Thibo Billiet

Diffusion tensor MRI of chemotherapy-induced cognitive impairment in non-CNS cancer patients: a review.

Patients with non-central nervous system cancers often experience subtle cognitive deficits after treatment with cytotoxic agents. Therapy-induced structural changes to the brain could be one of the possible causes underlying these reported cognitive deficits. In this review, we evaluate the use of diffusion tensor imaging (DTI) for assessing possible therapy-induced changes in the microstructure of the cerebral white matter (WM) and provide a critical overview of the published DTI research on therapy-induced cognitive impairment. Both cross-sectional and longitudinal DTI studies have demonstrated abnormal microstructural properties in WM regions involved in cognition. These findings correlated with cognitive performance, suggesting that there is a link between reduced “WM integrity” and chemotherapy-induced impaired cognition. In this paper, we will also introduce the basics of diffusion tensor imaging and how it can be applied to evaluate effects of therapy on structural changes in cerebral WM. The review concludes with considerations and discussion regarding DTI data interpretation and possible future directions for investigating therapy-induced WM changes in cancer patients. This review article is part of a Special Issue entitled: Neuroimaging Studies of Cancer and Cancer Treatment.

Characterizing the microstructural basis of "unidentified bright objects" in neurofibromatosis type 1: A combined in vivo multicomponent T2 relaxation and multi-shell diffusion MRI analysis.

Introduction The histopathological basis of “unidentified bright objects” (UBOs) (hyperintense regions seen on T2-weighted magnetic resonance (MR) brain scans in neurofibromatosis-1 (NF1)) remains unclear. New in vivo MRI-based techniques (multi-exponential T2 relaxation (MET2) and diffusion MR imaging (dMRI)) provide measures relating to microstructural change. We combined these methods and present previously unreported data on in vivo UBO microstructure in NF1. Methods 3-Tesla dMRI data were acquired on 17 NF1 patients, covering 30 white matter UBOs. Diffusion tensor, kurtosis and neurite orientation and dispersion density imaging parameters were calculated within UBO sites and in contralateral normal appearing white matter (cNAWM). Analysis of MET2 parameters was performed on 24 UBO–cNAWM pairs. Results No significant alterations in the myelin water fraction and intra- and extracellular (IE) water fraction were found. Mean T2 time of IE water was significantly higher in UBOs. UBOs furthermore showed increased axial, radial and mean diffusivity, and decreased fractional anisotropy, mean kurtosis and neurite density index compared to cNAWM. Neurite orientation dispersion and isotropic fluid fraction were unaltered. Conclusion Our results suggest that demyelination and axonal degeneration are unlikely to be present in UBOs, which appear to be mainly caused by a shift towards a higher T2-value of the intra- and extracellular water pool. This may arise from altered microstructural compartmentalization, and an increase in ‘extracellular-like’, intracellular water, possibly due to intramyelinic edema. These findings confirm the added value of combining dMRI and MET2 to characterize the microstructural basis of T2 hyperintensities in vivo.

No Association of Lower Hippocampal Volume With Alzheimer’s Disease Pathology in Late-Life Depression

OBJECTIVE Hippocampal volume is commonly decreased in late-life depression. According to the depression-as-late-life-neuropsychiatric-disorder model, lower hippocampal volume in late-life depression is associated with neurodegenerative changes. The purpose of this prospective study was to examine whether lower hippocampal volume in late-life depression is associated with Alzheimers disease pathology. METHOD Of 108 subjects who participated, complete, good-quality data sets were available for 100: 48 currently depressed older adults and 52 age- and gender-matched healthy comparison subjects who underwent structural MRI, [18F]flutemetamol amyloid positron emission tomography imaging, apolipoprotein E genotyping, and neuropsychological assessment. Hippocampal volumes were defined manually and normalized for total intracranial volume. Amyloid binding was quantified using the standardized uptake value ratio in one cortical composite volume of interest. The authors investigated group differences in hippocampal volume (both including and excluding amyloid-positive participants), group differences in amyloid uptake and in the proportion of positive amyloid scans, and the association between hippocampal volume and cortical amyloid uptake. RESULTS A significant difference was observed in mean normalized total hippocampal volume between patients and comparison subjects, but there were no group differences in cortical amyloid uptake or proportion of amyloid-positive subjects. The difference in hippocampal volume remained significant after the amyloid-positive subjects were excluded. There was no association between hippocampal volume and amyloid uptake in either patients or comparison subjects. CONCLUSIONS Lower hippocampal volume was not related to amyloid pathology in this sample of patients with late-life depression. These data counter the common belief that changes in hippocampal volume in late-life depression are due to prodromal Alzheimers disease.

