Characterizing aging in the human brainstem using quantitative multimodal MRI analysis.

Aging is ubiquitous to the human condition. The MRI correlates of healthy aging have been extensively investigated using a range of modalities, including volumetric MRI, quantitative MRI (qMRI), and diffusion tensor imaging. Despite this, the reported brainstem related changes remain sparse. This is, in part, due to the technical and methodological limitations in quantitatively assessing and statistically analyzing this region. By utilizing a new method of brainstem segmentation, a large cohort of 100 healthy adults were assessed in this study for the effects of aging within the human brainstem in vivo. Using qMRI, tensor-based morphometry (TBM), and voxel-based quantification (VBQ), the volumetric and quantitative changes across healthy adults between 19 and 75 years were characterized. In addition to the increased R2* in substantia nigra corresponding to increasing iron deposition with age, several novel findings were reported in the current study. These include selective volumetric loss of the brachium conjunctivum, with a corresponding decrease in magnetization transfer and increase in proton density (PD), accounting for the previously described “midbrain shrinkage.” Additionally, we found increases in R1 and PD in several pontine and medullary structures. We consider these changes in the context of well-characterized, functional age-related changes, and propose potential biophysical mechanisms. This study provides detailed quantitative analysis of the internal architecture of the brainstem and provides a baseline for further studies of neurodegenerative diseases that are characterized by early, pre-clinical involvement of the brainstem, such as Parkinson’s and Alzheimer’s diseases

Magnetic resonance imaging techniques for diagnostics in Parkinson’s disease and atypical parkinsonism

Background: Parkinson’s disease (PD) is a neurodegenerative disease characterized by rigidity, hypokinesia, tremor and postural instability. PD is a clinical diagnosis based on neurological examination, patient history and treatment response. Similar symptoms can be caused by other movement disorders such as progressive supranuclear palsy (PSP) and multiple system atrophy (MSA), making it difficult to clinically separate them in early stages. However, these diseases differ in underlying pathology, treatment and prognosis. PSP and MSA have more rapid deterioration and develop additional symptoms such as impaired eye movements or autonomic dysfunction. Magnetic resonance imaging (MRI) is commonly performed as part of the clinical work-up in patients presenting with parkinsonism. There are no overt changes on structural MRI in PD. In atypical parkinsonian syndromes there are typically no visible changes until later disease stages. Purpose: The aim of this thesis is to evaluate novel MRI techniques for diagnostics and for investigation of disease processes in Parkinson’s disease, PSP and MSA. Paper I: A retrospective cohort from Karolinska University Hospital (102 participants; 62 PD, 15 PSP, 11 MSA, 14 controls) was assessed using susceptibility mapping processed from susceptibility weighted imaging. We show that there is elevated susceptibility in the red nucleus and the globus pallidus in PSP compared to PD, MSA and controls. Higher susceptibility levels were also seen in MSA compared to PD in the putamen, and in PD compared to controls in the substantia nigra. Using the red nucleus susceptibility as a diagnostic biomarker, PSP could be separated from PD with an accuracy of 97% (based on the area under the receiver operating characteristic curve, AUC), from MSA with AUC 75% and from controls with AUC 98%. We concluded that susceptibility changes, particularly in the red nucleus in PSP, could be potential biomarkers for differential diagnostics in parkinsonism. Paper II: A prospective cohort from Lund, the BioFINDER study (199 participants; 134 PD, 11 PSP, 10 MSA, 44 controls), was investigated using the susceptibility mapping pipeline developed for Paper I. The finding from Paper I with elevated susceptibility in the red nucleus was validated for PSP compared to PD, MSA and controls. The elevated putaminal susceptibility was also confirmed in MSA compared to PD. The potential role of red nucleus susceptibility as a biomarker for separating PSP from PD and MSA was also similar to the results in Paper I, with AUC 98% for separating PSP from PD and AUC 96% for separating PSP from MSA. We concluded that we could confirm our previous findings from Paper I, with the red nucleus susceptibility being a potential biomarker for separating PSP from PD and MSA. Paper III: A retrospective cohort from Karolinska University Hospital (196 participants; 140 PD, 29 PSP, 27 MSA) was evaluated to employ automated volumetric brainstem segmentation using FreeSurfer. The volumetric approach was compared to manual planimetric measurements: midbrain-pons ratio, magnetic resonance parkinsonism index 1.0 and 2.0. Intra- and inter-scanner as well as intra- and inter-rater reliability were calculated. We found good repeatability in both automated volumetric and manual planimetric measurements. Normalized midbrain volume performed better than the planimetric measurements for separating PSP from PD. We concluded that, if further developed and incorporated in a radiology workflow, automated brainstem volumetry could increase availability of brainstem metrics and possibly save time for radiologists conducting manual measurements. Paper IV: Two cohorts, a retrospective from Karolinska University Hospital (184 participants; 129 PD, 28 PSP, 27 MSA) and a prospective from Lund (185 participants; 125 PD, 11 PSP, 8 MSA, 41 controls), were studied to investigate a new method of creating T1-/T2-weighted ratio images and its diagnostic capabilities in differentiating parkinsonian disorders. In the explorative retrospective cohort, differences in white matter normalized T1-/T2- weighted ratios were seen in the caudate nucleus, putamen, thalamus, subthalamic nucleus and red nucleus in PSP compared to PD; in the caudate nucleus and putamen in MSA compared to PD and in the subthalamic nucleus and the red nucleus in PSP compared to MSA. These differences were validated externally in the prospective cohort, where the changes could be confirmed in the subthalamic nucleus and the red nucleus in PSP compared to PD and MSA. We concluded that there are different patterns of white matter normalized T1-/T2-weighted ratio between the disorders and that this reflects differences in underlying pathophysiology. The T1-/T2-weighted ratio should be further investigated for better understanding of pathological processes in parkinsonian disorders and could possibly be utilized for diagnostic purposes if further developed

