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Clinical and neurobiological characterization of muscarinic receptor-deficit schizophrenia (MRDS)

Projectomschrijving

Psychotische stoornissen gaan vaak samen met geheugenproblemen. Deze problemen blijven vaak bestaan nadat andere psychotische symptomen zijn verdwenen en zijn erg bepalend voor het dagelijks functioneren. Aangezien we niet weten hoe geheugenproblemen bij psychose ontstaan en hoe we ze moeten behandelen, hebben we met dit onderzoek geprobeerd dit
beter te begrijpen. Door middel van hersenscans hebben we de rol van het boodschapperstofje acetylcholine en de receptoren waar acetylcholine aanbindt in de hersenen onderzocht bij mensen met een psychose. De resultaten lieten zien dat de acetylcholine receptoren een rol spelen bij geheugen. Dit suggereert dat medicijnen die aangrijpen op deze receptor een positief effect op geheugen zouden kunnen hebben bij psychose.

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Titel: Pharmacological interventions for the MATRICS cognitive domains in schizophrenia: what’s the evidence?
Auteur: Wilhelmina A. M. Vingerhoets, Oswald J. N. Bloemen, Geor Bakker and Therese A. M. J. van Amelsvoort

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Samenvatting van de aanvraag

Schizophrenia is a serious chronic disorder, usually starting in early adulthood. Cognitive impairments, probably the most disabling characteristics of the disease and associated with functional outcome, are untouched by currently available antipsychotics. Basic research strongly supports a role of acetylcholine in cognitive processes. Recently, results from a hallmark post-mortem study identified a subgroup of patients with “muscarinic receptor-deficit schizophrenia (MRDS)” and up to 75% loss of muscarinic receptors in approximately 25% of schizophrenic cases. It is not known whether MRDS patients present schizophrenia-associated cognitive deficits. My research team believes that clinical characterization of MRDS may help identify the neurobiological basis of cognitive impairments in schizophrenia. In this study I will test the hypothesis that subjects with MRDS can be identified in-vivo, have cognitive deficits characteristic for schizophrenia and an altered response to an acute cholinergic challenge during functional magnetic resonance imaging (fMRI). Central muscarinic M1 receptor density will be assessed using single photon emission computed tomography (SPECT) in patients with first-episode psychosis, and control subjects. Subjects will receive a SPECT scan, and on 2 occasions an fMRI scan; one following a cholinergic challenge with the muscarinic antagonist scopolamine, and one following placebo. A learning and memory task from a standardized battery will be done on both test days during the fMRI session. I hypothesize that 1) there will be a subgroup with MRDS identified by reduced M1 receptor binding, 2) the group with MRDS perform significantly worse than those without MRDS on cognitive tests 3) those with MDRS have reduced hippocampal activation in response to scopolamine during fMRI compared to those without MDRS. The results of the proposed study will give insight into the role of muscarinic cholinergic neurotransmission in cognitive impairments associated with schizophrenia, and help developing a new class of antipsychotics targeting its most disabling, still untreatable symptoms.

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Projectnummer:
91712394
Looptijd: 100%
Looptijd: 100 %
2013
2019
Gerelateerde subsidieronde:
Projectleider en penvoerder:
Prof. dr. T.A.M.J. van Amelsvoort MD PhD
Verantwoordelijke organisatie:
Amsterdam UMC - locatie AMC