Structural and functional analyzes in Parkinson's disease

Orientadores: Fernando Cendes, Anelyssa Cysne Frota D'AbreuTese (doutorado) - Universidade Estadual de Campinas, Faculdade de Ciências MédicasResumo: Introdução: A doença de Parkinson (DP) é a segunda doença neurodegenerativa mais comum no mundo. Ela é uma doença multi-sistêmica, caracterizada por sintomas motores e não-motores. A fisiopatologia da DP ainda não foi totalmente elucidada e a maioria dos estudos de imagem já realizados, utilizaram a técnica de morfometria baseada em voxels, comparando subgrupos de pacientes, com ou sem determinados sintomas. Objetivos: Avaliar indivíduos com DP através de diferentes técnicas de análise de imagem. Métodos: Avaliamos 101 pacientes (71 homens) e 69 controles. Oitenta e cinco pacientes passaram por avaliação clínica e destes, 36 apresentaram o primeiro sintoma em hemicorpo direito, e em 56 o principal sintoma foi o tremor. Os pacientes foram avaliados através das escalas Unified Parkinson¿s Disease Rating Scale (UPDRS) (59,33±9.8), Hoehn &Yahr (H&Y) (2.84±1.2), Scales for Outcomes in Parkinson¿s Disease-Cognition (SCOPA-COG) (19.24±6.8), Scales for Outcomes in Parkinson¿s Disease - Psychiatric Complications (SCOPA-PC) (3.6±7.8), Non-Motor Symptoms Scale (NMSS) (69.57±48.19) e Escala de Schwab & England para atividades de vida diária (73%±22%).Utilizamos as seguintes técnicas de análise de imagem: imagem por tensor de difusão (DTI), análise de espessura cortical (EC) e ressonância magnética funcional em estado de repouso (rs-fMRI). Resultados: Na análise de DTI nós avaliamos três tratos: corticoespinhal, cíngulo e corpo caloso. No trato corticoespinhal encontramos aumento de anisotropia fracional (FA) e diminuição nos valores de difusividade média (MD), difusividade axial (AD) e radial (RD). No cíngulo não encontramos diferenças significativas, e no corpo caloso encontramos diminuição de FA nos pacientes. Evidenciamos também associação entre MD e RD em trato corticoespinhal e cíngulo com a SCOPA-COG; FA e RD em corpo caloso com a UPDRS-III. Valores de FA menores que 0.559467 no trato corticoespinhal, diferenciaram corretamente pacientes de controles em 85.04% dos casos, com sensibilidade de 89.04% e especificidade de 79.63%. Na análise de EC não encontramos diferenças significativas entre pacientes e controles, porém, quando dividimos os pacientes em subgrupos leve, moderado e grave encontramos diferenças nos 3 grupos. O grupo leve apresentou diminuição da EC em giro temporal superior, giro reto e córtex olfatório, já o grupo moderado apresentou diminuição da EC em giro pós-central, área motora suplementar e giro frontal inferior, e o grupo grave em giro frontal inferior, giros pré- e pós-central, área motora suplementar, giro frontal inferior, giro reto, polo temporal, giro fusiforme, giro temporal médio e giro occipital. Encontramos correlação entre os escores da UPDRS-III e EC. Considerando a análise funcional encontramos alteração de conectividade em diversas regiões como lobos frontal, temporal e occipital, tálamo e tronco cerebral. Em relação às redes funcionais encontramos alteração de conectividade na default mode network e rede visual. Conclusão: Utilizamos técnicas complementares para avaliar alterações cerebrais na DP. Demonstramos alterações estruturais e funcionais em regiões análogas, entretanto, ainda não é possível determinar se as alterações funcionais são consequência ou causa direta das alterações estruturais, ou ocorrem em paralelo como resultado da fisiopatologia da doença. Valores de FA no trato corticoespinhal podem ser utilizadas como biomarcador, porém estudos longitudinais são necessários para confirmar estes achadosAbstract: Introduction: Parkinson's disease (PD) is the second most common neurodegenerative disease in the world. It is a multisystemic disorder characterized by motor and non-motor symptoms. The pathophysiology of PD has not been fully elucidated and previous imaging studies mostly used voxel-based morphometry, comparing subgroups of patients, with or without certain symptoms. Objectives: The aim of this study was to evaluate individuals with PD through different imaging techniques. Methods: We evaluated 101 patients (71 men) and 69 controls. Eighty-five patients underwent clinical evaluation and of those, 36 had the first symptom at right, and in 56 the main symptom was tremor. Patients were assessed through scales: Unified Parkinson's Disease Rating Scale (UPDRS) (59.33 ± 9.8), Hoehn & Yahr (H & Y) (2.84 ± 1.2), Scales for Outcomes in Parkinson's Disease-Cognition (SCOPA-COG) (19:24 ± 6.8), Scales for Outcomes in Parkinson's Disease - Psychiatric Complications (SCOPA-PC) (3.6 ± 7.8), Non-Motor Symptoms Scale (NMSS) (69.57 ± 48.19) and Schwab & England scale for activities of daily living (73% ± 22%). We use the following image analysis techniques: diffusion tensor imaging (DTI), cortical thickness analysis (CTA) and resting state functional magnetic resonance imaging (rs-fMRI). Results: In the DTI, we evaluated three tracts: corticospinal, cingulum and corpus callosum. In the corticospinal tract, we found increased fractional anisotropy (FA) and decreased mean diffusivity (MD), axial diffusivity (AD) and radial diffusivity (RD). There were no significant differences in the cingulum, and we observed decreased FA in the corpus callosum. There was an association between MD and RD in the corticospinal tract and cingulum with the SCOPA-COG scores, and between the FA and RD in the corpus callosum and the UPDRS-III. FA values ??lower than 0.559467 in the corticospinal tract, properly differentiated patients from controls in 85.04 % of cases, with a sensitivity of 89.04% and sensitivity of 79.63%. There were no significant differences between patients and controls in CTA, however, when the patients were divided into mild, moderate and severe subgroups, we found differences in the three groups. The mild group had decreased CT in the superior temporal gyrus, gyrus rectus and the olfactory cortex, the moderate group exhibited reduced CT in the postcentral gyrus, the supplementary motor area and the inferior frontal gyrus, while the severe group presented decreased CT in the inferior frontal gyrus, precentral and postcentral gyrus, supplementary motor area, inferior frontal gyrus, gyrus rectus, temporal pole, fusiform gyrus, middle temporal gyrus and occipital gyrus. We found an association between the UPDRS-III scores and CT. We found decreased connectivity between various areas in the frontal, temporal and occipital lobes, thalamus and brainstem. We found reduced connectivity in the default mode network and the visual network. Conclusion: We used three complementary techniques to assess brain changes in PD. We demonstrated structural and functional changes in similar regions; however, it is still not possible to determine whether the functional deficits occur due to structural changes or vice versa. FA values ??in the corticospinal tract may be used as a biomarker; however, longitudinal studies are necessary to confirm these findingsDoutoradoFisiopatologia MédicaDoutora em Ciências2011/19958-4FAPES

