Putaminal Volume Research Articles

Surface-Based Neuroimaging Pattern of Multiple System Atrophy

Overlapping parkinsonism, cerebellar ataxia, and pyramidal signs render challenges in the clinical diagnosis of multiple system atrophy (MSA). The neuroimaging pattern is valuable to understand its pathophysiology and improve its diagnostic effect. We retrospectively obtained magnetic resonance imaging and susceptibility-weighted imaging in patients with MSA (including parkinsonian type [MSA-P] and cerebellar type [MSA-C]), Parkinson's disease, and normal controls. We quantified neuroimaging features to identify the optimal threshold for diagnosis. Furthermore, we explore neuroimaging patterns of MSA by mapping the subcortical morphological alterations and constructing a diagnostic model. Compared to controls, normalized putaminal volume significantly decreased in patients with MSA-P (P<.001) and normalized pontine volume significantly decreased in patients with MSA-C (P<.001). The Youden index of the threshold-based clinical prediction model was 0.871-0.928 in patients with MSA. The neuroimaging pattern in patients with MSA was jointly located in the lateral putamen, and the neuroimaging pattern prediction model achieved a classification accuracy of 83.9%-100%. The quantitative neuroimaging features and surface-based morphologic anomalies represent the markers of MSA and open new avenues for personalized clinical diagnosis.

The Endophenotypic Effect of the SORL1 Variant rs2298813 on Regional Brain Volume in Patients with Alzheimer’s Disease

AbstractBackgroundTwo common variants of sortilin‐related receptor 1 gene (SORL1), rs2298813 and rs1784933, have been associated with late‐onset Alzheimer’s disease (AD) in the Han Chinese population in Taiwan. However, neuroimaging correlates of these two SORL1 variants remain unknown. We aimed to determine whether the two SORL1 polymorphisms were associated with any volumetric differences in brain regions in AD patients.MethodsWe recruited 200 patients with late‐onset AD from Taipei Veterans General Hospital. All patients received a structural magnetic resonance imaging brain scan and completed a battery of neurocognitive tests at enrollment. We followed up to assess changes in Mini‐Mental State Examination (MMSE) scores in 155 patients (77.5%) at an interval of 2 years. Volumetric measures and cortical thickness of various brain regions were performed using FreeSurfer. Regression analysis controlled for apolipoprotein E status. Multiple comparisons were corrected for using the false discovery rate.ResultThe rs2298813 and rs1783933 genotypes were not associated with cognitive test performance or clinical progression. The homozygous major allele of rs2298813 was associated with larger volumes in the right putamen (p = 0.0442) and right pallidum (p = 0.0346). There was no link of the rs1784933 genotypes with any of the imaging measures. In the rs2298813 homozygous major allele carriers, the right putaminal volume was associated with verbal fluency (p = 0.008) and clinical progression (p = 0.020). In the minor allele carriers, the right putaminal and right pallidal volumes were not significantly related to cognitive test scores or clinical progression.ConclusionThe major and minor alleles of rs2298813 had differential effects on the right lentiform nucleus volume and distinctively modulated the association between the regional volume and cognitive function.

Neuroimaging findings in DYT1 dystonia and the pathophysiological implication: A systematic review.

Primary generalized dystonia due to the DYT1 gene is an autosomal dominant disorder caused by a GAG deletion on chromosome 9q34. It is a well-defined, genetically proven, isolated dystonia syndrome. However, its pathophysiology remains unclear. This study was aimed at profiling the functional neuroimaging findings in DYT1 dystonia and harmonizing the pathophysiological implications for DYT1 dystonia from the standpoint of different neuroimaging techniques. A systematic review was conducted using identified studies published in English from Medline, PsycINFO, Embase, CINAHL, and the Cochrane Database of Systematic Reviews (CDSR), between 1985 and December 2019 (PROSPERO protocol CRD42018111211). All DYT1 gene carriers irrespective of clinical penetrance have reduced striatal GABA, dopamine receptors and increased metabolic activity in the lentiform nucleus, supplementary motor area, and cerebellum in addition to an abnormal cerebellothalamocortical pathway. Nonmanifesting carriers on the other hand have a disruption of the distal (thalamocortical) segment and have larger putaminal volumes than manifesting carriers and healthy controls. Activation of the midbrain, thalamus, and sensorimotor cortex was only found in the manifesting carriers. Therefore, we propose that DYT1 dystonia is a cerebellostriatothalamocortical network disorder affecting either the structure or function of the different structures or nodes in the network.