Early detection of idiopathic Parkinson's disease based on magnetic resonance imaging

The diagnosis of idiopathic Parkinson's disease (IPD) is entirely clinical. The fact that neuronal damage begins 5-10 years before occurrence of sub-clinical signs, underlines the importance of preclinical diagnosis. A new approach for in-vivo pathophysiological assessment of IPD-related neurodegeneration was implemented based on recently developed neuroimaging methods. It is based on non- invasive magnetic resonance data sensitive to brain tissue property changes that precede macroscopic atrophy in the early stages of IPD. This research aims to determine the brain tissue property changes induced by neurodegeneration that can be linked to clinical phenotypes which will allow us to create a predictive model for early diagnosis in IPD. We hypothesized that the degree of disease progression in IPD patients will have a differential and specific impact on brain tissue properties used to create a predictive model of motor and non-motor impairment in IPD. We studied the potential of in-vivo quantitative imaging sensitive to neurodegeneration- related brain tissue characteristics to detect changes in patients with IPD. We carried out methodological work within the well established SPM8 framework to estimate the sensitivity of tissue probability maps for automated tissue classification for detection of early IPD. We performed whole-brain multi parameter mapping at high resolution followed by voxel-based morphometric (VBM) analysis and voxel-based quantification (VBQ) comparing healthy subjects to IPD patients. We found a trend demonstrating non-significant tissue property changes in the olfactory bulb area using the MT and R1 parameter with p<0.001. Comparing to the IPD patients, the healthy group presented a bilateral higher MT and R1 intensity in this specific functional region. These results did not correlate with age, severity or duration of disease. We failed to demonstrate any changes with the R2* parameter. We interpreted our findings as demyelination of the olfactory tract, which is clinically represented as anosmia. However, the lack of correlation with duration or severity complicates its implications in the creation of a predictive model of impairment in IPD

New tissue priors for improved automated classification of subcortical brain structures on MRI.

Despite the constant improvement of algorithms for automated brain tissue classification, the accurate delineation of subcortical structures using magnetic resonance images (MRI) data remains challenging. The main difficulties arise from the low gray-white matter contrast of iron rich areas in T1-weighted (T1w) MRI data and from the lack of adequate priors for basal ganglia and thalamus. The most recent attempts to obtain such priors were based on cohorts with limited size that included subjects in a narrow age range, failing to account for age-related gray-white matter contrast changes. Aiming to improve the anatomical plausibility of automated brain tissue classification from T1w data, we have created new tissue probability maps for subcortical gray matter regions. Supported by atlas-derived spatial information, raters manually labeled subcortical structures in a cohort of healthy subjects using magnetization transfer saturation and R2* MRI maps, which feature optimal gray-white matter contrast in these areas. After assessment of inter-rater variability, the new tissue priors were tested on T1w data within the framework of voxel-based morphometry. The automated detection of gray matter in subcortical areas with our new probability maps was more anatomically plausible compared to the one derived with currently available priors. We provide evidence that the improved delineation compensates age-related bias in the segmentation of iron rich subcortical regions. The new tissue priors, allowing robust detection of basal ganglia and thalamus, have the potential to enhance the sensitivity of voxel-based morphometry in both healthy and diseased brains