Modelling the Neuroanatomical Progression of Alzheimer's Disease and Posterior Cortical Atrophy

In order to find effective treatments for Alzheimer's disease (AD), we need to identify subjects at risk of AD as early as possible. To this end, recently developed disease progression models can be used to perform early diagnosis, as well as predict the subjects' disease stages and future evolution. However, these models have not yet been applied to rare neurodegenerative diseases, are not suitable to understand the complex dynamics of biomarkers, work only on large multimodal datasets, and their predictive performance has not been objectively validated. In this work I developed novel models of disease progression and applied them to estimate the progression of Alzheimer's disease and Posterior Cortical atrophy, a rare neurodegenerative syndrome causing visual deficits. My first contribution is a study on the progression of Posterior Cortical Atrophy, using models already developed: the Event-based Model (EBM) and the Differential Equation Model (DEM). My second contribution is the development of DIVE, a novel spatio-temporal model of disease progression that estimates fine-grained spatial patterns of pathology, potentially enabling us to understand complex disease mechanisms relating to pathology propagation along brain networks. My third contribution is the development of Disease Knowledge Transfer (DKT), a novel disease progression model that estimates the multimodal progression of rare neurodegenerative diseases from limited, unimodal datasets, by transferring information from larger, multimodal datasets of typical neurodegenerative diseases. My fourth contribution is the development of novel extensions for the EBM and the DEM, and the development of novel measures for performance evaluation of such models. My last contribution is the organization of the TADPOLE challenge, a competition which aims to identify algorithms and features that best predict the evolution of AD.Comment: PhD thesis; Defended in Jan 2019 at University College Londo

