Denoising approach with deep learning-based reconstruction for neuromelanin-sensitive MRI: image quality and diagnostic performance

[Purpose]Neuromelanin-sensitive MRI (NM-MRI) has proven useful for diagnosing Parkinson’s disease (PD) by showing reduced signals in the substantia nigra (SN) and locus coeruleus (LC), but requires a long scan time. The aim of this study was to assess the image quality and diagnostic performance of NM-MRI with a shortened scan time using a denoising approach with deep learning-based reconstruction (dDLR).[Materials and methods]We enrolled 22 healthy volunteers, 22 non-PD patients and 22 patients with PD who underwentNM-MRI, and performed manual ROI-based analysis. Signal-to-noise ratio (SNR) and contrast-to-noise ratio (CNR) in ten healthy volunteers were compared among images with a number of excitations (NEX) of 1 (NEX1), NEX1 images with dDLR (NEX1+dDLR) and 5-NEX images (NEX5). Acquisition times for NEX1 and NEX5 were 3 min 12 s and 15 min 58 s, respectively. Diagnostic performances using the contrast ratio (CR) of the SN (CR_SN) and LC (CR_LC) and those by visual assessment for diferentiating PD from non-PD were also compared between NEX1 and NEX1+dDLR.[Results]Image quality analyses revealed that SNRs and CNRs of the SN and LC in NEX1+dDLR were signifcantly higherthan in NEX1, and comparable to those in NEX5. In diagnostic performance analysis, areas under the receiver operating characteristic curve (AUC) using CR_SN and CR_LC of NEX1+dDLR were 0.87 and 0.75, respectively, which had no signifcant diference with those of NEX1. Visual assessment showed improvement of diagnostic performance by applying dDLR.[Conclusion]Image quality for NEX1+dDLR was comparable to that of NEX5. dDLR has the potential to reduce scan time of NM-MRI without degrading image quality. Both 1-NEX NM-MRI with and without dDLR showed high AUCs for diagnosing PD by CR. The results of visual assessment suggest advantages of dDLR. Further tuning of dDLR would be expected to provide clinical merits in diagnosing PD

Quantifying Neuromelanin Content Across Varying Magnetic Field Strengths: A Comparative Analysis

Neuromelanin (NM) is an insoluble dark pigment molecule that is found in the substantia nigra of the human brain. Due to its paramagnetic nature, NM can be imaged using MRI in the form of neuromelanin sensitive contrast. This method, known as Neuromelanin Sensitive Magnetic Resonance Imaging (NM-MRI) allows non-invasive imaging of the human substantia nigra through its by-product, NM. NM-MRI research has been mostly done using lower field strength (3 or 1.5 Tesla) MRI scans. The advent of high field strength imaging, e.g., 7 Tesla (7T) provides the opportunity to study neuromelanin production sites with higher spatial resolution and enhanced detail. Since NM-MRI research has not been conducted with high field strength imaging platforms, it is unknown whether the techniques used for quantifying NM at a lower field strength reliably extend to a high field strength platform. In the absence of this information, it is impossible to establish whether these two sequences generate the same estimates of NM. Thus, before it is possible to harness the advantages of high field strength imaging, it is critical to investigate the convergence of NM-MRI signal between 3T and 7T NM-MRI. The current study employs a within-subjects design to answer this question. Neuromelanin sensitive images were obtained from 28 healthy adult participants at both 3T and 7T. NM images were segmented both manually and with the help of a standard atlas. NM in the substantia nigra was quantified in the form of Contrast to Noise Ratio (CNR). Spearman’s rank order correlations assessed statistical dependence between the ranking of participant CNR values at 3T and 7T. We found that CNR values at 3T predicted those at 7T when standard deviation (as opposed to the mean) of the background region was used for defining noise. In addition, CNR values didn’t increase with an increase in field strength. In fact, CNR values at 7T were lower as compared to 3T. This effect was mainly due to a disproportionate increase in noise at 7T. An increased susceptibility noise is a common trade-off for better contrast associated with high field strength imaging. We discuss our findings and comment on the utility of employing high field strength NM- MRI

