Towards high-resolution quantitative assessment of vascular dysfunction

Neurovascular alterations are increasingly recognized as a key feature of many brain diseases. They can manifest as a reduction in resting cerebral blood flow or cerebrovascular reactivity (CVR) in the whole brain or in specific regions, depending on the underlying condition. Neurovascular impairment is observed in hypertension, Alzheimer’s disease, stroke, multiple sclerosis and cerebral small vessel disease. Magnetic resonance imaging (MRI)-derived CVR mapping is a reliable marker of vascular dysfunction and has been performed mainly at standard functional MRI (fMRI) resolutions of 2–3 mm using the blood oxygen level dependent (BOLD) contrast. However, vascular alterations may occur at a finer scale (i.e., in the capillary bed) which would be better characterized with smaller voxel sizes. Capillaries in gray matter deliver oxygen and glucose to neural tissue and are arranged in a mesh structure, with variable density across the cortical depth. Given that the human cortex is, on average, 2.5 mm thick, submillimetric voxel sizes are effective in increasing the spatial specificity of measurements of hemodynamic and metabolic changes. Novel MRI sequences offer the possibility to map physiological parameters at high resolution with relatively simple experimental setups. In particular, pairing the BOLD acquisition with a contrast sensitive to blood volume changes, while administering a mild hypercapnic challenge, allows for simultaneous mapping of CVR, cerebral metabolic rate of oxygen consumption and other relevant parameters at a high resolution and can be performed at the clinical field strength of 3 T. We propose that this approach will help provide crucial insights into vascular impairment

Multi-echo quantitative susceptibility mapping: how to combine echoes for accuracy and precision at 3 Tesla

MRI; Multi-echo QSM; Quantitative susceptibility mappingImágen por resonancia magnética; QSM de ecos múltiples; Mapeo cuantitativo de susceptibilidadImatge per ressonància magnètica; QSM de ressò múltiple; Mapeig quantitatiu de susceptibilitatPurpose To compare different multi-echo combination methods for MRI QSM. Given the current lack of consensus, we aimed to elucidate how to optimally combine multi-echo gradient-recalled echo signal phase information, either before or after applying Laplacian-base methods (LBMs) for phase unwrapping or background field removal. Methods Multi-echo gradient-recalled echo data were simulated in a numerical head phantom, and multi-echo gradient-recalled echo images were acquired at 3 Tesla in 10 healthy volunteers. To enable image-based estimation of gradient-recalled echo signal noise, 5 volunteers were scanned twice in the same session without repositioning. Five QSM processing pipelines were designed: 1 applied nonlinear phase fitting over TEs before LBMs; 2 applied LBMs to the TE-dependent phase and then combined multiple TEs via either TE-weighted or SNR-weighted averaging; and 2 calculated TE-dependent susceptibility maps via either multi-step or single-step QSM and then combined multiple TEs via magnitude-weighted averaging. Results from different pipelines were compared using visual inspection; summary statistics of susceptibility in deep gray matter, white matter, and venous regions; phase noise maps (error propagation theory); and, in the healthy volunteers, regional fixed bias analysis (Bland–Altman) and regional differences between the means (nonparametric tests). Results Nonlinearly fitting the multi-echo phase over TEs before applying LBMs provided the highest regional accuracy of and the lowest phase noise propagation compared to averaging the LBM-processed TE-dependent phase. This result was especially pertinent in high-susceptibility venous regions. Conclusion For multi-echo QSM, we recommend combining the signal phase by nonlinear fitting before applying LBMs.Supported by the UK Engineering and Physical Sciences Research Council (EPSRC), award number: 1489882 (e.b.); by the EPSRC-funded UCL Centre for Doctoral Training in Medical Imaging, grant EP/L016478/1 (a.k.), and the Department of Health's National Institute for Health Research funded Biomedical Research Centre at University College London Hospitals (a.k.); by the UCL Leonard Wolfson Experimental Neurology Centre, grant PR/ylr/18575 (d.l.t) The Queen Square MS Centre, where part of the MRI scans for this work were performed, is supported by grants from the UK MS Society and by the National Institute for Health Research University College London Hospitals Biomedical Research Centre (UCLH/BRC). F. Grussu was supported by PREdICT, a study at the Vall d'Hebron Institute of Oncology in Barcelona funded by AstraZeneca (f.g.), and funding from the postdoctoral fellowships program Beatriu de Pinós (2020 BP 00117), funded by the Secretary of Universities and Research, Government of Catalonia (f.g.

