Normalized Brain Volume Research Articles

Brain volume is related to neurological impairment and to copper overload in Wilson\u2019s disease

IntroductionTo determine whether brain volume was associated with functional and neurological impairments and with copper overload markers in patients with Wilson’s disease.MethodsIn 48 treatment-naïve patients, we assessed functional and neurological impairments with the Unified Wilson’s Disease Rating Scale, measured normalized brain volumes based on magnetic resonance images, and assessed concentration of non-ceruloplasmin-bound copper. We correlated brain volume measures with functional and neurological impairment scores and copper overload indices.ResultsFunctional and neurological impairments correlated with all brain volume measures, including the total brain volume and the volumes of white matter and gray matter (both peripheral gray matter and deep brain nuclei). Higher non-ceruloplasmin-bound copper concentrations were associated with greater functional and neurological impairments and lower brain volumes.ConclusionsOur findings provided the first in vivo evidence that the severity of brain atrophy is a correlate of functional and neurological impairments in patients with Wilson’s disease and that brain volume could serve as a marker of neurodegeneration induced by copper.

Thalamic Atrophy Without Whole Brain Atrophy Is Associated With Absence of 2-Year NEDA in Multiple Sclerosis.

Purpose: To study which brain volume measures best differentiate early relapsing MS (RMS) and secondary progressive MS (SPMS) patients and correlate with disability and cognition. To test whether isolated thalamic atrophy at study baseline correlates with NEDA (no evidence of disease activity) at 2 years.Methods: Total and regional brain volumes were measured from 24 newly diagnosed RMS patients 6 months after initiation of therapy and 2 years thereafter, and in 36 SPMS patients. Volumes were measured by SIENAX and cNeuro. The patients were divided into subgroups based on whole brain parenchyma (BP) and thalamic atrophy at baseline. Standard scores (z-scores) were computed by comparing individual brain volumes against healthy controls. A z-score cut-off of −1.96 was applied to separate atrophic from normal brain volumes. The Expanded Disability Status Scale (EDSS) and Symbol Digit Modalities Test (SDMT) were assessed at baseline and at 2 years. Differences in achieving NEDA-3, NEDA-4, EDSS progression, and SDMT change were analyzed between patients with no thalamic or BP atrophy and in patients with isolated thalamic atrophy at baseline.Results: At baseline, 7 SPMS and 12 RMS patients had no brain atrophy, 8 SPMS and 10 RMS patients had isolated thalamic atrophy and 2 RMS and 20 SPMS patients had both BP and thalamic atrophy. NEDA-3 was reached in 11/19 patients with no brain atrophy but only in 2/16 patients with isolated thalamic atrophy (p = 0.012). NEDA-4 was reached in 7/19 patients with no brain atrophy and in 1/16 of the patients with isolated thalamic atrophy (p = 0.047). At 2 years, EDSS was same or better in 16/19 patients with no brain atrophy but only in 5/17 patients with isolated thalamic atrophy (p = 0.002). There was no significant difference in the EDSS, relapses or SDMT between patients with isolated thalamic atrophy and no atrophy at baseline.Conclusion: Patients with isolated thalamic atrophy were at a higher risk for not reaching 2-year NEDA-3 and for EDSS increase than patients with no identified brain atrophy. The groups were clinically indistinguishable. A single measurement of thalamic and whole brain atrophy could help identify patients needing most effective therapies from early on.

Relationship between changes in resting-state spontaneous brain activity and cognitive impairment in patients with CADASIL

BackgroundCerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) mainly manifests with cognitive impairment. Cognitive deficits in patients with CADASIL are correlated with structural brain changes such as lacunar lesion burden, normalized brain volume, and anterior thalamic radiation lesions, but changes in resting-state functional brain activity in patients with CADASIL have not been reported.MethodsThis study used resting-state functional magnetic resonance imaging (fMRI) to measure the amplitude of low-frequency fluctuation (ALFF) in 22 patients with CADASIL and 44 healthy matched controls. A seed-based functional connectivity (FC) analysis was used to investigate whether the dysfunctional areas identified by ALFF analysis exhibited abnormal FC with other brain areas. Pearson’s correlation analysis was used to detect correlations between the ALFF z-score of abnormal brain areas and clinical scores in patients with CADASIL.ResultsPatients with CADASIL exhibited significantly lower ALFF values in the right precuneus and cuneus (Pcu/CU) and higher ALFF values in the bilateral superior frontal gyrus (SFG) and left cerebellar anterior and posterior lobes compared with controls. Patients with CADASIL showed weaker FC between the areas with abnormal ALFF (using peaks in the left and right SFG and the right Pcu/CU) and other brain areas. Importantly, the ALFF z-scores for the left and right SFG were negatively associated with cognitive performance, including Mini-Mental State Examination (MMSE) and Montreal Cognitive Assessment scores (MoCA), respectively, whereas those of the right Pcu/CU were positively correlated with the MMSE score.ConclusionsThis preliminary study provides evidence for changes in ALFF of the right Pcu/CU, bilateral SFG and left cerebellar anterior and posterior lobes, and associations between ALFF values for abnormal brain areas and cognitive performance in patients with CADASIL. Therefore, spontaneous brain activity may be a novel imaging biomarker of cognitive impairment in this population.

