Robert A. Brown

Diurnal fluctuations in brain volume: Statistical analyses of MRI from large populations.

We investigated fluctuations in brain volume throughout the day using statistical modeling of magnetic resonance imaging (MRI) from large populations. We applied fully automated image analysis software to measure the brain parenchymal fraction (BPF), defined as the ratio of the brain parenchymal volume and intracranial volume, thus accounting for variations in head size. The MRI data came from serial scans of multiple sclerosis (MS) patients in clinical trials (n=755, 3269 scans) and from subjects participating in the Alzheimers Disease Neuroimaging Initiative (ADNI, n=834, 6114 scans). The percent change in BPF was modeled with a linear mixed effect (LME) model, and the model was applied separately to the MS and ADNI datasets. The LME model for the MS datasets included random subject effects (intercept and slope over time) and fixed effects for the time-of-day, time from the baseline scan, and trial, which accounted for trial-related effects (for example, different inclusion criteria and imaging protocol). The model for ADNI additionally included the demographics (baseline age, sex, subject type [normal, mild cognitive impairment, or Alzheimers disease], and interaction between subject type and time from baseline). There was a statistically significant effect of time-of-day on the BPF change in MS clinical trial datasets (-0.180 per day, that is, 0.180% of intracranial volume, p=0.019) as well as the ADNI dataset (-0.438 per day, that is, 0.438% of intracranial volume, p<0.0001), showing that the brain volume is greater in the morning. Linearly correcting the BPF values with the time-of-day reduced the required sample size to detect a 25% treatment effect (80% power and 0.05 significance level) on change in brain volume from 2 time-points over a period of 1year by 2.6%. Our results have significant implications for future brain volumetric studies, suggesting that there is a potential acquisition time bias that should be randomized or statistically controlled to account for the day-to-day brain volume fluctuations.

Correlation between brain volume change and T2 relaxation time induced by dehydration and rehydration: implications for monitoring atrophy in clinical studies.

Brain volume change measured from magnetic resonance imaging (MRI) provides a widely used and useful in vivo measure of irreversible tissue loss. These measurements, however, can be influenced by reversible factors such as shifts in brain water content. Given the strong effect of water on T2 relaxation, we investigated whether an estimate of T2 relaxation time would correlate with brain volume changes induced by physiologically manipulating hydration status. We used a clinically feasible estimate of T2 (“pseudo-T2”) computed from a dual turbo spin-echo MRI sequence and correlated pseudo-T2 changes to percent brain volume changes in 12 healthy subjects after dehydration overnight (16-hour thirsting) and rehydration (drinking 1.5 L of water). We found that the brain volume significantly increased between the dehydrated and rehydrated states (mean brain volume change = 0.36%, p = 0.0001) but did not change significantly during the dehydration interval (mean brain volume change = 0.04%, p = 0.57). The changes in brain volume and pseudo-T2 significantly correlated with each other, with marginal and conditional correlations (R2) of 0.44 and 0.65, respectively. Our results show that pseudo-T2 may be used in conjunction with the measures of brain volume to distinguish reversible water fluctuations and irreversible brain tissue loss (atrophy) and to investigate disease mechanisms related to neuro-inflammation, e.g., in multiple sclerosis, where edema-related water fluctuations may occur with disease activity and anti-inflammatory treatment.

Segmentation of magnetization transfer ratio lesions for longitudinal analysis of demyelination and remyelination in multiple sclerosis.

We demonstrate a new technique to quantify longitudinal changes in magnetization transfer ratio (MTR) magnetic resonance imaging (MRI). These changes are indicative of demyelination and remyelination. This technique comprises a definition of ΔMTR lesions, which are identified directly from the MTR images, and an automatic procedure for segmenting these lesions. We used this technique to analyze MTR changes in lesions of subjects with rapidly progressing multiple sclerosis before and after treatment with immunoablation and autologous stem cell transplant. Subjects who experienced clinical improvement after treatment showed significantly improved MTR recovery in lesions that were recovering during treatment (p<0.0001) while those who were clinically stable after treatment showed significantly poorer MTR recovery (p=0.002). The statistical power of this technique to detect treatment effects on MTR recovery was shown to be considerably better than previous methods. These results suggest that longitudinal measurements of MTR in ΔMTR lesions may be an important technique for the assessment of treatment effects on remyelination in clinical trials.