Modern Developments in Transcranial Magnetic Stimulation (TMS) – Applications and Perspectives in Clinical Neuroscience

Transcranial magnetic stimulation (TMS) is being increasingly used in neuroscience and clinics. Modern advances include but are not limited to the combination of TMS with precise neuronavigation as well as the integration of TMS into a multimodal environment, e.g., by guiding the TMS application using complementary techniques such as functional magnetic resonance imaging (fMRI), electroencephalography (EEG), diffusion tensor imaging (DTI), or magnetoencephalography (MEG). Furthermore, the impact of stimulation can be identified and characterized by such multimodal approaches, helping to shed light on the basic neurophysiology and TMS effects in the human brain. Against this background, the aim of this Special Issue was to explore advancements in the field of TMS considering both investigations in healthy subjects as well as patients

Effects of Diversity and Neuropsychological Performance in an NFL Cohort

Objective: The aim of this study was to examine the effect of ethnicity on neuropsychological test performance by comparing scores of white and black former NFL athletes on each subtest of the WMS. Participants and Methods: Data was derived from a de-identified database in South Florida consisting of 63 former NFL white (n=28, 44.4%) and black (n=35, 55.6%) athletes (Mage= 50.38; SD= 11.57). Participants completed the following subtests of the WMS: Logical Memory I and II, Verbal Paired Associates I and II, and Visual Reproduction I and II. Results: A One-Way ANOVA yielded significant effect between ethnicity and performance on several subtests from the WMS-IV. Black athletes had significantly lower scores compared to white athletes on Logical Memory II: F(1,61) = 4.667, p= .035, Verbal Paired Associates I: F(1,61) = 4.536, p = .037, Verbal Paired Associates: II F(1,61) = 4.677, p = .034, and Visual Reproduction I: F(1,61) = 6.562, p = .013. Conclusions: Results suggest significant differences exist between white and black athletes on neuropsychological test performance, necessitating the need for proper normative samples for each ethnic group. It is possible the differences found can be explained by the psychometric properties of the assessment and possibility of a non-representative sample for minorities, or simply individual differences. Previous literature has found white individuals to outperform African-Americans on verbal and non-verbal cognitive tasks after controlling for socioeconomic and other demographic variables (Manly & Jacobs, 2002). This highlights the need for future investigators to identify cultural factors and evaluate how ethnicity specifically plays a role on neuropsychological test performance. Notably, differences between ethnic groups can have significant implications when evaluating a sample of former athletes for cognitive impairment, as these results suggest retired NFL minorities may be more impaired compared to retired NFL white athletes

Distinguishing Performance on Tests of Executive Functions Between Those with Depression and Anxiety

Objective: To see if there are differences in executive functions between those diagnosed with Major Depressive Disorder (MDD) and those with Generalized Anxiety Disorder (GAD).Participants and Methods: The data were chosen from a de-identified database at a neuropsychological clinic in South Florida. The sample used was adults diagnosed with MDD (n=75) and GAD (n=71) and who had taken the Halstead Category Test, Trail Making Test, Stroop Test, and the Wisconsin Card Sorting Test. Age (M=32.97, SD=11.75), gender (56.7% female), and race (52.7% White) did not differ between groups. IQ did not differ but education did (MDD=13.41 years, SD=2.45; GAD=15.11 years, SD=2.40), so it was ran as a covariate in the analyses. Six ANCOVAs were run separately with diagnosis being held as the fixed factor and executive function test scores held as dependent variables. Results: The MDD group only performed worse on the Category Test than the GAD group ([1,132]=4.022, p\u3c .05). Even though both WCST scores used were significantly different between the two groups, both analyses failed Levene’s test of Equality of Error Variances, so the data were not interpreted. Conclusions: Due to previous findings that those diagnosed with MDD perform worse on tests of executive function than normal controls (Veiel, 1997), this study wanted to compare executive function performance between those diagnosed with MDD and those with another common psychological disorder. The fact that these two groups only differed on the Category Test shows that there may not be much of a difference in executive function deficits between those with MDD and GAD. That being said, not being able to interpret the scores on the WCST test due to a lack of homogeneity of variance indicates that a larger sample size is needed to compare these two types of patients, as significant differences may be found. The results of this specific study, however, could mean that the Category Test could be used in assisting the diagnosis of a MDD patient