David L. Thomas

YNICL Journal 2026 Journal Article

Blood-brain barrier water exchange in relation to amyloid, cognition and cerebrovascular burden

• Beatriz E. Padrela
• Sandra Tecelão
• Bjørn-Eivind Kirsebom
• Oliver Geier
• Mario Tranfa
• Federico Masserini
• Markus H. Sneve
• Maksim Slivka

Blood-brain barrier (BBB) water exchange may serve as a sensitive early biomarker for Alzheimer's disease and age-related cognitive decline. This study applied a non-invasive multi-echo arterial spin labeling (ASL) technique to measure BBB water exchange time (Tex), cerebral blood flow (CBF), and arterial transit time (ATT) in 160 adults aged 50 years and older. Participants were classified as cognitively normal (CN), having subjective cognitive decline (SCD), or mild cognitive impairment (MCI). They were assessed for amyloid status and cerebrovascular burden. Compared to CN participants, Tex was significantly lower in both SCD (-9.5 %) and MCI (-14.5 %) groups, suggesting that reductions in BBB water exchange emerge early in the course of cognitive decline. In contrast, CBF was reduced only in MCI participants (-20.8 % compared to CN), and ATT was significantly increased only in individuals with severe cerebrovascular burden (Fazekas score 3). Notably, Tex showed a stepwise decrease with increasing Fazekas scores (1-2), supporting its sensitivity to moderate small vessel disease. No associations were found between Tex and amyloid positivity after adjusting for age and sex. These findings indicate that Tex alterations may precede changes in traditional perfusion markers and are more closely related to vascular and early cognitive changes than to amyloid pathology. BBB water exchange mapping may therefore provide a promising, non-invasive tool to detect early neurovascular dysfunction that contributes to cognitive decline in aging populations, potentially offering a useful biomarker for early intervention trials targeting vascular contributions to dementia.

YNIMG Journal 2025 Journal Article

Editorial for special issue: Emerging methods for mapping neurofluid circulation and exchange

• Danny JJ Wang
• Xingfeng Shao
• Li Zhao
• David L. Thomas
• Laura M Parkes

YNICL Journal 2022 Journal Article

The Open-Access European Prevention of Alzheimer’s Dementia (EPAD) MRI dataset and processing workflow

• Luigi Lorenzini
• Silvia Ingala
• Alle Meije Wink
• Joost P.A. Kuijer
• Viktor Wottschel
• Mathijs Dijsselhof
• Carole H. Sudre
• Sven Haller

The European Prevention of Alzheimer Dementia (EPAD) is a multi-center study that aims to characterize the preclinical and prodromal stages of Alzheimer's Disease. The EPAD imaging dataset includes core (3D T1w, 3D FLAIR) and advanced (ASL, diffusion MRI, and resting-state fMRI) MRI sequences. Here, we give an overview of the semi-automatic multimodal and multisite pipeline that we developed to curate, preprocess, quality control (QC), and compute image-derived phenotypes (IDPs) from the EPAD MRI dataset. This pipeline harmonizes DICOM data structure across sites and performs standardized MRI preprocessing steps. A semi-automated MRI QC procedure was implemented to visualize and flag MRI images next to site-specific distributions of QC features - i.e. metrics that represent image quality. The value of each of these QC features was evaluated through comparison with visual assessment and step-wise parameter selection based on logistic regression. IDPs were computed from 5 different MRI modalities and their sanity and potential clinical relevance were ascertained by assessing their relationship with biological markers of aging and dementia. The EPAD v1500.0 data release encompassed core structural scans from 1356 participants 842 fMRI, 831 dMRI, and 858 ASL scans. From 1356 3D T1w images, we identified 17 images with poor quality and 61 with moderate quality. Five QC features - Signal to Noise Ratio (SNR), Contrast to Noise Ratio (CNR), Coefficient of Joint Variation (CJV), Foreground-Background energy Ratio (FBER), and Image Quality Rate (IQR) - were selected as the most informative on image quality by comparison with visual assessment. The multimodal IDPs showed greater impairment in associations with age and dementia biomarkers, demonstrating the potential of the dataset for future clinical analyses.

