The Utility of Neuroimaging in the Differential Diagnosis of Parkinsonian Syndromes

The differential diagnosis of parkinsonian syndromes can be challenging, particularly in early disease stages. However, prognosis and therapeutic regimes are not alike in Parkinson disease and atypical parkinsonism, and thus a correct diagnosis at the earliest possible stage is desirable. Over the past two decades, magnetic resonance imaging and radiotracer-based imaging techniques have proven to be helpful tools to enhance the accuracy of clinical diagnosis in these disorders. Here, we review recent advances in neuroimaging for the differential diagnosis of parkinsonian syndromes

Imaging Cognitive Impairment and Impulse Control Disorders in Parkinson's Disease

Dementia and mild forms of cognitive impairment as well as neuropsychiatric symptoms (i. e., impulse control disorders) are frequent and disabling non-motor symptoms of Parkinson's disease (PD). The identification of changes in neuroimaging studies for the early diagnosis and monitoring of the cognitive and neuropsychiatric symptoms associated with Parkinson's disease, as well as their pathophysiological understanding, are critical for the development of an optimal therapeutic approach. In the current literature review, we present an update on the latest structural and functional neuroimaging findings, including high magnetic field resonance and radionuclide imaging, assessing cognitive dysfunction and impulse control disorders in PD

Influence of Analytic Techniques on Comparing Dti-Derived Measurements in Early Stage Parkinson\u27s Disease

Diffusion tensor imaging (DTI) studies in early Parkinson\u27s disease (PD) to understand pathologic changes in white matter (WM) organization are variable in their findings. Evaluation of different analytic techniques frequently employed to understand the DTI-derived change in WM organization in a multisite, well-characterized, early stage PD cohort should aid the identification of the most robust analytic techniques to be used to investigate WM pathology in this disease, an important unmet need in the field. Thus, region of interest (ROI)-based analysis, voxel-based morphometry (VBM) analysis with varying spatial smoothing, and the two most widely used skeletonwise approaches (tract-based spatial statistics, TBSS, and tensor-based registration, DTI-TK) were evaluated in a DTI dataset of early PD and Healthy Controls (HC) from the Parkinson\u27s Progression Markers Initiative (PPMI) cohort. Statistical tests on the DTI-derived metrics were conducted using a nonparametric approach from this cohort of early PD, after rigorously controlling for motion and signal artifacts during DTI scan which are frequent confounds in this disease population. Both TBSS and DTI-TK revealed a significantly negative correlation of fractional anisotropy (FA) with disease duration. However, only DTI-TK revealed radial diffusivity (RD) to be driving this FA correlation with disease duration. HC had a significantly positive correlation of MD with cumulative DaT score in the right middle-frontal cortex after a minimum smoothing level (at least 13mm) was attained. The present study found that scalar DTI-derived measures such as FA, MD, and RD should be used as imaging biomarkers with caution in early PD as the conclusions derived from them are heavily dependent on the choice of the analysis used. This study further demonstrated DTI-TK may be used to understand changes in DTI-derived measures with disease progression as it was found to be more accurate than TBSS. In addition, no singular region was identified that could explain both disease duration and severity in early PD. The results of this study should help standardize the utilization of DTI-derived measures in PD in an effort to improve comparability across studies and time, and to minimize variability in reported results due to variation in techniques

Effects of dance therapy on balance, gait and neuro-psychological performances in patients with Parkinson's disease and postural instability

Postural Instability (PI) is a core feature of Parkinson’s Disease (PD) and a major cause of falls and disabilities. Impairment of executive functions has been called as an aggravating factor on motor performances. Dance therapy has been shown effective for improving gait and has been suggested as an alternative rehabilitative method. To evaluate gait performance, spatial-temporal (S-T) gait parameters and cognitive performances in a cohort of patients with PD and PI modifications in balance after a cycle of dance therapy

