Changes in diffusion tensor imaging indices in basal ganglia and thalamus of patients with Relapsing-Remitting Multiple Sclerosis and relation with clinical conditions: A case-control study.

Background: Multiple sclerosis (MS) is recognized as the most prevalent autoimmune abnormality of the CNS. T1WI, T2WI, and FLAIR are limited in the quantification of tissue damage and detection of tissue alterations in white and grey matter in MS. This study aimed to the evaluation of changes in DTI indices in these patients at the thalamus and basal ganglia. Methods: 30 relapsing-remitting MS (RRMS) cases and 30 normal individuals were included. Conventional MRI (T2, FLAIR) was acquired to confirm NAGM in MS patients. A T1 MPRAGE protocol was used to normalize DTI images. FSL, SPM, and Explore DTI software were employed to reach Mean Diffusivities (MD), Axial Diffusivities (AD), Fractional anisotropy (FA), and Radial Diffusivity (RD) at the thalamus and the basal ganglia. Results: The FA and RD of the thalamus were decreased in healthy controls compared to MS cases (0.319 vs. 0.296 and 0.0009 vs. 0.0006, respectively) (P < 0.05). The AD value in the thalamus and the FA value in the caudate nucleus were significantly lower in MS cases than in controls (0.0009 vs. 0.0011 and 0.16 vs. 0.18, respectively) (P < 0.05). MD values in the thalamus or basal ganglia were not significantly different between groups. Conclusions: DTI measures including FA, RD, and AD have a good diagnostic performance in detecting microstructural changes in the normal-appearing thalamus in cases with RRMS while they had no significant relationship with clinical signs in terms of EDSS. Availability of data and material: Not applicable.

Tensor-valued diffusion magnetic resonance imaging in a radiotherapy setting.

Background and purpose: Diagnostic information about cell density variations and microscopic tissue anisotropy can be gained from tensor-valued diffusion magnetic resonance imaging (MRI). These properties of tissue microstructure have the potential to become novel imaging biomarkers for radiotherapy response. However, tensor-valued diffusion encoding is more demanding than conventional encoding, and its compatibility with MR scanners that are dedicated to radiotherapy has not been established. Thus, our aim was to investigate the feasibility of tensor-valued diffusion MRI with radiotherapy dedicated MR equipment. Material and methods: A tensor-valued diffusion protocol was implemented, and five healthy volunteers were scanned with different resolutions using conventional head coil and radiotherapy coil setup with fixation masks. Signal-to-noise-ratio (SNR) was evaluated to assess the risk of signal bias due to rectified noise floor. We also evaluated the repeatability and reproducibility of the microstructure parameters. One patient with brain metastasis was scanned to investigate the image quality and the transferability of the setup to diseased tissue. Results: A resolution of 3 × 3 × 3 mm3 provided images with SNR > 3 for 93 % of the voxels using radiotherapy coil setup. The parameter maps and repeatability characteristics were comparable to those observed with a conventional head coil. The patient evaluation demonstrated successful parameter analysis also in tumor tissue, with SNR > 3 for 93 % of the voxels. Conclusion: We demonstrate that tensor-valued diffusion MRI is compatible with radiotherapy fixation masks and coil setup for investigations of microstructure parameters. The reported reproducibility may be used to plan future investigations of imaging biomarkers in brain cancer radiotherapy.

Intracisternal administration of tanshinone IIA-loaded nanoparticles leads to reduced tissue injury and functional deficits in a porcine model of ischemic stroke.