Imaging of repeated episodes of demyelination and remyelination in multiple sclerosis

Multiple sclerosis (MS) is characterized by the formation of demyelinating lesions in the white matter (WM). However, the timecourse of the evolution of healthy white matter into fully demyelinated lesions in MS is not well understood. We use a recently proposed technique to examine magnetization transfer ratio (MTR) timecourses in lesions segmented from MTR images in patients with relapsing–remitting MS (RRMS) and secondary progressive MS (SPMS). In both groups we found MTR lesions forming both in previously normal appearing WM (de novo lesions) as well as in previously lesional tissue that appears to be experiencing a second round of inflammatory demyelination (repeat lesions). Both de novo and repeat lesions exhibited significant, but incomplete MTR recovery, suggesting partial remyelination; post-lesion MTR values in de novo lesions were similar to pre-lesion values in repeat lesions. Both de novo and repeat lesions were found in subjects in relapsing–remitting and secondary progressive stages of MS, and repeat lesions appeared relatively more common in the secondary progressive phase. These observations support the hypothesis that entirely demyelinated lesions found on histopathology are the result of multiple episodes of demyelination and incomplete remyelination, and may have implications for MS treatment development efforts aimed at neuroprotection and enhancing remyelination.

Magnetization transfer ratio recovery in new lesions decreases during adolescence in pediatric-onset multiple sclerosis patients

Children and adolescents diagnosed with multiple sclerosis rarely accrue physical disability early in their disease. This could be explained by greater remyelination in children, a capacity that may be lost in adolescence or early adulthood. Magnetization transfer ratio (MTR) MRI can be used to quantify changes in myelin in MS. We used serial MTR imaging and longitudinal random effects analysis to quantify recovery of MTR in acute lesions and to evaluate MTR changes in normal-appearing tissue in 19 adolescent MS patients. Our objective was to determine whether younger adolescents have a greater capacity for remyelination and whether this decreases as patients approach adulthood. We detected a significant decrease in MTR recovery between ages 16 and 20 years (p = 0.023), with older subjects approaching typical recovery levels for adult-onset MS. MTR recovery in acute MS lesions decreases with age in adolescents, suggesting loss of remyelination capacity. This may be related to the conclusion of primary myelination or other developmental factors.

Brain atrophy after bone marrow transplantation for treatment of multiple sclerosis.

Background: A cohort of patients with poor-prognosis multiple sclerosis (MS) underwent chemotherapy-based immune ablation followed by immune reconstitution with an autologous hematopoietic stem cell transplant (IA/aHSCT). This eliminated new focal inflammatory activity, but resulted in early acceleration of brain atrophy. Objective: We modeled the time course of whole-brain volume in 19 patients to identify the baseline predictors of atrophy and to estimate the average rate of atrophy after IA/aHSCT. Methods: Percentage whole-brain volume changes were calculated between the baseline and follow-up magnetic resonance imaging (MRI; mean duration: 5 years). A mixed-effects model was applied using two predictors: total busulfan dose and baseline volume of T1-weighted white-matter lesions. Results: Treatment was followed by accelerated whole-brain volume loss averaging 3.3%. Both the busulfan dose and the baseline lesion volume were significant predictors. The atrophy slowed progressively over approximately 2.5 years. There was no evidence that resolution of edema contributed to volume loss. The mean rate of long-term atrophy was −0.23% per year, consistent with the rate expected from normal aging. Conclusion: Following IA/aHSCT, MS patients showed accelerated whole-brain atrophy that was likely associated with treatment-related toxicity and degeneration of “committed” tissues. Atrophy eventually slowed to that expected from normal aging, suggesting that stopping inflammatory activity in MS can reduce secondary degeneration and atrophy.

White matter changes in paediatric multiple sclerosis and monophasic demyelinating disorders.

See Hacohen et al. (doi:10.1093/awx075) for a scientific commentary on this article. Most children who experience an acquired demyelinating syndrome of the central nervous system will have a monophasic disease course, with no further clinical or radiological symptoms. A subset will be diagnosed with multiple sclerosis, a life-long disorder. Using linear mixed effects models we examined longitudinal diffusion properties of normal-appearing white matter in 505 serial scans of 132 paediatric participants with acquired demyelinating syndromes followed for a median of 4.4 years, many from first clinical presentation, and 106 scans of 80 healthy paediatric participants. Fifty-three participants with demyelinating syndromes eventually received a diagnosis of paediatric-onset multiple sclerosis. Diffusion tensor imaging measures properties of water diffusion through tissue, which normally becomes increasingly restricted and anisotropic in the brain during childhood and adolescence, as fibre bundles develop and myelinate. In the healthy paediatric participants, our data demonstrate the expected trajectory of more restricted and anisotropic white matter diffusivity with increasing age. However, in participants with multiple sclerosis, fractional anisotropy decreased and mean diffusivity of non-lesional, normal-appearing white matter progressively increased after clinical presentation, suggesting not only a failure of age-expected white matter development but also a progressive loss of tissue integrity. Surprisingly, patients with monophasic disease failed to show age-expected changes in diffusion parameters in normal-appearing white matter, although they did not show progressive loss of integrity over time. Further analysis demonstrated that participants with monophasic disease experienced different post-onset trajectories in normal-appearing white matter depending on their presenting phenotype: those with acute disseminated encephalomyelitis demonstrated abnormal trajectories of diffusion parameters compared to healthy paediatric participants, as did patients with non-acute disseminated encephalomyelitis presentations associated with lesions in the brain at onset. Patients with monofocal syndromes such as optic neuritis, transverse myelitis, or isolated brainstem syndromes in whom multifocal brain lesions were absent, showed trajectories more closely approximating normal-appearing white matter development. Our findings also suggest the existence of sexual dimorphism in the effects of demyelinating syndromes on normal-appearing white matter development. Overall, we demonstrate failure of white matter maturational changes and progressive loss of white matter integrity in paediatric-onset multiple sclerosis, but also show that even a single demyelinating attack-when associated with white matter lesions in the brain-negatively impacts subsequent normal-appearing white matter development.