Complex networks reveal early MRI markers of Parkinson's disease

Parkinson's disease (PD) is the most common neurological disorder, after Alzheimer's disease, and is characterized by a long prodromal stage lasting up to 20 years. As age is a prominent factor risk for the disease, next years will see a continuous increment of PD patients, making urgent the development of efficient strategies for early diagnosis and treatments. We propose here a novel approach based on complex networks for accurate early diagnoses using magnetic resonance imaging (MRI) data; our approach also allows us to investigate which are the brain regions mostly affected by the disease. First of all, we define a network model of brain regions and associate to each region proper connectivity measures. Thus, each brain is represented through a feature vector encoding the local relationships brain regions interweave. Then, Random Forests are used for feature selection and learning a compact representation. Finally, we use a Support Vector Machine to combine complex network features with clinical scores typical of PD prodromal phase and provide a diagnostic index. We evaluated the classification performance on the Parkinson's Progression Markers Initiative (PPMI) database, including a mixed cohort of 169 normal controls (NC) and 374 PD patients. Our model compares favorably with existing state-of-the-art MRI approaches. Besides, as a difference with previous approaches, our methodology ranks the brain regions according to disease effects without any a priori assumption

Neural Correlates of Parkinsonian Syndromes

The thesis investigated objective neuroimaging biomarkers in parkinsonian syndromes, which could be applied to increase diagnostic accuracy. To find convergence of the literature concerning disease-specific patterns in Parkinson’s disease and progressive supranuclear palsy, we conducted meta-analyses. In Parkinson’s disease glucose hypometabolism was re- vealed in bilateral inferior parietal cortex and left caudate nucleus and focal gray matter atrophy in the middle occipital gyrus. In progressive supranu- clear palsy we identified gray matter atrophy in the midbrain and white mat- ter atrophy in the cerebral/cerebellar pedunculi and midbrain. In sum, in Parkinson’s disease hypometabolism outperforms atrophy and in progres- sive supranuclear palsy we validated pathognomonic markers as disease- specific. Our studies create a novel framework to investigate disease- specific regional alterations for use in clinical routine. Further, we inves- tigated neural correlates by voxel-based morphometry and discriminated disease and clinical syndrome by multivariate pattern recognition in sin- gle patients with corticobasal syndrome and corticobasal syndrome with a unique syndrome - alien/ anarchic limb phenomenon. We found gray matter volume differences between patients and controls in asymmetric frontotem- poral/ occipital regions, motor areas, and insulae. The frontoparietal gyrus including the supplementary motor area contralateral to the side of the af- fected limb was specific for alien/ anarchic limb phenomenon. The predic- tion of the disease among controls was 79.0% accurate. The prediction of the specific syndrome within a disease reached an accuracy of 81.3%. In conclusion, we reliably classified patients and controls by objective pattern recognition. Moreover, we were able to predict a specific clinical syndrome within a disease, paving the way to individualized disease prediction.:SELBSTSTÄNDIGKEITSERKLÄRUNG I ACKNOWLEDGMENTS II SUMMARY III ZUSAMMENFASSUNG VIII BIBLIOGRAPHISCHE DARSTELLUNG XIV CONTENTS XVI 1 GENERAL INTRODUCTION 1 1.1 ParkinsonianSyndromes .................... 2 1.2 Parkinson’sDisease ....................... 2 1.2.1 DiagnosticCriteria .................... 3 1.3 ProgressiveSupranuclearPalsy ................ 4 1.3.1 DiagnosticCriteria .................... 5 1.4 CorticobasalDegeneration ................... 5 1.4.1 DiagnosticCriteria .................... 7 1.5 ImagingBiomarkers ....................... 7 1.6 CurrentThesis .......................... 9 1.6.1 MotivationandFramework ............... 9 1.6.2 ResearchQuestions................... 9 2 GENERAL MATERIALS AND METHODS 12 2.1 MagneticResonanceImaging.................. 12 2.2 AnalyticalMethods........................ 13 2.2.1 Meta-Analysis ...................... 13 2.2.2 Voxel-BasedMorphometry ............... 14 2.2.3 Support-Vector Machine Classification . . . . . . . . . 15 2.3 Multi-CentricData ........................ 16 2.4 ClinicalAssessment ....................... 17 3 Study 1 4 Study 2 5 Study 3 6 Study 4 7 Study 5 8 DISCUSSION 73 8.1 MainFindings........................... 73 8.2 Statistical Approaches to Find Imaging Biomarker . . . . . . 76 8.3 Brain Alterations and their Utility as Imaging Biomarker . . . . 77 8.4 Limitations ............................ 78 8.5 Contributions of the Current Thesis and Future Directions . . 79 9 REFERENCES APPENDIX XVIII LIST OF AUTHORSHIP XXVII CURRICULUM VITÆ XXXVII