BACKGROUND: The absolute number of new stroke patients is annually increasing and there still remains only a few Food and Drug Administration (FDA) approved treatments with significant limitations available to patients. Tanshinone IIA (Tan IIA) is a promising potential therapeutic for ischemic stroke that has shown success in pre-clinical rodent studies but lead to inconsistent efficacy results in human patients. The physical properties of Tan-IIA, including short half-life and low solubility, suggests that Poly (lactic-co-glycolic acid) (PLGA) nanoparticle-assisted delivery may lead to improve bioavailability and therapeutic efficacy. The objective of this study was to develop Tan IIA-loaded nanoparticles (Tan IIA-NPs) and to evaluate their therapeutic effects on cerebral pathological changes and consequent motor function deficits in a pig ischemic stroke model. RESULTS: Tan IIA-NP treated neural stem cells showed a reduction in SOD activity in in vitro assays demonstrating antioxidative effects. Ischemic stroke pigs treated with Tan IIA-NPs showed reduced hemispheric swelling when compared to vehicle only treated pigs (7.85 ± 1.41 vs. 16.83 ± 0.62%), consequent midline shift (MLS) (1.72 ± 0.07 vs. 2.91 ± 0.36 mm), and ischemic lesion volumes (9.54 ± 5.06 vs. 12.01 ± 0.17 cm3) when compared to vehicle-only treated pigs. Treatment also lead to lower reductions in diffusivity (-37.30 ± 3.67 vs. -46.33 ± 0.73%) and white matter integrity (-19.66 ± 5.58 vs. -30.11 ± 1.19%) as well as reduced hemorrhage (0.85 ± 0.15 vs 2.91 ± 0.84 cm3) 24 h post-ischemic stroke. In addition, Tan IIA-NPs led to a reduced percentage of circulating band neutrophils at 12 (7.75 ± 1.93 vs. 14.00 ± 1.73%) and 24 (4.25 ± 0.48 vs 5.75 ± 0.85%) hours post-stroke suggesting a mitigated inflammatory response. Moreover, spatiotemporal gait deficits including cadence, cycle time, step time, swing percent of cycle, stride length, and changes in relative mean pressure were less severe post-stroke in Tan IIA-NP treated pigs relative to control pigs. CONCLUSION: The findings of this proof of concept study strongly suggest that administration of Tan IIA-NPs in the acute phase post-stroke mitigates neural injury likely through limiting free radical formation, thus leading to less severe gait deficits in a translational pig ischemic stroke model. With stroke as one of the leading causes of functional disability in the United States, and gait deficits being a major component, these promising results suggest that acute Tan IIA-NP administration may improve functional outcomes and the quality of life of many future stroke patients.

Cerebral Micro-Structural Changes in COVID-19 Patients - An MRI-based 3-month Follow-up Study.

BACKGROUND: Increasing evidence supported the possible neuro-invasion potential of SARS-CoV-2. However, no studies were conducted to explore the existence of the micro-structural changes in the central nervous system after infection. We aimed to identify the existence of potential brain micro-structural changes related to SARS-CoV-2. METHODS: In this prospective study, diffusion tensor imaging (DTI) and 3D high-resolution T1WI sequences were acquired in 60 recovered COVID-19 patients (56.67% male; age: 44.10 ± 16.00) and 39 age- and sex-matched non-COVID-19 controls (56.41% male; age: 45.88 ± 13.90). Registered fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD) were quantified for DTI, and an index score system was introduced. Regional volumes derived from Voxel-based Morphometry (VBM) and DTI metrics were compared using analysis of covariance (ANCOVA). Two sample t-test and Spearman correlation were conducted to assess the relationships among imaging indices, index scores and clinical information. FINDINGS: In this follow-up stage, neurological symptoms were presented in 55% COVID-19 patients. COVID-19 patients had statistically significantly higher bilateral gray matter volumes (GMV) in olfactory cortices, hippocampi, insulas, left Rolandic operculum, left Heschl's gyrus and right cingulate gyrus and a general decline of MD, AD, RD accompanied with an increase of FA in white matter, especially AD in the right CR, EC and SFF, and MD in SFF compared with non-COVID-19 volunteers (corrected p value <0.05). Global GMV, GMVs in left Rolandic operculum, right cingulate, bilateral hippocampi, left Heschl's gyrus, and Global MD of WM were found to correlate with memory loss (p value <0.05). GMVs in the right cingulate gyrus and left hippocampus were related to smell loss (p value <0.05). MD-GM score, global GMV, and GMV in right cingulate gyrus were correlated with LDH level (p value <0.05). INTERPRETATION: Study findings revealed possible disruption to micro-structural and functional brain integrity in the recovery stages of COVID-19, suggesting the long-term consequences of SARS-CoV-2. FUNDING: Shanghai Natural Science Foundation, Youth Program of National Natural Science Foundation of China, Shanghai Sailing Program, Shanghai Science and Technology Development, Shanghai Municipal Science and Technology Major Project and ZJ Lab.

Kinematic Measures of Bimanual Performance are Associated With Callosum White Matter Change in People With Chronic Stroke.

