Imaging of Brain Connectivity in Dementia: Clinical Implications for Diagnosis of its Underlying Diseases

In this thesis we investigated the use of advanced magnetic resonance imaging (MRI) techniques in identifying subtle brain abnormalities, associating brain abnormalities with disease symptomatology, and improving early (differential) diagnosis in several diseases underlying dementia. Presenile dementia (occurring before 65 years of age) is a neurodegenerative disorder affecting white matter (WM) and grey matter (GM) in different regions of the brain. The two most common underlying diseases are Alzheimer’s disease (AD) and frontotemporal dementia (FTD). FTD is the umbrella term for several types of dementia, such as behavioural variant FTD (bvFTD) and semantic dementia (SD). Additionally, phenocopy frontotemporal dementia (phFTD), a rare syndrome clinically similar to bvFTD, may also belong to this FTD spectrum. In early stages of these diseases, symptoms may still be mild or unspecific. Consequently, early-stage (differential) diagnosis can be difficult. MRI of the brain supports diagnosis, but may still appear normal or show unspecific brain abnormalities in early stages of dementia. More advanced MRI techniques may aid diagnosis by detecting subtle abnormalities that remain unrevealed using conventional (structural) MRI. Additionally, advanced MRI can be quantified, which allows for comparing patients to reference values of the healthy population, and allows for combining WM and GM measures to investigate relations between subtle WM and GM changes in dementia. In this thesis several advanced MRI techniques were explored, specifically diffusion tensor imaging (DTI), resting state functional MRI (rs-fMRI) and arterial spin labelling (ASL). DTI and rs-fMRI can be used to assess brain connectivity in terms of respectively WM microstructure and functional connectivity of resting state networks. Arterial spin labelling can be used to assess whole-brain or region-specific perfusion in GM. Additionally, advanced post-processing tools can be applied to conventional (structural) MRI, which may allow for identifying smaller GM volume changes. The main findings of this thesis allow for the conclusion that advanced MRI techniques identify subtle brain abnormalities in AD, bvFTD, SD and phFTD, that are not otherwise detected using conventional (structural) MR imaging. These subtle brain abnormalities aid to the understanding of brain processes in dementia, and especially DTI and ASL may aid clinical diagnosis and differentiation of the dementia subtypes

Quantitative magnetisation transfer imaging in relapsing-remitting multiple sclerosis: a systematic review and meta-analysis

Myelin-sensitive MRI such as magnetization transfer imaging has been widely used in multiple sclerosis. The influence of methodology and differences in disease subtype on imaging findings is, however, not well established. Here, we systematically review magnetization transfer brain imaging findings in relapsing-remitting multiple sclerosis. We examine how methodological differences, disease effects and their interaction influence magnetization transfer imaging measures. Articles published before 06/01/2021 were retrieved from online databases (PubMed, EMBASE and Web of Science) with search terms including ‘magnetization transfer’ and ‘brain’ for systematic review, according to a pre-defined protocol. Only studies that used human in vivo quantitative magnetization transfer imaging in adults with relapsing-remitting multiple sclerosis (with or without healthy controls) were included. Additional data from relapsing-remitting multiple sclerosis subjects acquired in other studies comprising mixed disease subtypes were included in meta-analyses. Data including sample size, MRI acquisition protocol parameters, treatments and clinical findings were extracted and qualitatively synthesized. Where possible, effect sizes were calculated for meta-analyses to determine magnetization transfer (i) differences between patients and healthy controls; (ii) longitudinal change and (iii) relationships with clinical disability in relapsing-remitting multiple sclerosis. Eighty-six studies met inclusion criteria. MRI acquisition parameters varied widely, and were also underreported. The majority of studies examined the magnetization transfer ratio in white matter, but magnetization transfer metrics, brain regions examined and results were heterogeneous. The analysis demonstrated a risk of bias due to selective reporting and small sample sizes. The pooled random-effects meta-analysis across all brain compartments revealed magnetization transfer ratio was 1.17 per cent units (95% CI −1.42 to −0.91) lower in relapsing-remitting multiple sclerosis than healthy controls (z-value: −8.99, P < 0.001, 46 studies). Linear mixed-model analysis did not show a significant longitudinal change in magnetization transfer ratio across all brain regions [β = 0.12 (−0.56 to 0.80), t-value = 0.35, P = 0.724, 14 studies] or normal-appearing white matter alone [β = 0.037 (−0.14 to 0.22), t-value = 0.41, P = 0.68, eight studies]. There was a significant negative association between the magnetization transfer ratio and clinical disability, as assessed by the Expanded Disability Status Scale [r = −0.32 (95% CI −0.46 to −0.17); z-value = −4.33, P < 0.001, 13 studies]. Evidence suggests that magnetization transfer imaging metrics are sensitive to pathological brain changes in relapsing-remitting multiple sclerosis, although effect sizes were small in comparison to inter-study variability. Recommendations include: better harmonized magnetization transfer acquisition protocols with detailed methodological reporting standards; larger, well-phenotyped cohorts, including healthy controls; and, further exploration of techniques such as magnetization transfer saturation or inhomogeneous magnetization transfer ratio