The spatiotemporal changes in dopamine, neuromelanin and iron characterizing Parkinson’s disease

Dopamine transporter; Iron; NeuromelaninTransportador de dopamina; Hierro; NeuromelaninaTransportador de dopamina; Ferro; NeuromelaninaIn Parkinson’s disease, there is a progressive reduction in striatal dopaminergic function, and loss of neuromelanin-containing dopaminergic neurons and increased iron deposition in the substantia nigra. We tested the hypothesis of a relationship between impairment of the dopaminergic system and changes in the iron metabolism. Based on imaging data of patients with prodromal and early clinical Parkinson’s disease, we assessed the spatiotemporal ordering of such changes and relationships in the sensorimotor, associative and limbic territories of the nigrostriatal system. Patients with Parkinson’s disease (disease duration < 4 years) or idiopathic REM sleep behaviour disorder (a prodromal form of Parkinson’s disease) and healthy controls underwent longitudinal examination (baseline and 2-year follow-up). Neuromelanin and iron sensitive MRI and dopamine transporter single-photon emission tomography were performed to assess nigrostriatal levels of neuromelanin, iron, and dopamine. For all three functional territories of the nigrostriatal system, in the clinically most and least affected hemispheres separately, the following was performed: cross-sectional and longitudinal intergroup difference analysis of striatal dopamine and iron, and nigral neuromelanin and iron; in Parkinson’s disease patients, exponential fitting analysis to assess the duration of the prodromal phase and the temporal ordering of changes in dopamine, neuromelanin or iron relative to controls; and voxel-wise correlation analysis to investigate concomitant spatial changes in dopamine-iron, dopamine-neuromelanin and neuromelanin-iron in the substantia nigra pars compacta. The temporal ordering of dopaminergic changes followed the known spatial pattern of progression involving first the sensorimotor, then the associative and limbic striatal and nigral regions. Striatal dopaminergic denervation occurred first followed by abnormal iron metabolism and finally neuromelanin changes in the substantia nigra pars compacta, which followed the same spatial and temporal gradient observed in the striatum but shifted in time. In conclusion, dopaminergic striatal dysfunction and cell loss in the substantia nigra pars compacta are interrelated with increased nigral iron content.The ICEBERG study was funded by grants from the Investissements d'Avenir, IAIHU-06 (Paris Institute of Neurosciences – IHU), ANR-11-INBS-0006, Fondation d’Entreprise EDF, Biogen Inc., Fondation Thérèse and René Planiol, Fondation Saint Michel, Unrestricted support for Research on Parkinson’s disease from Energipole (M. Mallart), M.Villain and Société Française de Médecine Esthétique (M. Legrand)

Quantitative susceptibility mapping identifies hippocampal and other subcortical grey matter tissue composition changes in temporal lobe epilepsy