OBJECTIVES: To investigate the relationship between bimanual performance deficits measured using kinematics and callosum (CC) white matter changes that occur in people with chronic stroke. DESIGN: Cross-sectional, observational study of participants with chronic stroke and age-matched controls. SETTING: Recruitment and assessments occurred at a stroke recovery research center. Behavioral assessments were performed in a controlled laboratory setting. Magnetic resonance imaging scans were performed at the Center for Biomedical Imaging. PARTICIPANTS: Individuals were enrolled and completed the study (N=39; 21 participants with chronic stroke; 18 age-matched controls with at least 2 stroke risk factors). MAIN OUTCOME MEASURES: Diffusion imaging metrics were obtained for each individual's CC and corticospinal tract (CST), including mean kurtosis (MK) and fractional anisotropy (FA). A battery of motor assessments, including bimanual kinematics, were collected from individuals while performing bimanual reaching. RESULTS: Participants with stroke had lower FA and MK in the CST of the lesioned hemisphere when compared with the non-lesioned hemisphere. The FA and MK values in the CST were correlated with measures of unimanual hand performance. In addition, participants with stroke had significantly lower FA and MK in the CC than matched controls. CC diffusion metrics positively correlated with hand asymmetry and trunk displacement during bimanual performance, even when correcting for age and lesion volume. CONCLUSIONS: These data confirm previous studies that linked CST integrity to unimanual performance and provide new data demonstrating a link between CC integrity and both bimanual motor deficits and compensatory movements.

Decreased Value of Highly Accurate Fractional Anisotropy Using 3-Tesla ZOOM Diffusion Tensor Imaging After Decompressive Surgery in Patients with Cervical Spondylotic Myelopathy: Aligned Fibers Effect.

BACKGROUND: Diffusion tensor imaging (DTI) is widely used; however, most of the prior studies have resulted in presurgical decreased fractional anisotropy (FA) values in patients with cervical spondylotic myelopathy (CSM). We used ZOOM DTI and could acquire highly accurate FA values during perioperative periods, which indicated different insights than preceding studies. The objective of this study was to assess the perioperative FA change in patients with CSM and determine the prognostic factor. METHODS: Twenty-eight patients with CSM and healthy control subjects were enrolled in this study. Twenty patients (71%) had intracordal high intensity before surgery. All patients underwent decompressive surgery. ZOOM DTI and the Japanese Orthopaedic Association (JOA) assessment were performed before and after surgery. The region of interest was manually contoured to omit the surrounding cerebrospinal fluid. The axial plane of the most stenotic cervical level was assessed. RESULTS: FA values before surgery and at 1 week after surgery, and FA values at 1 week after surgery and at 6 months after surgery differed significantly as determined. The FA values of patients with intracordal high intensity significantly decreased after surgery and significantly increased from 1 week to 6 months, whereas those of patients without intracordal high intensity did not significantly change. JOA scores at 6 months after surgery (13.1) improved significantly compared with JOA scores before surgery (10.8). Only FA values at 1 week after surgery had a significant positive relationship with JOA scores presurgery and at 6 months after surgery. CONCLUSIONS: The presurgical FA value in patients with CSM did not differ from that of normal control subjects, but significantly decreased after surgery, and significantly increased 6 months after surgery. We concluded that the postsurgical FA value approximates the proper state of the damaged cord and the presurgical FA value includes a masked effect as an aligned fiber effect because of compression by degenerative construction. Only the FA value at 1 week had a significant positive relationship with the JOA score presugery and at 6 months, which established that the postsurgical FA value may be a more accurate prognostic factor than the presurgical FA value.

Efficacy of diffusion tensor imaging in identification of degenerative cervical spondylotic myelopathy.

AIM AND OBJECTIVES: To study the diagnostic accuracy of Diffusion tensor imaging technique in detection of cervical spondylotic myelopathy changes. MATERIAL AND METHOD: Study population included 50 patients with symptoms of cervical myelopathy. The patients were evaluated based on symptoms using the European myelopathy scoring system and were divided into: Grade 1, including patients with mild symptoms; Grade 2, referring to patients with moderate symptoms and Grade 3, which included patients revealing severe symptoms. All the patients were investigated with a 1.5 T MRI unit acquiring DWI and DTI sequences. FA and ADC values from each spinal segment were analyzed in terms of Frequency, Percentage, Mean, Standard Deviation and Confidence Intervals. The comparison of values was done by ANOVA and post hoc analysis by bonferroni test. Comparison of accuracy of FA, ADC and T2WI in recognizing myelopathic changes was done by t-test. Receiver Operating Characteristics (ROC) analysis was performed to obtain a cut off value of FA and ADC for each spinal level to identify myelopathic change in the spinal cord. RESULTS: The study revealed a significant difference in the mean FA and ADC value of stenotic and Non-stenotic segments. T2WI was highly significant (p = 0.000) in recognizing myelopathy changes in patients falling under Grade 2(moderate) and Grade 3(severe) according to European Myelopathy scoring system. Regarding patients under Grade 1 (mild) FA and ADC values showed significant difference compared to T2WI. The collective sensitivity in the identification of myelopathic changes was highest with FA (79%) as compared to ADC (71%) and T2WI (50%). ROC analysis was done to determine the cut off values of FA and ADC at each cervical spine segments. The proposed cut off, for FA and ADC at the level of C1-C2 is 0.68 and 0.92, C2-C3 is 0.65 and 1.03, C3-C4 is 0.63 and 1.01, C4-C5 0.61 and 0.98, At C5-C6 0.57 and 1.04, At C6-C7 0.56 and 0.96 respectively. CONCLUSION: FA and ADC values enhance the efficacy and accuracy of MRI in the diagnosis of cervical spondylotic myelopathy. Hence diffusion tensor imaging can be used as a non-invasive modality to recognize spondylotic myelopathy changes even in the early stages, which can be helpful in deciding on appropriate timing of decompression surgery before the irreversible chronic changes set in.

