3D and Subtraction MR imaging in Multiple Sclerosis : Improved detection of spatiotemporal disease activity

Barkhof, F. [Promotor]Polman, C.H. [Promotor]Geurts, J.J.G. [Copromotor]Vrenken, H. [Copromotor

Cosmic ray energy changes at the termination shock and in the heliosheath

Voyager 1 crossed the termination shock of the solar wind in December 2004 at 94 AU and currently measures the cosmic ray intensity in the heliosheath. To better understand this modulation region beyond the shock, where adiabatic energy changes should be small, we review the net effect of energy changes during the modulation process, including adiabatic deceleration in the solar wind, acceleration at the termination shock, and the possibility that stochastic acceleration in the heliosheath may also make a contribution

Cosmic-ray energy changes in the heliosphere. II. The effect on K-capture electron secondaries

Recent accurate measurements of the cosmic-ray intensity ratio ^(51)V/^(51)Cr below 1 GeV nucleon^(-1) provide a powerful new tool to study cosmic-ray modulation in the heliosphere. This paper describes how energy changes during this modulation process influence this ratio. In particular, our model includes acceleration at the solar wind termination shock, and we find that this mechanism significantly enhances the ^(51)V/^(51)Cr ratio at 1 AU. It is also shown that this acceleration makes the ratio more sensitive to the form of local low-energy interstellar spectra, below ~100 MeV nucleon^(-1), than without it. Specifically, this acceleration provides an independent confirmation of the consensus that low-energy spectra should be flatter than their high-energy power-law forms

Clinico-radiological dissociation of disease activity in MS patients: frequency and clinical relevance

Objective: To investigate the prevalence and clinical relevance regarding disability progression in multiple sclerosis patients with a dissociation in clinical and radiological disease expression. / Methods: We prospectively selected patients with early relapsing–remitting multiple sclerosis (MS) or a clinically isolated syndrome (CIS) from the Amsterdam MS cohort. Patients underwent clinical examination at baseline, after 2 years, 6 years and a subset also after 11 years, including the Expanded Disability Status Scale (EDSS), 25-foot walk test (25-FWT) and 9-hole peg test (9-HPT). Brain and spinal cord MRI scans were obtained at baseline and after 2 years. Two years after baseline, patients with dissociation in their clinical and radiological disease progression were identified as: (1) patients with high clinical disease activity (defined by relapses) and low radiological disease activity (defined by white-matter lesions on T2-weighted imaging); or (2) patients with low clinical disease activity and high radiological disease activity. Binary logistic regression analyses were performed to predict disability progression after 6 and 11 years of follow-up. Patients with low clinical and low radiological disease activity were used as the reference group. / Results: The prevalence of clinico-radiological dissociation was low (6.4% had high clinical and low radiological disease activity and 5.1% had a combination of low clinical and high radiological disease activity) compared to 88.5% of patients without a dissociation. Patients with a dissociation of clinical and radiological disease activity did not show a statistically significant difference in risk of disability progression after 6 and 11 years. / Conclusions: A clinico-radiological dissociation is rather a rare phenomenon in MS patients. The clinical relevance of such a dissociation regarding the prediction of disability progression is questionable

Upper cervical cord atrophy is independent of cervical cord lesion volume in early multiple sclerosis: A two-year longitudinal study

Background: Upper cervical cord atrophy and lesions have been shown to be associated with disease and disability progression already in early relapsing-remitting multiple sclerosis (RRMS). However, their longitudinal relationship remains unclear. Objective: To investigate the cross-sectional and longitudinal relation between focal T2 cervical cord lesion volume (CCLV) and regional and global mean upper cervical cord area (UCCA), and their relations with disability. Methods: Over a two-year interval, subjects with RRMS (n = 36) and healthy controls (HC, n = 16) underwent annual clinical and MRI examinations. UCCA and CCLV were obtained from C1 through C4 level. Linear mixed model analysis was performed to investigate the relation between UCCA, CCLV, and disability over time. Results: UCCA at baseline was significantly lower in RRMS subjects compared to HCs (p = 0.003), but did not decrease faster over time (p ≥ 0.144). UCCA and CCLV were independent of each other at any of the time points or cervical levels, and over time. Lower baseline UCCA, but not CCLV, was related to worsening of both upper and lower extremities function over time. Conclusion: UCCA and CCLV are independent from each other, both cross-sectionally and longitudinally, in early MS. Lower UCCA, but not CCLV, was related to increasing disability over time

Real-world keystroke dynamics are a potentially valid biomarker for clinical disability in multiple sclerosis

