Brain connectivity and cognitive impairment in Parkinson’s disease Hugo César Baggio Aquesta tesi doctoral està subjecta a la llicència Reconeixement- NoComercial – SenseObraDerivada 3.0. Espanya de Creative Commons. Esta tesis doctoral está sujeta a la licencia Reconocimiento - NoComercial – SinObraDerivada 3.0. España de Creative Commons. This doctoral thesis is licensed under the Creative Commons Attribution-NonCommercial- NoDerivs 3.0. Spain License. Brain connectivity and cognitive impairment in Parkinson’s disease Thesis presented by Hugo César Baggio to obtain the degree of doctor from the University of Barcelona in accordance with the requirements of the international PhD diploma Supervised by Dr. Carme Junqué i Plaja Faculty of Medicine, University of Barcelona Medicine Doctoral Program 2014 The studies presented in this thesis were performed at the Neuropsychology Group, Department of Psychiatry and Clinical Psychobiology, University of Barcelona. Funding for these studies was provided by a the Generalitat de Catalunya, by the Spanish Ministry of Science and Innovation, and CIBERNED. Barcelona, 03 September 2014 Carme Junqué i Plaja, Professor at the University of Barcelona, Certifies that she has guided and supervised the doctoral thesis entitled Brain connectivity and cognitive impairment in Parkinson’s disease presented by Hugo César Baggio. She hereby asserts that this thesis fulfills the requirements to present his defense to be awarded the title of Doctor. Signature, Dr. Carme Junqué i Plaja 11 15 chapter 1 17 17 general aspects 17 cognitive impairment 19 20 epidemiology 20 diagnosis 21 disease severity – rating scales 21 treatment of parkinsonism 22 24 mild cognitive impairment in PD 26 28 30 GM structural neuroimaging - methods 31 GM structural neuroimaging in PD – previous studies 33 WM structural neuroimaging - methods 35 WM structural neuroimaging in PD – previous studies 36 37 large-scale functional networks 38 resting-state functional connectivity fMRI techniques – methods 40 graph-theory 43 resting-state fMRI connectivity in PD – previous studies 46 49 chapter 2 59 59 59 60 chapter 3 61 61 64 66 68 chapter 4 69 study 1 71 study 2 91 study 3 113 study 4 129 study 5 141 study 6 155 study 7 169 chapter 5 181 181 181 184 186 187 189 chapter 6 191 chapter 7 193 chapter 8 195 chapter 9 197 Sporadic Parkinson’s disease (PD), an idiopathic chronic progressive neurological disease with several motor and non-motor features, is the second most common neurodegenerative disease after Alzheimer’s disease. The negative impact of PD is manifold. It represents a significant economic burden on health services and on individuals that is only expected to grow as the world population ages. Mortality in PD patients is uniformly described to be higher than in the general population. Importantly, the major impact of PD on quality of life reveals the relevance of its spectrum of manifestations. Motor, autonomic, psychiatric and cognitive symptoms place a heavy burden on both patients and their caregivers. Considerable progress has been made in the symptomatic treatment of motor and some non-motor symptoms of PD since the introduction of levodopa in the late nineteen sixties. The same cannot be said about cognitive impairments. It is vital that we try to gain more knowledge about the pathophysiology of cognitive decline in PD so as to define potential future therapeutic targets and identify candidates for early, potentially disease-modifying treatments. This thesis represents an attempt to characterize the mechanisms underlying cognitive impairments in PD through advanced neuroimaging techniques. The theoretical framework on which it is based is that the human brain is a complex network made up of functionally specialized regions, and that normal cognition relies on their coordinated activity. Normal coordinated activity, in turn, depends on the integrity of these functional subunits and of the lines of communication between them. Neuroimaging techniques based on this framework can help us gain insight into the disease process; additionally, by shedding light on the relationship between brain organization and function, they can help us learn more about the underpinnings of normal cognition. This thesis is presented for the degree of Doctor by the University of Barcelona, and is the result of the work carried out over four years at the Department of Psychiatry and Clinical Psychobiology of the University of Barcelona. During this period, I have obtained the degree of Master of Neuroscience, linked to the Doctorate in Medicine Program (Quality Mention MCD2008-00023; Mention Towards Excellence MEE2011-0316) at the University of Barcelona. This four-year work resulted in the production of the seven scientific papers