The Serum BDNF Level Offers Minimum Predictive Value for Motor Function Recovery After Stroke.

Brain-derived neurotrophic factor (BDNF) plays an important role in neuroplasticity and neurogenesis following ischemic and non-ischemic brain injury. The predictive value of BDNF for short-term outcome after stroke is controversial. The objective of this study was to investigate the relationship among serum BDNF level, fractional anisotropy (FA), and functional outcome during post-acute stroke rehabilitation. Serum BDNF levels were measured on admission to an acute inpatient rehabilitation hospital. The primary functional outcome was functional independence measure (FIM) motor subscore at discharge. The secondary outcome measures were FIM total score at discharge, FIM motor subscore on admission, length of stay in the hospital, and discharge destination. We investigated the relationship among the level of serum BDNF and FA as well as functional outcome measures. Three hundred forty-eight consecutive stroke subjects were included in the analysis. Serum BDNF levels on admission were statistically but not clinically correlated with FIM motor subscore at discharge (r = 0.173, P = 0.001) and FIM total score at discharge (r = 0.155, P = 0.004). Receiver operating characteristic (ROC) analysis of BDNF as a predictor for FIM motor subscore improvement showed low accuracy of prediction with an area under the curve (AUC) of 0.581 (P = 0.026). Serum BDNF significantly correlated with FA in the high FIM motor group (n = 10, r = 0.609, P = 0.031) but not in the low FIM motor group (n = 11, r = - 0.132, P = 0.349). The serum BDNF level alone offers minimum predictive value for recovery of motor function during post-acute rehabilitation. Our findings suggest that serum BDNF level may be correlated with FA.

Single-subject classification of presymptomatic frontotemporal dementia mutation carriers using multimodal MRI.

Background: Classification models based on magnetic resonance imaging (MRI) may aid early diagnosis of frontotemporal dementia (FTD) but have only been applied in established FTD cases. Detection of FTD patients in earlier disease stages, such as presymptomatic mutation carriers, may further advance early diagnosis and treatment. In this study, we aim to distinguish presymptomatic FTD mutation carriers from controls on an individual level using multimodal MRI-based classification. Methods: Anatomical MRI, diffusion tensor imaging (DTI) and resting-state functional MRI data were collected in 55 presymptomatic FTD mutation carriers (8 microtubule-associated protein Tau, 35 progranulin, and 12 chromosome 9 open reading frame 72) and 48 familial controls. We calculated grey and white matter density features from anatomical MRI scans, diffusivity features from DTI, and functional connectivity features from resting-state functional MRI. These features were applied in a recently introduced multimodal behavioural variant FTD (bvFTD) classification model, and were subsequently used to train and test unimodal and multimodal carrier-control models. Classification performance was quantified using area under the receiver operator characteristic curves (AUC). Results: The bvFTD model was not able to separate presymptomatic carriers from controls beyond chance level (AUC = 0.570, p = 0.11). In contrast, one unimodal and several multimodal carrier-control models performed significantly better than chance level. The unimodal model included the radial diffusivity feature and had an AUC of 0.646 (p = 0.021). The best multimodal model combined radial diffusivity and white matter density features (AUC = 0.680, p = 0.005). Conclusions: FTD mutation carriers can be separated from controls with a modest AUC even before symptom-onset, using a newly created carrier-control classification model, while this was not possible using a recent bvFTD classification model. A multimodal MRI-based classification score may therefore be a useful biomarker to aid earlier FTD diagnosis. The exclusive selection of white matter features in the best performing model suggests that the earliest FTD-related pathological processes occur in white matter.

