Impact of long-term white matter hyperintensity changes on mobility and dexterity.

White matter hyperintensities (WMH), a common feature of cerebral small vessel disease, are related to worse clinical outcomes after stroke. We assessed the impact of white matter hyperintensity changes over 1 year after minor stroke on change in mobility and dexterity, including differences between the dominant and non-dominant hands and objective in-person assessment versus patient-reported experience. We recruited participants with lacunar or minor cortical ischaemic stroke, performed medical and cognitive assessments and brain MRI at presentation and at 1 year. At both time points, we used the timed-up and go test and the 9-hole peg test to assess mobility and dexterity. At 1 year, participants completed the Stroke Impact Scale. We ran two linear mixed models to assess change in timed-up and go and 9-hole peg test, adjusted for age, sex, stroke severity (National Institutes of Health Stroke Scale), dependency (modified Rankin Score), vascular risk factor score, white matter hyperintensity volume (as % intracranial volume) and additionally for 9-hole peg test: Montreal cognitive assessment, hand (dominant/non-dominant), National Adult Reading Test (premorbid IQ), index lesion side. We performed ordinal logistic regression, corrected for age and sex, to assess relations between timed-up and go and Stroke Impact Scale mobility, and 9-hole peg test and Stroke Impact Scale hand function. We included 229 participants, mean age 65.9 (standard deviation = 11.13); 66% male. 215/229 attended 1-year follow-up. Over 1 year, timed-up and go time increased with aging (standardized ß [standardized 95% Confidence Interval]: 0.124[0.011, 0.238]), increasing National Institutes of Health Stroke Scale (0.106[0.032, 0.180]), increasing modified Rankin Score (0.152[0.073, 0.231]) and increasing white matter hyperintensity volume (0.176[0.061, 0.291]). Men were faster than women (-0.306[0.011, 0.238]). Over 1 year, slower 9-hole peg test was related to use of non-dominant hand (0.290[0.155, 0.424]), aging (0.102[0.012, 0.192]), male sex (0.182[0.008, 0.356]), increasing National Institutes of Health Stroke Scale (0.160 [0.094, 0.226]), increasing modified Rankin Score (0.100[0.032, 0.169]), decreasing Montreal cognitive assessment score (-0.090[-0.167, -0.014]) and increasing white matter hyperintensity volume (0.104[0.015, 0.193]). One year post-stroke, Stroke Impact Scale mobility worsened per second increase on timed-up and go, odds ratio 0.67 [95% confidence interval 0.60, 0.75]. Stroke Impact Scale hand function worsened per second increase on the 9-hole peg test for the dominant hand (odds ratio 0.79 [0.71, 0.86]) and for the non-dominant hand (odds ratio 0.88 [0.83, 0.93]). Decline in mobility and dexterity is associated with white matter hyperintensity volume increase, independently of stroke severity. Mobility and dexterity declined more gradually for stable and regressing white matter hyperintensity volume. Dominant and non-dominant hands might be affected differently. In-person measures of dexterity and mobility are associated with self-reported experience 1-year post-stroke.

Magnetic Resonance Imaging Tissue Signatures Associated With White Matter Changes Due to Sporadic Cerebral Small Vessel Disease Indicate That White Matter Hyperintensities Can Regress.