Deep learning segmentation results in precise delineation of the putamen in multiple system atrophy

ObjectivesThe precise segmentation of atrophic structures remains challenging in neurodegenerative diseases. We determined the performance of a Deep Neural Patchwork (DNP) in comparison to established segmentation algorithms regarding the ability to delineate the putamen in multiple system atrophy (MSA), Parkinson’s disease (PD), and healthy controls.MethodsWe retrospectively included patients with MSA and PD as well as healthy controls. A DNP was trained on manual segmentations of the putamen as ground truth. For this, the cohort was randomly split into a training (N = 131) and test set (N = 120). The DNP’s performance was compared with putaminal segmentations as derived by Automatic Anatomic Labelling, Freesurfer and Fastsurfer. For validation, we assessed the diagnostic accuracy of the resulting segmentations in the delineation of MSA vs. PD and healthy controls.ResultsA total of 251 subjects (61 patients with MSA, 158 patients with PD, and 32 healthy controls; mean age of 61.5 ± 8.8 years) were included. Compared to the dice-coefficient of the DNP (0.96), we noted significantly weaker performance for AAL3 (0.72; p < .001), Freesurfer (0.82; p < .001), and Fastsurfer (0.84, p < .001). This was corroborated by the superior diagnostic performance of MSA vs. PD and HC of the DNP (AUC 0.93) versus the AUC of 0.88 for AAL3 (p = 0.02), 0.86 for Freesurfer (p = 0.048), and 0.85 for Fastsurfer (p = 0.04).ConclusionBy utilization of a DNP, accurate segmentations of the putamen can be obtained even if substantial atrophy is present. This allows for more precise extraction of imaging parameters or shape features from the putamen in relevant patient cohorts.Clinical relevance statementDeep learning-based segmentation of the putamen was superior to currently available algorithms and is beneficial for the diagnosis of multiple system atrophy.Key Points• A Deep Neural Patchwork precisely delineates the putamen and performs equal to human labeling in multiple system atrophy, even when pronounced putaminal volume loss is present.• The Deep Neural Patchwork–based segmentation was more capable to differentiate between multiple system atrophy and Parkinson’s disease than the AAL3 atlas, Freesurfer, or Fastsurfer.

Parkinsonism Is Associated with Altered SMA-Basal Ganglia Structural and Functional Connectivity in Frontotemporal Degeneration.

Patients with frontotemporal degeneration (FTD) often manifest parkinsonism, which likely results from cortical and subcortical degeneration of brain structures involved in motor control. We used a multimodal magnetic resonance imaging (MRI) approach to investigate possible structural and/or functional alterations in FTD patients with and without parkinsonism (Park+ and Park-). Thirty FTD patients (12 Park+, 18 Park-) and 30 healthy controls were enrolled and underwent 3T MRI scanning. MRI analyses included: (1) surface-based morphometry; (2) basal ganglia and thalamic volumetry; (3) diffusion-based probabilistic tractography of fiber tracts connecting the supplementary motor area (SMA) and primary motor cortex (M1) to the putamen, globus pallidus, and thalamus; and (4) resting-state functional connectivity (RSFC) between the aforementioned regions. Patients in Park+ and Park- groups showed comparable patterns of cortical thinning in frontotemporal regions and reduced thalamic volume with respect to controls. Only Park+ patients showed reduced putaminal volume and reduced fractional anisotropy of the fibers connecting the SMA to the globus pallidus, putamen, and thalamus, with respect to controls. Park+ patients also showed decreased RSFC between the SMA and putamen with respect to both Park- patients and controls. The present findings support the hypothesis that FTD patients with parkinsonism are characterized by neurodegenerative processes in specific corticobasal ganglia-thalamocortical motor loops.

