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Universidad de Sevilla. Máster Universitario en Patrimonio Artístico Andaluz y su Proyección Iberoamerican

Brain iron deposition is linked with cognitive severity in Parkinson’s disease

Background: Dementia is common in Parkinson’s disease (PD) but measures that track cognitive change in PD are lacking. Brain tissue iron accumulates with age and co-localises with pathological proteins linked to PD dementia such as amyloid. We used quantitative susceptibility mapping (QSM) to detect changes related to cognitive change in PD. Methods: We assessed 100 patients with early-stage to mid-stage PD, and 37 age-matched controls using the Montreal Cognitive Assessment (MoCA), a validated clinical algorithm for risk of cognitive decline in PD, measures of visuoperceptual function and the Movement Disorders Society Unified Parkinson’s Disease Rating Scale part 3 (UPDRS-III). We investigated the association between these measures and QSM, an MRI technique sensitive to brain tissue iron content. Results: We found QSM increases (consistent with higher brain tissue iron content) in PD compared with controls in prefrontal cortex and putamen (p<0.05 corrected for multiple comparisons). Whole brain regression analyses within the PD group identified QSM increases covarying: (1) with lower MoCA scores in the hippocampus and thalamus, (2) with poorer visual function and with higher dementia risk scores in parietal, frontal and medial occipital cortices, (3) with higher UPDRS-III scores in the putamen (all p<0.05 corrected for multiple comparisons). In contrast, atrophy, measured using voxel-based morphometry, showed no differences between groups, or in association with clinical measures. Conclusions: Brain tissue iron, measured using QSM, can track cognitive involvement in PD. This may be useful to detect signs of early cognitive change to stratify groups for clinical trials and monitor disease progression

Magnetic resonance imaging of the human locus coeruleus: A systematic review

The locus coeruleus (LC), the major origin of noradrenergic modulation of the central nervous system, innervates extensive areas throughout the brain and is implicated in a variety of autonomic and cognitive functions. Alterations in the LC-noradrenergic system have been associated with healthy ageing and neuropsychiatric disorders including Parkinson's disease, Alzheimer's disease and depression. The last decade has seen advances in imaging the structure and function of the LC, and this paper systematically reviews the methodology and outcomes of sixty-nine structural and functional MRI studies of the LC in humans. Structural MRI studies consistently showed lower LC signal intensity and volume in clinical groups compared to healthy controls. Within functional studies, the LC was activated by a variety of tasks/stimuli and had functional connectivity to a range of brain regions. However, reported functional LC location coordinates were widely distributed compared to previously published neuroanatomical locations. Methodological and demographic factors potentially contributing to these differences are discussed, together with recommendations to optimize the reliability and validity of future LC imaging studies

A new discrete dipole kernel for quantitative susceptibility mapping

PURPOSE: Most approaches for quantitative susceptibility mapping (QSM) are based on a forward model approximation that employs a continuous Fourier transform operator to solve a differential equation system. Such formulation, however, is prone to high-frequency aliasing. The aim of this study was to reduce such errors using an alternative dipole kernel formulation based on the discrete Fourier transform and discrete operators. METHODS: The impact of such an approach on forward model calculation and susceptibility inversion was evaluated in contrast to the continuous formulation both with synthetic phantoms and in vivo MRI data. RESULTS: The discrete kernel demonstrated systematically better fits to analytic field solutions, and showed less over-oscillations and aliasing artifacts while preserving low- and medium-frequency responses relative to those obtained with the continuous kernel. In the context of QSM estimation, the use of the proposed discrete kernel resulted in error reduction and increased sharpness. CONCLUSION: This proof-of-concept study demonstrated that discretizing the dipole kernel is advantageous for QSM. The impact on small or narrow structures such as the venous vasculature might by particularly relevant to high-resolution QSM applications with ultra-high field MRI - a topic for future investigations. The proposed dipole kernel has a straightforward implementation to existing QSM routines

FDG-PET assessment of the locus coeruleus in Alzheimer’s disease

Sensitive and reliable in vivo imaging of the locus coeruleus (LC) is important to develop and evaluate its potential as a biomarker in neurodegenerative diseases such as Alzheimer’s disease (AD). It is not known whether AD-related alterations in LC integrity can be detected using 18F-labelled fluoro-2-deoxyglucose (FDG) positron emission tomography (PET). Mean FDG-PET images from AD patients (N ​= ​193) and controls (N ​= ​256) from the ADNI database were co-registered to a study-wise anatomical template. Regional LC median standardized uptake value ratio (SUVR) values were obtained using four previously published LC masks and normalized to values from pons and cerebellar vermis reference regions. To support the validity of our methods, other regions previously reported to be most and least affected metabolically in AD were also compared to controls. The LC did not show between-group differences in FDG-PET signal, whereas the mammillary bodies did, despite these regions having comparable volumes and SUVR ranges. Brain regions previously reported to be most and least affected metabolically in AD compared to controls showed medium-to-large and small effect sizes for SUVR differences respectively. The results do not support the current application of LC FDG-PET signal as an in vivo biomarker for AD. Methodological and demographic factors potentially contributing to these findings are discussed. Future research may investigate age-related differences in LC FDG-PET signal and higher resolution images to fully explore its biomarker potential