listed below. Five of these papers have been published and one is accepted for publication in international indexed journals. The last paper is currently under review in an indexed journal. – 11 – . Baggio HC, Segura B, Sala-Llonch R, Marti MJ, Valldeoriola F, Compta Y, Tolosa E, Junqué C. Cognitive impairment and resting-state network connectivity in Parkinson’s disease. Human Brain Mapping 2014 DOI: 10.1002/hbm.22622 (in press). IF (2013): 6.924. Q1. Segura B, Baggio HC, Marti MJ, Valldeoriola F, Compta Y, Garcia-Diaz AI, Vendrell P, Bargallo N, Tolosa E, Junqué C. Cortical thinning associated with mild cognitive impairment in Parkinson's disease. Movement Disorders 2014 DOI: 10.1002/mds.25982. IF (2013): 5.634. Q1. Baggio HC, Sala-Llonch R, Segura B, Marti MJ, Valldeoriola F, Compta Y, Tolosa E, Junqué C. Functional brain networks and cognitive deficits in Parkinson's disease. Human Brain Mapping 2014, 35:4620-34. IF (2013): 6.924. Q1. Segura B, Ibarretxe-Bilbao N, Sala-Llonch R, Baggio HC, Martí MJ, Valldeoriola F, Vendrell P, Bargalló N, Tolosa E, Junqué C. Progressive changes in a recognition memory network in Parkinson's disease. Journal of Neurology Neurosurgery and Psychiatry 2013, 84:370-8. IF (2013): 5.58. Q1. Ibarretxe-Bilbao N, Junqué C, Segura B, Baggio HC, Marti MJ, Valldeoriola F, Bargallo N, Tolosa E. Progression of cortical thinning in early Parkinson's disease. Movement Disorders 2012, 27:1746-53. IF (2012): 4.558. Q1. Baggio HC, Segura B, Ibarretxe-Bilbao N, Valldeoriola F, Marti MJ, Compta Y, Tolosa E, Junqué C. Structural correlates of facial emotion recognition deficits in Parkinson's disease patients. Neuropsychologia 2012, 50:2121-8. IF (2012): 3.477. Q1. Baggio HC, Segura B, Garrido-Millán JL, Marti MJ, Compta Y, Valldeoriola F, Tolosa E, Junqué C. Resting-state frontostriatal functional connectivity in Parkinson’s disease-related apathy. Submitted. – 12 – – 13 – – 14 – ACC anterior cingulate cortex LB Lewy body AD Alzheimer's disease LEDD levodopa equivalent daily dose AS Starkstein's apathy scale LN Lewy neurite BDI Beck Depression Inventory-II MAOI monoamine oxidase B inhibitor BNT Boston Naming Test MCI mild cognitive impairment BOLD blood-oxygen level-dependent MD mean diffusivity COMT cathecol-O-methyltransferase inhibitor MDS Movement Disorder Society CSF cerebrospinal fluid MEG magnetoencephalography CTh cortical thickness MNI Montreal Neurological Institute MNI152 DAN dorsal attention network standard template DBS deep-brain stimulation MRI magnetic resonance imaging DMN default mode network NPI Cumming’s Neuropsychiatric Inventory DTI diffusion tensor imaging OFC orbitofrontal cortex EEG electroencephalography PCC posterior cingulate cortex FA fractional anisotropy PD Parkinson's disease FDR false-discovery rate PD-A Parkinson's disease patients with apathy FER facial emotion recognition PDD Parkinson's disease-related dementia FLAIR Fluid-attenuated inversion recovery PD-MCI Parkinson’s disease patients with mild fMRI functional magnetic resonance imaging cognitive impairment FPN frontoparietal network PD-NMCI Parkinson’s disease patients without mild FWE familywise error rate cognitive impairment FWHM full width at half maximum PD-NA Parkinson's disease patients without GM gray matter apathy HC healthy control PET positron emission tomography HY Hoehn and Yahr scale PFC prefrontal cortex ICA independent component analysis RAVLT Rey's Auditory Verbal Learning Test ICDs impulse control disorders RBD rapid-eye-movement behavior sleep ICN resting-state intrinsic connectivity network disorder JLO Benton's Judgment of Line Orientation ROI region of interest test SD standard deviation – 15 – SDMT Symbol Digits Modalities Tests TR repetition time SNR signal-to-noise ratio UPDRS unified Parkinson's disease rating scale TE echo time VBM voxel-based morphometry TMT A-B difference between Trail Making Test VFD Benton's Visual Form Discrimination test parts A and B VTA ventral tegmental area TMT-A Trail-Making Test, part A WM white matter TMT-B Trail-Making Test, part B – 16 – chapter 1 chapter 1 general aspects Susceptible neurons in Parkinson's disease (PD) patients show eosinophilic perikaryal inclusions known as Lewy bodies (LB) and thread-like formations located in the neuronal processes, the Lewy neurites (LN) [Braak et al., 2003]. LB and LN are characterized by the accumulation of filamentous protein inclusions, the main component of which is phosphorylated, ubiquitinated and acetylated insoluble α-synuclein [Anderson et al., 2006]. The aggregation of abnormal α-synuclein is considered to precede the formation of these inclusions, and LN possibly antecede LB [Stefanis, 2012]. The factors that trigger the cascade of events that culminates with α-synuclein misfolding, loss of function