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

Sandwich spatial saturation for neuromelanin-sensitive MRI: Development and multi-center trial

Neuromelanin (NM)-sensitive MRI using a magnetization transfer (MT)-prepared T1-weighted sequence has been suggested as a tool to visualize NM contents in the brain. In this study, a new NM-sensitive imaging method, sandwichNM, is proposed by utilizing the incidental MT effects of spatial saturation RF pulses in order to generate consistent high-quality NM images using product sequences. The spatial saturation pulses are located both superior and inferior to the imaging volume, increasing MT weighting while avoiding asymmetric MT effects. When the parameters of the spatial saturation were optimized, sandwichNM reported a higher NM contrast ratio than those of conventional NM-sensitive imaging methods with matched parameters for comparability with sandwichNM (SandwichNM: 23.6 ± 5.4%; MT-prepared TSE: 20.6 ± 7.4%; MT-prepared GRE: 17.4 ± 6.0%). In a multi-vendor experiment, the sandwichNM images displayed higher means and lower standard deviations of the NM contrast ratio across subjects in all three vendors (SandwichNM vs. MT-prepared GRE; Vendor A: 28.4 ± 1.5% vs. 24.4 ± 2.8%; Vendor B: 27.2 ± 1.0% vs. 13.3 ± 1.3%; Vendor C: 27.3 ± 0.7% vs. 20.1 ± 0.9%). For each subject, the standard deviations of the NM contrast ratio across the vendors were substantially lower in SandwichNM (SandwichNM vs. MT-prepared GRE; subject 1: 1.5% vs. 8.1%, subject 2: 1.1 % vs. 5.1%, subject 3: 0.9% vs. 4.0%, subject 4: 1.1% vs. 5.3%), demonstrating consistent contrasts across the vendors. The proposed method utilizes product sequences, requiring no alteration of a sequence and, therefore, may have a wide practical utility in exploring the NM imaging.ope

Locus coeruleus features are linked to vagus nerve stimulation response in drug-resistant epilepsy

peer reviewedThe locus coeruleus–norepinephrine system is thought to be involved in the clinical effects of vagus nerve stimulation. This system is known to prevent seizure development and induce long-term plastic changes, particularly with the release of norepinephrine in the hippocampus. However, the requisites to become responder to the therapy and the mechanisms of action are still under investigation. Using MRI, we assessed the structural and functional characteristics of the locus coeruleus and microstructural properties of locus coeruleus-hippocampus white matter tracts in patients with drug-resistant epilepsy responding or not to the therapy. Twenty-three drug-resistant epileptic patients with cervical vagus nerve stimulation were recruited for this pilot study, including 13 responders or partial responders and 10 non-responders. A dedicated structural MRI acquisition allowed in vivo localization of the locus coeruleus and computation of its contrast (an accepted marker of LC integrity). Locus coeruleus activity was estimated using functional MRI during an auditory oddball task. Finally, multi-shell diffusion MRI was used to estimate the structural properties of locus coeruleus-hippocampus tracts. These characteristics were compared between responders/partial responders and non-responders and their association with therapy duration was also explored. In patients with a better response to the therapy, trends toward a lower activity and a higher contrast were found in the left medial and right caudal portions of the locus coeruleus, respectively. An increased locus coeruleus contrast, bilaterally over its medial portions, correlated with duration of the treatment. Finally, a higher integrity of locus coeruleus-hippocampus connections was found in patients with a better response to the treatment. These new insights into the neurobiology of vagus nerve stimulation may provide novel markers of the response to the treatment and may reflect neuroplasticity effects occurring in the brain following the implantation