Correlation of brain segmental volume changes with clinical parameters: a longitudinal study in multiple sclerosis patients

To measure the cranial volume differences from 15 different parts in the follow-up of relapsing-remitting multiple sclerosis (RRMS) patients and correlate them with clinical parameters. Forty-seven patients with RRMS were included in the study. Patients were grouped into two categories; low Expanded Disability Status Scale (EDSS) (< 3; group 1), and moderate-high EDSS (≥ 3; group 2). Patients were evaluated with Beck Depression Inventory (BDI), Montreal Cognitive Assessment (MOCA), Symbol Digit Modalities Test (SDMT), Fatigue Severity Scale (FSS), and calculated Annualized Relapse Rate (ARR) scores. Magnetic resonance imaging (MRI) was performed with a 1.5T MRI device (Magnetom AERA, Siemens, Erlangen, Germany) twice in a 1-year period. Volumetric analysis was performed by a free, automated, online MRI brain volumetry software. The differences in volumetric values between the two MRI scans were calculated and correlated with the demographic and clinical parameters of the patients. The number of attacks, disease duration, BDI, and FSS scores were higher in group 2; SDMT was higher in group 1. As expected, volumetric analyses have shown volume loss in total cerebral white matter in follow-up patients (p < 0.001). In addition, putaminal volume loss was related to a higher number of attacks. Besides, a negative relation between FSS with total amygdala volumes, a link between atrophy of globus pallidus and ARR, and BDI scores was found with the aid of network analysis. Apart from a visual demonstration of volume loss, cranial MRI with volumetric analysis has a great potential for revealing covert links between segmental volume changes and clinical parameters.

Motor Symptoms in Early- versus Late-Onset Alzheimer's Disease.

Age at onset was suggested as one possible risk factor for motor dysfunction in Alzheimer's disease (AD). We investigated the association of motor symptoms with cognition or neurodegeneration in patients with AD, and whether this association differs by the age at onset. We included 113 amyloid positive AD patients and divided them into early-onset AD (EOAD) and late-onset AD (LOAD), who underwent the Unified Parkinson's Disease Rating Scale (UPDRS)-Part III (=UPDRS) scoring, Mini-Mental State Examination (MMSE)/Clinical Deterioration Rating Sum-of-Boxes (CDR-SOB), and magnetic resonance image (MRI). Multiple linear regression was used to evaluate the association of UPDRS and MMSE/CDR-SOB or MRI neurodegeneration measures, and whether the association differs according to the group. The prevalence of motor symptoms and their severity did not differ between the groups. Lower MMSE (β= -1.1, p < 0.001) and higher CDR-SOB (β= 2.0, p < 0.001) were significantly associated with higher UPDRS. There was no interaction effect between MMSE/CDR-SOB and AD group on UPDRS. Global or all regional cortical thickness and putaminal volume were negatively associated with UPDRS score, but the interaction effect of neurodegeneration and AD group on UPDRS score was significant only in parietal lobe (p for interaction = 0.035), which showed EOAD to have a more pronounced association between parietal thinning and motor symptoms. Our study suggested that the severity of motor deterioration in AD is related to the severity of cognitive impairment itself rather than age at onset, and motor symptoms might occur through multiple mechanisms including cortical and subcortical atrophy.

Endophenotypic effects of the SORL1 variant rs2298813 on regional brain volume in patients with late-onset Alzheimer's disease.

Introduction: Two common variants of sortilin-related receptor 1 gene (SORL1), rs2298813 and rs1784933, have been associated with late-onset Alzheimer’s disease (AD) in the Han Chinese population in Taiwan. However, neuroimaging correlates of these two SORL1 variants remain unknown. We aimed to determine whether the two SORL1 polymorphisms were associated with any volumetric differences in brain regions in late-onset AD patients.Methods: We recruited 200 patients with late-onset AD from Taipei Veterans General Hospital. All patients received a structural magnetic resonance (MR) imaging brain scan and completed a battery of neurocognitive tests at enrollment. We followed up to assess changes in Mini-Mental State Examination (MMSE) scores in 155 patients (77.5%) at an interval of 2 years. Volumetric measures and cortical thickness of various brain regions were performed using FreeSurfer. Regression analysis controlled for apolipoprotein E status. Multiple comparisons were corrected for using the false discovery rate.Results: The homozygous major allele of rs2298813 was associated with larger volumes in the right putamen (p = 0.0442) and right pallidum (p = 0.0346). There was no link between the rs1784933 genotypes with any regional volume or thickness of the brain. In the rs2298813 homozygous major allele carriers, the right putaminal volume was associated with verbal fluency (p = 0.008), and both the right putaminal and pallidal volumes were predictive of clinical progression at follow-up (p = 0.020). In the minor allele carriers, neither of the nuclei was related to cognitive test performance or clinical progression.Conclusion: The major and minor alleles of rs2298813 had differential effects on the right lentiform nucleus volume and distinctively modulated the association between the regional volume and cognitive function in patients with AD.