BACKGROUND: White matter hyperintensities (WMHs) might regress and progress contemporaneously, but we know little about underlying mechanisms. We examined WMH change and underlying quantitative magnetic resonance imaging tissue measures over 1 year in patients with minor ischemic stroke with sporadic cerebral small vessel disease. METHODS AND RESULTS: We defined areas of stable normal-appearing white matter, stable WMHs, progressing and regressing WMHs based on baseline and 1-year brain magnetic resonance imaging. In these areas we assessed tissue characteristics with quantitative T1, fractional anisotropy (FA), mean diffusivity (MD), and neurite orientation dispersion and density imaging (baseline only). We compared tissue signatures cross-sectionally between areas, and longitudinally within each area. WMH change masks were available for N=197. Participants' mean age was 65.61 years (SD, 11.10), 59% had a lacunar infarct, and 68% were men. FA and MD were available for N=195, quantitative T1 for N=182, and neurite orientation dispersion and density imaging for N=174. Cross-sectionally, all 4 tissue classes differed for FA, MD, T1, and Neurite Density Index. Longitudinally, in regressing WMHs, FA increased with little change in MD and T1 (difference estimate, 0.011 [95% CI, 0.006-0.017]; -0.002 [95% CI, -0.008 to 0.003] and -0.003 [95% CI, -0.009 to 0.004]); in progressing and stable WMHs, FA decreased (-0.022 [95% CI, -0.027 to -0.017] and -0.009 [95% CI, -0.011 to -0.006]), whereas MD and T1 increased (progressing WMHs, 0.057 [95% CI, 0.050-0.063], 0.058 [95% CI, 0.050 -0.066]; stable WMHs, 0.054 [95% CI, 0.045-0.063], 0.049 [95% CI, 0.039-0.058]); and in stable normal-appearing white matter, MD increased (0.004 [95% CI, 0.003-0.005]), whereas FA and T1 slightly decreased and increased (-0.002 [95% CI, -0.004 to -0.000] and 0.005 [95% CI, 0.001-0.009]). CONCLUSIONS: Quantitative magnetic resonance imaging shows that WMHs that regress have less abnormal microstructure at baseline than stable WMHs and follow trajectories indicating tissue improvement compared with stable and progressing WMHs.

Paranasal sinus occupancy assessed from magnetic resonance images-associations with clinical indicators in patients with systemic lupus erythematosus.

OBJECTIVES: Nasal, paranasal sinus and mucosal disorders are common symptoms in autoimmune rheumatic diseases. Soft tissue changes and fluid accumulation in the osteomeatal complexes and paranasal sinuses manifest as opaqueness on radiological images which can be assessed using visual scoring and computational methods on CT scans, but their results do not always correlate. Using MRI, we investigate the applicability of different image analysis methods in SLE. METHODS: We assessed paranasal sinus opaqueness on MRI from 51 SLE patients, using three visual scoring systems and expert-delineated computational volumes, and examined their association with markers of disease activity, inflammation, endothelial dysfunction and common small vessel disease (SVD) indicators, adjusting for age and sex-at-birth. RESULTS: The average paranasal sinus volume occupation was 4.55 (6.47%) [median (interquartile range) = 0.67 (0.25-2.65) ml], mainly in the maxillary and ethmoid sinuses. It was highly correlated with Lund-Mackay (LM) scores modified at 50% opaqueness cut-off (Spearman's ρ: 0.71 maxillary and 0.618 ethmoids, P < 0.001 in all), and with more granular variations of the LM system. The modified LM scores were associated with SVD scores (0: B = 5.078, s.e. = 1.69, P = 0.0026; 2: B = -0.066, s.e. = 0.023, P = 0.0045) and disease activity (anti-dsDNA: B = 4.59, s.e. = 2.22, P = 0.045; SLEDAI 3-7: 2.86 < B < 4.30; 1.38 < s.e. < 1.63; 0.0083 ≤ P ≤ 0.0375). Computationally derived percent opaqueness yielded similar results. CONCLUSION: In patients with SLE, MRI computational assessment of sinuses opaqueness and LM scores modified at a 50% cut-off may be useful tools in understanding the relationships among paranasal sinus occupancy, disease activity and SVD markers.

Characterizing the Neurobiological Mechanisms of Action of Exercise and Cognitive-Behavioral Interventions for Rheumatoid Arthritis Fatigue: A Magnetic Resonance Imaging Brain Study.

OBJECTIVE: Chronic fatigue is a major clinical unmet need among patients with rheumatoid arthritis (RA). Current therapies are limited to nonpharmacological interventions, such as personalized exercise programs (PEPs) and cognitive-behavioral approaches (CBAs); however, most patients still continue to report severe fatigue. To inform more effective therapies, we conducted a magnetic resonance imaging (MRI) brain study of PEPs and CBAs, nested within a randomized controlled trial (RCT), to identify their neurobiological mechanisms of fatigue reduction in RA. METHODS: A subgroup of patients with RA (n = 90), participating in an RCT of PEPs and CBAs for fatigue, undertook a multimodal MRI brain scan following randomization to either usual care (UC) alone or in addition to PEPs and CBAs and again after the intervention (six months). Brain regional volumetric, functional, and structural connectivity indices were curated and then computed employing a causal analysis framework. The primary outcome was fatigue improvement (Chalder fatigue scale). RESULTS: Several structural and functional connections were identified as mediators of fatigue improvement in both PEPs and CBAs compared to UC. PEPs had a more pronounced effect on functional connectivity than CBAs; however, structural connectivity between the left isthmus cingulate cortex (L-ICC) and left paracentral lobule (L-PCL) was shared, and the size of mediation effect ranked highly for both PEPs and CBAs (ßAverage = -0.46, SD 0.61; ßAverage = -0.32, SD 0.47, respectively). CONCLUSION: The structural connection between the L-ICC and L-PCL appears to be a dominant mechanism for how both PEPs and CBAs reduce fatigue among patients with RA. This supports its potential as a substrate of fatigue neurobiology and a putative candidate for future targeting.