Utilidade dos exames de ressonância magnética no diagnóstico da doença de Parkinson : revisão sistemática e meta análise

Tese de mestrado, Neurociências, Faculdade de Medicina, Universidade de Lisboa, 2014Com a atual tendência para o envelhecimento da população e sendo a doença de Parkinson (DP) uma patologia que atinge cerca de 2% da população acima dos 65 anos, podemos prever um aumento da sua prevalência. Por outro lado devido às questões éticas e à morbilidade que implicariam as biopsias cerebrais como método de diagnóstico definitivo, a necessidade de encontrar métodos de diagnóstico precoce e não invasivos são de extrema importância. Mesmo nos melhores centros de diagnóstico há uma percentagem importante de desacordo entre o diagnóstico efetuado em vida, de base clínica e o diagnóstico pós-morte, que é histopatológico. A Ressonância Magnética, nas suas diferentes modalidades, proporciona-nos um meio de investigar “in vivo” as regiões corticais e subcorticais que se sabem estarem afetadas na DP. Diversos estudos recentes procuram demonstrar a utilidade destes testes como bio marcadores de diagnóstico e progressão da doença de Parkinson. Procurei efetuar uma revisão sistemática e meta análise em relação aos exames de Imagens de Ressonância Magnética (IRM) de modo a verificar a sua utilidade no diagnóstico da doença de Parkinson e se poderão ter potencial para serem considerados bio marcadores de diagnóstico e seguimento dos doentes. Objetivo Revisão sistemática dos estudos que compararem, a precisão das diferentes modalidades de ressonância magnética no diagnóstico da doença de Parkinson, com diagnóstico clínico e controlos saudáveis, explorando suas potencialidades como bio marcadores. Material e métodos Procedeu-se a uma pesquisa na literatura publicada sobre a temática, recorrendo à base de dados PubMed/MEDLINE, Embase, B-on, Google Scholar e ainda na bibliografia dos estudos considerados relevantes. Foram utilizadas as palavras-chave "Parkinson", "Magnetic resonance imaging", "MRI", "DTI", "Diffusion tensor imaging", "Spectroscopy", "MRI of Iron", "fMRI", "bold", “Neuromelanin”, combinados com operadores booleanos apropriados para cada pesquisa. Foram selecionados estudos redigidos em Inglês, Francês, Espanhol e Português. Critérios de inclusão: Estudos neurorradiológicos, com mais de cinco pacientes, até a presente data, que envolvam Imagens de ressonância magnética (MRI) de diferentes modalidades tais como: Exames Estruturais (T1, T2, Neuromelanina, Ferro e outras técnicas); Diffusion Tensor Imaging (DTI); Espectroscopia em Ressonância Magnética (MRSI); Ressonância Magnética Funcional (fMRI) no diagnóstico da Doença de Parkinson e que comparem a precisão do teste com diagnóstico clínico e controlos saudáveis, explorando suas potencialidades como bio marcadores. Foram excluídos, estudos que não usaram critérios formais de diagnóstico clínico, estudos incluindo pacientes submetidos a estimulação cerebral profunda, parkinsonismo idiopático ou vascular, casos relatados, editoriais, comentários, cartas, estudos em animais, estudos de diagnóstico diferencial com outras síndromes parkinsonianos e demências da DP. Resultados Dos 834 estudos identificados e atendendo aos critérios de seleção foram separados 109 estudos que após a leitura dos “Abstracts” verificou-se que apenas 52 preenchiam os requisitos dos critérios de inclusão. Destes estudos, foram obtidas as versões integrais publicadas, que foram integralmente lidas e sempre que existentes registados por mim, os seguintes dados: a referência, o ano, o título, o número de pacientes e controlos, a idade média, o estádio Hoehn & Yahr, a medicação, a modalidade de IRM, a região estudada, a intensidade do campo magnético do sistema, as conclusões e ainda se possível, a especificidade, a sensibilidade, a área sob a curva ROC e valores-p (Sigma) do teste t-Student (t-test) da comparação entre os valores obtidos dos exames dos pacientes com DP e a dos controlos saudáveis. Os resultados obtidos foram divididos em quatro grupos, em função da modalidade de estudo de IRM (imagens de ressonância magnética), para avaliação: 1º exames estruturais utilizando os métodos clássicos e IRM do ferro e da Neuromelanina; 2º exames utilizando DTI (Diffusion Tensor Imaging); 3º exames de espectroscopia de RMN; 4º fMRI (ressonância magnética funcional) incluindo a de em estado de repouso (RS-fMRI). 