Volumes of brain structures in captive wild-type and laboratory rats: 7T magnetic resonance in vivo automatic atlas-based study.

Selective breeding of laboratory rats resulted in changes of their behavior. Concomitantly, the albino strains developed vision related pathologies. These alterations certainly occurred on the background of modifications in brain morphology. The aim of the study was to assess and compare volumes of major structures in brains of wild-captive, laboratory albino and laboratory pigmented rats. High resolution T2-weighted images of brains of adult male Warsaw Wild Captive Pisula-Stryjek rats (WWCPS, a model of wild type), laboratory pigmented (Brown Norway strain, BN) and albino rats (Wistar strain, WI) were obtained with a 7T small animal-dedicated magnetic resonance tomograph. Volume quantification of whole brains and 50 brain structures within each brain were performed with the digital Schwarz rat brain atlas and a custom-made MATLAB/SPM8 scripts. Brain volumes were scaled to body mass, whereas volumes of brain structures were normalized to individual brain volumes. Normalized brain volume was similar in WWCPS and BN, but lower in WI. Normalized neocortex volume was smaller in both laboratory strains than in WWCPS and the visual cortex was smaller in albino WI rats than in WWCPS and BN. Relative volumes of phylogenetically older structures, such as hippocampus, amygdala, nucleus accumbens and olfactory nuclei, also displayed certain strain-related differences. The present data shows that selective breeding of laboratory rats markedly affected brain morphology, the neocortex being most significantly altered. In particular, albino rats display reduced volume of the visual cortex, possibly related to retinal degeneration and the development of blindness.

Damage of the lateral geniculate nucleus in MS: Assessing the missing node of the visual pathway.

To study if the thalamic lateral geniculate nucleus (LGN) is affected in multiple sclerosis (MS) due to anterograde degeneration from optic neuritis (ON) or retrograde degeneration from optic radiation (OR) pathology, and if this is relevant for visual function. In this cross-sectional study, LGN volume of 34 patients with relapsing-remitting MS and 33 matched healthy controls (HC) was assessed on MRI using atlas-based automated segmentation (MAGeT). ON history, thickness of the ganglion cell-inner plexiform layer (GC-IPL), OR lesion volume, and fractional anisotropy (FA) of normal-appearing OR (NAOR-FA) were assessed as measures of afferent visual pathway damage. Visual function was tested, including low-contrast letter acuity (LCLA) and Hardy-Rand-Rittler (HRR) plates for color vision. LGN volume was reduced in patients vs HC (165.5 ± 45.5 vs 191.4 ± 47.7 mm3, B = -25.89, SE = 5.83, p < 0.001). It was associated with GC-IPL thickness (B = 0.95, SE = 0.33, p = 0.006) and correlated with OR lesion volume (Spearman ρ = -0.53, p = 0.001), and these relationships remained after adjustment for normalized brain volume. There was no association between NAOR-FA and LGN volume (B = -133.28, SE = 88.47, p = 0.137). LGN volume was not associated with LCLA (B = 5.5 × 10-5, SE = 0.03, p = 0.998), but it correlated with HRR color vision (ρ = 0.39, p = 0.032). LGN volume loss in MS indicates structural damage with potential functional relevance. Our results suggest both anterograde degeneration from the retina and retrograde degeneration from the OR lesions as underlying causes. LGN volume is a promising marker reflecting damage of the visual pathway in MS, with the advantage of individual measurement per patient on conventional MRI.

Dosimetric comparison of fractionated radiosurgery plans using frameless Gamma Knife ICON and CyberKnife systems with linear accelerator-based radiosurgery plans for multiple large brain metastases.

