Spinal Cord Atrophy Predicts Progressive Disease in Relapsing Multiple Sclerosis.

OBJECTIVE: A major challenge in multiple sclerosis (MS) research is the understanding of silent progression and Progressive MS. Using a novel method to accurately capture upper cervical cord area from legacy brain MRI scans we aimed to study the role of spinal cord and brain atrophy for silent progression and conversion to secondary progressive disease (SPMS). METHODS: From a single-center observational study, all RRMS (n = 360) and SPMS (n = 47) patients and 80 matched controls were evaluated. RRMS patient subsets who converted to SPMS (n = 54) or silently progressed (n = 159), respectively, during the 12-year observation period were compared to clinically matched RRMS patients remaining RRMS (n = 54) or stable (n = 147), respectively. From brain MRI, we assessed the value of brain and spinal cord measures to predict silent progression and SPMS conversion. RESULTS: Patients who developed SPMS showed faster cord atrophy rates (-2.19%/yr) at least 4 years before conversion compared to their RRMS matches (-0.88%/yr, p < 0.001). Spinal cord atrophy rates decelerated after conversion (-1.63%/yr, p = 0.010) towards those of SPMS patients from study entry (-1.04%). Each 1% faster spinal cord atrophy rate was associated with 69% (p < 0.0001) and 53% (p < 0.0001) shorter time to silent progression and SPMS conversion, respectively. INTERPRETATION: Silent progression and conversion to secondary progressive disease are predominantly related to cervical cord atrophy. This atrophy is often present from the earliest disease stages and predicts the speed of silent progression and conversion to Progressive MS. Diagnosis of SPMS is rather a late recognition of this neurodegenerative process than a distinct disease phase. ANN NEUROL 2022;91:268-281.

Susceptibility-based imaging aids accurate distinction of pediatric-onset MS from myelin oligodendrocyte glycoprotein antibody-associated disease.

BACKGROUND: Myelin oligodendrocyte glycoprotein (MOG) antibody-associated disease (MOGAD) and pediatric-onset multiple sclerosis (POMS) share clinical and magnetic resonance imaging (MRI) features but differ in prognosis and management. Early POMS diagnosis is essential to avoid disability accumulation. Central vein sign (CVS), paramagnetic rim lesions (PRLs), and central core lesions (CCLs) are susceptibility-based imaging (SbI)-related signs understudied in pediatric populations that may help discerning POMS from MOGAD. METHODS: T2-FLAIR and SbI (three-dimensional echoplanar imaging (3D-EPI)/susceptibility-weighted imaging (SWI) or similar) were acquired on 1.5T/3T scanners. Two readers assessed CVS-positive rate (%CVS+), and their average score was used to build a receiver operator curve (ROC) assessing the ability to discriminate disease type. PRLs and CCLs were identified using a consensual approach. RESULTS: The %CVS+ distinguished 26 POMS cases (mean age 13.7 years, 63% females, median EDSS 1.5) from 14 MOGAD cases (10.8 years, 35% females, EDSS 1.0) with ROC = 1, p < 0.0001, (cutoff 41%). PRLs were only detectable in POMS participants (mean 2.1±2.3, range 1-10), discriminating the two conditions with a sensitivity of 69% and a specificity of 100%. CCLs were more sensitive (81%) but less specific (71.43%). CONCLUSION: The %CVS+ and PRLs are highly specific markers of POMS. After proper validation on larger multicenter cohorts, consideration should be given to including such imaging markers for diagnosing POMS at disease onset.

Junctional Scotoma and Patterns of Visual Field Defects Produced by Lesions Involving the Optic Chiasm.