1º Exames estruturais utilizando os métodos clássicos e IRM, do ferro e Neuromelanina. Neste grupo de estudos podemos verificar que, utilizando T1 imagens Inversão de recuperação (a área) 24; T2W (o volume) 33; T1p (sensível á perda neuronal) 46; MRI sensível á Neuromelanina (medição do volume) 23, encontramos uma diminuição significativa na SN (substância nigra) dos pacientes com DP, quando comparados com controlos saudáveis pareados por idade, e um aumento significativo dos valores do R2 * (= 1/T2 *) e T2p, (sensível à deposição de ferro) em pacientes com DP 41, 27, quando comparados com controlos saudáveis. É de salientar que estas alterações se mantem ainda que tenhamos valores de sistemas com diferentes intensidades dos campos magnéticos 3T; 4T; 7T. 2º Exames utilizando DTI (Diffusion Tensor Imaging). Com este tipo de exames podemos detetar em pacientes com DP, alterações na AF (anisotropia fracionada) e DM (difusibilidade média) em todo o cérebro 74, mas que são mais pronunciadas na substância branca frontal e parietal refletindo deste modo um dano microestrutural generalizado. Estas alterações ocorrem nos estádios iniciais da PD75, em fibras de projeção do tálamo 11. Os valores da MK (mean kurtosis) e da AF foram significativamente menores no cíngulo anterior 22, na área motora, na pré-motora e motora suplementar do córtex 64,nas áreas de substância branca próximas das áreas motoras suplementares, cápsulas externa e interna, tálamo direito, putamen esquerdo 65 e como se demonstra na meta-análise há uma redução significativa da AF na SN. 3º Exames de espectroscopia de RMN Na espectroscopia dos metabolitos Substância Nigra na doença de Parkinson foram observadas diferenças significativas entre doentes PD e controlos saudáveis nas razões, NAA / Cr, NAA / Cho, NAA / (Co + Cr) 66, 76. Com estes exames podemos obter um in perfil neuro-químico “in vivo”, incluindo neurotransmissores (Glu e GABA) e os níveis de antioxidantes (GSH), que estão em excelente concordância com a literatura neuro química 70. Na pré-SMA, a razão NAA / Cr diminuiu seletivamente, em paralelo com disfunção neuronal nos DP (P = 0,045) 73. No putamen e mesencéfalo foi encontrada uma redução bilateral de fosfatos de alta energia, como adenosina trifosfato e fosfocreatina como recetores finais da energia da fosforilação oxidativa mitocondrial 71. 4º Exames de fMRI ressonância magnética funcional incluindo os de em estado de repouso (RS-fMRI). Usando diferentes paradigmas e comparando pacientes com DP, com controlos saudáveis, encontramos nos diferentes estudos uma redução da percentagem de mudança de sinal em todos os núcleos dos gânglios da base contra lateral e ipsilateral, tálamo lateral e medial, M1 (córtex motor primário) e área motora suplementar. Foram detetadas correlações negativas significativas entre a UPDRS e a ativação BOLD bilateralmente nos núcleos, caudado e putamen, segmento externo contra lateral do globo pálido, bilateralmente nos núcleos sub-talâmicos, substantia nigra e tálamo contra lateral. A bradicinesia é o sintoma que mais consistentemente previu a ativação BOLD nos gânglios da base e tálamo. Além disso, a ativação BOLD no globo pálido interno contra lateral, estava relacionada com tremor. A atividade cortical reduzida no córtex motor primário e na área motora suplementar nos pacientes com DP recém-diagnosticada, não se relacionam com sintomas motores 58. Durante a execução de movimentos automáticos, os pacientes com doença de Parkinson em comparação com os controlos saudáveis, necessitam de mais atividade cerebral no cerebelo, na área pré-motora, no córtex parietal, no precuneus e córtex pré-frontal para compensar a disfunção dos gânglios basais 51. Usando