YNICL Journal 2021 Journal Article

Differential early subcortical involvement in genetic FTD within the GENFI cohort

• Martina Bocchetta
• Emily G. Todd
• Georgia Peakman
• David M. Cash
• Rhian S. Convery
• Lucy L. Russell
• David L. Thomas
• Juan Eugenio Iglesias

BACKGROUND: Studies have previously shown evidence for presymptomatic cortical atrophy in genetic FTD. Whilst initial investigations have also identified early deep grey matter volume loss, little is known about the extent of subcortical involvement, particularly within subregions, and how this differs between genetic groups. METHODS: 480 mutation carriers from the Genetic FTD Initiative (GENFI) were included (198 GRN, 202 C9orf72, 80 MAPT), together with 298 non-carrier cognitively normal controls. Cortical and subcortical volumes of interest were generated using automated parcellation methods on volumetric 3 T T1-weighted MRI scans. Mutation carriers were divided into three disease stages based on their global CDR® plus NACC FTLD score: asymptomatic (0), possibly or mildly symptomatic (0.5) and fully symptomatic (1 or more). RESULTS: In all three groups, subcortical involvement was seen at the CDR 0.5 stage prior to phenoconversion, whereas in the C9orf72 and MAPT mutation carriers there was also involvement at the CDR 0 stage. In the C9orf72 expansion carriers the earliest volume changes were in thalamic subnuclei (particularly pulvinar and lateral geniculate, 9-10%) cerebellum (lobules VIIa-Crus II and VIIIb, 2-3%), hippocampus (particularly presubiculum and CA1, 2-3%), amygdala (all subregions, 2-6%) and hypothalamus (superior tuberal region, 1%). In MAPT mutation carriers changes were seen at CDR 0 in the hippocampus (subiculum, presubiculum and tail, 3-4%) and amygdala (accessory basal and superficial nuclei, 2-4%). GRN mutation carriers showed subcortical differences at CDR 0.5 in the presubiculum of the hippocampus (8%). CONCLUSIONS: C9orf72 expansion carriers show the earliest and most widespread changes including the thalamus, basal ganglia and medial temporal lobe. By investigating individual subregions, changes can also be seen at CDR 0 in MAPT mutation carriers within the limbic system. Our results suggest that subcortical brain volumes may be used as markers of neurodegeneration even prior to the onset of prodromal symptoms.

YNICL Journal 2021 Journal Article

Disease-related cortical thinning in presymptomatic granulin mutation carriers

• Sergi Borrego-Écija
• Roser Sala-Llonch
• John van Swieten
• Barbara Borroni
• Fermín Moreno
• Mario Masellis
• Carmela Tartaglia
• Caroline Graff

Mutations in the granulin gene (GRN) cause familial frontotemporal dementia. Understanding the structural brain changes in presymptomatic GRN carriers would enforce the use of neuroimaging biomarkers for early diagnosis and monitoring. We studied 100 presymptomatic GRN mutation carriers and 94 noncarriers from the Genetic Frontotemporal dementia initiative (GENFI), with MRI structural images. We analyzed 3T MRI structural images using the FreeSurfer pipeline to calculate the whole brain cortical thickness (CTh) for each subject. We also perform a vertex-wise general linear model to assess differences between groups in the relationship between CTh and diverse covariables as gender, age, the estimated years to onset and education. We also explored differences according to TMEM106B genotype, a possible disease modifier. Whole brain CTh did not differ between carriers and noncarriers. Both groups showed age-related cortical thinning. The group-by-age interaction analysis showed that this age-related cortical thinning was significantly greater in GRN carriers in the left superior frontal cortex. TMEM106B did not significantly influence the age-related cortical thinning. Our results validate and expand previous findings suggesting an increased CTh loss associated with age and estimated proximity to symptoms onset in GRN carriers, even before the disease onset.