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

Robust 3D Bloch-Siegert based B 1 + mapping using multi-echo general linear modeling

PURPOSE: Quantitative MRI applications, such as mapping the T1 time of tissue, puts high demands on the accuracy and precision of transmit field ( B 1 + ) estimation. A candidate approach to satisfy these requirements exploits the difference in phase induced by the Bloch-Siegert frequency shift (BSS) of 2 acquisitions with opposite off-resonance frequency radiofrequency pulses. Interleaving these radiofrequency pulses ensures robustness to motion and scanner drifts; however, here we demonstrate that doing so also introduces a bias in the B 1 + estimates. THEORY AND METHODS: It is shown here by means of simulation and experiments that the amplitude of the error depends on MR pulse sequence parameters, such as repetition time and radiofrequency spoiling increment, but more problematically, on the intrinsic properties, T1 and T2 , of the investigated tissue. To solve these problems, a new approach to BSS-based B 1 + estimation that uses a multi-echo acquisition and a general linear model to estimate the correct BSS-induced phase is presented. RESULTS: In line with simulations, phantom and in vivo experiments confirmed that the general linear model-based method removed the dependency on tissue properties and pulse sequence settings. CONCLUSION: The general linear model-based method is recommended as a more accurate approach to BSS-based B 1 + mapping

Disrupted iron regulation in the brain and periphery in cocaine addiction

Stimulant drugs acutely increase dopamine neurotransmission in the brain, and chronic use leads to neuroadaptive changes in the mesolimbic dopamine system and morphological changes in basal ganglia structures. Little is known about the mechanisms underlying these changes but preclinical evidence suggests that iron, a coenzyme in dopamine synthesis and storage, may be a candidate mediator. Iron is present in high concentrations in the basal ganglia and stimulant drugs may interfere with iron homeostasis. We hypothesised that morphological brain changes in cocaine addiction relate to abnormal iron regulation in the brain and periphery. We determined iron concentration in the brain, using quantitative susceptibility mapping, and in the periphery, using iron markers in circulating blood, in 44 patients with cocaine addiction and 44 healthy controls. Cocaine-addicted individuals showed excess iron accumulation in the globus pallidus, which strongly correlated with duration of cocaine use, and mild iron deficiency in the periphery, which was associated with low iron levels in the red nucleus. Our findings show that iron dysregulation occurs in cocaine addiction and suggest that it arises consequent to chronic cocaine use. Putamen enlargement in these individuals was unrelated to iron concentrations, suggesting that these are co-occurring morphological changes that may respectively reflect predisposition to, and consequences of cocaine addiction. Understanding the mechanisms by which cocaine affects iron metabolism may reveal novel therapeutic targets, and determine the value of iron levels in the brain and periphery as biomarkers of vulnerability to, as well as progression and response to treatment of cocaine addiction

Whole brain white matter histogram analysis of diffusion tensor imaging data detects microstructural damage in mild cognitive impairment and Alzheimer’s disease patients

ABSTRACT Background: Amnestic mild cognitive impairment (MCI) is a transitional stage between normal aging and Alzheimer’s disease (AD). However, the clinical conversion from MCI to AD is unpredictable. Hence, identification of non-invasive biomarkers able to detect early changes induced by dementia is a pressing need. Purpose: To explore the added value of histogram analysis applied to measures derived from diffusion tensor imaging (DTI) for detecting brain tissue differences between AD, MCI and healthy subjects (HS). Study type: Retrospective. Population/subjects: Local cohort (57 AD, 28 MCI, 23 HS), Alzheimer’s Disease Neuroimaging Initiative (ADNI) cohort (41 AD, 58 MCI, 41 HS). Field Strength: 3T. Dual echo TSE; FLAIR; MDEFT; IR-SPGR; DTI. Assessment: Normal appearing white matter (NAWM) masks were obtained using the T1-weighted volumes for tissue segmentation and T2-weighted images for removal of hyperintensities/lesions. From DTI images, fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AXD) and radial diffusivity (RD) were obtained. NAWM histograms of FA, MD, AXD and RD were derived and characterized estimating: peak height, peak location, mean value (MV), and quartiles (C25, C50, C75), which were compared between groups. Receiver operating characteristic (ROC) and area under ROC curves (AUC) were calculated. To confirm our results, the same analysis was repeated on ADNI dataset. Statistical tests: One-way ANOVA, post-hoc Student’s t-test, multi-class ROC analysis. Results: For the local cohort, C25 of AXD had the maximum capability of group discrimination with AUC of 0.80 for “HS vs patients” comparison and 0.74 for “AD vs others” comparison. For ADNI cohort, MV of AXD revealed the maximum group discrimination capability with AUC of 0.75 for “HS vs patients” comparison and 0.75 for “AD vs others” comparison. Data conclusion: AXD of NAWM might be an early marker of microstructural brain tissue changes occurring during AD course and might be useful for assessing disease progression