Early brain pseudoatrophy while on natalizumab therapy is due to white matter volume changes

Background: Investigation of atrophy data from a pivotal natalizumab trial has demonstrated an increased rate of volume loss, compared to placebo, after the first year of therapy. It was considered to be probably due to a pseudoatrophy effect. Objective: To assess grey and white matter volume changes and their relation to global brain volume changes and to baseline inflammation, for patients under natalizumab therapy. Methods: We selected 45 patients on natalizumab therapy for at least 24 months, with magnetic resonance imaging (MRI) scans at baseline, 12 and 24 months. We calculated the percentage brain volume change (PBVC) for the first and second year, using SIENA software. Grey and white matter fractions (GMF and WMF, respectively) for the first year were calculated with SPM5, using lesion masks. After quality checks, six patients were excluded. We studied the predictive variables of change in brain volumes. Results: The PBVC decrease was faster during the first year (−1.10% ± 1.43%), as compared to the second (−0.51% ± 0.96%) ( p = 0.037). These differences were more marked in patients with baseline gadolinium-enhancing lesions ( p = 0.005). Mean GMF and WMF changes during the first year of treatment were +1.15% (n.s.) and −1.72% ( p = 0.017), respectively. The presence of active lesions at baseline MRI predicted PBVC ( p = 0.022) and WMF change ( p = 0.026) during the first year of treatment, after adjusting for age and corticosteroid treatment. No predictors were found for GMF volume changes. Conclusion: Early brain volume loss during natalizumab therapy is mainly due to WMF volume loss and it is related to the inflammatory activity present at the onset of therapy. We found that the pseudoatrophy effect is mostly due to white matter volume changes.

Download Full-text

Brain volume reductions in medication-naive patients with schizophrenia in relation to intelligence quotient

Psychological Medicine ◽

10.1017/s0033291712000098 ◽

2012 ◽

Vol 42 (9) ◽

pp. 1847-1856 ◽

Cited By ~ 20

Author(s):

M. Rais ◽

W. Cahn ◽

H. G. Schnack ◽

H. E. Hulshoff Pol ◽

R. S. Kahn ◽

...

Keyword(s):

White Matter ◽

Healthy Subjects ◽

Intelligence Quotient ◽

Brain Volume ◽

First Episode ◽

Volume Loss ◽

White Matter Volume ◽

Matter Volume ◽

Brain Volume Loss ◽

First Episode Schizophrenia

BackgroundGlobal brain abnormalities such as brain volume loss and grey- and white-matter deficits are consistently reported in first-episode schizophrenia patients and may already be detectable in the very early stages of the illness. Whether these changes are dependent on medication use or related to intelligence quotient (IQ) is still debated.MethodMagnetic resonance imaging scans were obtained for 20 medication-naive patients with first-episode schizophrenia and 26 matched healthy subjects. Volume measures of total brain grey and white matter, third and lateral ventricles and cortical thickness/surface were obtained. Differences between the groups were investigated, taking into account the effect of intelligence.ResultsMedication-naive patients showed statistically significant reductions in whole-brain volume and cerebral grey- and white-matter volume together with lateral ventricle enlargement compared to healthy subjects. IQ was significantly lower in patients compared to controls and was positively associated with brain and white-matter volume in the whole group. No significant differences in cortical thickness were found between the groups but medication-naive patients had a significantly smaller surface in the left superior temporal pole, Heschl's gyrus and insula compared to controls.ConclusionsOur findings suggest that brain volume loss is present at illness onset, and can be explained by the reduced surface of the temporal and insular cortex. These abnormalities are not related to medication, but IQ.

Download Full-text

Causal effect of atrial fibrillation on brain white or grey matter volume: A Mendelian randomization study

10.1101/2020.12.17.20248314 ◽

2020 ◽

Author(s):

Sehoon Park ◽

Soojin Lee ◽

Yaerim Kim ◽

Semin Cho ◽

Kwangsoo Kim ◽

...