Striatal volumes as potential biomarkers in Eating Disorders: A pilot study

IntroductionDifferences in bulimic and impulsive behaviours in Eating Disorders (ED) have been associated with cortico-striatal circuit dysfunction at a neurobiological level. We sought to investigate neo-striatal volume as a biomarker in ED subgroups as well as the possible relationship with trauma history. Material and methodsWe studied 24 female patients: Anorexia Nervosa AN (n=8), Bulimia Nervosa BN (n=9), comorbid ED with borderline personality disorder (EDc; n=7), and a group of Healthy Controls (n=19). Binge eating behaviours and impulsivity scales were used to characterize our sample as well as Trauma Questionnaires and Magnetic resonance imaging (MRI) volumetric manual measurements of caudate and putamen nuclei (striatum). ResultsOur preliminary results showed a significantly larger left putaminal volume in AN compared to the other three groups [C (p=0.008), BN (p<.001) and EDc (p=.001)] and a smaller right putaminal volume in EDc compared to controls (p=.045) and AN (p=.039).Some negative correlations were found between bilateral putaminal volumes and self-reported general and early traumatization scores. ConclusionThis pilot study suggested that striatal volumes might differentiate AN from BN and EDc at a neurobiological level with implications for treatment strategies. Larger scale studies should be carried out that allow replication of these data.

Associations of Brain Atrophy and Cerebral Iron Accumulation at MRI with Clinical Severity in Wilson Disease.

Background Abnormal findings at brain MRI in patients with neurologic Wilson disease (WD) are characterized by signal intensity changes and cerebral atrophy. T2 signal hypointensities and atrophy are largely irreversible with treatment; their relationship with permanent disability has not been systematically investigated. Purpose To investigate associations of regional brain atrophy and iron accumulation at MRI with clinical severity in participants with neurologic WD who are undergoing long-term anti-copper treatment. Materials and Methods Participants with WD and controls were compared in a prospective study performed from 2015 to 2019. MRI at 3.0 T included three-dimensional T1-weighted and six-echo multigradient-echo pulse sequences for morphometry and quantitative susceptibility mapping, respectively. Neurologic severity was assessed with the Unified WD Rating Scale (UWDRS). Automated multi-atlas segmentation pipeline with dual contrast (susceptibility and T1) was used for the calculation of volumes and mean susceptibilities in deep gray matter nuclei. Additionally, whole-brain analysis using deformation and surface-based morphometry was performed. Least absolute shrinkage and selection operator regression was used to assess the association of regional volumes and susceptibilities with the UWDRS score. Results Twenty-nine participants with WD (mean age, 47 years ± 9 [standard deviation]; 15 women) and 26 controls (mean age, 45 years ± 12; 14 women) were evaluated. Whole-brain analysis demonstrated atrophy of the deep gray matter nuclei, brainstem, internal capsule, motor cortex and corticospinal pathway, and visual cortex and optic radiation in participants with WD (P < .05 at voxel level, corrected for family-wise error). The UWDRS score was negatively correlated with volumes of putamen (r = -0.63, P < .001), red nucleus (r = -0.58, P = .001), globus pallidus (r = -0.53, P = .003), and substantia nigra (r = -0.50, P = .006) but not with susceptibilities. Only the putaminal volume was identified as a stable factor associated with the UWDRS score (R2 = 0.38, P < .001) using least absolute shrinkage and selection operator regression. Conclusion Individuals with Wilson disease (WD) had widespread brain atrophy most pronounced in the central structures. The putaminal volume was associated with the Unified WD Rating Scale score and can be used as a surrogate imaging marker of clinical severity. © RSNA, 2021 Supplemental material is available for this article. See also the editorial by Du and Bydder in this issue.

Impact of aerobic exercise on clinical and magnetic resonance imaging biomarkers in persons with multiple sclerosis: An exploratory randomized controlled trial.