Parcellation of the human substantia nigra based on anatomical connectivity to the striatum

Substantia nigra/ventral tegmental area (SN/VTA) subregions, defined by dopaminergic projections to the striatum, are differentially affected by health (e.g. normal aging) and disease (e.g. Parkinson's disease). This may have an impact on reward processing which relies on dopaminergic regions and circuits. We acquired diffusion tensor imaging (DTI) with probabilistic tractography in 30 healthy older adults to determine whether subregions of the SN/VTA could be delineated based on anatomical connectivity to the striatum. We found that a dorsomedial region of the SN/VTA preferentially connected to the ventral striatum whereas a more ventrolateral region connected to the dorsal striatum. These SN/VTA subregions could be characterised by differences in quantitative structural imaging parameters, suggesting different underlying tissue properties. We also observed that these connectivity patterns differentially mapped onto reward dependence personality trait. We show that tractography can be used to parcellate the SN/VTA into anatomically plausible and behaviourally meaningful compartments, an approach that may help future studies to provide a more fine-grained synopsis of pathological changes in the dopaminergic midbrain and their functional impact

Magnetic resonance imaging of the substantia nigra in parkinson’s disease : neuromelanin, iron and diffusion tensor imaging

Tese de doutoramento, Medicina (Imagiologia), Universidade de Lisboa, Faculdade de Medicina, 2015In the last years, extensive developments in neuroimaging MR techniques have profoundly changed the study of Parkinson’s disease (PD), evolving from the role of excluding secondary parkinsonism to the emergence as a disease biomarker. MR advanced sequences in high field magnets opened the possibility to visualize in vivo the substantia nigra (SN) and to investigate specific PD pathological changes, enabling the development of high accuracy tools for disease diagnosis in early stages and for the comprehension of disease pathophysiology. Our work was centered on the application of new MR imaging techniques to study the SN in PD, early in the disease course, mainly focusing on untreated patients at the time of clinical diagnosis. The primary objectives were centered on the application of high field MR imaging sequences in two main areas: diagnosis of PD in early disease stages and differential diagnosis with Essential tremor (ET). The development and application of neuromelanin sensitive MR imaging in 3.0 Tesla allowed the detection of significant changes in the SN of PD patients, with high sensitivity and specificity for disease diagnosis, even in early disease stages (namely at the time of clinical diagnosis). These imaging findings reproduced in vivo the characteristic pathological changes of PD with greater alteration in the ventrolateral SN region and preservation of the dorsal segment. These results were obtained with several image evaluation methods: semi-automated area assessments, manual width measurements and simple visual inspection by Neuroradiologists, corroborating the reproducibility of the data and enabling wider applications of this image technique in the clinical practice. The MR correlation of neuromelanin with iron in the SN of PD patients allowed the in vivo investigation of the influence of local iron concentration in the SN on the signal of neuromelanin-sensitive sequences. A quantification T2-relaxometry study showed that the SN paramagnetic iron effects do not seem to influence significantly the neuromelanin MR signal reduction in PD patients. Several studies with diffusion tensor MR imaging (DTI) have allowed the detection of microstructural changes in the SN of PD patients in early disease changes, emerging as a possible disease biomarker. So, the reproducibility of DTI metrics in this specific brain area was particularly relevant for future applications of this MR technique. We conducted a reproducibility DTI study in PD patients that showed a good reproducibility of DTI metrics supporting the use of these measurements in further studies, namely longitudinal within-subject evaluation, and cross-sectional comparisons. The differential diagnosis of PD with ET is particularly relevant and there was the need of high accurate tools