Influence of threshold selection and image sequence in in-vivo segmentation of enlarged perivascular spaces.

BACKGROUND: Growing interest surrounds perivascular spaces (PVS) as a clinical biomarker of brain dysfunction given their association with cerebrovascular risk factors and disease. Neuroimaging techniques allowing quick and reliable quantification are being developed, but, in practice, they require optimisation as their limits of validity are usually unspecified. NEW METHOD: We evaluate modifications and alternatives to a state-of-the-art (SOTA) PVS segmentation method that uses a vesselness filter to enhance PVS discrimination, followed by thresholding of its response, applied to brain magnetic resonance images (MRI) from patients with sporadic small vessel disease acquired at 3 T. RESULTS: The method is robust against inter-observer differences in threshold selection, but separate thresholds for each region of interest (i.e., basal ganglia, centrum semiovale, and midbrain) are required. Noise needs to be assessed prior to selecting these thresholds, as effect of noise and imaging artefacts can be mitigated with a careful optimisation of these thresholds. PVS segmentation from T1-weighted images alone, misses small PVS, therefore, underestimates PVS count, may overestimate individual PVS volume especially in the basal ganglia, and is susceptible to the inclusion of calcified vessels and mineral deposits. Visual analyses indicated the incomplete and fragmented detection of long and thin PVS as the primary cause of errors, with the Frangi filter coping better than the Jerman filter. COMPARISON WITH EXISTING METHODS: Limits of validity to a SOTA PVS segmentation method applied to 3 T MRI with confounding pathology are given. CONCLUSIONS: Evidence presented reinforces the STRIVE-2 recommendation of using T2-weighted images for PVS assessment wherever possible. The Frangi filter is recommended for PVS segmentation from MRI, offering robust output against variations in threshold selection and pathology presentation.

Cerebrovascular Reactivity in Patients With Small Vessel Disease: A Cross-Sectional Study.

BACKGROUND: Cerebrovascular reactivity (CVR) is inversely related to white matter hyperintensity severity, a marker of cerebral small vessel disease (SVD). Less is known about the relationship between CVR and other SVD imaging features or cognition. We aimed to investigate these cross-sectional relationships. METHODS: Between 2018 and 2021 in Edinburgh, we recruited patients presenting with lacunar or cortical ischemic stroke, whom we characterized for SVD features. We measured CVR in subcortical gray matter, normal-appearing white matter, and white matter hyperintensity using 3T magnetic resonance imaging. We assessed cognition using Montreal Cognitive Assessment. Statistical analyses included linear regression models with CVR as outcome, adjusted for age, sex, and vascular risk factors. We reported regression coefficients with 95% CIs. RESULTS: Of 208 patients, 182 had processable CVR data sets (median age, 68.2 years; 68% men). Although the strength of association depended on tissue type, lower CVR in normal-appearing tissues and white matter hyperintensity was associated with larger white matter hyperintensity volume (BNAWM=-0.0073 [95% CI, -0.0133 to -0.0014] %/mm Hg per 10-fold increase in percentage intracranial volume), more lacunes (BNAWM=-0.00129 [95% CI, -0.00215 to -0.00043] %/mm Hg per lacune), more microbleeds (BNAWM=-0.00083 [95% CI, -0.00130 to -0.00036] %/mm Hg per microbleed), higher deep atrophy score (BNAWM=-0.00218 [95% CI, -0.00417 to -0.00020] %/mm Hg per score point increase), higher perivascular space score (BNAWM=-0.0034 [95% CI, -0.0066 to -0.0002] %/mm Hg per score point increase in basal ganglia), and higher SVD score (BNAWM=-0.0048 [95% CI, -0.0075 to -0.0021] %/mm Hg per score point increase). Lower CVR in normal-appearing tissues was related to lower Montreal Cognitive Assessment without reaching convention statistical significance (BNAWM=0.00065 [95% CI, -0.00007 to 0.00137] %/mm Hg per score point increase). CONCLUSIONS: Lower CVR in patients with SVD was related to more severe SVD burden and worse cognition in this cross-sectional analysis. Longitudinal analysis will help determine whether lower CVR predicts worsening SVD severity or vice versa. REGISTRATION: URL: https://www.isrctn.com; Unique identifier: ISRCTN12113543.

