Automated Neuromelanin Imaging as a Diagnostic Biomarker for Parkinson's Disease

Published onlineWe aimed to analyze the diagnostic accuracy of an automated segmentation and quantification method of the SNc and locus coeruleus (LC) volumes based on neuromelanin (NM)-sensitive MRI (NM-MRI) in patients with idiopathic (iPD) and monogenic (iPD) Parkinson's disease (PD). Thirty-six patients (23 idiopathic and 13 monogenic PARKIN or LRRK2 mutations) and 37 age-matched healthy controls underwent 3T-NM-MRI. SNc and LC volumetry were performed using fully automated multi-image atlas segmentation. The diagnostic performance to differentiate PD from controls was measured using the area under the curve (AUC) and likelihood ratios based on receiver operating characteristic (ROC) analyses. We found a significant reduction of SNc and LC volumes in patients, when compared to controls. ROC analysis showed better diagnostic accuracy when using SNc volume than LC volume. Significant differences between ipsilateral and contralateral SNc volumes, in relation to the more clinically affected side, were found in patients with iPD (P=0.007). Contralateral atrophy in the SNc showed the highest power to discriminate PD subjects from controls (AUC, 0.93-0.94; sensitivity, 91%-92%; specificity, 89%; positive likelihood ratio: 8.4-8.5; negative likelihood ratio: 0.09-0.1 at a single cut-off point). Interval likelihood ratios for contralateral SNc volume improved the diagnostic accuracy of volumetric measurements. SNc and LC volumetry based on NM-MRI resulting from the automated segmentation and quantification technique can yield high diagnostic accuracy for differentiating PD from health and might be an unbiased disease biomarker.Supported by the Fund for Health Research Foundation (FIS-ISCIII), Spanish Ministry of Economy and Competitiveness (reference: PI 13/02211); Spanish Ministry of Science and Innovation SAF2006-10126 (2006-2009), SAF2010-22329-C02-01 (2011-2013), and SAF2013-47939-R (to P.P.); project 061131 from the “Fundació La Marató de TV3” and by the UTE project FIMA, Spain (to P.P.). C.O.d.S. and A.M.B. were supported by Spanish Ministry of Economy and Competitiveness DPI2012-38090-C03-02 and TEC2013-48552-C2-1-R, respectively.Publicad

The Neuromelanin-related T2* Contrast in Postmortem Human Substantia Nigra with 7T MRI

High field magnetic resonance imaging (MRI)-based delineation of the substantia nigra (SN) and visualization of its inner cellular organization are promising methods for the evaluation of morphological changes associated with neurodegenerative diseases; however, corresponding MR contrasts must be matched and validated with quantitative histological information. Slices from two postmortem SN samples were imaged with a 7 Tesla (7T) MRI with T1 and T2* imaging protocols and then stained with Perl???s Prussian blue, Kluver-Barrera, tyrosine hydroxylase, and calbindin immunohistochemistry in a serial manner. The association between T2* values and quantitative histology was investigated with a co-registration method that accounts for histology slice preparation. The ventral T2* hypointense layers between the SNr and the crus cerebri extended anteriorly to the posterior part of the crus cerebri, which demonstrates the difficulty with an MRI-based delineation of the SN. We found that the paramagnetic hypointense areas within the dorsolateral SN corresponded to clusters of neuromelanin (NM). These NM-rich zones were distinct from the hypointense ventromedial regions with high iron pigments. Nigral T2* imaging at 7T can reflect the density of NM-containing neurons as the metal-bound NM macromolecules may decrease T2* values and cause hypointense signalling in T2* imaging at 7T.ope

Quantitative MRI provides markers of intra-, inter-regional, and age-related differences in young adult cortical microstructure

Measuring the structural composition of the cortex is critical to understanding typical development, yet few investigations in humans have charted markers in vivo that are sensitive to tissue microstructural attributes. Here, we used a well-validated quantitative MR protocol to measure four parameters (R1, MT, R2*, PD*) that differ in their sensitivity to facets of the tissue microstructural environment (R1, MT: myelin, macromolecular content; R2*: myelin, paramagnetic ions, i.e., iron; PD*: free water content). Mapping these parameters across cortical regions in a young adult cohort (18–39 years, N = 93) revealed expected patterns of increased macromolecular content as well as reduced tissue water content in primary and primary adjacent cortical regions. Mapping across cortical depth within regions showed decreased expression of myelin and related processes – but increased tissue water content – when progressing from the grey/white to the grey/pial boundary, in all regions. Charting developmental change in cortical microstructure cross-sectionally, we found that parameters with sensitivity to tissue myelin (R1 & MT) showed linear increases with age across frontal and parietal cortex (change 0.5–1.0% per year). Overlap of robust age effects for both parameters emerged in left inferior frontal, right parietal and bilateral pre-central regions. Our findings afford an improved understanding of ontogeny in early adulthood and offer normative quantitative MR data for inter- and intra-cortical composition, which may be used as benchmarks in further studies

Elevated Pontine and Putamenal GABA Levels in Mild-Moderate Parkinson Disease Detected by 7 Tesla Proton MRS