BACKGROUND: Lesions of the optic chiasm (OC) typically produce bitemporal hemianopia (BTH) on visual field (VF) testing, whereas lesions located at the nasal optic nerve-chiasmal (ON-OC) junction have been proposed to produce junctional scotoma (JXS), a central defect in the ipsilateral eye with temporal field loss in the contralateral eye. In this study, we investigated whether the pattern of VF loss in patients with chiasmal compression predicted the appearance of the causative lesion on neuroimaging and described the clinical presentation of these patients with different types of VF defect. METHODS: Retrospective chart review of patients seen in tertiary neuro-ophthalmology practice over 6 consecutive years with lesions abutting or displacing the OC was performed. Lesion size and location relative to the OC on neuroimaging was determined and correlated with VF defects as well as optical coherence tomography (OCT) of the peripapillary retinal nerve fiber layer and macular ganglion cell complex (GCC). RESULTS: Fifty-three patients were enrolled. VFs demonstrated JXS (n = 18), BTH (n = 14), monocular VF defect (n = 4), and no VF defect (n = 17); 64.7% of cases with normal VFs had radiologic OC compression. Lesion volume was highest in the JXS group, and these patients also had the poorest presenting visual acuity. All patients with JXS showed involvement of the ON-OC junction; however, not all cases showed compression of the OC from the nasal direction (15 of 18), and 17 of 18 also showed compression of one or both prechiasmatic ONs. Compression of the ON-OC junction was also seen in 79% of BTH, 100% of monocular VF defect, and 59% of no VF defect cases. Fifty percent of patients with normal VFs already had thinning of the GCC on OCT. GCC thinning was most pronounced nasally in the BTH group, but diffuse bilateral thinning was found in 38% of cases compared with 60% of JXS. VFs improved in 6 of 6 patients with BTH but only in 5 of 8 JXS cases after treatment. CONCLUSIONS: JXS is more often seen with larger lesions and when there is compression of both the prechiasmatic ON and ON-OC junction. These patients have worse presenting visual acuity and poorer outcomes. Not all patients with radiologic compression had VF defects, although 50% of patients with normal VFs had evidence of compression on the macular GCC analysis, emphasizing the importance of macular OCT in the evaluation of patients with lesions involving the OC.

A novel in-home digital treatment to improve processing speed in people with multiple sclerosis: A pilot study.

OBJECTIVE: To assess whether a videogame-like digital treatment is superior to a control in improving processing speed in adults with multiple sclerosis (MS). METHODS: Adults with MS and baseline Symbol Digit Modalities Test (SDMT) z-scores between -2 and 0 were enrolled in a double-blind randomized controlled clinical trial. After completing a baseline in-clinic evaluation (Visit 1), they were randomized to complete an in-home, tablet-based videogame-like digital treatment (AKL-T03) or control word game (AKL-T09) for up to 25 minutes/day, 5 days/week, for 6 weeks. A repeat in-clinic evaluation occurred at 6 weeks (Visit 2), and again 8 weeks later to determine persistence of effects (Visit 3). The pre-specified primary outcome was change in SDMT score between Visits 1 and 2. RESULTS: SDMT increased at Visit 2 for participants randomized to both AKL-T03 (p < 0.001) and AKL-T09 (p = 0.024). These respective mean improvements were +6.10 and +3.55 (comparison p = 0.21). At Visit 3, 70% of participants randomized to AKL-T03 maintained a clinically meaningful 4+-point increase in SDMT above their baseline, compared with 37% for AKL-T09 (p = 0.038). CONCLUSION: This in-home digital intervention resulted in substantial and durable improvements in processing speed. A larger randomized controlled clinical trial is planned. TRIAL REGISTRATION: This trial is registered on ClinicalTrials.gov under "NCT03569618," https://clinicaltrials.gov/ct2/show/NCT03569618.

Intravoxel incoherent motion as a tool to detect early microstructural changes in meningiomas treated with proton therapy.

PURPOSE: To assess early microstructural changes of meningiomas treated with proton therapy through quantitative analysis of intravoxel incoherent motion (IVIM) and diffusion-weighted imaging (DWI) parameters. METHODS: Seventeen subjects with meningiomas that were eligible for proton therapy treatment were retrospectively enrolled. Each subject underwent a magnetic resonance imaging (MRI) including DWI sequences and IVIM assessments at baseline, immediately before the 1st (t0), 10th (t10), 20th (t20), and 30th (t30) treatment fraction and at follow-up. Manual tumor contours were drawn on T2-weighted images by two expert neuroradiologists and then rigidly registered to DWI images. Median values of the apparent diffusion coefficient (ADC), true diffusion (D), pseudo-diffusion (D*), and perfusion fraction (f) were extracted at all timepoints. Statistical analysis was performed using the pairwise Wilcoxon test. RESULTS: Statistically significant differences from baseline to follow-up were found for ADC, D, and D* values, with a progressive increase in ADC and D in conjunction with a progressive decrease in D*. MRI during treatment showed statistically significant differences in D values between t0 and t20 (p = 0.03) and t0 and t30 (p = 0.02), and for ADC values between t0 and t20 (p = 0.04), t10 and t20 (p = 0.02), and t10 and t30 (p = 0.035). Subjects that showed a volume reduction greater than 15% of the baseline tumor size at follow-up showed early D changes, whereas ADC changes were not statistically significant. CONCLUSION: IVIM appears to be a useful tool for detecting early microstructural changes within meningiomas treated with proton therapy and may potentially be able to predict tumor response.