BackgroundThere is insufficient knowledge about how aerobic exercise impacts the disease process of multiple sclerosis, which is characterized by accumulation of white matter lesions and accelerated brain atrophy.ObjectiveTo examine the effect of aerobic exercise on neuroinflammation and neurodegeneration by magnetic resonance imaging and clinical measures of disease activity and progression in persons with multiple sclerosis.Patients and methodsAn exploratory 12-week randomized control trial including an intervention group (n = 14, 12 weeks of aerobic exercise twice weekly) and a control group (n = 14, continuation of usual lifestyle). Primary outcomes were magnetic resonance imaging measures (lesion load, brain structure volume change), while secondary outcomes included disability measures, blood cytokine levels, cognitive tests and patient-reported outcomes.ResultsThe effects of aerobic exercise on whole brain and grey matter atrophy were minor. Surprisingly, the observed effect on volume (atrophy) in selected brain substructures was heterogeneous. Putaminal and posterior cingulate volumes decreased, parahippocampal gyrus volume increased, thalamus and amygdala volume remained the same, and active lesion load and count decreased. However, apart from weak improvements in walking speed and brain-derived neurotrophic factor levels, there was no effect of aerobic exercise on other clinical, cognitive or patient-reported outcomes.ConclusionThese results suggest that aerobic exercise in persons with multiple sclerosis has a positive effect on the volume of some of the substructures of the brain, possibly indicating a slowing of the neurodegenerative process in these regions, but a negative impact on the volume of some other substructures, with unclear implications. Further research is needed to determine whether the slight decrease in active lesion volume and count implies an anti- inflammatory effect of aerobic exercise, and the exact significance of the heterogeneous results of volumetric assessments.LAY ABSTRACTThe aim of this study was to evaluate the effects of aerobic exercise (physical exercise in the form of aerobics) on people with multiple sclerosis who were being treated with fingolimod. Two groups of patients with multiple sclerosis were studied: an intervention group (n = 14) who undertook 12 weeks of exercise training, and a control group (n = 14) who continued with their usual lifestyle. Magnetic resonance imaging, bloodwork analysis and some other clinical assessments were performed before and after the 12-week period, and the patients completed several questionnaires about their wellbeing and accompanying symptoms of multiple sclerosis. The results suggest that aerobic exercise (combined with appropriate pharmacological treatment) can positively affect some of the brain regions in people with MS by reducing the rate of their degeneration and might decrease the inflammatory activity. However, longer and larger studies should be performed to evaluate whether such rehabilitation is effective and could, in the long-term, possibly slow down the rate of disability accrual.

Structural Alterations in Deep Brain Structures in Type 1 Diabetes.

Even though well known in type 2 diabetes, the existence of brain changes in type 1 diabetes (T1D) and both their neuroanatomical and clinical features are less well characterized. To fill the void in the current understanding of this disease, we sought to determine the possible neural correlate in long-duration T1D at several levels, including macrostructural, microstructural cerebral damage, and blood flow alterations. In this cross-sectional study, we compared a cohort of 61 patients with T1D with an average disease duration of 21 years with 54 well-matched control subjects without diabetes in a multimodal MRI protocol providing macrostructural metrics (cortical thickness and structural volumes), microstructural measures (T1-weighted/T2-weighted [T1w/T2w] ratio as a marker of myelin content, inflammation, and edema), and cerebral blood flow. Patients with T1D had higher T1w/T2w ratios in the right parahippocampal gyrus, the executive part of both putamina, both thalami, and the cerebellum. These alterations were reflected in lower putaminal and thalamic volume bilaterally. No cerebral blood flow differences between groups were found in any of these structures, suggesting nonvascular etiologies of these changes. Our findings implicate a marked nonvascular disruption in T1D of several essential neural nodes engaged in both cognitive and motor processing.

Striatal volumes as potential biomarkers in Eating Disorders: A pilot study.