Keyword(s):

Atrial Fibrillation ◽

White Matter ◽

Grey Matter ◽

Mendelian Randomization ◽

Brain Volume ◽

Causal Effect ◽

Grey Matter Volume ◽

Volume Loss ◽

White Matter Volume ◽

Matter Volume

AbstractBackgroundAtrial fibrillation (AF) and brain volume loss are prevalent in older individuals. Further study investigating the causal effect of AF on brain volume is warranted.MethodsThis study was a Mendelian randomization (MR) analysis. The genetic instrument for AF was constructed from a previous genome-wide association study (GWAS) meta-analysis and included 537,409 individuals of European ancestry. The outcome summary statistics for quantile-normalized white or grey matter volume measured by magnetic resonance imaging were provided by the previous GWAS of 8426 white British UK Biobank participants. The main MR method was the inverse variance weighted method, supported by sensitivity MR analysis including MR-Egger regression and the weighted median method. The causal estimates from AF to white or grey matter volume were further adjusted for effects of any stroke or ischemic stroke by multivariable MR analysis.ResultsA higher genetic predisposition for AF (one standard deviation increase) was significantly associated with lower white matter volume [beta −0.128 (−0.208, −0.048)] but not grey matter volume [beta −0.041 (−0.101, 0.018)], supported by all utilized sensitivity MR analyses. The multivariable MR analysis indicated that AF is causally linked to lower white matter volume independent of the stroke effect.ConclusionsAF is a causative factor for white matter volume loss. The effect of AF on grey matter volume was inapparent in this study. A future trial is necessary to confirm whether appropriate AF management can be helpful in preventing cerebral white matter volume loss or related brain disorders in AF patients.

Download Full-text

NIMG-55. A QUANTITATIVE ANALYSIS OF BRAIN VOLUME DYNAMICS IN PCNSL PATIENTS TREATED WITH HIGH-DOSE METHOTREXATE-BASED THERAPY

Neuro-Oncology ◽

10.1093/neuonc/noaa215.668 ◽

2020 ◽

Vol 22 (Supplement_2) ◽

pp. ii160-ii160

Author(s):

Ananyaa Sivakumar ◽

David Kamson ◽

Fayez Estephan ◽

Sebastian Lambrecht ◽

Omar Dzaye ◽

...

Keyword(s):

White Matter ◽

Brain Volume ◽

Primary Cns Lymphoma ◽

Cns Lymphoma ◽

High Dose ◽

High Dose Methotrexate ◽

Volume Loss ◽

Brain Volumes ◽

Brain Volume Loss ◽

Dose Methotrexate

Abstract BACKGROUND Primary CNS lymphoma (PCNSL) is a rare, infiltrative disease. High-dose methotrexate (HD-MTX) is the backbone of induction regimens for PCNSL. While MTX-associated white matter changes are well-described, treatment-related brain volume loss is much less understood, especially in radiotherapy-naïve cohorts. Here, we aimed to longitudinally quantify the rates of brain volume loss in PCNSL patients treated with HD-MTX. SUBJECTS/METHODS We included 12 radiotherapy-naïve patients (age mean±SD 61±15y, range 37-84y, 9F) with histopathologically confirmed PCNSL who received HD-MTX induction (mean±SD 12±4 cycles, range 8-18) +/-rituximab. MRIs were collected from within 1 month of HD-MTX initiation until the end of follow-up (mean±SD: 3.7±2.9y). Longitudinal whole-brain segmentation was performed on FLAIR images using the Sequence Adaptive Multimodal Segmentation tool of FreeSurfer. Brain volumes were normalized to the initial scan, white matter lesion volumes were normalized to cerebral volume (nWML). RESULTS The average rate of cerebral volume change was -2.1±1.9%/year. Half of patients showed marked cerebral volume loss in the first year (-5.6±1.4% vs. -2.0±1.4%; n=10; p=0.003) with the most prominent change occurring within 6-months of treatment initiation (-4.2±1.7% vs. -0.5±1.6; n=12; p=0.004). Cerebral volume loss reached a plateau after the 1-year mark in both groups (0.3±0.8%/year vs. 1.4±3.3%/year; n=8; p=0.4). Patients younger than 61 years exhibited markedly higher rates of cerebral volume loss (-6.2±1.1%/year vs. 2.4±1.5%/year p=0.003), which was corroborated by strong inverse correlation between age and cerebral volume loss (Pearson’s r=-0.82, p=0.004). Neither the cerebellar volume, nor the nWML load correlated with age. CONCLUSION In the present cohort, brain volume loss was approximately four-fold higher than what is described in the healthy aging. Younger patients treated with HD-MTX exhibited more severe cerebral volume loss, which may be due to higher initial brain volume reserve. Detailed analyses of a larger sample are underway.

Download Full-text

Childhood multiple sclerosis is associated with reduced brain volumes at first clinical presentation and brain growth failure

Multiple Sclerosis Journal ◽

10.1177/1352458519829698 ◽

2019 ◽

Vol 25 (7) ◽

pp. 927-936 ◽

Cited By ~ 8

Author(s):

Frederik Bartels ◽

Katharina Nobis ◽

Graham Cooper ◽

Eva Wendel ◽

Robert Cleaveland ◽

...