Temporal lobe epilepsy (TLE) is associated with widespread brain alterations. Using quantitative susceptibility mapping (QSM) alongside transverse relaxation rate ( ), we investigated regional brain susceptibility changes in 36 patients with left-sided (LTLE) or right-sided TLE (RTLE) secondary to hippocampal sclerosis, and 27 healthy controls (HC). We compared three susceptibility calculation methods to ensure image quality. Correlations of susceptibility and with age of epilepsy onset, frequency of focal-to-bilateral tonic–clonic seizures (FBTCS), and neuropsychological test scores were examined. Weak-harmonic QSM (WH-QSM) successfully reduced noise and removed residual background field artefacts. Significant susceptibility increases were identified in the left putamen in the RTLE group compared to the LTLE group, the right putamen and right thalamus in the RTLE group compared to HC, and a significant susceptibility decrease in the left hippocampus in LTLE versus HC. LTLE patients who underwent epilepsy surgery showed significantly lower left-versus-right hippocampal susceptibility. Significant changes were found between TLE and HC groups in the amygdala, putamen, thalamus, and in the hippocampus. Specifically, decreased R2* was found in the left and right hippocampus in LTLE and RTLE, respectively, compared to HC. Susceptibility and were significantly correlated with cognitive test scores in the hippocampus, globus pallidus, and thalamus. FBTCS frequency correlated positively with ipsilateral thalamic and contralateral putamen susceptibility and with in bilateral globi pallidi. Age of onset was correlated with susceptibility in the hippocampus and putamen, and with in the caudate. Susceptibility and changes observed in TLE groups suggest selective loss of low-myelinated neurons alongside iron redistribution in the hippocampi, predominantly ipsilaterally, indicating QSM's sensitivity to local pathology. Increased susceptibility and in the thalamus and putamen suggest increased iron content and reflect disease severity

Cerebrovascular reactivity in multiple sclerosis is restored with reduced inflammation during immunomodulation

Cerebrovascular reactivity (CVR) reflects the capacity of the brain’s vasculature to increase blood flow following a vasodilatory stimulus. Reactivity is an essential property of the brain’s blood vessels that maintains nutrient supplies in the face of changing demand. In Multiple Sclerosis (MS), CVR may be diminished with brain inflammation and this may contribute to neurodegeneration. We test the hypothesis that CVR is altered with MS neuroinflammation and that it is restored when inflammation is reduced. Using a breath-hold task during functional Magnetic Resonance Imaging (MRI), we mapped grey matter and white matter CVRs (CVRGM and CVRWM, respectively) in 23 young MS patients, eligible for disease modifying therapy, before and during Interferon beta treatment. Inflammatory activity was inferred from the presence of Gadolinium enhancing lesions at MRI. Eighteen age and gender-matched healthy controls (HC) were also assessed. Enhancing lesions were observed in 12 patients at the start of the study and in 3 patients during treatment. Patients had lower pre-treatment CVRGM (p = 0.04) and CVRWM (p = 0.02) compared to HC. In patients, a lower pre-treatment CVRGM was associated with a lower GM volume (r = 0.60, p = 0.003). On-treatment, there was an increase in CVRGM (p = 0.02) and CVRWM (p = 0.03) that negatively correlated with pre-treatment CVR (GM: r = − 0.58, p = 0.005; WM: r = − 0.60, p = 0.003). CVR increased when enhancing lesions reduced in number (GM: r = − 0.48, p = 0.02, WM: r = − 0.62, p = 0.003). Resolution of inflammation may restore altered cerebrovascular function limiting neurodegeneration in MS. Imaging of cerebrovascular function may thereby inform tissue physiology and improve treatment monitoring

Pathophysiology of multiple sclerosis damage and repair: Linking cerebral hypoperfusion to the development of irreversible tissue loss in multiple sclerosis using magnetic resonance imaging