RS-fMRI para estudar a conectividade funcional (CF), verificou-se que os pacientes PD apresentam uma disrupção da rede motora. O aumento CF em estado de repouso entre os núcleos sub-talâmicos (NST) e áreas motoras corticais e os sintomas de rigidez e tremor na PD podem estar relacionados a um acoplamento anormal dessas áreas. Com estudos selecionados foram efetuadas meta análises ponderando o efeito de tamanho da amostra nos 1º e 2º grupo, tendo-se verificado que neles há diferenças significativas (em t-test utilizando p-value) no que respeita á redução de volume e da anisotropia fracionada (AF) da Substância Nigra (SN) entre os doentes de Parkinson e os controlos saudáveis. Foi detetada uma redução média de volume da SN, estimada pela tamanho do efeito das IRM Estruturais de (-0,877, 95% intervalo de confiança de -1,049 a -0.705, p <0.0001) apresentando os estudos um baixo nível de heterogeneidade (Q [12] =14,598 p =0,264 I2 =17,795). Na AF da SN em DTI a redução média dos valores da AF estimada atendendo ao efeito tamanho dos estudos foi de (-0,811, 95% intervalo de confiança de -1,036 a -0,586, p <0,0001) com um baixo nível de heterogeneidade entre os estudos (Q [6] =7,327, p =0,396 I2 = 4,465). Conclusões Estes resultados são encorajadores pois pode-se concluir que os exames de imagem de ressonância magnética possuem uma boa capacidade discriminativa dos doentes de Parkinson em relação aos controlos saudáveis e poderão desempenhar um papel importante na deteção, na monitorização da progressão e no impacto terapêutico na DP. Entretanto, serão necessários estudos longitudinais e prospetivos com um número mais elevado de doentes utilizando as várias modalidades, isoladamente ou em associação, para melhorar a acuidade diagnóstica e confirmar a sua utilização como bio marcadores.Objectives: We performed a systematic review of the studies comparing the accuracy of the different modalities of magnetic resonance imaging in the diagnosis of Parkinson's disease with clinical diagnosis and healthy controls, exploring its potentials as biomarkers. Methods: We searched for studies and research reviews in, the MEDLINE, EMBASE, B-on (the online knowledge Library) databases, and in bibliography cited in relevant studies, comparing the MRI differences between Parkinson’s disease patients and healthy controls to access the accuracy of the different methods, the results were extracted and estimates were pooled by random-effects meta-analysis. Results: 834 studies were identified using MRI in PD but only 48 studies were eligible for inclusion, with a total of 1362 Parkinson’s disease patients and 1023 healthy controls, whose results were divided into four groups: 1st- Structural, Iron and Neuromelanin MRI; 2nd- DTI (diffusion tensor imaging) with FA and MD; 3rd- Spectroscopy (MRS); 4th- fMRI that includes RS-fMRI (resting state fMRI). It was found changes in basal ganglia, thalamus, white and gray matter in the different MRI modalities. In the 1st and 2nd group we performed a meta-analysis for the Volume and Fractional Anisotropy (FA) of the Substantia Nigra (SN) respectively. A good effect size of the reduction was found for both in the PD patients versus controls in structural MRI (-0,877, 95% confidence interval -1,049 to -0.705, p < 0.0001) and in DTI (-0,811, 95% confidence interval -1,036 to -0,586, p < 0,0001). With a low level of heterogeneity. Conclusions: Magnetic Resonance Imaging has a good accuracy in separate PD patients from Healthy Controls, and could have a role in detecting pre manifest disease, monitoring progression and drug therapeutic impact. Larger prospective and longitudinal studies using DTI, Spectroscopy, fMRI, RS-fMRI and other modalities of MRI on larger cohorts of patients with Parkinson´s disease are needed to investigate some of the actual encouraging preliminary findings. Standardization of protocols is a need and will be a reality in the future and that will help us to get better and comparable results. Combination of modalities could improve the diagnostic accuracy