Background: Parkinson disease (PD) is characterized by the degeneration of nigrostriatal dopaminergic neurons. However, postmortem evidence indicates that the pathology of lower brainstem regions, such as the pons and medulla, precedes nigral involvement. Consistently, pontomedullary damage was implicated by structural and PET imaging in early PD. Neurochemical correlates of this early pathological involvement in PD are unknown. Methodology/Principal Finding: To map biochemical alterations in the brains of individuals with mild-moderate PD we quantified neurochemical profiles of the pons, putamen and substantia nigra by 7 tesla (T) proton magnetic resonance spectroscopy. Thirteen individuals with idiopathic PD (Hoehn & Yahr stage 2) and 12 age- and gender-matched healthy volunteers participated in the study. c-Aminobutyric acid (GABA) concentrations in the pons and putamen were significantly higher in patients (N = 11, off medications) than controls (N = 11, p,0.001 for pons and p,0.05 for putamen). The GABA elevation was more pronounced in the pons (64%) than in the putamen (32%). No other neurochemical differences were observed between patients and controls. Conclusion/Significance: The GABA elevation in the putamen is consistent with prior postmortem findings in patients with PD, as well as with in vivo observations in a rodent model of PD, while the GABA finding in the pons is novel. The more significant GABA elevation in the pons relative to the putamen is consistent with earlier pathological involvement of th

Lifespan pigmentation changes of the substantia nigra detected by neuromelanin-sensitive MRI

Background: Neuromelanin is a pigment with strong iron-chelating properties preferentially found in dopaminergic neurons of the substantia nigra, pars compacta (SNpc). Parkinson's disease is characterized by pronounced, MRI detectable neuromelanin loss, but the neuroprotective or neurotoxic role of neuromelanin remains debated. Histological studies demonstrated neuromelanin increases with age, but this has not been confirmed in vivo and there is uncertainty whether neuromelanin declines, stabilizes or increases from middle age.Methods: This study aimed to establish physiological changes of pigmentation of the SNpc using a pooled dataset of neuromelanin-sensitive 3T MRI from 134 healthy individuals, aged 5~83 years. Neuromelanin-related brightness (regional contrast-to-ratio) and calibrated hyperintense volumes were analyzed using linear and non-linear regression models to characterize age effects. Laterality, sex, and subregional effects were also assessed.Results: For brightness, age effects were best described as a quadratic trajectory explaining 81.5% of the observed variance in SNpc showing a strong increase from childhood to adolescence, with plateauing in middle age and a decline in older age. Similar but less pronounced effects were seen in hyperintense volumes. We also show an anteriorposterior gradient in SNpc contrast, larger normalized NM-rich volume in women >47 of age, but no laterality effect.Conclusions: Using optimized neuromelanin-MRI in a lifespan sample, we demonstrate a strong age effect with an inverted U-shape of SNpc pigmentation-related contrast from childhood to old age. This age trajectory of physiological SNpc pigmentation needs to be taken into account for diagnostic applications of depigmentation. The study also paves the way for systematic investigations of the mechanisms of neuromelanin in healthy and pathological brain development and aging

Ueber stereochemische Untersuchungen in der Piperidinreihe

UEBER STEREOCHEMISCHE UNTERSUCHUNGEN IN DER PIPERIDINREIHE Ueber stereochemische Untersuchungen in der Piperidinreihe ([1]) Einband ( - ) Titelseite ([1]) Widmung ([3]) I. Theil. Über stereochemische Untersuchungen in der Piperidinreihe. ([5]) Geschichtliches und Theoretisches. ([5]) Experimenteller Teil. (26) A. Über die Entwicklung von Jod auf die Thiocarbaminate der α- und β-para Aminotrimethylpiperidine. (26) B. Über weitere Versuche die α und β para-Aminotrimethylpiperidine in Körper mit Brückenbindung umzuwandeln. (42) II. Theil. Über Semicarbazone und Phenylhydrazone des Vinyldiacetonamins, Benzaldiacetonamins und Triacetonamins. (50) Danksagung ( - ) Lebenslauf. ( - ) Einband ( -

Investigating the human brainstem with structural and functional MRI

The brainstem is one of the least understood parts of the human brain despite its prime importance for the maintenance of basic vital functions. Owing to its role as a relay station between spinal cord, cerebellum and neocortex, the brainstem contains vital nodes of all functional systems in the central nervous system, including the visual, auditory, gustatory, vestibular, somatic and visceral senses, and the somatomotor as well as autonomic nervous systems. While the brainstem has been extensively studied in animals using invasive methods, human studies remain scarce. Magnetic resonance imaging (MRI) as a non-invasive and widely available method is one possibility to access the brainstem in humans and measure its structure as well as function. The close vicinity of the brainstem to large arteries and ventricles and the small size of the anatomical structures, however, place high demands on imaging as well as data analysis methods. Nevertheless, the field of brainstem-(f)MRI has significantly advanced in the past few years, largely due to the development of several new tools that facilitate studying this critical part of the human brain. Within this scope, the goal of this Research Topic is to compile work representing the state of the art in functional and structural MRI of the human brainstem