Paranasal sinuses opacification on magnetic resonance imaging in relation to brain health in sporadic small vessel disease - Systematic review and pilot analysis.

BACKGROUND: The paranasal sinus mucosal thickening, visible in magnetic resonance imaging (MRI), maybe a source of inflammation in microvessels, but its relationship with small vessel disease (SVD) is unclear. We reviewed the literature and analysed a sample of patients with sporadic SVD to identify any association between paranasal sinus opacification severity and SVD neuroimaging markers. METHODS: We systematically reviewed MEDLINE and EMBASE databases up to April 2020 for studies on paranasal sinus mucosal changes in patients with SVD, cerebrovascular disease (CVD), and age-related neurodegenerative diseases. We analysed clinical and MRI data from 100 participants in a prospective study, the Mild Stroke Study 3 (ISRCTN 12113543) at 1-3, 6 and 12 months following a minor stroke to test key outcomes from the literature review. We used multivariate linear regression to explore associations between modified Lund-Mackay (LM) scores and brain, white matter hyperintensities (WMH), enlarged perivascular spaces (PVS) volumes at each time point, adjusted for baseline age, sex, diabetes, hypercholesterolaemia, hypertension and smoking. RESULTS: The literature review, after screening 3652 publications, yielded 11 primary studies, for qualitative synthesis with contradictory results, as positive associations/higher risk from 5/7 CVD studies were contradicted by the two studies with largest samples, and data from dementia studies was equally split in their outcome. From the pilot sample of patients analysed (female N = 33, mean age 67.42 (9.70) years), total LM scores had a borderline negative association with PVS in the centrum semiovale at baseline and 6 months (B = -0.25, SE = 0.14, p = 0.06) but were not associated with average brain tissue, WMH or normal-appearing white matter volumes. CONCLUSION: The inconclusive results from the literature review and empirical study justify larger studies between PVS volume and paranasal sinuses opacification in patients with sporadic SVD.

Sleep quality, perivascular spaces and brain health markers in ageing - A longitudinal study in the Lothian Birth Cohort 1936.

BACKGROUND: Sleep is thought to play a major role in brain health and general wellbeing. However, few longitudinal studies have explored the relationship between sleep habits and imaging markers of brain health, particularly markers of brain waste clearance such as perivascular spaces (PVS), of neurodegeneration such as brain atrophy, and of vascular disease, such as white matter hyperintensities (WMH). We explore these associations using data collected over 6 years from a birth cohort of older community-dwelling adults in their 70s. METHOD: We analysed brain MRI data from ages 73, 76 and 79 years, and self-reported sleep duration, sleep quality and vascular risk factors from community-dwelling participants in the Lothian Birth Cohort 1936 (LBC1936) study. We calculated sleep efficiency (at age 76), quantified PVS burden (at age 73), and WMH and brain volumes (age 73 to 79), calculated the white matter damage metric, and used structural equation modelling (SEM) to explore associations and potential causative pathways between indicators related to brain waste cleaning (i.e., sleep and PVS burden), brain and WMH volume changes during the 8th decade of life. RESULTS: Lower sleep efficiency was associated with a reduction in normal-appearing white matter (NAWM) volume (ß = 0.204, P = 0.009) from ages 73 to 79, but not concurrent volume (i.e. age 76). Increased daytime sleep correlated with less night-time sleep (r = -0.20, P < 0.001), and with increasing white matter damage metric (ß = -0.122, P = 0.018) and faster WMH growth (ß = 0.116, P = 0.026). Shorter night-time sleep duration was associated with steeper 6-year reduction of NAWM volumes (ß = 0.160, P = 0.011). High burden of PVS at age 73 (volume, count, and visual scores), was associated with faster deterioration in white matter: reduction of NAWM volume (ß = -0.16, P = 0.012) and increasing white matter damage metric (ß = 0.37, P < 0.001) between ages 73 and 79. On SEM, centrum semiovale PVS burden mediated 5% of the associations between sleep parameters and brain changes. CONCLUSION: Sleep impairments, and higher PVS burden, a marker of impaired waste clearance, were associated with faster loss of healthy white matter and increasing WMH in the 8th decade of life. A small percentage of the effect of sleep in white matter health was mediated by the burden of PVS consistent with the proposed role for sleep in brain waste clearance.