For patients with multiple large brain metastases with at least 1 target volume larger than 10 cm3, multifractionated stereotactic radiosurgery (MF-SRS) has commonly been delivered with a linear accelerator (LINAC). Recent advances of Gamma Knife (GK) units with kilovolt cone-beam CT and CyberKnife (CK) units with multileaf collimators also make them attractive choices. The purpose of this study was to compare the dosimetry of MF-SRS plans deliverable on GK, CK, and LINAC and to discuss related clinical issues. Ten patients with 2 or more large brain metastases who had been treated with MF-SRS on LINAC were identified. The median planning target volume was 18.31 cm3 (mean 21.31 cm3, range 3.42-49.97 cm3), and the median prescribed dose was 27.0 Gy (mean 26.7 Gy, range 21-30 Gy), administered in 3 to 5 fractions. Clinical LINAC treatment plans were generated using inverse planning with intensity modulation on a Pinnacle treatment planning system (version 9.10) for the Varian TrueBeam STx system. GK and CK planning were retrospectively performed using Leksell GammaPlan version 10.1 and Accuray Precision version 1.1.0.0 for the CK M6 system. Tumor coverage, Paddick conformity index (CI), gradient index (GI), and normal brain tissue receiving 4, 12, and 20 Gy were used to compare plan quality. Net beam-on time and approximate planning time were also collected for all cases. Plans from all 3 modalities satisfied clinical requirements in target coverage and normal tissue sparing. The mean CI was comparable (0.79, 0.78, and 0.76) for the GK, CK, and LINAC plans. The mean GI was 3.1 for both the GK and the CK plans, whereas the mean GI of the LINAC plans was 4.1. The lower GI of the GK and CK plans would have resulted in significantly lower normal brain volumes receiving a medium or high dose. On average, GK and CK plans spared the normal brain volume receiving at least 12 Gy and 20 Gy by approximately 20% in comparison with the LINAC plans. However, the mean beam-on time of GK (∼ 64 minutes assuming a dose rate of 2.5 Gy/minute) plans was significantly longer than that of CK (∼ 31 minutes) or LINAC (∼ 4 minutes) plans. All 3 modalities are capable of treating multiple large brain lesions with MF-SRS. GK has the most flexible workflow and excellent dosimetry, but could be limited by the treatment time. CK has dosimetry comparable to that of GK with a consistent treatment time of approximately 30 minutes. LINAC has a much shorter treatment time, but residual rotational error could be a concern.

Tumor control and survival in patients with ten or more brain metastases treated with stereotactic radiosurgery: a retrospective analysis.

To assess tumor control and survival in patients treated with stereotactic radiosurgery (SRS) for 10 or more metastatic brain tumors. Patients were retrospectively identified. Clinical records were reviewed for follow-up data, and post-treatment MRI studies were used to assess tumor control. For tumor control studies, patients were separated based on synchronous or metachronous treatment, and control was assessed at 3-month intervals. The Kaplan-Meier method was employed to create survival curves, and regression analyses were employed to study the effects of several variables. Fifty-five patients were treated for an average of 17 total metastases. Forty patients received synchronous treatment, while 15 received metachronous treatment. Univariate analysis revealed an association between larger brain volumes irradiated with 12Gy and decreased overall survival (p = 0.0406); however, significance was lost on multivariate analysis. Among patients who received synchronous treatment, the median percentage of tumors controlled was 100%, 91%, and 82% at 3, 6, and 9 months, respectively. Among patients who received metachronous treatment, the median percentage of tumors controlled after each SRS encounter was 100% at all three time points. SRS can be used to treat patients with 10 or more total brain metastases with an expectation of tumor control and overall survival that is equivalent to that reported for patients with four or fewer tumors. Development of new metastases leading to repeat SRS is not associated with worsened tumor control or survival. Survival may be adversely affected in patients having a higher volume of normal brain irradiated.

Dosimetric comparisons of different hypofractionated stereotactic radiotherapy techniques in treating intracranial tumors > 3 cm in longest diameter.

The authors sought to compare the dosimetric quality of hypofractionated stereotactic radiosurgery in treating sizeable brain tumors across the following treatment platforms: GammaKnife (GK) Icon, CyberKnife (CK) G4, volumetric modulated arc therapy (VMAT) on the Varian TrueBeam STx, double scattering proton therapy (DSPT) on the Mevion S250, and intensity modulated proton therapy (IMPT) on the Varian ProBeam. In this retrospective study, stereotactic radiotherapy treatment plans were generated for 10 patients with sizeable brain tumors (> 3 cm in longest diameter) who had been treated with VMAT. Six treatment plans, 20-30 Gy in 5 fractions, were generated for each patient using the same constraints for each of the following radiosurgical methods: 1) GK, 2) CK, 3) coplanar arc VMAT (VMAT-C), 4) noncoplanar arc VMAT (VMAT-NC), 5) DSPT, and 6) IMPT. The coverage; conformity index; gradient index (GI); homogeneity index; mean and maximum point dose of organs at risk; total dose volume (V) in Gy to the normal brain for 2 Gy (V2), 5 Gy (V5), and 12 Gy (V12); and integral dose were compared across all platforms. Among the 6 techniques, GK consistently produced a sharper dose falloff despite a greater central target dose. GK gave the lowest GI, with a mean of 2.7 ± 0.1, followed by CK (2.9 ± 0.1), VMAT-NC (3.1 ± 0.3), and VMAT-C (3.5 ± 0.3). The highest mean GIs for the proton beam treatments were 3.8 ± 0.4 for DSPT and 3.9 ± 0.4 for IMPT. The GK consistently targeted the lowest normal brain volume, delivering 5 to 12 Gy when treating relatively smaller- to intermediate-sized lesions (less than 15-20 cm3). Yet, the differences across the 6 modalities relative to GK decreased with the increase of target volume. In particular, the proton treatments delivered the lowest V5 to the normal brain when the target size was over 15-20 cm3 and also produced the lowest integral dose to the normal brain regardless of the target size. This study provides an insightful understanding of dosimetric quality from both photon and proton treatment across the most advanced stereotactic radiotherapy platforms.