Classification of patients with parkinsonian syndromes using medical imaging and artificial intelligence algorithms

The distinction of Parkinsonian Syndromes (PS) is challenging due to similarities of symptoms and signs at early stages of disease. Thus, the need of accurate methods for differential diagnosis at those early stages has emerged. To improve the evaluation of medical images, artificial intelligence turns out to be a useful tool. Parkinson’s Disease, the commonest PS, is characterized by the degeneration of dopamine neurons in the substantia nigra which is detected by the dopamine transporter scan (DaTscanTM), a single photon-emission tomography (SPECT) exam that uses of a radiotracer that binds dopamine receptors. In fact, by using such exam it was possible to identify a sub-group of PD patients known as “Scans without evidence of dopaminergic deficit” (SWEDD) that present a normal exam, unlike PD patients. In this study, an approach based on Convolutional Neural Networks (CNNs) was proposed for classifying PD patients, SWEDD patients and healthy subjects using SPECT and Magnetic Resonance Imaging (MRI) images. Then, these images were divided into subsets of slices in the axial view that contains particular regions of interest since 2D images are the norm in clinical practice. The classifier evaluation was performed with Cohen’s Kappa and Receiver Operating Characteristic (ROC) curve. The results obtained allow to conclude that the CNN using imaging information of the Basal Ganglia and the mesencephalon was able to distinguish PD patients from healthy subjects since achieved 97.4% accuracy using MRI and 92.4% accuracy using SPECT, and PD from SWEDD with 97.3% accuracy using MRI and 93.3% accuracy using SPECT. Nonetheless, using the same approach, it was not possible to discriminate SWEDD patients from healthy subjects (60% accuracy) using DaTscanTM and MRI. These results allow to conclude that this approach may be a useful tool to aid in PD diagnosis in the future

Cognitive and neuroanatomical correlates of neuropsychiatric symptoms in Parkinson's disease: A systematic review

Introduction Neuropsychiatric symptoms are one of the most common non-motor symptoms in Parkinson's disease (PD). These symptoms have a negative impact on daily living activities and cognitive abilities. This review will be centred on published articles which focused on clarifying the cognitive and neuroanatomical features associated with the appearance of specific neuropsychiatric symptoms in this disease. Methods All articles indexed in the Web of Science and PubMed databases were reviewed for potential inclusion in October 2014. In the first stage of the review, we identified 41 articles that investigated neuropsychiatric symptoms and cognitive impairments in PD. In the second stage, there were 26 published articles on the neural bases of neuropsychiatric symptoms in PD. Results The main findings revealed that executive dysfunctions were common in patients with depression, apathy, visual hallucinations (VH), impulse control disorders (ICDs) and anxiety, whereas, memory deficits were associated mainly with depression and VH. Imaging studies have shown that frontal lobe atrophy was frequently observed in patients with depression, apathy, VH and ICDs. Conclusion This review gives a snapshot of those cognitive and neural correlates of neuropsychiatric symptoms in PD. Methodological shortcoming in the available studies were identified, however, of which the most critical appeared neglecting the presence of multiple neuropsychiatric symptoms in some of the patients included in studies of specific individual symptoms. Additionally, in most studies only patients in the moderate to severe stages were included which limits possible inferences to the early stage of the disease