Retinal capillary microvessel morphology changes are associated with vascular damage and dysfunction in cerebral small vessel disease.

Cerebral small vessel disease (SVD) is a cause of stroke and dementia. Retinal capillary microvessels revealed by optical coherence tomography angiography (OCTA) are developmentally related to brain microvessels. We quantified retinal vessel density (VD) and branching complexity, investigating relationships with SVD lesions, white matter integrity on diffusion tensor imaging (DTI) and cerebrovascular reactivity (CVR) to CO2 in patients with minor stroke. We enrolled 123 patients (mean age 68.1 ± SD 9.9 years), 115 contributed retinal data. Right (R) and left (L) eyes are reported. After adjusting for age, eye disease, diabetes, blood pressure and image quality, lower VD remained associated with higher mean diffusivity (MD) (standardized ß; R -0.16 [95%CI -0.32 to -0.01]) and lower CVR (L 0.17 [0.03 to 0.31] and R 0.19 [0.02 to 0.36]) in normal appearing white matter (NAWM). Sparser branching remained associated with sub-visible white matter damage shown by higher MD (R -0.24 [-0.08 to -0.40]), lower fractional anisotropy (FA) (L 0.17 [0.01 to 0.33]), and lower CVR (R 0.20 [0.02 to 0.38]) in NAWM. OCTA-derived metrics provide evidence of microvessel abnormalities that may underpin SVD lesions in the brain.

Deep attention super-resolution of brain magnetic resonance images acquired under clinical protocols.

Vast quantities of Magnetic Resonance Images (MRI) are routinely acquired in clinical practice but, to speed up acquisition, these scans are typically of a quality that is sufficient for clinical diagnosis but sub-optimal for large-scale precision medicine, computational diagnostics, and large-scale neuroimaging collaborative research. Here, we present a critic-guided framework to upsample low-resolution (often 2D) MRI full scans to help overcome these limitations. We incorporate feature-importance and self-attention methods into our model to improve the interpretability of this study. We evaluate our framework on paired low- and high-resolution brain MRI structural full scans (i.e., T1-, T2-weighted, and FLAIR sequences are simultaneously input) obtained in clinical and research settings from scanners manufactured by Siemens, Phillips, and GE. We show that the upsampled MRIs are qualitatively faithful to the ground-truth high-quality scans (PSNR = 35.39; MAE = 3.78E-3; NMSE = 4.32E-10; SSIM = 0.9852; mean normal-appearing gray/white matter ratio intensity differences ranging from 0.0363 to 0.0784 for FLAIR, from 0.0010 to 0.0138 for T1-weighted and from 0.0156 to 0.074 for T2-weighted sequences). The automatic raw segmentation of tissues and lesions using the super-resolved images has fewer false positives and higher accuracy than those obtained from interpolated images in protocols represented with more than three sets in the training sample, making our approach a strong candidate for practical application in clinical and collaborative research.

Associations of Peak-Width Skeletonized Mean Diffusivity and Post-Stroke Cognition.

Post-stroke cognitive impairment is common and can have major impact on life after stroke. Peak-width of Skeletonized Mean Diffusivity (PSMD) is a diffusion imaging marker of white matter microstructure and is also associated with cognition. Here, we examined associations between PSMD and post-stroke global cognition in an ongoing study of mild ischemic stroke patients. We studied cross-sectional associations between PSMD and cognition at both 3-months (N = 229) and 1-year (N = 173) post-stroke, adjusted for premorbid IQ, sex, age, stroke severity and disability, as well as the association between baseline PSMD and 1-year cognition. At baseline, (mean age = 65.9 years (SD = 11.1); 34% female), lower Montreal Cognitive Assessment (MoCA) scores were associated with older age, lower premorbid IQ and higher stroke severity, but not with PSMD (ßstandardized = −0.116, 95% CI −0.241, 0.009; p = 0.069). At 1-year, premorbid IQ, older age, higher stroke severity and higher PSMD (ßstandardized = −0.301, 95% CI −0.434, −0.168; p < 0.001) were associated with lower MoCA. Higher baseline PSMD was associated with lower 1-year MoCA (ßstandardized = −0.182, 95% CI −0.308, −0.056; p = 0.005). PSMD becomes more associated with global cognition at 1-year post-stroke, possibly once acute effects have settled. Additionally, PSMD in the subacute phase after a mild stroke could help predict long-term cognitive impairment.