Arteriovenous Malformation (AVM) Treated with Robotic Radiosurgery: Impact of Beam Reduction in 12 Gy Normal Brain Volume and It’s Clinical Implication

Purpose: Dosimetric study to evaluate impact of “beam” reduction in AVM radiosurgery on normal brain dose parameters and it’s clinical implications. Materials and Methods: Five small volume AVMs (nidus volume 0.31 - 1.94 cc) planned for single fraction SRS with robotic radiosurgery system. Planning scans done with CT scan brain, CT & MR angiography, then nidus volume and organ at risk (OARs) were contoured. Planning was done with multiplan planning system. Plan evaluated as per Flickenger model parameters of 12 Gy nomal brain vol & marginal dose. 7.5 mm and 10 mm cons used, optimization done with seqential algorithm. 20 Gy was prescribed to isodose with appropriate nidus coverage (>98%). Total beams of five plans were 85 - 250, monitor unit 17,259 - 24,602 MU. 12 Gy normal brain volume is 0.9 - 7.6 cc. Then beam reduction is done by reducing beams with minimum MU in steps of 50, 100, 150, 200, 250 MU and after beam reduction, re-optimization done. Prescription isodose was changed to keep the nidus coverage > 98%. Impacts of beam reduction on 12 Gy normal brain vol and conformity/homogeniety index were analyzed. Results: Optimal plans of five patients with 20 Gy prescribed to 88% - 90% isodose, nidus coverage more than 98%. In dosimetric parameters, mean CI was 1.36 - 1.51, nCI 1.41 - 1.51, HI 1.1 - 1.4 and mean 12 Gy normal brain volume 0.17, 1.44, 5.3, 5.5 and 7.6cc respectively. After beam reduction of less than 50 MU contribution (in case#1), prescibing at suitable isodose (85%) beam reduces to 79 and 12 Gy volume marginally increases to 26.4 cc. Beam reduction of less than 100 MU reduces to 53 - 92 beamlets. Reduction of beams with less than 150 MU contribution did not significantly change the 12Gy normal brain volume. However, reduction of beamlets with more than 200 MU, 250 MU, 300 MU, 450 MU and 550 MU significantly affects the 12 Gy normal brain volume. Prescription-isodose modified from 83% to 50% to have >98% coverage. CI and HI increased from 1.36 - 1.51 to 2.51 - 2.63 and 1.1 - 1.4 to 1.52 - 1.54 respectively. There was exponential increase in 12 Gy volume with reduction of beams with higher proportion in larger nidus. Conclusions: In robotic radiosurgery system, beam reduction even after re-optimization impairs the conformity index and increase 12 Gy normal brain volume, hence long-term toxicity. Optimal beam numbers are required for optimal plan generation.

Imaging markers of disability in aquaporin-4 immunoglobulin G seropositive neuromyelitis optica: a graph theory study.

Neuromyelitis optica spectrum disorders lack imaging biomarkers associated with disease course and supporting prognosis. This complex and heterogeneous set of disorders affects many regions of the central nervous system, including the spinal cord and visual pathway. Here, we use graph theory-based multimodal network analysis to investigate hypothesis-free mixed networks and associations between clinical disease with neuroimaging markers in 40 aquaporin-4-immunoglobulin G antibody seropositive patients (age = 48.16 ± 14.3 years, female:male = 36:4) and 31 healthy controls (age = 45.92 ± 13.3 years, female:male = 24:7). Magnetic resonance imaging measures included total brain and deep grey matter volumes, cortical thickness and spinal cord atrophy. Optical coherence tomography measures of the retina and clinical measures comprised of clinical attack types and expanded disability status scale were also utilized. For multimodal network analysis, all measures were introduced as nodes and tested for directed connectivity from clinical attack types and disease duration to systematic imaging and clinical disability measures. Analysis of variance, with group interactions, gave weights and significance for each nodal association (hyperedges). Connectivity matrices from 80% and 95% F-distribution networks were analyzed and revealed the number of combined attack types and disease duration as the most connected nodes, directly affecting changes in several regions of the central nervous system. Subsequent multivariable regression models, including interaction effects with clinical parameters, identified associations between decreased nucleus accumbens (β = −0.85, P = 0.021) and caudate nucleus (β = −0.61, P = 0.011) volumes with higher combined attack type count and longer disease duration, respectively. We also confirmed previously reported associations between spinal cord atrophy with increased number of clinical myelitis attacks. Age was the most important factor associated with normalized brain volume, pallidum volume, cortical thickness and the expanded disability status scale score. The identified imaging biomarker candidates warrant further investigation in larger-scale studies. Graph theory-based multimodal networks allow for connectivity and interaction analysis, where this method may be applied in other complex heterogeneous disease investigations with different outcome measures.