A diffusion tensor imaging family study of the fornix in schizophrenia

Diffusion tensor imaging (DTI) studies suggest abnormalities in the white matter microstructure of the fornix in schizophrenia patients. Research evaluating schizophrenia patient and relatives also suggests that the white matter microstructure of the fornix is heritable. However, previous studies have been hindered by limited DTI methodology. Therefore, the goal of this study was to assess whether fornix abnormalities were related to the genetic liability for schizophrenia using the novel methodological approach of assessing multiple metrics of along-tract measurements, in addition to whole-tract means. Twenty-five schizophrenia patients, 24 adult non-psychotic first-degree biological relatives, and 27 community controls underwent neuroimaging. No group differences were found for any of the DTI metrics using the classical whole-tract measures of the fornix. Along-tract analysis detected local increases in fractional anisotropy (FA) in the right fimbria of the fornix for relatives compared to patients and controls corrected for false discovery rate. No significant associations were found between symptoms, global functioning, or IQ and whole-tract FA means in schizophrenia patients or relatives. Increased FA in non-psychotic relatives could represent a compensatory mechanism to guard against psychosis or an abnormality associated with the genetic liability for the disorder. These findings underscore the importance of obtaining along-tract measurements, in addition to whole-tract measurements to fully understand white matter abnormalities in schizophrenia.

Brain Connectivity and Cognitive Flexibility in Nonirradiated Adult Survivors of Childhood Leukemia

Background This study aimed to assess functional and structural brain connectivity in adult childhood leukemia survivors and the link with cognitive functioning and previously identified risk factors such as intrathecal methotrexate dose and age at start of therapy. Methods Thirty-one nonirradiated adult childhood leukemia survivors and 35 controls underwent cognitive testing and multimodal magnetic resonance imaging (resting state functional MRI, T1-weighted, diffusion-weighted, and myelin water imaging [MWI]). Analyses included dual regression, voxel-based morphometry, advanced diffusion, and MWI modeling techniques besides stepwise discriminant function analysis to identify the most affected executive cognitive domain. Correlations with discrete intrathecal MTX doses and (semi)continuous variables were calculated using Spearmans rank and Pearsons correlation, respectively. All correlation tests were two-sided. Positive and negative T-contrasts in functional and structural MRI analysis were one-sided. Results Survivors demonstrated lower functional connectivity between the default mode network (DMN) and inferior temporal gyrus (ITG; P < .008). Additionally, we observed higher fractional anisotropy (FA; P = .04) and lower orientation dispersion index (ODI; P = .008) at the left centrum semiovale, which could-given that several fiber bundles cross this region-suggest selective reduced integrity of the respective white matter tracts. Set shifting reaction time, a measure of cognitive flexibility, was mostly impaired and correlated with lower FA (r = -0.53, P = .003) and higher ODI (r = 0.40, P = .04) in survivors but not with DMN-ITG connectivity. There were no statistically significant differences between survivors and controls in WM or GM volume, nor was there a statistically significant correlation between imaging measurements and age at start of therapy or intrathecal methotrexate dose. Conclusions Adult, nonirradiated childhood leukemia survivors show altered brain connectivity, which is linked with cognitive flexibility.