Correction: Application of an Adaptive, Digital, Game-Based Approach for Cognitive Assessment in Multiple Sclerosis: Observational Study.

[This corrects the article DOI: 10.2196/24356.].

Application of an Adaptive, Digital, Game-Based Approach for Cognitive Assessment in Multiple Sclerosis: Observational Study.

BACKGROUND: Cognitive impairment is one of the most debilitating manifestations of multiple sclerosis. Currently, the assessment of cognition relies on a time-consuming and extensive neuropsychological examination, which is only available in some centers. OBJECTIVE: To enable simpler, more accessible cognitive screening, we sought to determine the feasibility and potential assessment sensitivity of an unsupervised, adaptive, video game-based digital therapeutic to assess cognition in multiple sclerosis. METHODS: A total of 100 people with multiple sclerosis (33 with cognitive impairment and 67 without cognitive impairment) and 24 adults without multiple sclerosis were tested with the tablet game (EVO Monitor) and standard measures, including the Brief International Cognitive Assessment for Multiple Sclerosis (which included the Symbol Digit Modalities Test [SDMT]) and Multiple Sclerosis Functional Composite 4 (which included the Timed 25-Foot Walk test). Patients with multiple sclerosis also underwent neurological evaluations and contributed recent structural magnetic resonance imaging scans. Group differences in EVO Monitor performance and the association between EVO Monitor performance and standard measures were investigated. RESULTS: Participants with multiple sclerosis and cognitive impairment showed worse performance in EVO Monitor compared with participants without multiple sclerosis (P=.01) and participants with multiple sclerosis without cognitive impairment (all P<.002). Regression analyses indicated that participants with a lower SDMT score showed lower performance in EVO Monitor (r=0.52, P<.001). Further exploratory analyses revealed associations between performance in EVO Monitor and walking speed (r=-0.45, P<.001) as well as brain volumetric data (left thalamic volume: r=0.47, P<.001; right thalamic volume: r=0.39, P=.002; left rostral middle frontal volume: r=0.28, P=.03; right rostral middle frontal volume: r=0.27, P=.03). CONCLUSIONS: These findings suggest that EVO Monitor, an unsupervised, video game-based digital program integrated with adaptive mechanics, is a clinically valuable approach to measuring cognitive performance in patients with multiple sclerosis. TRIAL REGISTRATION: ClinicalTrials.gov NCT03569618; https://clinicaltrials.gov/ct2/show/NCT03569618.

Silent progression in disease activity-free relapsing multiple sclerosis.

OBJECTIVE: Rates of worsening and evolution to secondary progressive multiple sclerosis (MS) may be substantially lower in actively treated patients compared to natural history studies from the pretreatment era. Nonetheless, in our recently reported prospective cohort, more than half of patients with relapsing MS accumulated significant new disability by the 10th year of follow-up. Notably, "no evidence of disease activity" at 2 years did not predict long-term stability. Here, we determined to what extent clinical relapses and radiographic evidence of disease activity contribute to long-term disability accumulation. METHODS: Disability progression was defined as an increase in Expanded Disability Status Scale (EDSS) of 1.5, 1.0, or 0.5 (or greater) from baseline EDSS = 0, 1.0-5.0, and 5.5 or higher, respectively, assessed from baseline to year 5 (±1 year) and sustained to year 10 (±1 year). Longitudinal analysis of relative brain volume loss used a linear mixed model with sex, age, disease duration, and HLA-DRB1*15:01 as covariates. RESULTS: Relapses were associated with a transient increase in disability over 1-year intervals (p = 0.012) but not with confirmed disability progression (p = 0.551). Relative brain volume declined at a greater rate among individuals with disability progression compared to those who remained stable (p < 0.05). INTERPRETATION: Long-term worsening is common in relapsing MS patients, is largely independent of relapse activity, and is associated with accelerated brain atrophy. We propose the term silent progression to describe the insidious disability that accrues in many patients who satisfy traditional criteria for relapsing-remitting MS. Ann Neurol 2019;85:653-666.