Differences in bulimic and impulsive behaviours in Eating Disorders (ED) have been associated with cortico-striatal circuit dysfunction at a neurobiological level. We sought to investigate neo-striatal volume as a biomarker in ED subgroups as well as the possible relationship with trauma history. We studied 24 female patients: Anorexia Nervosa AN (n=8), Bulimia Nervosa BN (n=9), comorbid ED with borderline personality disorder (EDc; n=7), and a group of Healthy Controls (n=19). Binge eating behaviours and impulsivity scales were used to characterize our sample as well as Trauma Questionnaires and Magnetic resonance imaging (MRI) volumetric manual measurements of caudate and putamen nuclei (striatum). Our preliminary results showed a significantly larger left putaminal volume in AN compared to the other three groups [C (p=0.008), BN (p<.001) and EDc (p=.001)] and a smaller right putaminal volume in EDc compared to controls (p=.045) and AN (p=.039). Some negative correlations were found between bilateral putaminal volumes and self-reported general and early traumatization scores. This pilot study suggested that striatal volumes might differentiate AN from BN and EDc at a neurobiological level with implications for treatment strategies. Larger scale studies should be carried out that allow replication of these data.

SCIDOT-35. A NOVEL MODEL FOR THE OPTIMIZATION OF DRUG-DEVICE COMBINATIONS FOR THE TREATMENT OF BRAIN TUMORS

Abstract BACKGROUND Failure of many brain tumor treatments has been attributed to the inability of a compound to cross the blood-brain barrier. Convection-enhanced delivery (CED) offers a method to administer drugs directly to the tumor site, thereby mitigating this limitation. CED has been used in several preclinical and clinical studies, though an approved treatment is yet to come to fruition. A medical device suitable for repeated intraparenchymal delivery is valuable for brain tumor treatment strategies, but a lack of appropriate preclinical models capable of infusing clinically relevant volumes has hindered progress in clinical translation. Currently utilized preclinical models include porcine, which have limited use due to their growth rates and canine and non-human primates, which are restricted by ethical considerations. This study investigates the functional characteristics and stability of the Renishaw clinical Neuroinfuse™ drug delivery system in an ovine model. METHODS A head fixation frame was refined for ovine stereotactic surgery. Eight Romney ewes were implanted with the drug delivery system, comprising of four catheters and a transcutaneous port allowing chronic re-access infusions without repeated surgery. A maximum of four infusions were performed per subject, at four to eight-week intervals. RESULTS The implantation of the Neuroinfuse™ drug delivery system was well-tolerated in all subjects, without serious device related adverse events. Artificial CSF/gadolinium infusions were performed on five subjects. Three subjects were maintained for a follow-up study. Putaminal and thalamic distribution volumes remained stable over the re-access period of up to six months post-implantation. CONCLUSION Romney ewes are suitable for the stereotactic implantation of the Neuroinfuse™ chronic drug delivery system. Transcutaneous ports remained integrated for the study duration, allowing repeated intraparenchymal delivery. This novel preclinical model provides a stable platform for infusion regime optimization of drug-device combinations for chronic CED, which will undoubtably de-risk clinical translation in the neuro-oncology CED field.

Deep grey matter involvement and altered sensory gating in multiple sclerosis

Background: Somatosensory temporal discrimination threshold (STDT) is altered in multiple sclerosis (MS). In healthy subjects (HS), voluntary movement modulates the STDT through mechanisms of subcortical sensory gating. Objective: With neurophysiological and magnetic resonance imaging (MRI) techniques, we investigated sensory gating and sensorimotor integration in MS. Methods: We recruited 38 relapsing-remitting multiple sclerosis (RR-MS) patients with no-to-mild disability and 33 HS. We tested STDT at rest and during index finger abductions and recorded the movement kinematics. Participants underwent a 3T MRI protocol. Results: Patients exhibited higher STDT values and performed slower finger movements than HS. During voluntary movement, STDT values increased in both groups, albeit to a lesser extent in patients, while the mean angular velocity of finger movements decreased in patients alone. Patients had a smaller volume of the thalamus, pallidum and caudate nucleus, and displayed higher mean diffusivity in the putamen, pallidum and thalamus. STDT correlated with thalamic volume while mean angular velocity correlated with putaminal volume. Changes in mean angular velocity during sensorimotor integration inversely correlated with mean diffusivity in the thalamus and pallidum. Changes in STDT and velocity were associated with fatigue score. Conclusion: Altered STDT and sensorimotor integration are related to structural damage in the thalamus and basal ganglia in MS and likely to affect motor performance.