to aid the clinical assessment. The application of neuromelanin-sensitive MR techniques was able to discriminate ET from early stage tremor-dominant PD with high sensitivity and specificity values, in the same range as nuclear medicine techniques and may become a useful clinical tool in the evaluation of tremor disorders. Our research showed an important role of neuromelanin sensitive MR imaging for the diagnosis PD in early disease stages and its differential diagnosis with ET. A multi-modal MR approach with iron assessment and diffusion tensor imaging can further elucidate the SN disease changes and aid future research of disease pathophysiology.Nos últimos anos, o extenso desenvolvimento das técnicas de neuroimagem modificou profundamente a investigação da Doença de Parkinson (PD), evoluindo de um simples papel na exclusão de parkinsonismo secundário para a emergência de biomarcadores imagiológicos da doença. Sequências avançadas de RM em aparelhos de alto campo magnético abriram a possibilidade de visualizar in vivo a substantia nigra (SN) e a investigação de alterações patológicas específicas da PD, permitindo o desenvolvimento de ferramentas com elevada fiabilidade para o diagnóstico em fases precoces da evolução da doença e para a compreensão da sua fisiopatologia. A nossa investigação centrou-se na aplicação de novas técnicas de imagem RM para estudar a SN na PD, em fases precoces da doença, com enfoque especial em doentes não tratados na altura do diagnóstico clínico. Os objectivos principais centraram-se na aplicação de sequências de RM em alto campo em duas áreas major: diagnóstico da PD em fases precoces da doença e o diagnóstico diferencial com o Tremor essencial (ET). O desenvolvimento e aplicação da imagem RM sensível à neuromelanina em 3.0T permitiu a detecção de alterações significativas na SN de doentes com PD, com elevada sensibilidade e especificidade para o diagnóstico da doença, mesmo em fases precoces da sua evolução dela (nomeadamente na altura do diagnóstico clínico). Estes achados de imagem reproduziram in vivo as alterações patológicas características da PD, com uma maior alteração na região ventero-lateral da SN e preservação do segmento dorsal. Estes resultados foram obtidos com vários métodos de avaliação de imagem: avaliação semi-automática da área, medição manual da espessura e avaliação visual por neurorradiologistas, corroborando a reproductibilidade dos dados e permitindo uma aplicação abrangente desta técnica de imagem na prática clínica. A correlação por RM da neuromelanina com o ferro, na SN de doentes com PD, permitiu a investigação in vivo da influência da concentração local de ferro na SN com o sinal das sequências sensíveis à neuromelanina. Um estudo quantitativo de relaxometria T2* mostrou que os efeitos paramagnéticos do ferro não influenciam significativamente a redução de sinal RM da neuromelanina em doentes com PD. Vários estudos com tensores de difusão (DT) permitiram a detecção de alterações microestruturais na SN de doentes com PD em fases precoces de doença, emergindo como um possível biomarcador de doença. Assim, a reproductibilidade das métricas de DTI, nesta área específica do encéfalo, é particularmente relevante para aplicações futuras desta técnica de RM. Conduzimos um estudo de reproductibilidade de DTI em doentes com PD que demonstrou uma boa reproductibilidade das métricas de DTI, suportando a utilização destas medidas em estudos futuros, nomeadamente avaliações longitudinais “within-subject” e comparações “cross-sectional”. O diagnóstico diferencial da PD com ET é particularmente relevante e ferramentas fiáveis para auxiliar a avaliação clínica eram necessárias. A aplicação de técnicas de RM sensíveis à neuromelanina possibilitou a discriminação de ET de PD “tremor-dominant” em fases precoces com elevados valores de sensibilidade e especificidade, no mesmo espectro das técnicas de medicina nuclear e pode tornar-se uma ferramenta clínica útil para a avaliação do tremor. A nossa investigação demonstrou um importante papel das técnicas de RM sensíveis à neuromelanina para o diagnóstico de PD em fases precoces da doença e para o seu diagnóstico diferencial com ET. Uma abordagem multi-modal de RM com avaliação do ferro e DTI pode, adicionalmente, permitir estudar as alterações da SN e auxiliar a investigação futura da fisiopatologia da doença