Contribution of white matter hyperintensities to ventricular enlargement in older adults.

Lateral ventricles might increase due to generalized tissue loss related to brain atrophy. Alternatively, they may expand into areas of tissue loss related to white matter hyperintensities (WMH). We assessed longitudinal associations between lateral ventricle and WMH volumes, accounting for total brain volume, blood pressure, history of stroke, cardiovascular disease, diabetes and smoking at ages 73, 76 and 79, in participants from the Lothian Birth Cohort 1936, including MRI data from all available time points. Lateral ventricle volume increased steadily with age, WMH volume change was more variable. WMH volume decreased in 20% and increased in remaining subjects. Over 6 years, lateral ventricle volume increased by 3% per year of age, 0.1% per mm Hg increase in blood pressure, 3.2% per 1% decrease of total brain volume, and 4.5% per 1% increase of WMH volume. Over time, lateral ventricle volumes were 19% smaller in women than men. Ventricular and WMH volume changes are modestly associated and independent of general brain atrophy, suggesting that their underlying processes do not fully overlap.

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 T2-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.

Rationale and design of the brain magnetic resonance imaging protocol for FutureMS: a longitudinal multi-centre study of newly diagnosed patients with relapsing-remitting multiple sclerosis in Scotland.

Introduction: Multiple sclerosis (MS) is a chronic neuroinflammatory and neurodegenerative disease. MS prevalence varies geographically and is notably high in Scotland. Disease trajectory varies significantly between individuals and the causes for this are largely unclear. Biomarkers predictive of disease course are urgently needed to allow improved stratification for current disease modifying therapies and future targeted treatments aimed at neuroprotection and remyelination. Magnetic resonance imaging (MRI) can detect disease activity and underlying damage non-invasively in vivo at the micro and macrostructural level. FutureMS is a prospective Scottish longitudinal multi-centre cohort study, which focuses on deeply phenotyping patients with recently diagnosed relapsing-remitting MS (RRMS). Neuroimaging is a central component of the study and provides two main primary endpoints for disease activity and neurodegeneration. This paper provides an overview of MRI data acquisition, management and processing in FutureMS. FutureMS is registered with the Integrated Research Application System (IRAS, UK) under reference number 169955. Methods and analysis: MRI is performed at baseline (N=431) and 1-year follow-up, in Dundee, Glasgow and Edinburgh (3T Siemens) and in Aberdeen (3T Philips), and managed and processed in Edinburgh. The core structural MRI protocol comprises T1-weighted, T2-weighted, FLAIR and proton density images. Primary imaging outcome measures are new/enlarging white matter lesions (WML) and reduction in brain volume over one year. Secondary imaging outcome measures comprise WML volume as an additional quantitative structural MRI measure, rim lesions on susceptibility-weighted imaging, and microstructural MRI measures, including diffusion tensor imaging and neurite orientation dispersion and density imaging metrics, relaxometry, magnetisation transfer (MT) ratio, MT saturation and derived g-ratio measures. Conclusions: FutureMS aims to reduce uncertainty around disease course and allow for targeted treatment in RRMS by exploring the role of conventional and advanced MRI measures as biomarkers of disease severity and progression in a large population of RRMS patients in Scotland.

Relationship between inferior frontal sulcal hyperintensities on brain MRI, ageing and cerebral small vessel disease.