YNIMG Journal 2021 Journal Article

Investigating the effect of flow compensation and quantitative susceptibility mapping method on the accuracy of venous susceptibility measurement

• Ronja C. Berg
• Christine Preibisch
• David L. Thomas
• Karin Shmueli
• Emma Biondetti

Quantitative susceptibility mapping (QSM) is a promising non-invasive method for obtaining information relating to oxygen metabolism. However, the optimal acquisition sequence and QSM reconstruction method for reliable venous susceptibility measurements are unknown. Full flow compensation is generally recommended to correct for the influence of venous blood flow, although the effect of flow compensation on the accuracy of venous susceptibility values has not been systematically evaluated. In this study, we investigated the effect of different acquisition sequences, including different flow compensation schemes, and different QSM reconstruction methods on venous susceptibilities. Ten healthy subjects were scanned with five or six distinct QSM sequence designs using monopolar readout gradients and different flow compensation schemes. All data sets were processed using six different QSM pipelines and venous blood susceptibility was evaluated in whole-brain segmentations of the venous vasculature and single veins. The quality of vein segmentations and the accuracy of venous susceptibility values were analyzed and compared between all combinations of sequences and reconstruction methods. The influence of the QSM reconstruction method on average venous susceptibility values was found to be 2.7-11.6 times greater than the influence of the acquisition sequence, including flow compensation. The majority of the investigated QSM reconstruction methods tended to underestimate venous susceptibility values in the vein segmentations that were obtained. In summary, we found that multi-echo gradient-echo acquisition sequences without full flow compensation yielded venous susceptibility values comparable to sequences with full flow compensation. However, the QSM reconstruction method had a great influence on susceptibility values and thus needs to be selected carefully for accurate venous QSM.

YNIMG Journal 2021 Journal Article

Pharmacological MRI with Simultaneous Measurement of Cerebral Perfusion and Blood-Cerebrospinal Fluid Barrier Function using Interleaved Echo-Time Arterial Spin Labelling

• Charith Perera
• Ian F. Harrison
• Mark F. Lythgoe
• David L. Thomas
• Jack A. Wells

Pharmacological MRI (phMRI) studies seek to capture changes in brain haemodynamics in response to a drug. This provides a methodological platform for the evaluation of novel therapeutics, and when applied to disease states, may provide diagnostic or mechanistic information pertaining to common brain disorders such as dementia. Changes to brain perfusion and blood-cerebrospinal fluid barrier (BCSFB) function can be probed, non-invasively, by arterial spin labelling (ASL) and blood-cerebrospinal fluid barrier arterial spin labelling (BCSFB-ASL) MRI respectively. Here, we introduce a method for simultaneous recording of pharmacological perturbation of brain perfusion and BCSFB function using interleaved echo-time ASL, applied to the anesthetized mouse brain. Using this approach, we capture an exclusive decrease in BCSFB-mediated delivery of arterial blood water to ventricular CSF, following anti-diuretic hormone, vasopressin, administration. The commonly used vasodilatory agent, CO2, induced similar increases (~21%) in both cortical perfusion and the BCSFB-ASL signal. Furthermore, we present evidence that caffeine administration triggers a marked decrease in BCSFB-mediated labelled water delivery (41%), with no significant changes in cortical perfusion. Finally, we demonstrate a marked decrease in the functional response of the BCSFB to, vasopressin, in the aged vs adult brain. Together these data, the first of such kind, highlight the value of this translational approach to capture simultaneous and differential pharmacological modulation of vessel tone at the blood brain barrier and BCSFB and how this relationship may be modified in the ageing brain.

YNIMG Journal 2021 Journal Article

Ultra-long-TE arterial spin labeling reveals rapid and brain-wide blood-to-CSF water transport in humans

• Leonie Petitclerc
• Lydiane Hirschler
• Jack A. Wells
• David L. Thomas
• Marianne A.A. van Walderveen
• Mark A. van Buchem
• Matthias J.P. van Osch

The study of brain clearance mechanisms is an active area of research. While we know that the cerebrospinal fluid (CSF) plays a central role in one of the main existing clearance pathways, the exact processes for the secretion of CSF and the removal of waste products from tissue are under debate. CSF is thought to be created by the exchange of water and ions from the blood, which is believed to mainly occur in the choroid plexus. This exchange has not been thoroughly studied in vivo. We propose a modified arterial spin labeling (ASL) MRI sequence and image analysis to track blood water as it is transported to the CSF, and to characterize its exchange from blood to CSF. We acquired six pseudo-continuous ASL sequences with varying labeling duration (LD) and post-labeling delay (PLD) and a segmented 3D-GRASE readout with a long echo train (8 echo times (TE)) which allowed separation of the very long-T2 CSF signal. ASL signal was observed at long TEs (793 ms and higher), indicating presence of labeled water transported from blood to CSF. This signal appeared both in the CSF proximal to the choroid plexus and in the subarachnoid space surrounding the cortex. ASL signal was separated into its blood, gray matter and CSF components by fitting a triexponential function with T2s taken from literature. A two-compartment dynamic model was introduced to describe the exchange of water through time and TE. From this, a water exchange time from the blood to the CSF (Tbl->CSF) was mapped, with an order of magnitude of approximately 60 s.