Longitudinal microstructural MRI markers of demyelination and neurodegeneration in early relapsing-remitting multiple sclerosis:Magnetisation transfer, water diffusion and g-ratio

INTRODUCTION: Quantitative microstructural MRI, such as myelin-sensitive magnetisation transfer ratio (MTR) or saturation (MTsat), axon-sensitive water diffusion Neurite Orientation Dispersion and Density Imaging (NODDI), and the aggregate g-ratio, may provide more specific markers of white matter integrity than conventional MRI for early patient stratification in relapsing-remitting multiple sclerosis (RRMS). The aim of this study was to determine the sensitivity of such markers to longitudinal pathological change within cerebral white matter lesions (WML) and normal-appearing white matter (NAWM) in recently diagnosed RRMS. METHODS: Seventy-nine people with recently diagnosed RRMS, from the FutureMS longitudinal cohort, were recruited to an extended MRI protocol at baseline and one year later. Twelve healthy volunteers received the same MRI protocol, repeated within two weeks. Ethics approval and written informed consent were obtained. 3T MRI included magnetisation transfer, and multi-shell diffusion-weighted imaging. NAWM and whole brain were segmented from 3D T1-weighted MPRAGE, and WML from T2-weighted FLAIR. MTR, MTsat, NODDI isotropic (ISOVF) and intracellular (ICVF) volume fractions, and g-ratio (calculated from MTsat and NODDI data) were measured within WML and NAWM. Brain parenchymal fraction (BPF) was also calculated. Longitudinal change in BPF and microstructural metrics was assessed with paired t-tests (α = 0.05) and linear mixed models, adjusted for confounding factors with False Discovery Rate (FDR) correction for multiple comparisons. Longitudinal changes were compared with test-retest Bland-Altman limits of agreement from healthy control white matter. The influence of longitudinal change on g-ratio was explored through post-hoc analysis in silico by computing g-ratio with realistic simulated MTsat and NODDI values. RESULTS: In NAWM, g-ratio and ICVF increased, and MTsat decreased over one year (adjusted mean difference = 0.007, 0.005, and −0.057 respectively, all FDR-corrected p < 0.05). There was no significant change in MTR, ISOVF, or BPF. In WML, MTsat, NODDI ICVF and ISOVF increased over time (adjusted mean difference = 0.083, 0.024 and 0.016, respectively, all FDR-corrected p < 0.05). Group-level longitudinal changes exceeded test-retest limits of agreement for NODDI ISOVF and ICVF in WML only. In silico analysis showed g-ratio may increase due to a decrease in MTsat or ISOVF, or an increase in ICVF. DISCUSSION: G-ratio and MTsat changes in NAWM over one year may indicate subtle myelin loss in early RRMS, which were not apparent with BPF or NAWM MTR. Increases in NAWM and WML NODDI ICVF were not anticipated, and raise the possibility of axonal swelling or morphological change. Increases in WML MTsat may reflect myelin repair. Changes in NODDI ISOVF are more likely to reflect alterations in water content. Competing MTsat and ICVF changes may account for the absence of g-ratio change in WML. Longitudinal changes in microstructural measures are significant at a group level, however detection in individual patients in early RRMS is limited by technique reproducibility. CONCLUSION: MTsat and g-ratio are more sensitive than MTR to early pathological changes in RRMS, but complex dependence of g-ratio on NODDI parameters limit the interpretation of aggregate measures in isolation. Improvements in technique reproducibility and validation of MRI biophysical models across a range of pathological tissue states are needed