Functional and structural connectivity of the amygdala underpins locus of control in mild cognitive impairment.

Locus of control (LOC) is an important personality trait. LOC over cognitive competency reflects an individual's perceived control of desired cognitive outcomes, which is critical for maintaining successful cognitive aging. It is important to understand the neural substrates of LOC over cognitive competency in older adults, especially for individuals at high risk of dementia. Here, we characterized a cohesive functional and structural connectivity profile underlying LOC among 55 older adults with amnestic mild cognitive impairment (aMCI), combining resting-state functional magnetic resonance imaging and diffusion tensor imaging. The results showed that both functional and structural connectivity between the medial prefrontal cortex and amygdala were significantly correlated with external LOC. The functional connectivity mediated the correlation between structural connectivity and external LOC. In addition, aging-associated neurodegeneration moderated the relationship between structural connectivity and external LOC, showing that the structural connectivity was positively correlated with external LOC in low, but not high neurodegeneration. Our results suggest a critical role of the functional amygdala-frontal network, which may serve as a bridge between its white matter tract and LOC over cognitive competency in groups at high risk for dementia.

Integrated imaging of [11C]-PBR28 PET, MR diffusion and magnetic resonance spectroscopy 1H-MRS in amyotrophic lateral sclerosis.

Objective: To determine the relationship between brain tissue metabolites measured by in vivo magnetic resonance spectroscopy (1H-MRS), and glial activation assessed with [11C]-PBR28 uptake in people with amyotrophic lateral sclerosis (ALS). Methods: Forty ALS participants were evaluated clinically using the revised ALS functional rating scale (ALSFRS-R) and upper motor neuron burden (UMNB). All participants underwent simultaneous brain [11C]-PBR28 PET and MR imaging including diffusion tensor imaging to acquire fractional anisotropy (FA). [11C]-PBR28 uptake was measured as standardized uptake values normalized by whole brain mean (SUVR). 1H-MRS metabolite ratios (myo-inositol/creatine, mI/Cr; N-acetylaspartate/creatine, NAA/Cr) were measured within the precentral gyri and brain stem (regions known to be involved in ALS pathophysiology), and precuneus (which served as a control region). Whole brain voxel-wise correlation analyses were employed to identify brain regions exhibiting an association between metabolites within the VOIs and [11C]-PBR28 uptake. Results: In the precentral gyri, [11C]-PBR28 uptake correlated positively with mI/Cr and negatively with NAA/Cr. The same correlations were not statistically significant in the brain stem, or in the control precuneus region. Whole brain voxel-wise correlation analyses between the estimated brain metabolites within the VOIs and SUVR were highly correlated in the precentral gyri. Decreased FA values in the precentral gyri were correlated with reduced NAA/Cr and elevated mI/Cr. Higher UMNB was correlated with increased [11C]-PBR28 uptake and mI/Cr, and decreased NAA/Cr. ALSFRS-R total score correlated positively with NAA/Cr and negatively with mI/Cr. Conclusion: Integrated PET-MR and 1H-MRS imaging demonstrates associations between markers for neuronal integrity and neuroinflammation and may provide valuable insights into disease mechanisms in ALS.

Urgent challenges in quantification and interpretation of brain grey matter atrophy in individual MS patients using MRI.

Atrophy of the brain grey matter (GM) is an accepted and important feature of multiple sclerosis (MS). However, its accurate measurement is hampered by various technical, pathological and physiological factors. As a consequence, it is challenging to investigate the role of GM atrophy in the disease process as well as the effect of treatments that aim to reduce neurodegeneration. In this paper we discuss the most important challenges currently hampering the measurement and interpretation of GM atrophy in MS. The focus is on measurements that are obtained in individual patients rather than on group analysis methods, because of their importance in clinical trials and ultimately in clinical care. We discuss the sources and possible solutions of the current challenges, and provide recommendations to achieve reliable measurement and interpretation of brain GM atrophy in MS.

Longitudinal structural gray matter and white matter MRI changes in presymptomatic progranulin mutation carriers.