Raised signal in cerebrospinal fluid (CSF) on fluid-attenuated inversion recovery (FLAIR) may indicate raised CSF protein or debris and is seen in inferior frontal sulci on routine MRI. To explore its clinical relevance, we assessed the association of inferior frontal sulcal hyperintensities (IFSH) on FLAIR with demographics, risk factors, and small vessel disease markers in three cohorts (healthy volunteers, n=44; mild stroke patients, n=105; older community-dwelling participants from Lothian birth cohort 1936, n=101). We collected detailed clinical data, scanned all subjects on the same 3T MRI scanner and 3-dimensional FLAIR sequence and developed a scale to rate IFSH. In adjusted analyses, the IFSH score increased with age (per 10-year increase; OR 1.69; 95% CI, 1.42-2.02), and perivascular spaces score in centrum semiovale in stroke patients (OR 1.73; 95% CI, 1.13-2.69). Since glymphatic CSF clearance declines with age and drains partially via the cribriform plate to the nasal lymphatics, IFSH on 3T MRI may be a non-invasive biomarker of altered CSF clearance and justifies further research in larger, more diverse samples.

Sources of systematic error in DCE-MRI estimation of low-level blood-brain barrier leakage.

PURPOSE: Dynamic contrast-enhanced (DCE) -MRI with Patlak model analysis is increasingly used to quantify low-level blood-brain barrier (BBB) leakage in studies of pathophysiology. We aimed to investigate systematic errors due to physiological, experimental, and modeling factors influencing quantification of the permeability-surface area product PS and blood plasma volume vp , and to propose modifications to reduce the errors so that subtle differences in BBB permeability can be accurately measured. METHODS: Simulations were performed to predict the effects of potential sources of systematic error on conventional PS and vp quantification: restricted BBB water exchange, reduced cerebral blood flow, arterial input function (AIF) delay and B1+ error. The impact of targeted modifications to the acquisition and processing were evaluated, including: assumption of fast versus no BBB water exchange, bolus versus slow injection of contrast agent, exclusion of early data from model fitting and B1+ correction. The optimal protocol was applied in a cohort of recent mild ischaemic stroke patients. RESULTS: Simulation results demonstrated substantial systematic errors due to the factors investigated (absolute PS error ≤ 4.48 × 10-4 min-1 ). However, these were reduced (≤0.56 × 10-4 min-1 ) by applying modifications to the acquisition and processing pipeline. Processing modifications also had substantial effects on in-vivo normal-appearing white matter PS estimation (absolute change ≤ 0.45 × 10-4 min-1 ). CONCLUSION: Measuring subtle BBB leakage with DCE-MRI presents unique challenges and is affected by several confounds that should be considered when acquiring or interpreting such data. The evaluated modifications should improve accuracy in studies of neurodegenerative diseases involving subtle BBB breakdown.

Rationale and design of a longitudinal study of cerebral small vessel diseases, clinical and imaging outcomes in patients presenting with mild ischaemic stroke: Mild Stroke Study 3.

BACKGROUND: Cerebral small vessel disease is a major cause of dementia and stroke, visible on brain magnetic resonance imaging. Recent data suggest that small vessel disease lesions may be dynamic, damage extends into normal-appearing brain and microvascular dysfunctions include abnormal blood-brain barrier leakage, vasoreactivity and pulsatility, but much remains unknown regarding underlying pathophysiology, symptoms, clinical features and risk factors of small vessel disease.Patients and Methods: The Mild Stroke Study 3 is a prospective observational cohort study to identify risk factors for and clinical implications of small vessel disease progression and regression among up to 300 adults with non-disabling stroke. We perform detailed serial clinical, cognitive, lifestyle, physiological, retinal and brain magnetic resonance imaging assessments over one year; we assess cerebrovascular reactivity, blood flow, pulsatility and blood-brain barrier leakage on magnetic resonance imaging at baseline; we follow up to four years by post and phone. The study is registered ISRCTN 12113543. SUMMARY: Factors which influence direction and rate of change of small vessel disease lesions are poorly understood. We investigate the role of small vessel dysfunction using advanced serial neuroimaging in a deeply phenotyped cohort to increase understanding of the natural history of small vessel disease, identify those at highest risk of early disease progression or regression and uncover novel targets for small vessel disease prevention and therapy.

Brain network reorganisation and spatial lesion distribution in systemic lupus erythematosus.