Abnormalities in grey matter structure in embouchure dystonia

IntroductionEmbouchure dystonia (ED) is a debilitating movement disorder in professional brass players leading to involuntary muscle contractions/spasms during play. To date, activity changes in sensorimotor cortices during motor tasks and tactile processing, as well as connectivity changes at rest in sensorimotor and auditory brain networks have been described in the disease. ObjectiveTo characterize differences in grey matter volume and asymmetry between brass musicians suffering from ED, healthy brass musicians and healthy nonmusicians. MethodsHigh-resolution structural magnetic resonance imaging was obtained from 24 brass musicians with ED, 23 healthy brass musicians and 24 healthy nonmusicians. Whole-brain voxel-wise morphometry and asymmetry analyses, as well as region-of-interest-based volumetry analysis were performed on the subjects’ images and compared between groups. Further, correlations with clinical parameters were investigated. ResultsED patients showed increased grey matter volume in the primary sensorimotor cortex in relation to both healthy brass players and nonmusicians. Both healthy and diseased musicians showed increased thalamic symmetry in relation to nonmusicians; diseased brass musicians additionally showed increased basal ganglia symmetry compared to nonmusicians. There was an inverse correlation of disease duration with both mean putaminal volume and the extent of basal ganglia asymmetry. ConclusionThis work provides first evidence for structural abnormalities in task-specific orofacial (musician's) dystonia. Somatotopy-related structural primary sensorimotor cortex changes underlying previously observed functional abnormalities underscore the role of maladaptive plasticity in the disease. The study further shows subcortical brain (a)symmetry changes in healthy brass players and hints at a possible role of such changes in focal dystonia.

Effect of disease-modifying therapies on subcortical gray matter atrophy in multiple sclerosis

Background: The effects of disease-modifying therapies (DMTs) on region-specific brain atrophy in multiple sclerosis (MS) are unclear. Objective: To determine the effects of higher versus lower efficacy DMTs on rates of brain substructure atrophy in MS. Methods: A non-randomized, observational cohort of people with MS followed with annual brain magnetic resonance imaging (MRI) was evaluated retrospectively. Whole brain, subcortical gray matter (GM), cortical GM, and cerebral white matter (WM) volume fractions were obtained. DMTs were categorized as higher (DMT-H: natalizumab and rituximab) or lower (DMT-L: interferon-beta and glatiramer acetate) efficacy. Follow-up epochs were analyzed if participants had been on a DMT for ⩾6 months prior to baseline and had at least one follow-up MRI while on DMTs in the same category. Results: A total of 86 DMT epochs (DMT-H: n = 32; DMT-L: n = 54) from 78 participants fulfilled the study inclusion criteria. Mean follow-up was 2.4 years. Annualized rates of thalamic (−0.15% vs −0.81%; p = 0.001) and putaminal (−0.27% vs −0.73%; p = 0.001) atrophy were slower during DMT-H compared to DMT-L epochs. These results remained significant in multivariate analyses including demographics, clinical characteristics, and T2 lesion volume. Conclusion: DMT-H treatment may be associated with slower rates of subcortical GM atrophy, especially of the thalamus and putamen. Thalamic and putaminal volumes are promising imaging biomarkers in MS.