Introduction: Mutations in the progranulin (GRN) gene are a major source of inherited frontotemporal degeneration (FTD) spectrum disorders associated with TDP-43 proteinopathy. We use structural MRI to identify regions of baseline differences and longitudinal changes in gray matter (GM) and white matter (WM) in presymptomatic GRN mutation carriers (pGRN+) compared to young controls (yCTL). Methods: Cognitively intact first-degree relatives of symptomatic GRN+ FTD patients with identified GRN mutations (pGRN+; N = 11, mean age = 41.4) and matched yCTL (N = 11, mean age = 53.6) were identified. They completed a MRI session with T1-weighted imaging to assess GM density (GMD) and diffusion-weighted imaging (DWI) to assess fractional anisotropy (FA). Participants completed a follow-up session with T1 and DWI imaging (pGRN+ mean interval 2.20 years; yCTL mean interval 3.27 years). Annualized changes of GMD and FA were also compared. Results: Relative to yCTL, pGRN+ individuals displayed reduced GMD at baseline in bilateral orbitofrontal, insular, and anterior temporal cortices. pGRN+ also showed greater annualized GMD changes than yCTL at follow-up in right orbitofrontal and left occipital cortices. We also observed reduced FA at baseline in bilateral superior longitudinal fasciculus, left corticospinal tract, and frontal corpus callosum in pGRN+ relative to yCTL, and pGRN+ displayed greater annualized longitudinal FA change in right superior longitudinal fasciculus and frontal corpus callosum. Conclusions: Longitudinal MRI provides evidence of progressive GM and WM changes in pGRN+ participants relative to yCTL. Structural MRI illustrates the natural history of presymptomatic GRN carriers, and may provide an endpoint during disease-modifying treatment trials for pGRN+ individuals at risk for FTD.

Comparison of probabilistic tractography and tract-based spatial statistics for assessing optic radiation damage in patients with autoimmune inflammatory disorders of the central nervous system.

Background: Diffusion Tensor Imaging (DTI) can evaluate microstructural tissue damage in the optic radiation (OR) of patients with clinically isolated syndrome (CIS), early relapsing-remitting multiple sclerosis and neuromyelitis optica spectrum disorders (NMOSD). Different post-processing techniques, e.g. tract-based spatial statistics (TBSS) and probabilistic tractography, exist to quantify this damage. Objective: To evaluate the capacity of TBSS-based atlas region-of-interest (ROI) combination with 1) posterior thalamic radiation ROIs from the Johns Hopkins University atlas (JHU-TBSS), 2) Juelich Probabilistic ROIs (JUEL-TBSS) and tractography methods using 3) ConTrack (CON-PROB) and 4) constrained spherical deconvolution tractography (CSD-PROB) to detect OR damage in patients with a) NMOSD with prior ON (NMOSD-ON), b) CIS and early RRMS patients with ON (CIS/RRMS-ON) and c) CIS and early RRMS patients without prior ON (CIS/RRMS-NON) against healthy controls (HCs). Methods: Twenty-three NMOSD-ON, 18 CIS/RRMS-ON, 21 CIS/RRMS-NON, and 26 HCs underwent 3 T MRI. DTI data analysis was carried out using JUEL-TBSS, JHU-TBSS, CON-PROB and CSD-PROB. Optical coherence tomography (OCT) and visual acuity testing was performed in the majority of patients and HCs. Results: Absolute OR fractional anisotropy (FA) values differed between all methods but showed good correlation and agreement in Bland-Altman analysis. OR FA values between NMOSD and HC differed throughout the methodologies (p-values ranging from p < 0.0001 to 0.0043). ROC-analysis and effect size estimation revealed higher AUCs and R2 for CSD-PROB (AUC = 0.812; R2 = 0.282) and JHU-TBSS (AUC = 0.756; R2 = 0.262), compared to CON-PROB (AUC = 0.742; R2 = 0.179) and JUEL-TBSS (AUC = 0.719; R2 = 0.161). Differences between CIS/RRMS-NON and HC were only observable in CSD-PROB (AUC = 0.796; R2 = 0.094). No significant differences between CIS/RRMS-ON and HC were detected by any of the methods. Conclusions: All DTI post-processing techniques facilitated the detection of OR damage in patient groups with severe microstructural OR degradation. The comparison of distinct disease groups by use of different methods may lead to different - either false-positive or false-negative - results. Since different DTI post-processing approaches seem to provide complementary information on OR damage, application of distinct methods may depend on the relevant research question.

Microstructure of the superior temporal gyrus and hallucination proneness - a multi-compartment diffusion imaging study.