Multi-parametric qualitative and quantitative MRI assessment as predictor of histological grading in previously treated meningiomas.

PURPOSE: Meningiomas are mainly benign tumors, though a considerable proportion shows aggressive behaviors histologically consistent with atypia/anaplasia. Histopathological grading is usually assessed through invasive procedures, which is not always feasible due to the inaccessibility of the lesion or to treatment contraindications. Therefore, we propose a multi-parametric MRI assessment as a predictor of meningioma histopathological grading. METHODS: Seventy-three patients with 74 histologically proven and previously treated meningiomas were retrospectively enrolled (42 WHO I, 24 WHO II, 8 WHO III) and studied with MRI including T2 TSE, FLAIR, Gradient Echo, DWI, and pre- and post-contrast T1 sequences. Lesion masks were segmented on post-contrast T1 sequences and rigidly registered to ADC maps to extract quantitative parameters from conventional DWI and intravoxel incoherent motion model assessing tumor perfusion. Two expert neuroradiologists assessed morphological features of meningiomas with semi-quantitative scores. RESULTS: Univariate analysis showed different distributions (p < 0.05) of quantitative diffusion parameters (Wilcoxon rank-sum test) and morphological features (Pearson's chi-square; Fisher's exact test) among meningiomas grouped in low-grade (WHO I) and higher grade forms (WHO II/III); the only exception consisted of the tumor-brain interface. A multivariate logistic regression, combining all parameters showing statistical significance in the univariate analysis, allowed discrimination between the groups of meningiomas with high sensitivity (0.968) and specificity (0.925). Heterogeneous contrast enhancement and low ADC were the best independent predictors of atypia and anaplasia. CONCLUSION: Our multi-parametric MRI assessment showed high sensitivity and specificity in predicting histological grading of meningiomas. Such an assessment may be clinically useful in characterizing lesions without histological diagnosis. Key points • When surgery and biopsy are not feasible, parameters obtained from both conventional and diffusion-weighted MRI can predict atypia and anaplasia in meningiomas with high sensitivity and specificity. • Low ADC values and heterogeneous contrast enhancement are the best predictors of higher grade meningioma.

PRNP expression predicts imaging findings in sporadic Creutzfeldt-Jakob disease.

OBJECTIVE: We explored the relationship between regional PRNP expression from healthy brain tissue and patterns of increased and decreased diffusion and regional brain atrophy in patients with sporadic Creutzfeldt-Jakob disease (sCJD). METHODS: We used PRNP microarray data from 6 healthy adult brains from Allen Brain Institute and T1-weighted and diffusion-weighted MRIs from 34 patients diagnosed with sCJD and 30 age- and sex-matched healthy controls to construct partial correlation matrices across brain regions for specific measures of interest: PRNP expression, mean diffusivity, volume, cortical thickness, and local gyrification index, a measure of cortical folding. RESULTS: Regional patterns of PRNP expression in the healthy brain correlated with regional patterns of diffusion signal abnormalities and atrophy in sCJD. Among different measures of cortical morphology, regional patterns of local gyrification index in sCJD most strongly correlated with regional patterns of PRNP expression. At the vertex-wise level, different molecular subtypes of sCJD showed distinct regional correlations in local gyrification index across the cortex. Local gyrification index correlation patterns most closely matched patterns of PRNP expression in sCJD subtypes known to have greatest pathologic involvement of the cerebral cortex. INTERPRETATION: These results suggest that the specific genetic and molecular environment in which the prion protein is expressed confer variable vulnerability to misfolding across different brain regions that is reflected in patterns of imaging findings in sCJD. Further work in larger samples will be needed to determine whether these regional imaging patterns can serve as reliable markers of distinct disease subtypes to improve diagnosis and treatment targeting.

Differences in Age-related Retinal and Cortical Atrophy Rates in Multiple Sclerosis.

