vulnerability and a reduced resilience and vice versa. We will verify this hypothesis by using a neuropsychological test battery which covers the domains of general intelligence, executive functions, memory and attention as well as Resilience and Social and Functioning Assessment Scale. The aim of this part of the study is to compare the profile and severity of cognitive deficits indicating vulnerability/resilience in patients with chronic schizophrenia, chronic EOS, first episode schizophrenia and first episode EOS as well as in ARMS.Working hypothesis 2: NeurobiologyOn the basis of current research and our preliminary study findings, we expect changes in mitochondrial function as well as abnormalities in oxidative stress and energy levels in blood cells of schizophrenia patients. We will verify this hypothesis by using a combined approach from gene profiling to functional aspects of mitochondria. Lymphocytes not only are easily accessible but, unlike postmortem brain tissue, can also be subjected to experimental manipulations. We will go beyond gene expression profiling from freshly drawn blood and to culture lymphocytes of patients and healthy controls under stress conditions related to energy homeostasis. This approach will allow for gaining a more comprehensive view on the complex interplay between genes and cellular function. The aim of this part of the project is to characterize patterns of mitochondrial vulnerability and resilience in blood cells from different schizophrenic patient groups.Working hypothesis 3: NeuroimagingIt is widely accepted that schizophrenia is associated with neuroanatomical abnormalities. However, the extent to which these are related to the vulnerability of the disorder, rather than the illness itself, is less certain. The overall hypothesis is that subjects with a liability for psychosis and an at-risk mental state (ARMS) will show brain structural and neurofunctional abnormalities relative to controls that are qualitatively similar to those in patients with first episode (FE) schizophrenia, early onset schizophrenia and chronic patients with schizophrenia. In particular, we expect a linear trend for more structural and neurofunctional abnormalities from ARMS < FE adult onset < FE early onset < chronic adult onset < chronic early onset compared to controls.We will use a wide range of structural (sMRI, DTI) and functional neuroimaging (fMRI) techniques to investigate the neurobiological basis of psychosis. Determining the mechanisms of structural and neural abnormalities will improve our knowledge of the neuronal circuits and cognitive processes that are implicated in biological vulnerability / resilience to mental illness.Expected values toward understanding resilience and vulnerability in schizophreniaWe want to relate disturbances in several patient groups in brain structure, brain function, information processing, and mitochondrial abnormalities at the molecular and cellular level to each other and to psychopathology in an interdisciplinary research setting addressing a translational approach. We expect disturbances in mitochondria at baseline to correlate with specific structural and functional brain changes and with disruption in information processing as measured with psychological and neurocognitive methods using complex data analyses.• Identification of resilience / vulnerability factors that are specific for a single patient collective• Identification of differences/similarities between the different patients group and/or versus controls• Characterization of associations between parameters of brain structure and function, defects in mitochondria and energy homeostasis and psychopathology• Characterization of putative endophenotypesThe present proposal provides a unique approach especially as such a documentation linking psychopathology to functional aspects of mitochondria and brain structure and function assessed by structural and functional MRI with specific regard to vulnerability and resilience factors in schizophrenia has never been attempted before.