Background and purpose: Reduced cerebral perfusion has been observed in multiple sclerosis (MS) and may contribute to tissue loss both acutely and chronically. Here, we test the hypothesis that hypoperfusion occurs in MS and relates to the presence of irreversible tissue damage. Methods: In 91 patients with relapsing MS and 26 healthy controls (HC), gray matter (GM) cerebral blood flow (CBF) was assessed using pulsed arterial spin labeling. GM volume, T1 hypointense and T2 hyperintense lesion volumes (T1LV and T2LV, respectively), and the proportion of T2‐hyperintense lesion volume that appears hypointense on T1‐weighted magnetic resonance imaging (T1LV/T2LV) were quantified. GM CBF and GM volume were evaluated globally, as well as regionally, using an atlas‐based approach. Results: Global GM CBF was lower in patients (56.9 ± 12.3 mL/100 g/min) than in HC (67.7 ± 10.0 mL/100 g/min; p < 0.001), a difference that was widespread across brain regions. Although total GM volume was comparable between groups, significant reductions were observed in a subset of subcortical structures. GM CBF negatively correlated with T1LV (r = −0.43, p = 0.0002) and T1LV/T2LV (r = −0.37, p = 0.0004), but not with T2LV. Conclusions: GM hypoperfusion occurs in MS and is associated with irreversible white matter damage, thus suggesting that cerebral hypoperfusion may actively contribute and possibly precede neurodegeneration by hampering tissue repair abilities in MS

Developing multi-modal analysis of brain anatomical connectivity using quantitative MRI data

The aim of this work is to develop a method to investigate connectivity properties of a specific set of Grey Matter regions in the brain, and its relationship with connectivity described by the fibre structure of underlying White Matter. Data were acquired with MRI, a flexible, widely available, non-invasive technique, which can picture in vivo the connectome, a comprehensive map of neural connections in the living brain. We worked with scans of healthy subjects and patients affected by M

Su alcune classi di sistemi lineari positivi

In molti sistemi reali, le variabili di stato rappresentano delle grandezze di valore necessariamente positivo o nullo. I casi sono numerosi, e appartengono ad ambiti talvolta molto distanti tra loro. I sistemi lineari in cui le variabili di stato assumono sempre valori non negativi sono detti positivi, e sono l'oggetto di studio di questo elaborato. Nel primo capitolo, si descrivono le caratteristiche e le proprietà che un sistema lineare deve possedere perché possa essere definito positivo. Nel secondo capitolo si descrivono due importanti esempi di sistemi lineari positivi, le catene di Markov ed i sistemi compartimental

Optimising MRI magnetic susceptibility mapping for the study of brain arteriovenous malformations

Magnetic resonance imaging (MRI) magnetic susceptibility mapping (SM) enables the calculation of the magnetic susceptibility of biological tissues based on the signal phase of a gradient-recalled echo (GRE) MRI acquisition. Because deoxygenated haemoglobin is paramagnetic, SM can be used to calculate the χ of venous blood which is proportional to venous oxygen saturation (SvO2). In this thesis, I investigated the feasibility of SM for the study of brain arteriovenous malformations (AVMs). AVMs are congenital vascular anomalies characterised by arteriovenous shunting through a network of coiled and tortuous vessels. Because of this anatomy, the venous drainage of an AVM contains high-pressure mixed arterial and venous blood. I investigated whether SM could detect any resulting increased oxygenation in the draining veins. Using numerical simulations and healthy volunteer data, I focussed on optimising the acquisition and processing of GRE phase data to achieve the best possible accuracy and precision for venous SM. I showed that acquiring multi-echo versus single-echo GRE data led to more accurate and precise susceptibility, and that combining the signal from multiple echoes before applying Laplacian-based phase unwrapping or background field removal increased the susceptibility’s accuracy. Based on healthy volunteer and patient data (before and after gamma knife radiosurgery (GKR)) I investigated the feasibility of SM of brain AVMs and the information provided by venous susceptibility on AVM pathophysiology. I showed that an AVM was detectable on a susceptibility map and that the AVM draining pattern had a significantly higher SvO2 compared to healthy veins. Flowing spins in blood cause an additional susceptibility-independent component in the GRE signal phase. Because clinical multi-echo GRE protocols, including the one developed here to study brain AVMs, do not compensate for flow-induced dephasing, I investigated the effect of flow compensation on venous susceptibility and SvO2 measurements and found only a minimal effect