YNIMG Journal 2021 Journal Article

Uncertainty analysis of MR-PET image registration for precision neuro-PET imaging

• Pawel J. Markiewicz
• Julian C. Matthews
• John Ashburner
• David M. Cash
• David L. Thomas
• Enrico De Vita
• Anna Barnes
• M. Jorge Cardoso

Accurate regional brain quantitative PET measurements, particularly when using partial volume correction, rely on robust image registration between PET and MR images. We argue here that the precision, and hence the uncertainty, of MR-PET image registration is mainly driven by the registration implementation and the quality of PET images due to their lower resolution and higher noise compared to the structural MR images. We propose a dedicated uncertainty analysis for quantifying the precision of MR-PET registration, centred around the bootstrap resampling of PET list-mode events to generate multiple PET image realisations with different noise (count) levels. The effects of PET image reconstruction parameters, such as the use of attenuation and scatter corrections and different number of iterations, on the precision and accuracy of MR-PET registration were investigated. In addition, the performance of four software packages with their default settings for rigid inter-modality image registration were considered: NiftyReg, Vinci, FSL and SPM. Four distinct PET image distributions made of two early time frames (similar to cortical FDG) and two late frames using two amyloid PET dynamic acquisitions of one amyloid positive and one amyloid negative participants were investigated. For the investigated four PET frames, the biggest impact on the uncertainty was observed between registration software packages (up to 10-fold difference in precision) followed by the reconstruction parameters. On average, the lowest uncertainty for different PET frames and brain regions was observed with SPM and two iterations of fully quantitative image reconstruction. The observed uncertainty for the varying PET count-level (from 5% to 60%) was slightly lower than for the reconstruction parameters. We also observed that the registration uncertainty in quantitative PET analysis depends on amyloid status of the considered PET frames, with increased uncertainty (up to three times) when using post-reconstruction partial volume correction. This analysis is applicable for PET data obtained from either PET/MR or PET/CT scanners.

YNIMG Journal 2020 Journal Article

ExploreASL: An image processing pipeline for multi-center ASL perfusion MRI studies

• Henk J.M.M. Mutsaerts
• Jan Petr
• Paul Groot
• Pieter Vandemaele
• Silvia Ingala
• Andrew D. Robertson
• Lena Václavů
• Inge Groote

Arterial spin labeling (ASL) has undergone significant development since its inception, with a focus on improving standardization and reproducibility of its acquisition and quantification. In a community-wide effort towards robust and reproducible clinical ASL image processing, we developed the software package ExploreASL, allowing standardized analyses across centers and scanners. The procedures used in ExploreASL capitalize on published image processing advancements and address the challenges of multi-center datasets with scanner-specific processing and artifact reduction to limit patient exclusion. ExploreASL is self-contained, written in MATLAB and based on Statistical Parameter Mapping (SPM) and runs on multiple operating systems. To facilitate collaboration and data-exchange, the toolbox follows several standards and recommendations for data structure, provenance, and best analysis practice. ExploreASL was iteratively refined and tested in the analysis of >10, 000 ASL scans using different pulse-sequences in a variety of clinical populations, resulting in four processing modules: Import, Structural, ASL, and Population that perform tasks, respectively, for data curation, structural and ASL image processing and quality control, and finally preparing the results for statistical analyses on both single-subject and group level. We illustrate ExploreASL processing results from three cohorts: perinatally HIV-infected children, healthy adults, and elderly at risk for neurodegenerative disease. We show the reproducibility for each cohort when processed at different centers with different operating systems and MATLAB versions, and its effects on the quantification of gray matter cerebral blood flow. ExploreASL facilitates the standardization of image processing and quality control, allowing the pooling of cohorts which may increase statistical power and discover between-group perfusion differences. Ultimately, this workflow may advance ASL for wider adoption in clinical studies, trials, and practice.