Prenatal stress exposure is associated with increased dyspnoea perception in adulthood

Dyspnoea is the aversive cardinal symptom in various prevalent conditions such as respiratory, cardiovascular and neuromuscular diseases and is associated with great individual and socioeconomic burden [1]. Over the past years, several physiological and also psychological factors have been demonstrated to affect the perception of dyspnoea [1, 2]. For example, high levels of anxiety in adulthood were associated with increased dyspnoea perception in patients with asthma or chronic obstructive pulmonary disease (COPD), but also in healthy controls [2]. Moreover, adverse, separation-related experiences in childhood were linked to the subsequent development of increased anxiety and dyspnoea [3]. However, the effects of adverse experiences in early, prenatal life on dyspnoea perception remain widely unknown, although prenatal exposure to maternal stress and anxiety has convincingly been related to the development of other health and behavioural problems later in life, including impairments of the respiratory control system and high anxiety levels [4–9]. Therefore, this study investigated the relationship between prenatal exposure to maternal stress and the perception of dyspnoea in adulthood 28 years later. Prenatal exposure to maternal stress is associated with increased perception of dyspnoea in adulthood 28 years later http://ow.ly/M6EH30d1NEQ

HLA genotype as a marker of multiple sclerosis prognosis: A pilot study

OBJECTIVE The identification of a biomarker with prognostic value is an unmet need in multiple sclerosis (MS). The objective of this study was to investigate a possible association of HLA genotype with disease status and progression in MS, based on comprehensive and sensitive clinical and magnetic resonance imaging (MRI) parameters to measure disease effects. METHOD A total of 118 MS patients (79 females, 39 males) underwent HLA typing. Patient MS status was assessed at two time points in a 2-year interval, based on clinical scores (including EDSS, MSSS, T25FW, 9-HPT, SDMT, BVMT, CVLT-II) and MRI evaluations. Quantitative brain MRI values were obtained for whole brain atrophy, FLAIR lesion volume change and number of new lesions using MSmetrix. Predefined HLA patient groups were compared as of disease status and progression. Global assessment was achieved by an overall t-statistic and assessment per measurement by a Welch test and/or Mann Whitney U test. The effects of multiple covariates, including age, gender and disease duration as well as scan parameters, were also evaluated using a regression analysis. RESULTS The HLA-A*02 allele was associated with better outcomes in terms of MSSS, EDSS and new lesion count (Welch test p-value<0.05). The HLA-B*07 and HLA-B*44 alleles showed a global negative effect on disease status, although none of the measurements reached significance (p-value<0.05). Results for the HLA-DRB1*15, HLA-DQB1*06 and HLA-B*08 alleles were inconclusive. The influence of the confounding variables on the statistical analysis was limited.

005 Filling in the gaps: precision MRI reporting in multiple sclerosis clinical practice

Introduction Clinical multiple sclerosis (MS) magnetic resonance imaging (MRI) brain reports provide important information to neurologists. The quantitative data reported varies between centres and radiologists. Structured MRI reporting and formal quantitative MRI (QMRI) analysis may assist clinicians with patient management. The objective is to compare quantitative data derived from standard clinical reports, structured neuroradiologist reviews, local QMRI analyses and fully-automated MSmetrix QMRI analyses, in a longitudinal clinical MS cohort. Methods Clinical brain MRI scans separated by one-year minimum, from the same patient on the same scanner, were evaluated. Quantitative information was extracted from the clinical reports and structured neuroradiologist reviews. MRI scan-pairs were analysed locally by imaging-analysts and centrally by MSmetrix. Results 50 MS patients, baseline age 39.02 (9.06) years, disease duration 9.11 (6.88) years and Expanded Disability Status Scale score 1.91 (1.62), were included. Compared to clinical reports, structured neuroradiologist reviews provided increased semi-/quantitative data; baseline T2 and T1 lesion burden (50% vs 100%; 2% vs 100%), baseline brain volume-loss (BVL; 72% vs 100%), new T1 lesions (0% vs 100%), regional brain atrophy (BA; 20% vs 100%). Lesion and brain volumes were not provided in radiology reports/reviews. Comparison of local and central QMRI revealed moderate-strong Pearson correlations for most metrics; Intra-class correlations varied more widely. Statistical consistency existed across all methods in detecting new T2 lesions. Radiologist-identified baseline BVL was associated with lower quantitatively-measured brain volumes. Local QMRI longitudinal BA rates >0.4% and >0.8%, were 48% and 26% respectively. Neuroradiologist review identified BA in 12%. Conclusion Structured neuroradiology review provided additional quantitative information over standard clinical reports. Quantitative data measured using local and MSmetrix pipelines were generally well associated but are not interchangeable. Longitudinal whole brain and regional atrophy is not reliably identified by radiologists and QMRI analysis provides a clear advantage in this regard. Structured reporting, and formal QMRI analysis, provide additional quantitative MRI data that may assist clinical decision-making in MS.