Previous studies reported that the volume of the left superior temporal gyrus (STG) is reduced in patients with schizophrenia and negatively correlated with hallucination severity. Moreover, diffusion-tensor imaging studies suggested a relationship between the brain microstructure in the STG of patients and auditory hallucinations. Hallucinations are also experienced in non-patient groups. This study investigated the relationship between hallucination proneness and the brain structure of the STG. Hallucination proneness was assessed by the Launey Slade Hallucination Scale (LSHS) in 25 healthy individuals who varied in their propensity to hear voices. Brain volume and microstructure of the STG was assessed by magnetic resonance imaging (MRI). Microstructure was examined by conventional diffusion-tensor imaging as well as by neurite orientation dispersion and density imaging (NODDI). The latter decomposes diffusion-based MRI into multiple compartments that characterize the brain microstructure by its neurite complexity known as orientation dispersion (ODI) and by its neurite density (NDI). Hallucination proneness was negatively correlated with the volume and microstructure (fractional anisotropy, neurite complexity) of the left but not the right STG. The strongest relationship (r = -0.563) was observed for neurite complexity (ODI). No correlation was observed for neurite density (NDI). These findings suggest that there is a relationship between the volume and the microstructure of the left STG and hallucination proneness. Dendritic complexity (but not neurite density) is inversely related to hallucination proneness. Metrics based on multi-compartment diffusion models seem to be more sensitive for hallucination-related neural processes than conventional MRI-based metrics.

Isolated focal dystonia phenotypes are associated with distinct patterns of altered microstructure.

Objective: Isolated adult-onset focal dystonia is considered a network disorder with disturbances to the motor basal ganglia and cerebellar circuits playing a pathophysiological role, but why specific body regions become affected remains unknown. We aimed to use diffusion tensor imaging to determine if the two most common phenotypes of focal dystonia are associated with distinguishing microstructural changes affecting the motor network. Methods: Fifteen blepharospasm patients, 20 cervical dystonia patients, and 30 age- and sex-matched healthy controls were recruited. Maps of fractional anisotropy and mean diffusivity were analyzed using a voxel-based approach and an automated region-of-interest technique to evaluate deep gray matter nuclei. Correlations between diffusion measures and dystonia severity were tested, and post hoc discriminant analyses were conducted. Results: Voxel-based analyses revealed significantly reduced fractional anisotropy in the right cerebellum and increased mean diffusivity in the left caudate of cervical dystonia patients compared to controls, as well as lower fractional anisotropy in the right cerebellum in cervical dystonia patients relative to blepharospasm patients. In addition to reduced fractional anisotropy in the bilateral caudate nucleus of cervical dystonia patients relative to controls and blepharospasm patients, region-of-interest analyses revealed significantly reduced fractional anisotropy in the right globus pallidus internus and left red nucleus of blepharospasm patients compared to both controls and cervical dystonia patients. Diffusivity measures in the red nucleus of blepharospasm patients correlated with disease severity. In a three-group discriminant analysis, participants were correctly classified with only modest reliability (67-75%), but in a two-group discriminant analysis, patients could be distinguished from each other with high reliability (83-100%). Conclusions: Different focal dystonia phenotypes are associated with distinct patterns of altered microstructure within constituent regions of basal ganglia and cerebellar circuits.

Autosomal dominant cerebellar ataxias: Imaging biomarkers with high effect sizes.

Objective: As gene-based therapies may soon arise for patients with spinocerebellar ataxia (SCA), there is a critical need to identify biomarkers of disease progression with effect sizes greater than clinical scores, enabling trials with smaller sample sizes. Methods: We enrolled a unique cohort of patients with SCA1 (n = 15), SCA2 (n = 12), SCA3 (n = 20) and SCA7 (n = 10) and 24 healthy controls of similar age, sex and body mass index. We collected longitudinal clinical and imaging data at baseline and follow-up (mean interval of 24 months). We performed both manual and automated volumetric analyses. Diffusion tensor imaging (DTI) and a novel tractography method, called fixel-based analysis (FBA), were assessed at follow-up. Effect sizes were calculated for clinical scores and imaging parameters. Results: Clinical scores worsened as atrophy increased over time (p < 0.05). However, atrophy of cerebellum and pons showed very large effect sizes (>1.2) compared to clinical scores (<0.8). FBA, applied for the first time to SCA, was sensitive to microstructural cross-sectional differences that were not captured by conventional DTI metrics, especially in the less studied SCA7 group. FBA also showed larger effect sizes than DTI metrics. Conclusion: This study showed that volumetry outperformed clinical scores to measure disease progression in SCA1, SCA2, SCA3 and SCA7. Therefore, we advocate the use of volumetric biomarkers in therapeutic trials of autosomal dominant ataxias. In addition, FBA showed larger effect size than DTI to detect cross-sectional microstructural alterations in patients relative to controls.

SPG11 mutations cause widespread white matter and basal ganglia abnormalities, but restricted cortical damage.