YNICL Journal 2019 Journal Article

Differences in hippocampal subfield volume are seen in phenotypic variants of early onset Alzheimer's disease

• Thomas D. Parker
• Catherine F. Slattery
• Keir X.X. Yong
• Jennifer M. Nicholas
• Ross W. Paterson
• Alexander J.M. Foulkes
• Ian B. Malone
• David L. Thomas

The most common presentation of early onset Alzheimer's disease (EOAD - defined as symptom onset <65 years) is with progressive episodic memory impairment - amnestic or typical Alzheimer's disease (tAD). However, EOAD is notable for its phenotypic heterogeneity, with posterior cortical atrophy (PCA) - characterised by prominent higher-order visual processing deficits and relative sparing of episodic memory - the second most common canonical phenotype. The hippocampus, which comprises a number of interconnected anatomically and functionally distinct subfields, is centrally involved in Alzheimer's disease and is a crucial mediator of episodic memory. The extent to which volumes of individual hippocampal subfields differ between different phenotypes in EOAD is unclear. The aim of this analysis was to investigate the hypothesis that patients with a PCA phenotype will exhibit differences in specific hippocampal subfield volumes compared to tAD. We studied 63 participants with volumetric T1-weighted MRI performed on the same 3T scanner: 39 EOAD patients [27 with tAD and 12 with PCA] and 24 age-matched controls. Volumetric estimates of the following hippocampal subfields for each participant were obtained using Freesurfer version 6.0: CA1, CA2/3, CA4, presubiculum, subiculum, hippocampal tail, parasubiculum, the molecular and granule cell layers of the dentate gryus (GCMLDG), the molecular layer, and the hippocampal amygdala transition area (HATA). Linear regression analyses comparing mean hippocampal subfield volumes between groups, adjusting for age, sex and head size, were performed. Using a Bonferonni-corrected p-value of p < 0.0025, compared to controls, tAD was associated with atrophy in all hippocampal regions, except the parasubiculum. In PCA patients compared to controls, the strongest evidence for volume loss was in the left presubiclum, right subiculum, right GCMLDG, right molecular layer and the right HATA. Compared to PCA, patients with tAD had strong evidence for smaller volumes in left CA1 and left hippocampal tail. In conclusion, these data provide evidence that hippocampal subfield volumes differ in different phenotypes of EOAD.

YNIMG Journal 2019 Journal Article

Investigating the oxygenation of brain arteriovenous malformations using quantitative susceptibility mapping

• Emma Biondetti
• Alvaro Rojas-Villabona
• Magdalena Sokolska
• Francesca B. Pizzini
• Hans Rolf Jäger
• David L. Thomas
• Karin Shmueli

Brain arteriovenous malformations (AVMs) are congenital vascular anomalies characterized by arteriovenous shunting through a network of coiled and tortuous vessels. Because of this anatomy, the venous drainage of an AVM is hypothesized to contain more oxygenated, arterialized blood than healthy veins. By exploiting the paramagnetic properties of deoxygenated hemoglobin in venous blood using magnetic resonance imaging (MRI) quantitative susceptibility mapping (QSM), we aimed to explore venous density and oxygen saturation (SvO2) in patients with a brain AVM. We considered three groups of subjects: patients with a brain AVM before treatment using gamma knife radiosurgery (GKR); patients three or more years post-GKR treatment; and healthy volunteers. First, we investigated the appearance of AVMs on QSM images. Then, we investigated whether QSM could detect increased SvO2 in the veins draining the malformations. In patients before GKR, venous density, but not SvO2, was significantly larger in the hemisphere containing the AVM compared to the contralateral hemisphere (p = 0. 03). Such asymmetry was not observed in patients after GKR or in healthy volunteers. Moreover, in all patients before GKR, the vein immediately draining the AVM nidus had a higher SvO2 than healthy veins. Therefore, QSM can be used to detect SvO2 alterations in brain AVMs. However, since factors such as flow-induced signal dephasing or the presence of hemosiderin deposits also strongly affect QSM image contrast, AVM vein segmentation must be performed based on alternative MRI acquisitions, e. g. , time of flight magnetic resonance angiography or T1-weighted images. This is the first study to show, non-invasively, that AVM draining veins have a significantly larger SvO2 than healthy veins, which is a finding congruent with arteriovenous shunting.