OBJECTIVE: This work investigates network organisation of brain structural connectivity in systemic lupus erythematosus (SLE) relative to healthy controls and its putative association with lesion distribution and disease indicators. METHODS: White matter hyperintensity (WMH) segmentation and connectomics were performed in 47 patients with SLE and 47 healthy age-matched controls from structural and diffusion MRI data. Network nodes were divided into hierarchical tiers based on numbers of connections. Results were compared between patients and controls to assess for differences in brain network organisation. Voxel-based analyses of the spatial distribution of WMH in relation to network measures and SLE disease indicators were conducted. RESULTS: Despite inter-individual differences in brain network organization observed across the study sample, the connectome networks of SLE patients had larger proportion of connections in the peripheral nodes. SLE patients had statistically larger numbers of links in their networks with generally larger fractional anisotropy weights (i.e. a measure of white matter integrity) and less tendency to aggregate than those of healthy controls. The voxels exhibiting connectomic differences were coincident with WMH clusters, particularly the left hemisphere's intersection between the anterior limb of the internal and external capsules. Moreover, these voxels also associated more strongly with disease indicators. CONCLUSION: Our results indicate network differences reflective of compensatory reorganization of the neural circuits, reflecting adaptive or extended neuroplasticity in SLE.

The Application of Optical Coherence Tomography Angiography in Cerebral Small Vessel Disease, Ischemic Stroke, and Dementia: A Systematic Review.

Objective: To investigate the application of optical coherence tomography angiography (OCTA) in cerebral small vessel disease (SVD), ischemic stroke and dementia. Methods: We conducted a systematic search in MEDLINE (from inception) and EMBASE (from 1980) to end 2019 for human studies that measured retinal parameters in cerebral SVD, ischemic stroke, and dementia using OCTA. Results: Fourteen articles (n = 989) provided relevant data. Ten studies included patients with Alzheimer disease (AD) and mild cognitive impairment (n = 679), two investigated pre-symptomatic AD participants (n = 154), and two investigated monogenic SVD patients with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (n = 32) and Fabry disease (n = 124). Methods to reduce bias and risk factor adjustment were poorly reported. Substantial methodological variations between studies precluded a formal meta-analysis. Quantitative measurements revealed significant yet inconclusive changes in foveal avascular zone, perfusion density, and vessel density (VD) in AD, presymptomatic AD, and SVD patients. Two (n = 160) of three studies (n = 192) showed association between decreased VD and increased white matter hyperintensities. In three (n = 297) of seven studies (n = 563), better cognitive function was associated with increased VD. One study (n = 52) suggested increased VD was associated with increased ganglion cell-inner plexiform layer thickness in AD yet with no covariate adjustment. Conclusions: Changes in retinal microvasculature identified using OCTA are associated with monogenic SVD and different stages of AD, but data are limited and partly confounded by methodological differences. Larger studies with risk factors adjustment and more consistent OCTA methods are needed to fully exploit this technology. PROSPERO registration number: CRD42020166929.

Dietary patterns, cognitive function, and structural neuroimaging measures of brain aging.

OBJECTIVE: To examine the cross-sectional associations between dietary patterns and cognitive and neuroimaging indices of brain health concurrently in the same sample of healthy older adults. METHODS: Dietary patterns were derived from a 130-item food frequency questionnaire for 511 individuals in the Lothian Birth Cohort 1936 (mean age 79.3 ± 0.6 years). Composite scores for global cognitive function, visuospatial ability, processing speed, memory, and verbal ability were assessed. Brain volumes and white matter microstructure were assessed in participants (n = 358) who also underwent structural magnetic resonance imaging. RESULTS: A Mediterranean-style dietary pattern and a processed dietary pattern were identified using principal component analysis of food frequency questionnaire items. In fully-adjusted linear regression models, adherence to the Mediterranean-style pattern was associated with better verbal ability (ß = 0.121, P = 0.002). Associations with global cognitive function (ß = 0.094, P = 0.043), visuospatial ability (ß = 0.113, P = 0.019), and memory (ß = 0.105, P = 0.029) did not survive correction for multiple comparisons. Associations between the processed pattern and lower cognitive scores were attenuated by around 50% following adjustment for prior (childhood) cognitive ability; only an association with verbal ability remained (ß = -0.130, P = 0.001). Neither dietary pattern was associated with brain volumes or white matter microstructure. Specific Mediterranean diet features-green leafy vegetables and a low intake of red meat-were associated with better cognitive functioning. CONCLUSIONS: These observational findings suggest that adherence to a Mediterranean-style diet is associated with better cognitive functioning, but not better brain structural integrity, in older adults.