End-to-end testing of automatic plan optimization using RayStation scripting for hypofractionated multimetastatic brain stereotactic radiosurgery

For external beam stereotactic radiosurgery of multiple brain metastatic lesions, it is difficult to select optimal treatment isocenters because the orientation and volume of each planning target volume (PTV) and its proximity to critical structures are unique for each patient. The RayStation treatment planning system offers Python-based scripting to optimize the placement of the treatment isocenter by comparing scenario-based plans. This can improve the plan quality by reducing the dose to the normal brain and increasing planning efficiency. The purpose of the current study was to compare the isocenter-optimized plans generated by RayStation with clinical plans created by the Pinnacle treatment planning system and to validate the RayStation treatment planning and delivery with end-to-end testing. Ten patient plans were automatically regenerated using the script in RayStation. For each patient, 4 plans with 4 different types of isocenters were generated: (1) 2 separate isocenters at the PTV centroids, (2) a single isocenter at the mid-point of 2 centroids, (3) a single isocenter at PTV1, and (4) a single isocenter at PTV2. The best plans were compared with paired Pinnacle plans using plan quality parameters, including normal brain volume excluding PTVs receiving 4 Gy (V4Gy), normal brain volume excluding PTVs receiving 12 Gy (V12Gy), maximum dose to the brainstem, homogeneity index, conformity indices, gradient index of each PTV, and monitor units per fraction. All plans were verified with a cylindrical quality assurance phantom, and end-to-end testing was performed with an anthropomorphic head phantom with a radiochromic film. The script was executed within 5-6 minutes to generate 4 scenario-based automatic plans. The homogeneity index and conformity indices showed small but statistically significant improvement with the RayStation plans. The gradient index (3.9 ± 0.9 for Pinnacle and 3.5 ± 0.6 for RayStation, p = 0.04) was also more favorable in the RayStation plans. V12Gy was significantly reduced by 13% and V4Gy was reduced by 5%. The total monitor units per fraction was significantly reduced by 20% for the RayStation plans. Plan optimization time using RayStation was reduced by 64%. The measured doses at each PTV centroid agreed within 3%, and all RayStation plans passed quality assurance verification tests. Scenario-based automatic plan generation using Python scripting helps identify an optimal treatment isocenter to reduce the dose to the normal brain and improve planning efficiency. RayStation plans provided better plan quality, especially lower doses to the normal brain, than Pinnacle plans. Thus, RayStation is a suitable planning modality for hypofractionated stereotactic radiosurgery for multiple brain metastases.

Single MRI-Based Volumetric Assessment in Clinical Practice Is Associated With MS-Related Disability.

The added value of brain volume measurements in the clinical practice of multiple sclerosis (MS) has been questioned. To investigate the contribution of volume measures obtained with magnetic resonance scans performed as part of regular care to predict measures of cognitive and physical MS disability in a real-world setting. Retrospective. In all, 470 adults with diagnosed MS. 3D fluid attenuation inversion recovery (FLAIR) and 3D T1 -weighted MR images at 3.0T MR. Lesion and brain volume were measured by an automated method, MSmetrix, developed by icometrix. We used stepwise linear regression models to assess the added value of a single volumetric assessment in predicting Expanded Disability Status Scale (EDSS) and Symbol Digit Modalities Test (SDMT). Brain volumes categorized into quartiles were used as predictive variables in a time-to-event analysis and Cox proportional hazard regression with time to worsening from baseline as outcome measures. Brain and lesion volume in relapsing onset MS strongly contributed to the best models, with a substantial role for age in the EDSS model and a modest role for education in the SDMT model. Adding MR volumetric information increased the explained variance from 17% to 28% in the best model for EDSS and from 9% to 25% in the best model for SDMT. A significantly reduced hazard (P < 0.05) of SDMT worsening was found in the highest normalized brain volume quartiles (1375-1608 ml), compared with the lowest quartile (1201-1374 ml) in the total study population. Our findings indicate that a single brain volumetric assessment contributes to the prediction of MS-related disability, with distinct patterns for EDSS as a measure of physical disability, and SDMT as a measure of cognitive disability. A threshold effect for the lowest brain volumes with regard to SDMT worsening over time was found. 3 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2019;49:1312-1321.

Concentrations of immunoglobulin free light chains in cerebrospinal fluid predict increased level of brain atrophy in multiple sclerosis.