YNIMG Journal 2019 Journal Article

Non-invasive MRI of brain clearance pathways using multiple echo time arterial spin labelling: an aquaporin-4 study

• Yolanda Ohene
• Ian F. Harrison
• Payam Nahavandi
• Ozama Ismail
• Eleanor V. Bird
• Ole P. Ottersen
• Erlend A. Nagelhus
• David L. Thomas

There is currently a lack of non-invasive tools to assess water transport in healthy and pathological brain tissue. Aquaporin-4 (AQP4) water channels are central to many water transport mechanisms, and emerging evidence also suggests that AQP4 plays a key role in amyloid-β (Aβ) clearance, possibly via the glymphatic system. Here, we present the first non-invasive technique sensitive to AQP4 channels polarised at the blood-brain interface (BBI). We apply a multiple echo time (multi-TE) arterial spin labelling (ASL) MRI technique to the mouse brain to assess BBI water permeability via calculation of the exchange time ( T e x w ), the time for magnetically labelled intravascular water to exchange across the BBI. We observed a 31% increase in exchange time in AQP4-deficient (Aqp4 −/− ) mice (452 ± 90 ms) compared to their wild-type counterparts (343 ± 91 ms) (p = 0. 01), demonstrating the sensitivity of the technique to the lack of AQP4 water channels. More established, quantitative MRI parameters: arterial transit time (δa), cerebral blood flow (CBF) and apparent diffusion coefficient (ADC) detected no significant changes with the removal of AQP4. This clinically relevant tool may be crucial to better understand the role of AQP4 in water transport across the BBI, as well as clearance of proteins in neurodegenerative conditions such as Alzheimer's disease.

YNIMG Journal 2019 Journal Article

The inner fluctuations of the brain in presymptomatic Frontotemporal Dementia: The chronnectome fingerprint

• Enrico Premi
• Vince D. Calhoun
• Matteo Diano
• Stefano Gazzina
• Maura Cosseddu
• Antonella Alberici
• Silvana Archetti
• Donata Paternicò

Frontotemporal Dementia (FTD) is preceded by a long period of subtle brain changes, occurring in the absence of overt cognitive symptoms, that need to be still fully characterized. Dynamic network analysis based on resting-state magnetic resonance imaging (rs-fMRI) is a potentially powerful tool for the study of preclinical FTD. In the present study, we employed a "chronnectome" approach (recurring, time-varying patterns of connectivity) to evaluate measures of dynamic connectivity in 472 at-risk FTD subjects from the Genetic Frontotemporal dementia research Initiative (GENFI) cohort. We considered 249 subjects with FTD-related pathogenetic mutations and 223 mutation non-carriers (HC). Dynamic connectivity was evaluated using independent component analysis and sliding-time window correlation to rs-fMRI data, and meta-state measures of global brain flexibility were extracted. Results show that presymptomatic FTD exhibits diminished dynamic fluidity, visiting less meta-states, shifting less often across them, and travelling through a narrowed meta-state distance, as compared to HC. Dynamic connectivity changes characterize preclinical FTD, arguing for the desynchronization of the inner fluctuations of the brain. These changes antedate clinical symptoms, and might represent an early signature of FTD to be used as a biomarker in clinical trials.

YNIMG Journal 2019 Journal Article

Tractography-based parcellation does not provide strong evidence of anatomical organisation within the thalamus

• Jonathan D. Clayden
• David L. Thomas
• Alexander Kraskov

Connectivity-based parcellation of subcortical structures using diffusion tractography is now a common paradigm in neuroscience. These analyses often imply voxel-level specificity of connectivity, and the formation of compact, spatially coherent clusters is often taken as strong imaging-based evidence for anatomically distinct subnuclei in an individual. In this study, we demonstrate that internal structure in diffusion anisotropy is not necessary for a plausible parcellation to be obtained, by spatially permuting diffusion parameters within the thalami and repeating the parcellation. Moreover, we show that, in a winner-takes-all paradigm, most voxels receive the same label before and after this shuffling process—a finding that is stable across image acquisitions and tractography algorithms. We therefore suggest that such parcellations should be interpreted with caution.