BACKGROUND AND OBJECTIVES: The timing of neurodegeneration in multiple sclerosis (MS) remains unclear. It is critical to understand the dynamics of neuroaxonal loss if we hope to prevent or forestall permanent disability in MS. We therefore used a deeply phenotyped longitudinal cohort to assess and compare rates of neurodegeneration in retina and brain throughout the MS disease course. METHODS: We analyzed 597 patients with MS who underwent longitudinal optical coherence tomography imaging annually for 4.5 ± 2.4 years and 432 patients who underwent longitudinal MRI scans for 10 ± 3.4 years, quantifying macular ganglion cell-inner plexiform layer (GCIPL) volume and cortical gray matter (CGM) volume. The association between the slope of decline in the anatomical structure and the age of entry in the cohort (categorized by the MRI cohort's age quartiles) was assessed by hierarchical linear models. RESULTS: The rate of CGM volume loss declined with increasing age of study entry (1.3% per year atrophy for the age of entry in the cohort younger than 35 years; 1.1% for older than 35 years and younger than 41; 0.97% for older than 41 years and younger than 49; 0.9% for older than 49 years) while the rate of GCIPL thinning was highest in patients in the youngest quartile, fell by more than 50% in the following age quartile, and then stabilized (0.7% per year thinning for the age of entry in the cohort younger than 35 years; 0.29% for age older than 35 and younger than 41 years; 0.34% for older than 41 and younger than 49 years; 0.33% for age older than 49 years). DISCUSSION: An age-dependent reduction in retinal and cortical volume loss rates during relapsing-remitting MS suggests deceleration in neurodegeneration in the earlier period of disease and further indicates that the period of greatest adaptive immune-mediated inflammatory activity is also the period with the greatest neuroaxonal loss.

Improving the characterization of meningioma microstructure in proton therapy from conventional apparent diffusion coefficient measurements using Monte Carlo simulations of diffusion MRI.

PURPOSE: Proton therapy could benefit from noninvasively gaining tumor microstructure information, at both planning and monitoring stages. The anatomical location of brain tumors, such as meningiomas, often hinders the recovery of such information from histopathology, and conventional noninvasive imaging biomarkers, like the apparent diffusion coefficient (ADC) from diffusion-weighted MRI (DW-MRI), are nonspecific. The aim of this study was to retrieve discriminative microstructural markers from conventional ADC for meningiomas treated with proton therapy. These markers were employed for tumor grading and tumor response assessment. METHODS: DW-MRIs from patients affected by meningioma and enrolled in proton therapy were collected before (n = 35) and 3 months after (n = 25) treatment. For the latter group, the risk of an adverse outcome was inferred by their clinical history. Using Monte Carlo methods, DW-MRI signals were simulated from packings of synthetic cells built with well-defined geometrical and diffusion properties. Patients' ADC was modeled as a weighted sum of selected simulated signals. The weights that best described a patient's ADC were determined through an optimization procedure and used to estimate a set of markers of tumor microstructure: diffusion coefficient (D), volume fraction (vf), and radius (R). Apparent cellularity (ρapp ) was estimated from vf and R for an easier clinical interpretability. Differences between meningothelial and atypical subtypes, and low- and high-grade meningiomas were assessed with nonparametric statistical tests, whereas sensitivity and specificity with ROC analyses. Similar analyses were performed for patients showing low or high risk of an adverse outcome to preliminary evaluate response to treatment. RESULTS: Significant (P < 0.05) differences in median ADC, D, vf, R, and ρapp values were found when comparing meningiomas' subtypes and grades. ROC analyses showed that estimated microstructural parameters reached higher specificity than ADC for subtyping (0.93 for D and vf vs 0.80 for ADC) and grading (0.75 for R vs 0.67 for ADC). High- and low-risk patients showed significant differences in ADC and microstructural parameters. The skewness of ρapp was the parameter with highest AUC (0.90) and sensitivity (0.75). CONCLUSIONS: Matching measured with simulated ADC yielded a set of potential imaging markers for meningiomas grading and response monitoring in proton therapy, showing higher specificity than conventional ADC. These markers can provide discriminative information about spatial patterns of tumor microstructure implying important advantages for patient-specific proton therapy workflows.

Fulminant inflammatory demyelination presenting as stroke-in-evolution in an elderly subject.