Recent studies showed that B cells play a major role in the pathogenesis of neurodegeneration in multiple sclerosis (MS). In this study, we aimed to determine the possible link between immunoglobulin free light chains (FLC) and brain atrophy in patients with MS. Ninety-two patients (32 males and 60 females) with MS were included. Kappa and lambda FLC concentrations in serum and cerebrospinal fluid (CSF) samples of MS patients were measured using ELISA assay. FLC quotients (Q-k and Q-λ, respectively) were calculated. In a cross-sectional group (n = 92), the MRI data were acquired within 6months from the date of the lumbar puncture. Twenty patients from this cohort performed a follow-up MRI after 1year of observation. Brain volumes were calculated with SIENAX and the brain atrophy (percentage brain volume change (PBVC)) was assessed with SIENA. Spearman's test was performed to assess correlations. We have shown statistically significant correlation of Expanded Disability Status Scale (EDSS) level with normalized brain volume (NBV, r = - 0.2721, p = 0.0062), white matter volume (WMV, r = - 0.2425, p = 0.015), and gray matter volume (GMV, r = - 0.216, p = 0.0309). Multiple Sclerosis Severity Score (MSSS) score correlated with NBV (r = - 0.2521, p = 0.0352) and WMV (r = - 0.315, p = 0.0079). Neither EDSS, nor MSSS scores correlated with the age of patients and relapse rate during the first year and 5years. In our study, we found statistically significant correlations of k-FLC in the CSF with NBV (r = - 0.311, p = 0.003) and with GMV (r = - 0.213, p = 0.0423). Q-k correlated only with NBV (r = - 0.340, p = 0.006) and Q-λ were negatively correlated with WMV (r = - 0.366, p = 0.003). We did not find correlations of k-FLC in CSF, λ-FLC in CSF, Q-k, and Q-λ with duration of MS course, EDSS, MSSS, number of relapses during the first year, and during the first 5years of disease. Additionally, we subdivided the study population in accordance with level of k-FLC CSF, Q-k, and Q-λ on the 25th and 75th percentile subgroups (25-k-FLCCSF/75-k-FLCCSF; 25-λ-FLCCSF/75-λ-FLCCSF; 25-Q-k/75-Q-k; 25-Q-λ/75-Q-λ). We found statistically significant difference of NBV and GMV between 25-k-FLCCSF and 75-k-FLCCSF subgroups (p = 0.0047, p = 0.0297 respectively), NBV between 25-Q-k and 75-Q-k subgroups (p = 0.038), and NBV and WMV between 25-Q-λ and 75-Q-λ subgroups (p = 0.0446, p = 0.0026 respectively). PBVC in the prospective group showed negative correlation with kappa FLC in the CSF (r = - 0.4853, p = 0.0301) and Q-k (r = - 0.6132, p = 0.0224), but not with other clinical, epidemiological data. In this study, we showed a strong negative correlation of k-FLC, Q-k, and Q-λ with brain atrophy in MS patients. Additionally, patients with high concentration of FLC had lower brain volumes. We did not find correlations of FLC with the relapse rate, age of patients, and MS time course. In the prospective group, the rate of atrophy was correlated with k-FLC and Q-k. We suggest that level of intrathecal production of FLC can be a good prognostic biomarker for MS.

Brain Atrophy Is Associated with Disability Progression in Patients with MS followed in a Clinical Routine.

The assessment of brain atrophy in a clinical routine is not performed routinely in multiple sclerosis. Our aim was to determine the feasibility of brain atrophy measurement and its association with disability progression in patients with MS followed in a clinical routine for 5 years. A total of 1815 subjects, 1514 with MS and 137 with clinically isolated syndrome and 164 healthy individuals, were collected retrospectively. Of 11,794 MR imaging brain scans included in the analysis, 8423 MRIs were performed on a 3T, and 3371 MRIs, on a 1.5T scanner. All patients underwent 3D T1WI and T2-FLAIR examinations at all time points of the study. Whole-brain volume changes were measured by percentage brain volume change/normalized brain volume change using SIENA/SIENAX on 3D T1WI and percentage lateral ventricle volume change using NeuroSTREAM on T2-FLAIR. Percentage brain volume change failed in 36.7% of the subjects; percentage normalized brain volume change, in 19.2%; and percentage lateral ventricle volume change, in 3.3% because of protocol changes, poor scan quality, artifacts, and anatomic variations. Annualized brain volume changes were significantly different between those with MS and healthy individuals for percentage brain volume change (P < .001), percentage normalized brain volume change (P = .002), and percentage lateral ventricle volume change (P = .01). In patients with MS, mixed-effects model analysis showed that disability progression was associated with a 21.9% annualized decrease in percentage brain volume change (P < .001) and normalized brain volume (P = .002) and a 33% increase in lateral ventricle volume (P = .004). All brain volume measures differentiated MS and healthy individuals and were associated with disability progression, but the lateral ventricle volume assessment was the most feasible.

Learning ability correlates with brain atrophy and disability progression in RRMS

ObjectiveTo assess the prognostic value of practice effect on Paced Auditory Serial Addition Test (PASAT) in multiple sclerosis.MethodsWe compared screening (day −14) and baseline (day 0) PASAT scores of 1009...

