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Multi-site MRI datasets are crucial for big data research. However, neuroimaging studies must face the batch effect. Here, we propose an approach that uses the predictive probabilities provided by Gaussian processes (GPs) to harmonize clinical-based studies. A multi-site dataset of 216 Parkinson's disease (PD) patients and 87 healthy subjects (HS) was used. We performed a site GP classification using MRI data. The outcomes estimated from this classification, redefined like Weighted HARMonization PArameters (WHARMPA), were used as regressors in two different clinical studies: A PD versus HS machine learning classification using GP, and a VBM comparison (FWE-p < .05, k = 100). Same studies were also conducted using conventional Boolean site covariates, and without information about site belonging. The results from site GP classification provided high scores, balanced accuracy (BAC) was 98.39% for grey matter images. PD versus HS classification performed better when the WHARMPA were used to harmonize (BAC = 78.60%; AUC = 0.90) than when using the Boolean site information (BAC = 56.31%; AUC = 0.71) and without it (BAC = 57.22%; AUC = 0.73). The VBM analysis harmonized using WHARMPA provided larger and more statistically robust clusters in regions previously reported in PD than when the Boolean site covariates or no corrections were added to the model. In conclusion, WHARMPA might encode global site-effects quantitatively and allow the harmonization of data. This method is user-friendly and provides a powerful solution, without complex implementations, to clean the analyses by removing variability associated with the differences between sites.

According neuropathological research limbic changes occur in Parkinson's disease with and without dementia. Structural MRI have reported atrophy of limbic structures including amygadala and hippocampus, in both demented and non-demented PD patients; and a progression of limbic atrophy over time. In addition, atrophy of paralimbic areas (i.e. paracingulate gyrus) and limbic association cortex (i.e orbitofrontal cortex) has also been reported in PD. Functional studies have also reported limbic dysfunctions in Parkinson's disease. PET studies reported that orbitofrontal and amygdalar presynaptic dopaminergic functions are altered in early PD and a significant decrease in the metabolism of the medial OFC in a follow-up study of patients with early PD. fMRI studies showed an abnormal amygdalar response in PD while recognizing fearful faces and lack of activation in the right hippocampus and amygdala while perceiving odorant stimuli inside the scanner. Neuropsychological studies pointed out that the functions that are known to depend on the integrity of limbic system are impaired in Parkinson's disease even in the early stages of the disease. Specifically, it has been reported and impairment in verbal memory, recognition of facial expressions of emotions, decision-making and olfactory function. However, the neuroanatomical and neurofunctional correlates of these dysfunctions are not known or are poorly investigated. For memory functions, hippocampal and amygdalar volumes have been reported to correlate with memory impairment. For decision making and recognition of emotions there are no studies of its correlates; and for olfactory dysfunctions one study reported a correlations between this impairment and a reduced fractional anisotropy in the cerebellum.The general aim of this thesis is to investigate the neuroanatomical and neurofunctional correlates of declarative memory, decision-making, recognition of emotions and olfactory dysfunctions in PD. We hypothesized that all these dysfunctions are due to the limbic degenerative changes associated with PD. We used structural MRI (T1-weighted MRI and DTI), functional MRI (fMRI) and neuropsychological testing to assess declarative memory, emotional processing and decision-making, and olfactory function. Firstly, we focused on the hippocampal atrophy putatively related to declarative memory dysfunctions and PD, and a possible neuroradiological marker for the evolution to dementia. This issue was investigated in papers I and II. Secondly, we aimed to investigate structural correlates of deficits in the recognition of emotions, decision-making and olfactory dysfunction reported early in the disease course by means of VBM and DTI (paper III and IV). Finally in paper V the functional correlates of recognition memory were assessed using fMRI.The main conclusions of this thesis, derived from the five studies, can be summarized as follows:1) The pattern of atrophy in non-demented PD patients affects the anterior region of the hippocampus and progresses to the posterior part in demented patients but preserves the middle part of this structure. This pattern and evolution is similar to that seen in Mild Cognitive Impairment of amnestic type and Alzheimer's disease.2) Declarative memory dysfunctions in PD depend on the atrophy of the head of the hippocampus. 3) Patients with visual hallucinations present progressive hippocampal atrophy and also show widespread atrophy involving the limbic, paralimbic and neocortical areas in agreement with the evolution towards dementia. In contrast, patients without VH only show gray matter loss in the motor regions and their cognitive functions remain spared.4) Early PD patients present gray matter loss in some limbic regions. We observed gray matter loss in the amygdala and orbitofrontal cortex but not in the anterior cingulate, enthorrinal cortex and accumbes nuclei. These results only partially support the stages proposed by Braak.5) Impairment in decision-making and recognition of facial expressions of emotions occurs at early stages of PD. These neuropsychological deficits are accompanied by degeneration of orbitofrontal cortex (OFC) and amygdala. Bilateral OFC reductions are associated with impaired recognition of emotions, and gray matter volume loss in left lateral OFC is related to decision-making impairment in PD.6) PD patients presented abnormal white matter microstructural changes in several brain regions including cortical and subcortical areas early in the disease course. However, only reduction of fractional anisotropy in the white matter of the central olfactory areas, specifically the white matter adjacent to the gyrus rectus, is associated with olfactory dysfunction in PD patients.7) There is a disruption of functional networks involved in memory and default mode in early PD., Está tesis está compuesta de 5 artículos originales y una revisión con un factor de impacto total de 14.441. A lo largo de los 5 estudios se abordan los correlatos neuroanatómicos y neurofuncionales de las disfunciones de memoria declarativa, emocionales y olfatorias en la enfermedad de Parkinson por medio de resonancia magnética estructural y funcional y una extensiva exploración neuropsicológica. En el primer y segundo estudio se aborda el estudio de la atrofia del hipocampo y su progresión a lo largo del tiempo (estudio transversal y longitudinal) mediante voxel-based morphometry. En el tercer estudio se abordan los correlatos de las disfunciones de toma de decisiones y reconocimineto de emociones en la enfermedad de Parkinson, encontrando una relación entre la atrofia de la corteza orbitofrontal y dichas funciones. En el cuarto estudio utilizamos diffusion tensor imaging para investigar las posible anormalidades microestructurales en el sistema central olfatorio y su relación con la identificación de olores en las fases inciales del Parkinson. Finalmente en el quinto estudio investigamos la conectividad funcional de areas cerebrales implicadas en la realización de una tarea de memoria, las cuales descubrimos que están alteradas desde las fases iniciales de la enfermedad.

Objective: To analyze longitudinal changes of retinal thickness and their predictive value as biomarkers of disease progression in idiopathic Parkinson’s disease (iPD). Methods: Patients with Lewy body diseases (LBDs) were enrolled and prospectively evaluated at 3 years, including patients with iPD (n=42), dementia with Lewy bodies (DLB, n=4), E46K-SNCA mutation carriers (n=4) and controls (n=17). All participants underwent Spectralis retinal optical coherence tomography and Montreal Cognitive Assessment (MoCA), and Unified Parkinson’s Disease Rating Scale (UPDRS) score was obtained in patients. Macular ganglion-inner plexiform layer complex (GCIPL) and peripapillary retinal nerve fiber layer (pRNFL) thickness reduction rates were estimated with linear mixed models. Risk ratios were calculated to evaluate the association between baseline GCIPL and pRNFL thickness and the risk of subsequent cognitive and motor worsening, using clinically meaningful cut-offs. Results: GCIPL thickness in the parafoveal region (1- to 3-mm ring) presented the largest reduction rate. The annualized atrophy rate was 0.63 µm in iPD patients and 0.23 µm in controls (p