The prevalence of paramagnetic rim lesions in multiple sclerosis: A systematic review and meta-analysis

BACKGROUND: Recent findings from several studies have shown that paramagnetic rim lesions identified using susceptibility-based MRI could represent potential diagnostic and prognostic biomarkers in multiple sclerosis (MS). Here, we perform a systematic review and meta-analysis of the existing literature to assess their pooled prevalence at lesion-level and patient-level. METHODS: Both database searching (PubMed and Embase) and handsearching were conducted to identify studies allowing the lesion-level and/or patient-level prevalence of rim lesions or chronic active lesions to be calculated. Pooled prevalence was estimated using the DerSimonian-Laird random-effects model. Subgroup analysis and meta-regression were performed to explore possible sources of heterogeneity. PROSPERO registration: CRD42020192282. RESULTS: 29 studies comprising 1230 patients were eligible for analysis. Meta-analysis estimated pooled prevalences of 9.8% (95% CI: 6.6–14.2) and 40.6% (95% CI: 26.2–56.8) for rim lesions at lesion-level and patient-level, respectively. Pooled lesion-level and patient-level prevalences for chronic active lesions were 12.0% (95% CI: 9.0–15.8) and 64.8% (95% CI: 54.3–74.0), respectively. Considerable heterogeneity was observed across studies (I(2)>75%). Subgroup analysis revealed a significant difference in patient-level prevalence between studies conducted at 3T and 7T (p = 0.0312). Meta-regression analyses also showed significant differences in lesion-level prevalence with respect to age (p = 0.0018, R(2) = 0.20) and disease duration (p = 0.0018, R(2) = 0.48). Other moderator analyses demonstrated no significant differences according to MRI sequence, gender and expanded disability status scale (EDSS). CONCLUSION: In this study, we show that paramagnetic rim lesions may be present in an important proportion of MS patients, notwithstanding significant variation in their assessment across studies. In view of their possible clinical relevance, we believe that clear guidelines should be introduced to standardise their assessment across research centres to in turn facilitate future analyses

Measuring axial length of the eye from magnetic resonance brain imaging

BACKGROUND: Metrics derived from the human eye are increasingly used as biomarkers and endpoints in studies of cardiovascular, cerebrovascular and neurological disease. In this context, it is important to account for potential confounding that can arise from differences in ocular dimensions between individuals, for example, differences in globe size. METHODS: We measured axial length, a geometric parameter describing eye size from T(2)-weighted brain MRI scans using three different image analysis software packages (Mango, ITK and Carestream) and compared results to biometry measurements from a specialized ophthalmic instrument (IOLMaster 500) as the reference standard. RESULTS: Ninety-three healthy research participants of mean age 51.0 ± SD 5.4 years were analyzed. The level of agreement between the MRI-derived measurements and the reference standard was described by mean differences as follows, Mango − 0.8 mm; ITK − 0.5 mm; and Carestream − 0.1 mm (upper/lower 95% limits of agreement across the three tools ranged from 0.9 mm to − 2.6 mm). Inter-rater reproducibility was between − 0.03 mm and 0.45 mm (ICC 0.65 to 0.93). Intra-rater repeatability was between 0.0 mm and − 0.2 mm (ICC 0.90 to 0.95). CONCLUSIONS: We demonstrate that axial measurements of the eye derived from brain MRI are within 3.5% of the reference standard globe length of 24.1 mm. However, the limits of agreement could be considered clinically significant. Axial length of the eye obtained from MRI is not a replacement for the precision of biometry, but in the absence of biometry it could provide sufficient accuracy to act as a proxy. We recommend measuring eye axial length from MRI in studies that do not have biometry but use retinal imaging to study neurodegenerative changes so as to control for differing eye size across individuals. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12886-022-02289-y