YNICL Journal 2019 Journal Article

White matter hyperintensities in progranulin-associated frontotemporal dementia: A longitudinal GENFI study

• Carole H. Sudre
• Martina Bocchetta
• Carolin Heller
• Rhian Convery
• Mollie Neason
• Katrina M. Moore
• David M. Cash
• Ione O.C. Woollacott

Frontotemporal dementia (FTD) is a heterogeneous group of neurodegenerative disorders with both sporadic and genetic forms. Mutations in the progranulin gene (GRN) are a common cause of genetic FTD, causing either a behavioural presentation or, less commonly, language impairment. Presence on T2-weighted images of white matter hyperintensities (WMH) has been previously shown to be more commonly associated with GRN mutations rather than other forms of FTD. The aim of the current study was to investigate the longitudinal change in WMH and the associations of WMH burden with grey matter (GM) loss, markers of neurodegeneration and cognitive function in GRN mutation carriers. 336 participants in the Genetic FTD Initiative (GENFI) study were included in the analysis: 101 presymptomatic and 32 symptomatic GRN mutation carriers, as well as 203 mutation-negative controls. 39 presymptomatic and 12 symptomatic carriers, and 73 controls also had longitudinal data available. Participants underwent MR imaging acquisition including isotropic 1 mm T1-weighted and T2-weighted sequences. WMH were automatically segmented and locally subdivided to enable a more detailed representation of the pathology distribution. Log-transformed WMH volumes were investigated in terms of their global and regional associations with imaging measures (grey matter volumes), biomarker concentrations (plasma neurofilament light chain, NfL, and glial fibrillary acidic protein, GFAP), genetic status (TMEM106B risk genotype) and cognition (tests of executive function). Analyses revealed that WMH load was higher in both symptomatic and presymptomatic groups compared with controls and this load increased over time. In particular, lesions were seen periventricularly in frontal and occipital lobes, progressing to medial layers over time. However, there was variability in the WMH load across GRN mutation carriers - in the symptomatic group 25.0% had none/mild load, 37.5% had medium and 37.5% had a severe load - a difference not fully explained by disease duration. GM atrophy was strongly associated with WMH load both globally and in separate lobes, and increased WMH burden in the frontal, periventricular and medial regions was associated with worse executive function. Furthermore, plasma NfL and to a lesser extent GFAP concentrations were seen to be associated with increased lesion burden. Lastly, the presence of the homozygous TMEM106B rs1990622 TT risk genotypic status was associated with an increased accrual of WMH per year. In summary, WMH occur in GRN mutation carriers and accumulate over time, but are variable in their severity. They are associated with increased GM atrophy and executive dysfunction. Furthermore, their presence is associated with markers of WM damage (NfL) and astrocytosis (GFAP), whilst their accrual is modified by TMEM106B genetic status. WMH load may represent a target marker for trials of disease modifying therapies in individual patients but the variability across the GRN population would prevent use of such markers as a global outcome measure across all participants in a trial.

YNICL Journal 2017 Journal Article

White matter hyperintensities are seen only in GRN mutation carriers in the GENFI cohort

• Carole H. Sudre
• Martina Bocchetta
• David Cash
• David L. Thomas
• Ione Woollacott
• Katrina M. Dick
• John van Swieten
• Barbara Borroni

