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Impaired Synaptic Function Is Linked to Cognition in Parkinson's Disease View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by UCL Discovery RESEARCH ARTICLE Impaired synaptic function is linked to cognition in Parkinson’s disease Per Selnes1,2 , Ane Løvli Stav1,2, Krisztina K. Johansen1, Atle Bjørnerud3,4, Christopher Coello5, Eirik Auning2,6, Lisa Kalheim1,2, Ina Selseth Almdahl1,2, Erik Hessen2,7, Henrik Zetterberg8,9,10,11, Kaj Blennow8,9, Dag Aarsland1,12,13 & Tormod Fladby1,2 1Department of Neurology, Akershus University Hospital, Lørenskog, Norway 2Institute of Clinical Medicine, University of Oslo, Campus Ahus, Oslo, Norway 3Department of Diagnostic Physics, Oslo University Hospital, Rikshospitalet, Oslo, Norway 4Department of Physics, University of Oslo, Oslo, Norway 5Neural Systems Laboratory, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway 6Department of Geriatric Psychiatry, Akershus University Hospital, Lørenskog, Norway 7Department of Psychology, University of Oslo, Oslo, Norway 8Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, the Sahlgrenska Academy at the University of Gothenburg, Molndal,€ Sweden 9Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Molndal,€ Sweden 10Department of Molecular Neuroscience, UCL Institute of Neurology, Queen Square, London, United Kingdom 11UK Dementia Research Institute, London, United Kingdom 12Department of Old Age Psychiatry, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, United Kingdom 13Center for Age-Related Diseases, Stavanger University Hospital, Stavanger, Norway Correspondence Abstract Per Selnes, Department of Neurology, Objective Akershus University Hospital, P.O. Box 1000, : Cognitive impairment is frequent in Parkinson’s disease, but the 1478 Lørenskog, Norway. Tel:+47 02900; underlying mechanisms are insufficiently understood. Because cortical metabo- Fax: 0047 67968132; E-mail: lism is reduced in Parkinson’s disease and closely associated with cognitive [email protected] impairment, and CSF amyloid-b species are reduced and correlate with neu- ropsychological performance in Parkinson’s disease, and amyloid-b release to Funding Information The study has received financial support from interstitial fluid may be related to synaptic activity; we hypothesize that synapse South-Eastern Norway Regional Health dysfunction links cortical hypometabolism, reduced CSF amyloid-b, and presy- Authority (grant reference number naptic deposits of a-synuclein. We expect a correlation between hypometabo- 20111093), the Research Council of Norway lism, CSF amyloid-b, and the synapse related-markers CSF neurogranin and a- (grant reference numbers 217780 and synuclein. Methods: Thirty patients with mild-to-moderate Parkinson’s disease 226074), EU-JPND via the Research Council and 26 healthy controls underwent a clinical assessment, lumbar puncture, of Norway (grant reference number 237250), MRI, 18F-fludeoxyglucose-PET, and a neuropsychological test battery (repeated Akershus University Hospital, the Swedish Results b Alzheimer Foundation, the Swedish Brain for the patients after 2 years). : All subjects had CSF amyloid- 1-42 Foundation, and the University of Oslo. KB within normal range. In Parkinson’s disease, we found strong significant corre- and HZ are supported by the Swedish lations between cortical glucose metabolism, CSF Ab, a-synuclein, and neuro- Research Council and Swedish State Support granin. All PET CSF biomarker-based cortical clusters correlated strongly with for Clinical Research. HZ holds an European cognitive parameters. CSF neurogranin levels were significantly lower in mild- Research Council consolidator grant. to-moderate Parkinson’s disease compared to controls, correlated with amyloid- b and a-synuclein, and with motor stage. There was little change in cognition Received: 30 June 2017; Accepted: 5 July 2017 after 2 years, but the cognitive tests that were significantly different, were also significantly associated with cortical metabolism. No such correlations were Annals of Clinical and Translational found in the control group. Interpretation: CSF Ab, a-synuclein, and neuro- Neurology 2017; 4(10): 700–713 granin concentrations are related to cortical metabolism and cognitive decline. Synaptic dysfunction due to Ab and a-synuclein dysmetabolism may be central doi: 10.1002/acn3.446 in the evolution of cognitive impairment in Parkinson’s disease. 700 ª 2017 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals, Inc on behalf of American Neurological Association. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made. P. Selnes et al. Synaptic Function in Parkinson’s Disease postmortem study suggests that loss of synaptic markers Introduction predicts cognitive decline in Lewy body diseases,29 to the Cognitive impairment is an important nonmotor symp- best of our knowledge, no direct links have been estab- tom of Parkinson’s disease (PD).1 Mean duration from lished between reduced glucose metabolism in PD and clinical disease onset to dementia is 10 years, but cogni- independent synaptic markers. tive impairment has been demonstrated already at the Because (1) cortical glucose metabolism is reduced and time of diagnosis.2 correlates with cognitive impairment in PD, and (2) CSF Several factors argue for early involvement of synaptic Ab species are decreased and correlate with neuropsycho- pathology in PD. Many of the proteins relevant in PD logical performance, and amyloid-b release to interstitial pathophysiology are involved in synaptic physiology (re- fluid may be related to synaptic activity; we hypothesize viewed in3). a-synuclein is considered the core pathologi- that synapse dysfunction is a common link between corti- cal substrate of PD, and in addition to accumulation in cal hypometabolism, CSF amyloid-b concentrations, and Lewy bodies, a major deposition site of CNS oligomeric presynaptic deposits of a-synuclein. We thus expect to a-synuclein is the presynapse, accompanied by transsy- find a correlation between levels of CSF Ab species and naptic dendritic spine loss.4,5 The presynaptic terminal is relative glucose metabolism, and also to possible markers the main site of function for both amyloid precursor pro- of synaptic dysfunction or loss, such as CSF a-synuclein tein (APP) and a-synuclein. a-synuclein is linked to and neurogranin. synaptic-vesicle complex formation and APP to synaptic- vesicle docking and priming. Neurogranin, a substrate of Materials and Methods protein kinase C, is abundantly expressed, and located preferentially at the postsynaptic dendritic spine plasma Subjects membrane.6 Intracellular metabolism of these proteins is performed This study is based on an ongoing longitudinal follow-up by overlapping sets of enzymes and subcellular compart- of patients in a university hospital-based neurological – ments.7 10 Presynaptic activity and endocytosis influence clinic. Thirty nondemented patients with mild-to-moder- release of amyloid-b (Ab) species to the interstitial fluid.11 ate stage PD were recruited between 2011 and 2014 and APP is initially cleaved at the presynaptic terminal to sev- examined by a neurologist with extensive experience in eral biologically active metabolites, including Ab 1-38 movement disorders, as previously described.15 (Ab38), Ab 1-40 (Ab40), and Ab 1-42 (Ab42), the latter The patient group and inclusion criteria in this study is particularly prone to brain parenchymal deposition.12,13 the same (aside from one subject excluded due to missing Most studies of CSF Ab species in PD have reported FDG-PET) as the one described in ref 15. In short, inclu- slight reductions.14,15 We and others have found a correla- sion criteria were diagnosis of PD according to the UK tion between CSF Ab42 levels and memory performance in Parkinson’s Disease Society Brain Bank clinical diagnostic PD,15,16 also in subjects with normal CSF Ab42 levels (thus criteria,30 Hoehn and Yahr stage <3, and disease duration without evidence for amyloid plaques).15,17 These changes <6 years. All PD subjects had a pathological dopamine relate to hippocampus subfield volumes18; experimental transporter single photon emission computed tomography studies show detrimental preplaque Ab effects on synaptic (DaT-SPECT). Exclusion criteria were dementia (see function,19 and human Ab turnover decreases from below for procedure) and other somatic or psychiatric approximately 40 years of age,20 suggesting preplaque diseases that might contribute to cognitive impairment. effects of Ab on cognition and synaptic physiology. The Unified Parkinson’s Disease Rating Scale (UPDRS), MRI studies show that slight gray matter atrophy is part III motor examination and Hoehn & Yahr staging involved in PD cognitive decline.21 Studies combining were performed. Patients had their medication as usual neuroimaging and CSF in PD are scarce, but CSF Ab cor- when assessed. Total daily levodopa equivalent dose was relate with reduced gray matter volume and associated calculated. All PD subjects underwent cognitive assess- neuropsychological function.22,23 FDG-PET studies have ment employing a well-validated neuropsychological test identified a widespread, specific pattern of reduced glu- battery thoroughly described previously.15,31 The battery
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