Keyword(s):

Multiple Sclerosis ◽

White Matter ◽

Clinical Presentation ◽

Brain Volume ◽

Volume Loss ◽

Brain Growth ◽

Whole Brain ◽

Brain Volumes ◽

Brain Volume Loss

Background: Paediatric multiple sclerosis (pedMS) patients at a single site were shown to have reduced brain volumes and failure of age-expected brain growth compared to healthy controls. However, the precise time of onset of brain volume loss remains unclear. Objective: To longitudinally study brain volumes in a multi-centre European cohort at first presentation and after 2 years. Methods: Brain volumes of high-resolution magnetic resonance imaging (MRI) data from 37 pedMS patients at first presentation prior to steroid therapy and at 2-year follow-up ( n = 21) were compared to matched longitudinal MRI data from the NIH Paediatric MRI Data Repository. Results: Patients showed significantly reduced whole brain, grey and white matter and increased ventricular volumes at initial presentation and at follow-up compared to controls. Over 2 years, patients exhibited significant reduction of whole brain and white matter volumes, accompanied by increased ventricular volume. Brain volume loss at follow-up correlated with a higher number of infratentorial lesions, relapses and an increased Expanded Disability Status Scale (EDSS) score. Conclusions: In pedMS patients, brain volume loss is present already at first clinical presentation and accelerated over 2 years. Increased disease activity is associated with more severe brain volume loss. MRI brain volume change might serve as an outcome parameter in future prospective pedMS studies.

Download Full-text

White Matter is Increased in the Brains of Adults With Neurofibromatosis 1

10.21203/rs.3.rs-898452/v1 ◽

2021 ◽

Author(s):

Su Wang ◽

Jan M. Friedman ◽

Per Suppa ◽

Ralph Buchert ◽

Victor-Felix Mautner

Keyword(s):

White Matter ◽

Grey Matter ◽

Brain Volume ◽

Neurofibromatosis 1 ◽

Brain Morphology ◽

White Matter Volume ◽

Total Brain Volume ◽

Brain Volumes ◽

Matter Volume ◽

Total Brain

Abstract Background: Neurofibromatosis 1 (NF1) is a rare autosomal dominant disease characterized by increased Schwann cell proliferation in peripheral nerves. Several small studies of brain morphology in children with NF1 have found increased total brain volume, total white matter volume and/or corpus callosum area. Several studies (mostly in children with NF1) also attempted to correlate changes in brain morphology and volume with cognitive or behavioural abnormalities, though findings were inconsistent. We aimed to characterize alterations in brain volumes by three-dimensional (3D) MRI in adults with NF1 in major intracranial sub-regions. We also aimed to assess the effect of age on these volumes and correlated brain white matter and grey matter volumes with neuropsychometric findings in adults with NF1.Methods: We obtained brain volume measurements using 3D magnetic resonance imaging for 351 adults with NF1 and, as a comparison group, 43 adults with neurofibromatosis 2 (NF2) or Schwannomatosis. We assessed a subset of 19 adults with NF1 for clinical severity of NF1 features and neurological problems and conducted psychometric testing for attention deficiencies and intelligence quotient. We compared brain volumes between NF1 patients and controls and correlated volumetric measurements to clinical and psychometric features in the NF1 patients. Results:Total brain volume and total and regional white matter volumes were all significantly increased in adults with NF1. Grey matter volume decreased faster with age in adults with NF1 than in controls. Greater total brain volume and white matter volume were correlated with lower attention deficits and higher intelligence quotients in adults with NF1.Conclusion:Our findings are consistent with the hypothesis that dysregulation of brain myelin production is a cardinal manifestation of NF1 and that these white matter changes may be functionally important in affected adults.

Download Full-text

Trajectories of brain volume change over 13 years in chronic schizophrenia

10.1101/2019.12.17.879429 ◽

2019 ◽

Author(s):

Claudia Barth ◽

Kjetil N. Jørgensen ◽

Laura A. Wortinger ◽

Stener Nerland ◽

Erik G. Jönsson ◽

...