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OBJECTIVES/SPECIFIC AIMS: To identify brain regions with the highest and least variable rate of multiple sclerosis (MS)-specific atrophy using an agnostic approach, and to perform simulation-based sample size calculations for Phase II s using these regions as primary endpoint. METHODS/STUDY POPULATION: In total, 601 subjects (2638 MRI scans) were analyzed; 520 subjects with relapsing forms of MS across the spectrum of disease severity and duration were followed in a single-center prospective cohort study at an academic MS Center between 2005 and 2010 with annual 3 T MRIs and clinical visits for 5 years, including standardized 1 mm3 3D T1-weighted images (3DT1s; 2483 MRIs). Separately, a convenience sample of 81 healthy controls (HC) was recruited from the same center and scanned longitudinally using the same MRI scanner and protocol (155 MRIs). 3DT1s were processed using FreeSurfer’s longitudinal pipeline (software version 5.3). Rates of change in all cortical and subcortical regions (n=119 brain regions) were estimated in MS patients and HC with linear mixed effects models. An effect size was calculated for each region as the difference in change over time between MS patients and HC divided by the standard error of the difference [d=β(MS×time)/SE β(MS×time)]. Regions were ranked according to absolute effect size, and the top regions were chosen for simulation-based sample size calculations to estimate the number of subjects needed to achieve 80% power to detect a slowing of MS atrophy down to normal aging, assuming significance levels of 5% and 10%. Ten percent was included because some have advocated for a more relaxed alpha in Phase II s. RESULTS/ANTICIPATED RESULTS: Four regions (putamen, subcortical grey matter, caudate, and thalamus) yielded the smallest sample sizes. At 80% power, ~50 subjects per arm would be needed with putamen or subcortical grey matter volume, or ~80–85 subjects per arm with caudate or thalamic volume as primary endpoint. For the remaining regions, &gt;140 subjects per arm would be needed. A 20%–30% increase in sample size was observed when α=5% was used. DISCUSSION/SIGNIFICANCE OF IMPACT: Using an agnostic approach considering all brain regions and simulation-based sample size calculations specifically designed for longitudinal studies, putaminal, subcortical grey, caudate, and thalamic volumes are sensitive to change over time and yield feasible sample sizes for Phase II studies in MS. Because the effect size estimates incorporate normal aging, these regions represent the most sensitive outcomes for testing therapeutic interventions that target irreversible, MS-specific brain atrophy. The clinical relevance of these regions is our next focus to help inform which of these regions should be favored as primary endpoint.

Serum iron concentration is associated with subcortical deep gray matter iron levels in multiple sclerosis patients

Iron deposition has been noted widely in the subcortical deep gray matter (SDGM) of multiple sclerosis (MS) patients. Recent evidence suggests that serum iron may cross the blood-brain barrier and might be associated with SDGM iron deposition. The aim of the current study was to assess whether an iron-sensitive MRI measure is related to serum iron concentrations. This was a retrospective, cross-sectional study of 22 MS patients and 24 healthy controls (HCs), group matched for age and sex. Participants were imaged on a 1.5-T MRI scanner. High-resolution T1-weighted images and susceptibility-weighted images were acquired for assessing SDGM volumes and iron deposition within the SDGM, respectively. All participants also had blood drawn for the measurement of serum iron concentrations. MS and HC groups were compared with respect to SDGM tissue volumes and iron content. Partial correlations, controlling for age, sex, and structural volume, were used to assess the relationship between serum iron and SDGM iron content. MS patients presented with significantly smaller SDGM tissue volumes of the caudate, globus pallidus, putamen, and thalamus (all P≤0.0001). With respect to HCs, increased iron content was observed for MS patients in the globus pallidus (P=0.009) only. In MS patients only, there was a significant relationship between serum iron and putaminal iron volume (partial r=0.449, P=0.041), whereas trends were evidenced for the caudate (partial r=0.396, P=0.078) and the globus pallidus (partial r=0.410, P=0.065). Serum iron content in MS patients may be related to SDGM iron content. These results warrant confirmation in a larger study of MS patients.

Global brain atrophy and metabolic dysfunction in LGI1 encephalitis: A prospective multimodal MRI study

BackgroundChronic cognitive deficits are frequent in leucin-rich glioma-inactivated 1 protein (LGI1) encephalitis. We examined structural and metabolic brain abnormalities following LGI1 encephalitis and correlated findings with acute and follow-up clinical outcomes. MethodsNine patients underwent prospective multimodal 3 Tesla MRI 33.1±18months after disease onset, including automated volumetry, diffusion tensor imaging (DTI) and magnetic resonance spectroscopy (MRS). Data were compared to 9 age- and sex-matched healthy controls. ResultsAlthough extratemporal lesions were not present on MRI in the acute stage, tract-based spatial statistics analyses of DTI during follow-up showed widespread changes in the cerebral and cerebellar white matter (WM), most prominent in the anterior parts of the corona radiata, capsula interna and corpus callosum. MRS revealed lower glutamine/glutamate WM levels compared to controls. Higher cerebellar gray matter volume was associated with better function at disease onset (measured by the modified Rankin Scale), and higher putaminal volume was associated with better cognition by Addenbrooke's Cognitive Examination test at 23.4±7.6months. ConclusionsPoor clinical outcome following LGI1 encephalitis is associated with global brain atrophy and disintegration of white matter tracts. The pathological changes affect not only temporomesial structures but also frontal lobes and the cerebellum.