Near-Term Decrease in Brain Volume following Mild Traumatic Injury Is Detectible in the Context of Preinjury Volumetric Stability: Neurobiologic Insights from Analysis of Historical Imaging Examinations.

Neurodegeneration after mild traumatic brain injury may manifest as decreasing regional brain volume that evolves from months to years following mild traumatic brain injury and is associated with worse clinical outcomes. We hypothesized that quantitative brain volume derived from CT of the head, performed for clinical indications during routine care, would change with time and provide insights into the putative neuroinflammatory response to mild traumatic brain injury. We searched the electronic medical record of our institution for NCCTs of the head performed in patients with mild traumatic brain injury and included those who also underwent NCCTs of the head 1 month to 1 year before and after mild traumatic brain injury for an indication unrelated to trauma. Controls underwent 3 sequential NCCTs of the head with indications unrelated to trauma. The whole-brain and intracranial volume groups were computed using ITK-SNAP. Brain volumes normalized to intracranial volumes were compared across time points using the Wilcoxon signed-rank test. We identified 48 patients from 2005 to 2015 who underwent NCCTs of the head in the emergency department for mild traumatic brain injury and had NCCTs of the head performed both before and after mild traumatic brain injury. Median normalized brain volumes significantly decreased on the follow-up study post-mild traumatic brain injury (0.86 versus 0.84, P < .001) and were similar compared with pre-mild traumatic brain injury studies (0.87 versus 0.86, P = .927). There was no significant difference between normalized brain volumes in the 48 controls. A decrease in brain volume following mild traumatic brain injury is detectable on CT and is not seen in similar patients with non-mild traumatic brain injury during a similar timeframe. Given the stability of brain volume before mild traumatic brain injury, CT volume loss may represent the subtle effects of neurodegeneration.

A comparison of brain magnetic resonance imaging lesions in multiple sclerosis by race with reference to disability progression

BackgroundWe compared the magnetic resonance imaging (MRI) features between Japanese and Caucasian patients with multiple sclerosis (MS), and identified the relationships between MRI features and disability.MethodsFrom the baseline data of phase II fingolimod trials, 95 Japanese and 246 Caucasian relapsing-remitting MS patients were enrolled. The number, volume, and distribution of brain MRI lesions were evaluated using T2-weighted (T2W) images. Cross-sectional total normalized brain volume (NBV), normalized cortical gray matter volume, normalized deep gray matter volume (NDGMV), normalized white matter volume (NWMV), and normalized thalamic volume were measured.ResultsJapanese patients had significantly lower Expanded Disability Status Scale (EDSS) scores than Caucasian patients (mean 2.0 vs. 2.3, p = 0.008), despite a similar disease duration. Japanese patients showed a trend towards fewer T2W-lesions (median 50 vs. 65, p = 0.08) and significantly lower frequencies of cerebellar and parietal lobe lesions (p = 0.02 for both) than Caucasian patients. There were no differences in T2W-lesion volume between races, whereas Japanese patients had a significantly larger T2W-lesion volume per lesion compared with Caucasian patients (median 140 mm3 vs. 85 mm3, p < 0.0001). T2W-lesion volumes were positively correlated with EDSS scores in Japanese patients (p < 0.0001). In both races, NBV, normalized cortical gray matter volume, NDGMV, and thalamic volume were negatively correlated with disease duration and EDSS scores (p < 0.01 for all). NWMV was negatively correlated with disease duration and EDSS scores only in Caucasian patients (p = 0.03 and p = 0.004, respectively). NBV, NDGMV, NWMV, and thalamic volume were consistently smaller in Japanese compared with Caucasian patients throughout the entire examined disease duration (p = 0.046, p = 0.01, p = 0.005, and p = 0.04, respectively). Japanese patients had a significantly faster reduction in NDGMV (p = 0.001), particularly for thalamic volume (p = 0.001), with disease duration compared with Caucasian patients.ConclusionsGray matter atrophy is a common denominator for disability in Japanese and Caucasian patients. Additional contributory factors for disability include T2W-lesion volume in Japanese patients and white matter atrophy in Caucasian patients. Less frequent parietal and cerebellar involvement with fewer T2W-lesions may underlie milder disability in Japanese patients.

Structural MRI Correlates of Cognitive Event-Related Potentials in Multiple Sclerosis.