Rim lesions are demonstrated in early relapsing–remitting multiple sclerosis using 3 T-based susceptibility-weighted imaging in a multi-institutional setting

PURPOSE: Rim lesions, characterised by a paramagnetic rim on susceptibility-based MRI, have been suggested to reflect chronic inflammatory demyelination in multiple sclerosis (MS) patients. Here, we assess, through susceptibility-weighted imaging (SWI), the prevalence, longitudinal volume evolution and clinical associations of rim lesions in subjects with early relapsing–remitting MS (RRMS). METHODS: Subjects (n = 44) with recently diagnosed RRMS underwent 3 T MRI at baseline (M0) and 1 year (M12) as part of a multi-centre study. SWI was acquired at M12 using a 3D segmented gradient-echo echo-planar imaging sequence. Rim lesions identified on SWI were manually segmented on FLAIR images at both time points for volumetric analysis. RESULTS: Twelve subjects (27%) had at least one rim lesion at M12. A linear mixed-effects model, with ‘subject’ as a random factor, revealed mixed evidence for the difference in longitudinal volume change between rim lesions and non-rim lesions (p = 0.0350 and p = 0.0556 for subjects with and without rim lesions, respectively). All 25 rim lesions identified showed T1-weighted hypointense signal. Subjects with and without rim lesions did not differ significantly with respect to age, disease duration or clinical measures of disability (p > 0.05). CONCLUSION: We demonstrate that rim lesions are detectable in early-stage RRMS on 3 T MRI across multiple centres, although their relationship to lesion enlargement is equivocal in this small cohort. Identification of SWI rims was subjective. Agreed criteria for defining rim lesions and their further validation as a biomarker of chronic inflammation are required for translation of SWI into routine MS clinical practice. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s00234-021-02768-x

Qualitative Assessment of Longitudinal Changes in Phenocopy Frontotemporal Dementia

Phenocopy frontotemporal dementia (phFTD) shares core characteristics with behavioral variant frontotemporal dementia (bvFTD), yet without associated cognitive deficits and brain abnormalities on conventional magnetic resonance imaging (MRI), and without progression. Using advanced MRI techniques, we previously observed subtle structural and functional brain changes in phFTD similar to bvFTD. The aim of the current study was to follow these as well as cognition in phFTD over time, by means of a descriptive case series. Cognition, gray matter (GM) volume and white matter (WM) microstructure, and perfusion of 6 phFTD patients were qualitatively compared longitudinally (3-years follow-up), and cross-sectionally with baseline data from 9 bvFTD patients and 17 controls. For functional brain changes, arterial spin labeling (ASL) was performed to assess GM perfusion. For structural brain changes, diffusion tensor imaging was performed to assess WM microstructure and T1w imaging to assess GM volume. MRI acquisition was performed at 3T (General Electric, US). Clinical profiles of phFTD cases at follow-up are described. At follow-up phFTD patients showed clinical symptomatology similar to bvFTD, but had a relatively stable clinical profile. Longitudinal qualitative comparisons in phFTD showed some deterioration of language and memory function, a stable pattern of structural brain abnormalities and increased perfusion over time. Additionally, both baseline and follow-up cognitive scores and structural values in phFTD were generally in between those of controls and bvFTD. Although a descriptive case series does not allow for strong conclusions, these observations in a unique longitudinal phFTD patient cohort are suggestive of the notion that phFTD and bvFTD may belong to the same disease spectrum. They may also provide a basis for further longitudinal studies in phFTD, specifically exploring the structural vs. functional brain changes. Such studies are essential for improved insight, accurate diagnosis, and appropriate treatment of phFTD