Neuroimaging of fetal cell therapy in Parkinson’s disease

Parkinson’s disease is the second most common neurodegenerative disease characterised by the elevated formation of α-synuclein-immunopositive intraneuronal proteinaceous inclusions (Lewy pathology) and the progressive loss of neuromelanin-laden dopaminergic cells of the substantia nigra pars compacta, resulting in the loss of striatal dopaminergic terminals and emergence of cardinal motor features including bradykinesia, rigidity, tremor and postural instability. Dopaminomimetic agents provide effective symptomatic relief in the early stages of illness, yet due to the inherently progressive nature of the disease and the induction of debilitating side effects their efficacy is eventually lost. Cellular restorative strategies involving intrastriatal transplantation of human fetal ventral mesencephalic (hfVM) tissue gained traction from the early 1990’s, when several multi-disciplinary teams reported drastic motoric improvements concomitant with graft-derived dopaminergic re-innervation. However, outcomes of double-blind randomised controlled trials and the presentation of novel dyskinetic movements persisting in the “off-state” called for substantial revision of cell delivery strategies. The current thesis utilises positron emission tomography to examine the effects of hfVM implantation under the Transeuro protocol on dopaminergic ([18F]FDOPA, [11C]PE2I) and serotonergic ([11C]DASB) systems in patients with Parkinson’s disease and elucidate the neural underpinnings of its clinical impact. The main findings are; 1) implanted hfVM tissue led to increases in putamenal dopamine synthesis and storage capacity, dopamine and serotonin transporter density as compared to non-transplanted patients; 2) modification to surgical procedures provided inhomogenous and inconsistent re-innervation; 3) hfVM transplantation was associated with clinical improvements in measures of bradykinesia, rigidity and tremor; 4) graft-related changes in posterior putamenal dopamine and serotonin transporter density predicted symptomatic relief of bradykinesia and tremor; 5) heterogeneity of posterior putamenal re-innervation may impact upon potential clinical benefit; 6) graft-induced dyskinesia was associated with greater post-operative increases in dopamine transporter expression in the anterior putamen; 7) there was no evidence that graft-induced dyskinesia was related to serotonergic hyperinnervation. The novel findings presented in this thesis have major implications for cell-based restorative strategies beyond the hfVM era and will likely foster informed [re]consideration of many aspects of therapeutic delivery and trial design. For its ability to provide mechanistic insight in vivo, neuroimaging may continue to play a central role in the optimisation of future interventions.Open Acces

Clinical and radiological studies in PSP and related conditions

This thesis examines clinical and radiological aspects of Progressive Supranuclear Palsy (PSP) and related conditions. Significant milestones occur sooner in pathologically confirmed PSP than multiple system atrophy (MSA); older age of onset and shorter duration to first milestone are associated with worse prognosis in both; in PSP, the Richardson’s syndrome phenotype and male gender and in MSA, early autonomic failure and the female gender are also predictive of poorer prognosis. Using objective measurements of bradykinesia we found progressive bradykinesia and hypokinesia in Parkinson’s disease (PD) which correlates with disability and responds to levodopa but hypokinesia without decrement in PSP. Using conventional MRI 72.7% of PSP and 76.9% of MSA are correctly identified. The ‘hummingbird sign’ was highly specific for PSP, but sensitvity was 68.4%. A simple measurement of the midbrain < 9.35mm had 100% specificity for a pathological diagnosis of PSP. In a clinically diagnosed PSP 90.5% had a measurement of < 9.35mm. Using high field 9.4 Tesla MRI, the anatomy of the subthalamic nucleus is clearly defined when compared to histology in post mortem material. The anteromedial portion was hypointense in correlation with Perls stain and there was variability in the volume, shape and location of its borders. The nigrosomes within the substantia nigra were visibile as high intensity bands which correlated with calbindin poor zones on immunohistochemical stains. The volume and anatomy were preserved in PD but not PSP. Multimodal 3 Telsla MRI during life revealed distinct patterns of atrophy in PSP and MSA using voxel-based morphometry. Tract-based spatial statistics revealed abnormalities in the frontal and parieto-occipital white matter changes in PSP more than MSA. Midbrain atrophy and frontal white matter increased mean diffusivity were associated with increasing PSP rating scale score, and frontal white matter reduced fractional anisotropy with disease duration