Advanced MR diffusion imaging and chemotherapy-related changes in cerebral white matter microstructure of survivors of childhood bone and soft tissue sarcoma?

With the increase of survival rates of pediatric cancer patients, the number of children facing potential cognitive sequelae has grown. Previous adult studies suggest that white matter (WM) microstructural changes may contribute to cognitive impairment. This study aims to investigate WM microstructure in childhood bone and soft tissue sarcoma. Differences in (micro‐)structure can be investigated using diffusion MRI (dMRI). The typically used diffusion tensor model (DTI) assumes Gaussian diffusion, and lacks information about fiber populations. In this study, we compare WM structure of childhood bone and soft tissue sarcoma survivors (n = 34) and matched controls (n = 34), combining typical and advanced voxel‐based models (DTI and NODDI model, respectively), as well as recently developed fixel‐based models (for estimations of intra‐voxel differences, apparent fiber density [AFD] and fiber cross‐section [FC]). Parameters with significant findings were compared between treatments, and correlated with subscales of the WAIS‐IV intelligence test, age at diagnosis, age at assessment and time since diagnosis. We encountered extensive regions showing lower fractional anisotropy, overlapping with both significant NODDI parameters and fixel‐based parameters. In contrast to these diffuse differences, the fixel‐based measure of AFD was reduced in the cingulum and corpus callosum only. Furthermore, AFD of the corpus callosum was significantly predicted by chemotherapy treatment and correlated positively with time since diagnosis, visual puzzles and similarities task scores. This study suggests altered WM structure of childhood bone and soft tissue sarcoma survivors. We conclude global chemotherapy‐related changes, with particular vulnerability of centrally located WM bundles. Finally, such differences could potentially recover after treatment.

Corpus callosum macro and microstructure in late-life depression

BACKGROUND Differences in corpus callosum (CC) morphology and microstructure have been implicated in late-life depression and may distinguish between late and early-onset forms of the illness. However, a multimodal approach using complementary imaging techniques is required to disentangle microstructural alterations from macrostructural partial volume effects. METHODS 107 older adults were assessed: 55 currently-depressed patients without dementia and 52 controls without cognitive impairment. We investigated group differences and clinical associations in 7 sub-regions of the mid-sagittal corpus callosum using T1 anatomical data, white matter hyperintensity (WMH) quantification and two different diffusion MRI (dMRI) models (multi-tissue constrained spherical deconvolution, yielding apparent fibre density, AFD; and diffusion tensor imaging, yielding fractional anisotropy, FA and radial diffusivity, RD). RESULTS Callosal AFD was lower in patients compared to controls. There were no group differences in CC thickness, surface area, FA, RD, nor whole brain or WMH volume. Late-onset of depression was associated with lower FA, higher RD and lower AFD. There were no associations between any imaging measures and psychotic features or depression severity as assessed by the geriatric depression scale. WMH volume was associated with lower FA and AFD, and higher RD in patients. LIMITATIONS Patients were predominantly treatment-resistant. Measurements were limited to the mid-sagittal CC. dMRI analysis was performed on a smaller cohort, n=77. AFD was derived from low b-value data. CONCLUSIONS Callosal structure is largely preserved in LLD. WMH burden may impact on CC microstructure in late-onset depression suggesting vascular pathology has additional deleterious effects in these patients.