Genetic frontotemporal dementia is most commonly caused by mutations in the progranulin (GRN), microtubule-associated protein tau (MAPT) and chromosome 9 open reading frame 72 (C9orf72) genes. Previous small studies have reported the presence of cerebral white matter hyperintensities (WMH) in genetic FTD but this has not been systematically studied across the different mutations. In this study WMH were assessed in 180 participants from the Genetic FTD Initiative (GENFI) with 3D T1- and T2-weighed magnetic resonance images: 43 symptomatic (7 GRN, 13 MAPT and 23 C9orf72), 61 presymptomatic mutation carriers (25 GRN, 8 MAPT and 28 C9orf72) and 76 mutation negative non-carrier family members. An automatic detection and quantification algorithm was developed for determining load, location and appearance of WMH. Significant differences were seen only in the symptomatic GRN group compared with the other groups with no differences in the MAPT or C9orf72 groups: increased global load of WMH was seen, with WMH located in the frontal and occipital lobes more so than the parietal lobes, and nearer to the ventricles rather than juxtacortical. Although no differences were seen in the presymptomatic group as a whole, in the GRN cohort only there was an association of increased WMH volume with expected years from symptom onset. The appearance of the WMH was also different in the GRN group compared with the other groups, with the lesions in the GRN group being more similar to each other. The presence of WMH in those with progranulin deficiency may be related to the known role of progranulin in neuroinflammation, although other roles are also proposed including an effect on blood-brain barrier permeability and the cerebral vasculature. Future studies will be useful to investigate the longitudinal evolution of WMH and their potential use as a biomarker as well as post-mortem studies investigating the histopathological nature of the lesions.

YNIMG Journal 2006 Journal Article

Improving whole brain structural MRI at 4.7 Tesla using 4 irregularly shaped receiver coils

• David W. Carmichael
• David L. Thomas
• Enrico De Vita
• Maria A. Fernández-Seara
• Navjeet Chhina
• Mark Cooper
• Colin Sunderland
• Chris Randell

Both higher magnetic field strengths (≥3 T) and multiple receiver ‘array coils’ can provide increased signal-to-noise ratio (SNR) for MRI. This increase in SNR can be used to obtain images with higher resolution, enabling better visualisation of structures within the human brain. However, high field strength systems also suffer from increased B1 non-uniformity and increased power deposition, reaching specific absorption rate (SAR) limits more quickly. For these problems to be mitigated, a careful choice of both the pulse sequence design and transmit RF coil is required. This paper describes the use of a prototype array coil consisting of 4 irregularly shaped coils within a standard configuration for neuroimaging at 4. 7 T (a head transmit/receive volume coil to minimise SAR and a head gradient insert for maximum gradient performance). With a fast spin echo (FSE) pulse sequence optimised for 4. 7 T, this provides dramatically increased quality and resolution over a large brain volume. Using the array coil, a SNR improvement relative to the volume coil of 1–1. 5 times in central brain areas and 2–3 times in cortical regions was obtained. Array coil images with a resolution of 352 × 352 × 2000 μm had a SNR of 16. 0 to 26. 2 in central regions and 19. 9 to 34. 8 in cortical areas. Such images easily demonstrate cortical myeloarchitecture, while still covering most of the brain in a ∼12 min scan.

YNIMG Journal 2002 Journal Article

Rapid Simultaneous Mapping of T2 and T2* by Multiple Acquisition of Spin and Gradient Echoes Using Interleaved Echo Planar Imaging (MASAGE-IEPI)

• David L. Thomas
• Mark F. Lythgoe
• David G. Gadian
• Roger J. Ordidge

A new MRI sequence for the rapid simultaneous measurement of T 2 and T 2 * is presented. The technique uses the multiple acquisition of spin and gradient echoes with interleaved echo planar imaging (MASAGE-IEPI). IEPI data sets are sampled during and between a pair of short and long echo time spin echoes, allowing the reconstruction of a set of images with different combinations of T 2 and T 2 * weighting and the calculation of T 2 and T 2 * maps. In the context of neuroimaging, these maps can provide information on cerebral hemodynamics and oxygenation status, either via the deoxyhemoglobin-based BOLD signal or by the effect of exogenous paramagnetic contrast agents. MASAGE-IEPI benefits from the inherent advantages of the IEPI approach, i. e. , high time resolution and minimal image distortion, and also has good time efficiency due to the acquisition of multiple image data sets following each excitation pulse. The accuracy of the sequence for the measurement of T 2 and T 2 * is verified on phantoms, and the technique is applied to monitor changing hemodynamics in the rat brain during episodes of hypoxia. Data for the generation of maps of T 2 and T 2 * are acquired with a time resolution of 12 s to accurately define the rapidly changing time course. As increasing emphasis is placed on the role of T 2 and T 2 * in the direct measurement of physiological parameters such as cerebral metabolic rate of oxygen consumption and blood vessel sizes, MASAGE-IEPI offers an efficient method for the measurement of these two important MRI parameters.