SPG11 mutations are the major cause of autosomal recessive Hereditary Spastic Paraplegia. The disease has a wide phenotypic variability indicating many regions of the nervous system besides the corticospinal tract are affected. Despite this, anatomical and phenotypic characterization is restricted. In the present study, we investigate the anatomical abnormalities related to SPG11 mutations and how they relate to clinical and cognitive measures. Moreover, we aim to depict how the disease course influences the regions affected, unraveling different susceptibility of specific neuronal populations. We performed clinical and paraclinical studies encompassing neuropsychological, neuroimaging, and neurophysiological tools in a cohort of twenty-five patients and age matched controls. We assessed cortical thickness (FreeSurfer software), deep grey matter volumes (T1-MultiAtlas tool), white matter microstructural damage (DTI-MultiAtlas) and spinal cord morphometry (Spineseg software) on a 3 T MRI scan. Mean age and disease duration were 29 and 13.2 years respectively. Sixty-four percent of the patients were wheelchair bound while 84% were demented. We were able to unfold a diffuse pattern of white matter integrity loss as well as basal ganglia and spinal cord atrophy. Such findings contrasted with a restricted pattern of cortical thinning (motor, limbic and parietal cortices). Electromyography revealed motor neuronopathy affecting 96% of the probands. Correlations with disease duration pointed towards a progressive degeneration of multiple grey matter structures and spinal cord, but not of the white matter. SPG11-related hereditary spastic paraplegia is characterized by selective neuronal vulnerability, in which a precocious and widespread white matter involvement is later followed by a restricted but clearly progressive grey matter degeneration.

Transient immediate postoperative homotopic functional disconnectivity in low-grade glioma patients.

Background and purpose: The aim of this longitudinal study is to evaluate large-scale perioperative resting state networks reorganization in patients with diffuse low-grade gliomas following awake surgery. Materials and methods: Eighty-two patients with diffuse low-grade gliomas were prospectively enrolled and underwent awake surgical resection. Resting-state functional images were acquired at three time points: preoperative (MRI-1), immediate postoperative (MRI-2) and three months after surgery (MRI-3). We simultaneously performed perfusion-weighted imaging. Results: Comparing functional connectivity between MRI-1 and MRI-2, we observed a statistically significant functional homotopy decrease in cortical and subcortical supratentorial structures (P < 0.05). A functional homotopy increase was observed between MRI-2 and MRI-3 in parietal lobes, cingulum and putamen (P < 0.05). No significant functional connectivity modification was noticed between MRI-1 and MRI-3. Regional cerebral blood flow appeared transiently reduced on MRI-2 (P < 0.05). No correlation between neurological deficit and interhemispheric connectivity results was found. Conclusion/interpretation: We found a supratentorial widely distributed functional homotopy disruption between preoperative and immediate postoperative time points with a complete restitution three months after surgery with simultaneous variation of regional cerebral blood flow.

Reconstruction of white matter fibre tracts using diffusion kurtosis tensor imaging at 1.5T: Pre-surgical planning in patients with gliomas.

Tractography studies for pre-surgical planning of primary brain tumors is typically done using diffusion tensor imaging (DTI), which cannot resolve crossing, kissing or highly angulated fibres. Tractography based on the estimation of the diffusion kurtosis (DK) tensor was recently demonstrated to enable tackling these limitations. However, its use in the clinical context at low 1.5T field has not yet been reported. PURPOSE: To evaluate if the estimation of whole-brain tractography using the DK tensor is feasible for pre-surgical investigation of patients with brain tumors at 1.5T. METHODS: Eight healthy subjects and 3 patients with brain tumors were scanned at 1.5T using a 12-channel head coil. Diffusion-weighted images were acquired with repetition/echo times of 5800/107 ms, 82 × 82 resolution, 3 × 3 × 3 mm3 voxel size, b-values of 0, 1000, 2000 s/mm2 and 64 gradient sensitising directions. Whole-brain tractography was estimated using the DK tensor and corticospinal tracts (CST) were isolated using regions-of-interest placed at the cerebral peduncles and motor gyrus. Tract size, DK metrics and CST deviation index (highest curvature point) were compared between healthy subjects and patients. RESULTS: Tract sizes did not differ between groups. The CST deviation index was significantly higher in patients compared to healthy subjects. Fractional anisotropy was significantly lower in patients, with higher mean kurtosis asymmetry index at the highest curvature point in patients. CONCLUSIONS: Corticospinal fibre bundles estimated using DK tensor in a 1.5T scanner presented similar properties in patients with brain gliomas as those reported in the literature using DTI-based tractography.