BACKGROUND: Fulminant inflammatory demyelination is a possible presentation of inflammatory demyelinating disorders, thus representing a potential stroke mimic especially in younger patients. AIMS OF THE STUDY: To describe clinical and diagnostic pitfalls in a case of fulminant inflammatory demyelination presenting with stroke-like symptoms in an elderly patient. METHODS: Case report and case-based review of the literature. RESULTS: A 67-year-old woman, who accessed the emergency room as suspect stroke for hyperacute onset of rapidly worsening speech impairment and drowsiness, was later diagnosed with a huge brain inflammatory demyelination. Clinical, laboratory, and neuroimaging tests did not allow to put a more specific diagnosis. Due to the rapidly deteriorating course, she received immunosuppression with benefit. CONCLUSION: This report is meant to highlight the diagnostic challenges connected with fulminant inflammatory demyelination, which sometime can resemble a stroke-in evolution and appear clinically unfitting for inclusion in any specific pathological entities within the broad-spectrum of inflammatory demyelinating disorders.

Cortically constrained shape recognition: Automated white matter tract segmentation validated in the pediatric brain.

BACKGROUND AND PURPOSE: Manual segmentation of white matter (WM) bundles requires extensive training and is prohibitively labor-intensive for large-scale studies. Automated segmentation methods are necessary in order to eliminate operator dependency and to enable reproducible studies. Significant changes in the WM landscape throughout childhood require flexible methods to capture the variance across the span of brain development. METHODS: Here, we describe a novel automated segmentation tool called Cortically Constrained Shape Recognition (CCSR), which combines two complementary approaches: (1) anatomical connectivity priors based on FreeSurfer-derived regions of interest and (2) shape priors based on 3-dimensional streamline bundle atlases applied using RecoBundles. We tested the performance and repeatability of this approach by comparing volume and diffusion metrics of the main language WM tracts that were both manually and automatically segmented in a pediatric cohort acquired at the UCSF Dyslexia Center (n = 59; 25 females; average age: 11 ± 2; range: 7-14). RESULTS: The CCSR approach showed high agreement with the expert manual segmentations: across all tracts, the spatial overlap between tract volumes showed an average Dice Similarity Coefficient (DSC) of 0.76, and the fractional anisotropy (FA) on average had a Lin's Concordance Correlation Coefficient (CCC) of 0.81. The CCSR's repeatability in a subset of this cohort achieved a DSC of 0.92 on average across all tracts. CONCLUSION: This novel automated segmentation approach is a promising tool for reproducible large-scale tractography analyses in pediatric populations and particularly for the quantitative assessment of structural connections underlying various clinical presentations in neurodevelopmental disorders.

Multimodal MRI staging for tracking progression and clinical-imaging correlation in sporadic Creutzfeldt-Jakob disease.