Cognitive impairment in multiple sclerosis has been associated with cognitive event-related potentials and MRI abnormalities. This study aims to explore for the first time the association between P300 and MRI in multiple sclerosis. Fifty-eight relapsing-remitting patients (41.5 ± 10.5 years old, 41 women, disease duration 139.7 ± 84.9 months) and 51 healthy controls were used. Visual P300 responses and a set of 2- or 3-dimensional MRI indices were obtained. Neuropsychological testing and psychological evaluations were also performed. Multiple sclerosis patients had significantly lower P300 amplitude and more prolonged P300 latencies and reaction times than healthy controls. In total, 67.2% of patients were identified with abnormal P300 response. These patients had greater disability and physical fatigue and had lower visuospatial memory scores than those with normal P300 response. Abnormally low P300 amplitude was associated with lower peripheral gray matter volume and was correlated only with normalized frontal horn width and normalized brain volume, after adjusting for age and education. The moderating role of brain reserve was also documented. P300 event-related potential was related to both linear and volumetric MRI markers. Future studies should expand these results in other disease types and longitudinally. Event-related potentials could serve as an ancillary tool for cognitive assessment in multiple sclerosis.

MRI Markers and Functional Performance in Patients With CIS and MS: A Cross-Sectional Study.

Introduction: Brain atrophy is a widely accepted marker of disease severity with association to clinical disability in multiple sclerosis (MS). It is unclear to which extent this association reflects common age effects on both atrophy and function.Objective: To explore how functional performance in gait, upper extremities and cognition is associated with brain atrophy in patients with Clinically Isolated Syndrome (CIS) and relapsing-remitting MS (RRMS), controlling for effects of age and sex.Methods: In 27 patients with CIS, 59 with RRMS (EDSS ≤3) and 63 healthy controls (HC), 3T MRI were analyzed for T2 lesion count (T2C), volume (T2V) and brain volumes [normalized brain volume (NBV), gray matter volume (NGMV), white matter volume (NWMV), thalamic volume (NThalV)]. Functional performance was measured with short maximum walking speed (SMSW speed), 9-hole peg test (9HPT) and symbol digit modalities test (SDMT). Linear regression models were created for functional variables with stepwise inclusion of age, sex and MR imaging markers.Results: CIS differed from HC only in T2C and T2V. RRMS differed from HC in NBV, NGMV and NThalV, T2C and T2V, but not in NWMV. A strong association with age was seen in HC, CIS and RRMS groups for NBV (r = −0.5 to −0.6) and NGMV (r = −0.6 to −0.8). Associations with age were seen in HC and RRMS but not CIS for NThalV (r = −0.3; r = −0.5), T2C (rs = 0.3; rs = 0.2) and T2V (rs = 0.3; rs = 0.3). No effect of age was seen on NWMV. Correlations of functional performance with age in RRMS were seen for SMSW speed, 9HPTand SDMT (r = −0.27 to −0.46). Regression analyses yielded significant models only in the RRMS group for 9HPT, SMSW speed and EDSS. These included NBV, NGMV, NThalV, NWMV, logT2V, age and sex as predictors. NThalV was the only MRI variable predicting a functional measure (9HPTr) with a higher standardized beta than age and sex (R2 = 0.36, p < 1e-04).Conclusion: Thalamic atrophy was a stronger predictor of hand function (9HPT) in RRMS, than age and sex. This underlines the clinical relevance of thalamic atrophy and the relevance of hand function as a clinical marker even in mildly disabled patients.

MRI-Based Brain Volumetry at a Single Time Point Complements Clinical Evaluation of Patients With Multiple Sclerosis in an Outpatient Setting.

Purpose: Thalamic atrophy and whole brain atrophy in multiple sclerosis (MS) are associated with disease progression. The motivation of this study was to propose and evaluate a new grouping scheme which is based on MS patients' whole brain and thalamus volumes measured on MRI at a single time point.Methods: In total, 185 MS patients (128 relapsing-remitting (RRMS) and 57 secondary-progressive MS (SPMS) patients) were included from an outpatient facility. Whole brain parenchyma (BP) and regional brain volumes were derived from single time point MRI T1 images. Standard scores (z-scores) were computed by comparing individual brain volumes against corresponding volumes from healthy controls. A z-score cut-off of −1.96 was applied to separate pathologically atrophic from normal brain volumes for thalamus and whole BP (accepting a 2.5% error probability). Subgroup differences with respect to the Symbol Digit Modalities Test (SDMT) and the Expanded Disability Status Scale (EDSS) were assessed.Results: Except for two, all MS patients showed either no atrophy (group 0: 61 RRMS patients, 10 SPMS patients); thalamic but no BP atrophy (group 1: 37 RRMS patients; 18 SPMS patients) or thalamic and BP atrophy (group 2: 28 RRMS patients; 29 SPMS patients). RRMS patients without atrophy and RRMS patients with thalamic atrophy did not differ in EDSS, however, patients with thalamus and BP atrophy showed significantly higher EDSS scores than patients in the other groups.Conclusion: MRI-based brain volumetry at a single time point is able to reliably distinguish MS patients with isolated thalamus atrophy (group 1) from those without brain atrophy (group 0). MS patients with isolated thalamus atrophy might be at risk for the development of widespread atrophy and disease progression. Since RRMS patients in group 0 and 1 are clinically not distinguishable, the proposed grouping may aid identification of RRMS patients at risk of disease progression and thus complement clinical evaluation in the routine patient care.