Background: Clinical measures in multiple sclerosis (MS) face limitations that may be overcome by utilising smartphone keyboard interactions acquired continuously and remotely during regular typing. Objective: The aim of this study was to determine the reliability and validity of keystroke dynamics to assess clinical aspects of MS. Methods: In total, 102 MS patients and 24 controls were included in this observational study. Keyboard interactions were obtained with the Neurokeys keyboard app. Eight timing-related keystroke features were assessed for reliability with intraclass correlation coefficients (ICCs); construct validity by analysing group differences (in fatigue, gadolinium-enhancing lesions on magnetic resonance imaging (MRI), and patients vs controls); and concurrent validity by correlating with disability measures. Results: Reliability was moderate in two (ICC = 0.601 and 0.742) and good to excellent in the remaining six features (ICC = 0.760–0.965). Patients had significantly higher keystroke latencies than controls. Latency between key presses correlated the highest with Expanded Disability Status Scale (r = 0.407) and latency between key releases with Nine-Hole Peg Test and Symbol Digit Modalities Test (ρ = 0.503 and r = −0.553, respectively), ps < 0.001. Conclusion: Keystroke dynamics were reliable, distinguished patients and controls, and were associated with clinical disability measures. Consequently, keystroke dynamics are a promising valid surrogate marker for clinical disability in MS

Feasibility of detecting atrophy relevant for disability and cognition in multiple sclerosis using 3D-FLAIR

BACKGROUND AND OBJECTIVES: Disability and cognitive impairment are known to be related to brain atrophy in multiple sclerosis (MS), but 3D-T1 imaging required for brain volumetrics is often unavailable in clinical protocols, unlike 3D-FLAIR. Here our aim was to investigate whether brain volumes derived from 3D-FLAIR images result in similar associations with disability and cognition in MS as do those derived from 3D-T1 images. METHODS: 3T-MRI scans of 329 MS patients and 76 healthy controls were included in this cross-sectional study. Brain volumes were derived using FreeSurfer on 3D-T1 and compared with brain volumes derived with SynthSeg and SAMSEG on 3D-FLAIR. Relative agreement was evaluated by calculating the intraclass correlation coefficient (ICC) of the 3D-T1 and 3D-FLAIR volumes. Consistency of relations with disability and average cognition was assessed using linear regression, while correcting for age and sex. The findings were corroborated in an independent validation cohort of 125 MS patients. RESULTS: The ICC between volume measured with FreeSurfer and those measured on 3D-FLAIR for brain, ventricle, cortex, total deep gray matter and thalamus was above 0.74 for SAMSEG and above 0.91 for SynthSeg. Worse disability and lower average cognition were similarly associated with brain (adj. R2 = 0.24-0.27, p < 0.01; adj. R2 = 0.26-0.29, p < 0.001) ventricle (adj. R2 = 0.27-0.28, p < 0.001; adj. R2 = 0.19-0.20, p < 0.001) and deep gray matter volumes (adj. R2 = 0.24-0.28, p < 0.001; adj. R2 = 0.27-0.28, p < 0.001) determined with all methods, except for cortical volumes derived from 3D-FLAIR. DISCUSSION: In this cross-sectional study, brain volumes derived from 3D-FLAIR and 3D-T1 show similar relationships to disability and cognitive dysfunction in MS, highlighting the potential of these techniques in clinical datasets

The effect of cosmic ray energy changes in the heliosphere on K-capture

In an accompanying paper we give a re-assessment of cosmic ray energy changes in the heliosphere to determine the effects of acceleration at the solar wind termination shock and modulation in the heliosheath beyond that. In this paper we show that these effects have important consequences for the interpretation of secondary to primary ratios of cosmic rays at energies below 1 GeV, i.e. in the region where they are strongly modulate

Smartphone-derived keystroke dynamics are sensitive to relevant changes in multiple sclerosis

BACKGROUND: To investigate smartphone keystroke dynamics (KD), derived from regular typing, on sensitivity to relevant change in disease activity, fatigue, and clinical disability in multiple sclerosis (MS). METHODS: Preplanned interim analysis of a cohort study with 102 MS patients assessed at baseline and 3-month follow-up for gadolinium-enhancing lesions on MRI, relapses, fatigue and clinical disability outcomes. Keyboard interactions were unobtrusively collected during typing using the Neurokeys App. From these interactions 15 keystroke features were derived and aggregated using 16 summary and time series statistics. Responsiveness of KD to clinical anchor-based change was assessed by calculating the area under the receiver operating characteristic curve (AUC). The optimal cut-point was used to determine the minimal clinically important difference (MCID) and compared to the smallest real change (SRC). Commonly used clinical measures were analyzed for comparison. RESULTS: 94 patients completed the follow-up. The five best performing keystroke features had AUC-values ranging from 0.72 to 0.78 for change in gadolinium-enhancing lesions, 0.67-0.70 for the Checklist Individual Strength Fatigue subscale, 0.66-0.79 for the Expanded Disability Status Scale, 0.69-0.73 for the Ambulation Functional System, and 0.72-0.75 for Arm function in MS Questionnaire. The MCID of these features exceeded the SRC on group level. KD had higher AUC-values than comparative clinical measures for the study outcomes, aside from ambulatory function. CONCLUSIONS: KD demonstrated good responsiveness to changes in disease activity, fatigue, and clinical disability in MS, and detected important change beyond measurement error on group level. Responsiveness of KD was better than commonly used clinical measures