Keyword(s):

Volume Change ◽

Brain Volume ◽

Chronic Schizophrenia ◽

Volume Loss ◽

Total Brain Volume ◽

Brain Volumes ◽

Matter Volume ◽

Brain Volume Loss ◽

Total Brain

AbstractImportanceSchizophrenia is a leading cause of disability worldwide, with an illness course that putatively deteriorates over time. Whether the notion of a progressive brain disease holds in its chronic stage is debated.ObjectiveTo investigate brain volume change and the impact of iatrogenic factors in chronic schizophrenia patients (duration of illness at baseline 16.17 ± 8.14 years) and controls over 13 years.DesignParticipants were recruited as part of the Human Brain Informatics study. Data acquisition took place between 1999 and 2018, including baseline, 5- and 13-years follow-up.SettingNaturalistic longitudinal case-control study.ParticipantsThe sample consisted of 143 participants, of whom 64 were patients with chronic schizophrenia (20% female, mean age at baseline 40.5 ± 7.7 years) and 79 healthy controls (37% female, mean age at baseline 42.8 ± 8.4 years). T1-weighted structural imaging and information about medication use were obtained at each time point.ExposureAntipsychotic medication and other prescribed drugs.Main Outcome(s) and Measure(s)Individual total and tissue-specific brain volumes, as well as two-time point percentage brain and ventricle volume change.ResultsPatients had lower total brain volume at baseline. Yet, trajectories in total brain volume and gray matter volume loss as well as ventricular enlargement did not differ relative to controls. White matter volume was similar between groups at baseline and 5-year but diverged between 5-year and 13-year follow-up, with accelerated loss in patients. While antipsychotic exposure did not show an association with brain volume loss over time, higher medication load was associated with lower brain volume across time points. Patients on second-generation antipsychotics alone showed lowest total brain volume, only after accounting for add-on drug use.Conclusion and RelevanceWe found limited evidence for progressive brain volume loss in chronic schizophrenia, beyond normal aging. Stable differences in patient brain volumes relative to controls may primarily occur during the first years of illness. All prescribed drugs need to be considered when examining the impact of antipsychotic medication on brain structure.Key PointsQuestionIs chronic schizophrenia associated with progressive brain volume loss beyond normal aging?FindingsWhile brain volume was lower at baseline, patient trajectories of brain volume change over a 13-year follow-up period differed little from healthy individuals. Small effects indicated greater white matter volume loss in patients during the late phase of follow-up. Stable differences in patient brain volumes seem explicable by antipsychotic medication class and respective add-on drugs.MeaningWe found limited evidence of progressive brain volume loss, beyond normal aging, in chronic schizophrenia over 13 years.

Download Full-text

Hemoglobin Level and Platelet Size Predicts Grey and White Matter Volume Loss Measured By Tensor Based Morphology in Sickle Cell Disease

Blood ◽

10.1182/blood.v128.22.2481.2481 ◽

2016 ◽

Vol 128 (22) ◽

pp. 2481-2481

Author(s):

Soyoung Choi ◽

Adam M Bush ◽

Matt Borzage ◽

Anand Joshi ◽

Thomas D. Coates ◽

...

Keyword(s):