Diffusion imaging is very useful for the diagnosis of sporadic Creutzfeldt-Jakob disease, but it has limitations in tracking disease progression as mean diffusivity changes non-linearly across the disease course. We previously showed that mean diffusivity changes across the disease course follow a quasi J-shaped curve, characterized by decreased values in earlier phases and increasing values later in the disease course. Understanding how MRI metrics change over-time, as well as their correlations with clinical deficits are crucial steps in developing radiological biomarkers for trials. Specifically, as mean diffusivity does not change linearly and atrophy mainly occurs in later stages, neither alone is likely to be a sufficient biomarker throughout the disease course. We therefore developed a model combining mean diffusivity and Volume loss (MRI Disease-Staging) to take into account mean diffusivity's non-linearity. We then assessed the associations between clinical outcomes and mean diffusivity alone, Volume alone and finally MRI Disease-Staging. In 37 sporadic Creutzfeldt-Jakob disease subjects and 30 age- and sex-matched healthy controls, high angular resolution diffusion and high-resolution T1 imaging was performed cross-sectionally to compute z-scores for mean diffusivity (MD) and Volume. Average MD and Volume were extracted from 41 GM volume of interest (VOI) per hemisphere, within the images registered to the Montreal Neurological Institute (MNI) space. Each subject's volume of interest was classified as either "involved" or "not involved" using a statistical threshold of ±â€¯2 standard deviation (SD) for mean diffusivity changes and/or -2 SD for Volume. Volumes of interest were MRI Disease-Staged as: 0 = no abnormalities; 1 = decreased mean diffusivity only; 2 = decreased mean diffusivity and Volume; 3 = normal ("pseudo-normalized") mean diffusivity, reduced Volume; 4 = increased mean diffusivity, reduced Volume. We correlated Volume, MD and MRI Disease-Staging with several clinical outcomes (scales, score and symptoms) using 4 major regions of interest (Total, Cortical, Subcortical and Cerebellar gray matter) or smaller regions pre-specified based on known neuroanatomical correlates. Volume and MD z-scores correlated inversely with each other in all four major ROIs (cortical, subcortical, cerebellar and total) highlighting that ROIs with lower Volumes had higher MD and vice-versa. Regarding correlations with symptoms and scores, higher MD correlated with worse Mini-Mental State Examination and Barthel scores in cortical and cerebellar gray matter, but subjects with cortical sensory deficits showed lower MD in the primary sensory cortex. Volume loss correlated with lower Mini-Mental State Examination, Barthel scores and pyramidal signs. Interestingly, for both Volume and MD, changes within the cerebellar ROI showed strong correlations with both MMSE and Barthel. Supporting using a combination of MD and Volume to track sCJD progression, MRI Disease-Staging showed correlations with more clinical outcomes than Volume or MD alone, specifically with Mini-Mental State Examination, Barthel score, pyramidal signs, higher cortical sensory deficits, as well as executive and visual-spatial deficits. Additionally, when subjects in the cohort were subdivided into tertiles based on their Barthel scores and their percentile of disease duration/course ("Time-Ratio"), subjects in the lowest (most impaired) Barthel tertile showed a much greater proportion of more advanced MRI Disease-Stages than the those in the highest tertile. Similarly, subjects in the last Time-Ratio tertile (last tertile of disease) showed a much greater proportion of more advanced MRI Disease-Stages than the earliest tertile. Therefore, in later disease stages, as measured by time or Barthel, there is overall more Volume loss and increasing MD. A combined multiparametric quantitative MRI Disease-Staging is a useful tool to track sporadic Creutzfeldt-Jakob- disease progression radiologically.

Ocular vestibular evoked myogenic potentials in response to air-conducted 500 Hz short tones: Effect of stimulation procedure (monaural or binaural), age and gender.

BACKGROUND: The ocular vestibular myogenic potentials (oVEMP) can be elicited by monaural air-conducted sound stimulation, and are usually recorded from the contralateral eye. In clinical setting a binaural stimulation would save time and require less effort from the subjects. OBJECTIVE: We evaluated the differences between monaural and binaural stimulation, and the possible effect of age and gender on oVEMP parameters. METHODS: Air-conducted oVEMP were recorded by binaural and by monaural stimulation in a group of 54 normal subjects, aged from 12 to 83 years, and in 50 vestibular patients. From each side, we measured the latency of the N1 component, and the peak-to-peak N1-P1 amplitude. For both parameters we also computed the asymmetry ratio. RESULTS: In normal subjects binaural stimulation produced slightly larger responses than monaural stimulation; detectability, latency and amplitude ratio were the same for the two techniques. We found no differences related to gender, and the age-induced amplitude decline was likely to be negligible.oVEMP recorded not in an acute phase of their disorder, proved to be abnormal in about 20% of the patients, and the normal or abnormal findings obtained either with monaural or with binaural stimulation were always concordant. CONCLUSIONS: The oVEMP obtained after binaural and monaural stimulation are very similar, and they are largely independent from age and gender.

Reading while moving: the functional assessment of VOR.

The head impulse test (HIT) is nowadays recognized as the gold standard for clinical testing of the angular vestibulo-ocular reflex (VOR). By imposing unpredictable, abrupt head rotations in canal pairs' planes it aims at unveiling the dysfunction of the semicircular canal towards which the head is rotated based on Ewald's II law. Functional testing of the VOR aims at assessing the ability of the reflex to stabilize gaze in space and thus allow clear vision during head movements. The HIT device (HITD) approach exploits impulsive head rotations spawning a range of angular accelerations while requiring subjects to identify optotypes briefly displayed on a screen. Here we also recorded eye movements, so that the evaluation of the individual subject is based both on the VOR gain and on the percentage of correct answers with respect to a population of controls. Here we used the HITD to study 14 patients suffering from vestibular neuritis and 7 of those were re-tested after three months. We found that the HITD was able to unveil the ipsilesional deficit and the contralesional impairment, together with the improvement in the follow-up test.