NM-MRI for treatment evaluation of Parkinson’s Disease patients

T1-weighted fast spin echo magnetic resonance imaging (MRI) sequences are able to depict neuromelanin (NM)-containing structures, such as the Substantia nigra (SN), as hyper-intense signal areas. NM-MRI can accurately discriminate Parkinson’s Disease (PD) patients from controls and could potentially be used to evaluate the effects of PD treatment - either surgery or medication. PD patients that are treated with Deep Brain Stimulation (DBS) can only undergo 1.5T MRI sequences with specific conditions that prevent the tissues surrounding the neurostimulators from overheating. However, NM-MRI sequences are usually not applied at 1.5T due to worse image quality. Nevertheless, it would be interesting to study how DBS and medication influence the NM signal as a path for a better understanding of the disease and to potentially evaluate the progression of PD after the surgical intervention. Firstly in this work, a NM-MRI sequence was adapted for scanning patients with implanted DBS systems at 1.5T. To evaluate the performance of the sequence, images were taken on the same day with 1.5T and 3T MRI systems. The contrast ratio of both sequences was evaluated and SN areas were measured resorting to a semi-automatic segmentation algorithm. The assessment of these measurements revealed a good agreement between the developed sequence and the original 3T sequence. A second study was carried out, in which SN areas of PD de novo patients were evaluated before and after two months of initiating pharmacological treatment. The median SN area tended to be increased after treatment, suggesting a potential increase of NM related to dopamine therapy. In conclusion, this work presented the first 1.5T NM-MRI sequence that enables SN area measurement of patients with implanted neurostimulators, for further investigation of this method as a diagnostic tool for assessment of disease progression and to better understand clinical effects on NM-MRI and PD itself

In vivo multi-parameter mapping of the habenula using MRI

The habenula is a small, epithalamic brain structure situated between the mediodorsal thalamus and the third ventricle. It plays an important role in the reward circuitry of the brain and is implicated in psychiatric conditions, such as depression. The importance of the habenula for human cognition and mental health make it a key structure of interest for neuroimaging studies. However, few studies have characterised the physical properties of the human habenula using magnetic resonance imaging because its challenging visualisation in vivo, primarily due to its subcortical location and small size. To date, microstructural characterization of the habenula has focused on quantitative susceptibility mapping. In this work, we complement this previous characterisation with measures of longitudinal and effective transverse relaxation rates, proton density and magnetisation transfer saturation using a high-resolution quantitative multi-parametric mapping protocol at 3T, in a cohort of 26 healthy participants. The habenula had consistent boundaries across the various parameter maps and was most clearly visualised on the longitudinal relaxation rate maps. We have provided a quantitative multi-parametric characterisation that may be useful for future sequence optimisation to enhance visualisation of the habenula, and additionally provides reference values for future studies investigating pathological differences in habenula microstructure

The whole-brain pattern of magnetic susceptibility perturbations in Parkinson's disease

Although iron-mediated oxidative stress has been proposed as a potential pathomechanism in Parkinson's disease, the global distribution of iron accumulation in Parkinson's disease has not yet been elucidated. This study used a new magnetic resonance imaging contrast, quantitative susceptibility mapping, and state-of-the-art methods to map for the first time the whole-brain landscape of magnetostatic alterations as a surrogate for iron level changes in n = 25 patients with idiopathic Parkinson's disease versus n = 50 matched controls. In addition to whole-brain analysis, a regional study including sub-segmentation of the substantia nigra into dorsal and ventral regions and qualitative assessment of susceptibility maps in single subjects were also performed. The most remarkable basal ganglia effect was an apparent magnetic susceptibility increase-consistent with iron deposition-in the dorsal substantia nigra, though an effect was also observed in ventral regions. Increased bulk susceptibility, additionally, was detected in rostral pontine areas and in a cortical pattern tightly concordant with known Parkinson's disease distributions of α-synuclein pathology. In contrast, the normally iron-rich cerebellar dentate nucleus returned a susceptibility reduction suggesting decreased iron content. These results are in agreement with previous post-mortem studies in which iron content was evaluated in specific regions of interest; however, extensive neocortical and cerebellar changes constitute a far more complex pattern of iron dysregulation than was anticipated. Such findings also stand in stark contrast to the lack of statistically significant group change using conventional magnetic resonance imaging methods namely voxel-based morphometry, cortical thickness analysis, subcortical volumetry and tract-based diffusion tensor analysis; confirming the potential of whole-brain quantitative susceptibility mapping as an in vivo biomarker in Parkinson's disease