White Matter ◽

Grey Matter ◽

Brain Volume ◽

Laboratory Data ◽

Volume Loss ◽

White Matter Volume ◽

Cell Disease ◽

Chronic Anemia ◽

Brain Morphometry ◽

Matter Volume

Abstract Background: Sickle cell disease (SCD) is a life-threatening genetic disease whose patients suffer from chronic anemia, hemolysis, vascular damage, and impaired cerebral blood flow that lead to early and cumulative neurological insults. Adverse effects associated with chronic anemia and hemolysis in SCD include progressive large vessel vasculopathy, stroke, silent cerebral infarctions, and ultimately, early mortality. Few studies have attempted to characterize the effects of this disease on brain morphometry and most have been limited to school age children, despite the progressive nature of the cerebrovascular disease. Thus, this study aims to quantify the hematological effects of SCD on brain morphometry in adolescents and young adults. Methods: 3D T1-weighted images (TE =3.8ms TR =8.3ms; resolution = 1mm3) were acquired on 25 clinically asymptomatic SCD patients (age=20.8 ± 6.7; F=13, M=12) and 26 ethnically matched control subjects (age=26.4 ± 7.7; F=17, M=9). MRI data were acquired on a 3T Philips Achieva (v.3.2.1) using an 8-channel head coil. All patients were recruited with informed consent or assent; the study was approved by the Institutional Review Board at Children's Hospital Los Angeles (CCI#11-00083). Exclusion criteria included pregnancy, previous overt stroke, acute chest, or pain crisis hospitalization within one month. T1-weighted images were processed using BrainSuite (brainsuite.org) in a semi-automated fashion to calculate whole brain gray matter volume (GMV), and white matter volume (WMV). Stepwise multivariate regression analysis was run on GMV and WMV against laboratory data and vital signs to find predictors of total brain volume. Laboratory data probed including complete blood counts and indices, quantitative hemoglobin electrophoresis, and markers of hemolysis (LDH, reticulocyte count, cell free hemoglobin). After correcting for age and sex, the remaining predictors of grey and white matter volume were used to probe for regional changes in brain volume through tensor based morphometry (Brain Suite Statistics Toolbox). Results: White matter, but not grey matter, was diffusely smaller in SCD patients. Sex, age (log transformed) and mean platelet volume (MPV) were the parameters retained in the multivariate model to predict GMV (r2=0.65; F ratio=28.9) where MPV had a positive correlation to GMV. Hemoglobin, sex, and MPV were found as predictors of WMV (r2=0.43; F ratio = 11.8) where both hemoglobin and MPV had a positive correlation to WMV. Using tensor based morphometry (TBM), both hemoglobin and MPV were positively associated with brain volume changes diffusely in the frontal, parietal, and temporal cortices (Figure 1). Hemoglobin had a strong localized effect on the subcortex (white matter and basal ganglia) (Figure 1) suggesting that anemia was associated with volume loss in these areas. MPV overall was found to have a strong effect on cortical morphology diffusely. Conclusion: Hemoglobin's relationship to brain volume and morphology suggests global white matter shrinkage due to anemia. The association is strongest in the phylogenetically younger portions of the brain and co-localizes with brain regions impacted by silent stroke. MPV was an unexpectedly strong predictor of cortical volumes in both SCD and control subjects. MPV is an indicator of platelet activation and is associated with ischemic stroke, hypertension, obstructive sleep apnea, and coronary artery syndromes in the general population, similar to C-reactive protein. However, the broad association of MPV and grey matter volumes in both SCD patients and controls, independently, suggests a developmental interplay between brain maturation and inflammatory signaling that requires further study. Disclosures Wood: Celgene: Consultancy; Ionis Pharmaceuticals: Consultancy; AMAG: Consultancy; Apopharma: Consultancy; Apopharma: Consultancy; Biomed Informatics: Consultancy; Biomed Informatics: Consultancy; AMAG: Consultancy; Celgene: Consultancy; Vifor: Consultancy; Ionis Pharmaceuticals: Consultancy; World Care Clinical: Consultancy; Vifor: Consultancy; World Care Clinical: Consultancy.

Download Full-text

Preliminary Evidence for a Relationship between Elevated Plasma TNFα and Smaller Subcortical White Matter Volume in HCV Infection Irrespective of HIV or AUD Comorbidity

International Journal of Molecular Sciences ◽

10.3390/ijms22094953 ◽

2021 ◽

Vol 22 (9) ◽

pp. 4953

Author(s):

Natalie M. Zahr ◽

Kilian M. Pohl ◽

Allison J. Kwong ◽

Edith V. Sullivan ◽

Adolf Pfefferbaum

Keyword(s):

White Matter ◽

Proinflammatory Cytokines ◽

Soluble Protein ◽

Subcortical White Matter ◽

Control Group ◽

White Matter Volume ◽

Brain Volumes ◽

Protein Levels ◽

Matter Volume ◽

Patient Groups

Classical inflammation in response to bacterial, parasitic, or viral infections such as HIV includes local recruitment of neutrophils and macrophages and the production of proinflammatory cytokines and chemokines. Proposed biomarkers of organ integrity in Alcohol Use Disorders (AUD) include elevations in peripheral plasma levels of proinflammatory proteins. In testing this proposal, previous work included a group of human immunodeficiency virus (HIV)-infected individuals as positive controls and identified elevations in the soluble proteins TNFα and IP10; these cytokines were only elevated in AUD individuals seropositive for hepatitis C infection (HCV). The current observational, cross-sectional study evaluated whether higher levels of these proinflammatory cytokines would be associated with compromised brain integrity. Soluble protein levels were quantified in 86 healthy controls, 132 individuals with AUD, 54 individuals seropositive for HIV, and 49 individuals with AUD and HIV. Among the patient groups, HCV was present in 24 of the individuals with AUD, 13 individuals with HIV, and 20 of the individuals in the comorbid AUD and HIV group. Soluble protein levels were correlated to regional brain volumes as quantified with structural magnetic resonance imaging (MRI). In addition to higher levels of TNFα and IP10 in the 2 HIV groups and the HCV-seropositive AUD group, this study identified lower levels of IL1β in the 3 patient groups relative to the control group. Only TNFα, however, showed a relationship with brain integrity: in HCV or HIV infection, higher peripheral levels of TNFα correlated with smaller subcortical white matter volume. These preliminary results highlight the privileged status of TNFα on brain integrity in the context of infection.

Download Full-text