Quantitative Measurement of tissue damage and recovery within new T2w lesions in pediatric- and adult-onset multiple sclerosis.

Background: Children and adolescents with relapsing–remitting multiple sclerosis (RRMS) have a similar T2 lesion burden as adults matched for disease duration. However, it is unknown whether the degree of tissue destruction within lesions is also similar. Persistent reduced T1-weighted signal intensity within lesions indicates loss of tissue integrity. Objective: We aimed to compare change over a 2-year period in T1 intensity within new T2 lesions, from pre-lesion levels to chronic post-lesion levels, between pediatric and adult-onset MS. Methods: A two-point intensity-normalization method was used to generate normalized T1-weighted (NT1) images from T1-weighted data in 29 pediatric MS patients (age(mean±SD, years), disease duration (years)=15.7±2.4, 3.9±2.6) and 24 adult MS patients (36.7±8.9, 6.9±4.8). Subjects were imaged at three consecutive timepoints, 1 year apart. For each subject, a ‘new-T2’ lesion mask was created and the NT1 intensities ‘pre-lesion’, ‘peri-lesion’ and ‘post-lesion’ were determined. A longitudinal model was used to capture NT1 changes. Results: The NT1 in both groups failed to recover to pre-lesion values by 1 year post-lesion (p=0.0002), with children showing significantly better recovery than adults (p=0.0089). Conclusions: Both groups showed a significant chronic reduction of T1 intensity within new T2 lesions. However, children showed a significantly greater recovery of T1 intensity, suggesting that MS lesions in the pediatric MS population are less destructive, or that pediatric patients have greater reparative capacity.

MTR recovery in brain lesions in the BECOME study of glatiramer acetate vs interferon β-1b

Objective: To compare magnetization transfer changes in new brain MRI lesions identified during monthly imaging in patients with multiple sclerosis (MS) randomized to treatment with 250 μg subcutaneous interferon-β-1b (IFN-β-1b) every other day or daily 20 mg glatiramer acetate (GA) in a post hoc study using data from the Betaseron Versus Copaxone for Relapsing Remitting or CIS Forms of MS Using Triple Dose Gad 3 T MRI (BECOME) trial. Methods: T1-weighted images acquired with and without fat saturation pulses in the BECOME study were evaluated and found to exhibit magnetization transfer ratio (MTR) effects, and were used to compute MTR images (FSMTR). Forty-three participants who had the required imaging and new lesions, from the 75 originally randomized into the BECOME study, were included in this post hoc analysis and evaluated longitudinally during treatment to determine FSMTRDrop, an experimental measure of the completeness of FSMTR recovery in new lesions. Two sets of new brain MRI lesions were defined, one based on the appearance of gadolinium contrast enhancement (Gd lesions) and the other based on FSMTR decreases (ΔFSMTR lesions). Results: A total of 887 Gd lesions were identified in 43 participants (19 GA, 24 IFN-β-1b) and 321 ΔFSMTR lesions in 32 participants (16 GA, 16 IFN-β-1b). Participants randomized to GA exhibited greater average postlesion FSMTR recovery than did those randomized to IFN-β-1b in both Gd (p < 0.0001) and ΔFSMTR (p < 0.0001) lesions. Conclusions: New brain lesions that developed during treatment with GA exhibited evidence of greater FSMTR recovery than during treatment with IFN-β-1b. Classification of evidence: This study provides Class III evidence that MTR recovery in patients with MS with new MRI brain lesions is greater with GA than with IFN-β-1b.

Normalization of White Matter Intensity on T1-Weighted Images of Patients with Acquired Central Nervous System Demyelination

Intensity variation between magnetic resonance images (MRI) hinders comparison of tissue intensity distributions in multicenter MRI studies of brain diseases. The available intensity normalization techniques generally work well in healthy subjects but not in the presence of pathologies that affect tissue intensity. One such disease is multiple sclerosis (MS), which is associated with lesions that prominently affect white matter (WM).