W Rashid

Normal cerebral perfusion measurements using arterial spin labeling: reproducibility, stability, and age and gender effects.

Before meaningful conclusions can be drawn from clinical measures of cerebral blood perfusion, the precision of the measurement must be determined and set in the context of inter‐ and intrasubject sources of variability. This work establishes the reproducibility of perfusion measurements using the noninvasive MRI technique of continuous arterial spin labeling (CASL). Perfusion was measured in 34 healthy normal subjects. Intersubject variability was assessed, and age and gender contributions were estimated. Intersubject variation was found to be large, with up to 100% perfusion difference for subjects of the same age and gender. Repeated measurements in one subject showed that perfusion remains remarkably stable in the short term when compared with intersubject variation and the large capacity for perfusion change in the brain. A significant decrease in the ratio of gray‐matter to white‐matter perfusion was found with increasing age (0.79% per year (P < 0.0005)). This appears to be due mainly to a reduction in gray‐matter perfusion, which was found to decrease by 0.45% per year (P = 0.04). Regional analysis suggested that the gray‐matter age‐related changes were predominantly localized in the frontal cortex. Whole‐brain perfusion was 13% higher (P = 0.02) in females compared to males. Magn Reson Med 51:736–743, 2004.

Gray and white matter volume changes in early RRMS : A 2-year longitudinal study

Background: Brain atrophy, in excess of that seen with normal aging, has been observed early in the clinical course of relapsing-remitting multiple sclerosis (RRMS). Previous work has suggested that at this stage of the disease, gray matter (GM) atrophy progresses more rapidly than the white matter (WM) atrophy. Objectives: To characterize the evolution of GM and WM volumes over 2 years, and their associations with lesion loads in a cohort of patients with clinically early RRMS. Methods: Twenty-one patients with RRMS (mean age 37.5 years, mean disease duration from symptom onset 2.1 years) and 10 healthy control subjects (mean age 37.1 years) were studied. Tissue volumes, as fractions of total intracranial volumes, were estimated at baseline and 1- and 2-year follow-up. Brain parenchymal fractions (BPF), GM fractions (GMF), and WM fractions (WMF) were estimated. In subjects with MS, brain lesion loads were determined on conventional T2-weighted along with pre- and post-gadolinium (Gd) enhanced T1-weighted images at each timepoint. Results: A decrease in GMF was observed in subjects with MS vs normal controls over the 2 years of the study (mean −2.1% vs −1.0%, p = 0.044), while no change was seen in WMF over the same period (mean −0.09% vs +0.09%, p = 0.812). However, when the MS cohort was divided in half, dependent upon change in Gd-enhancing lesion load over 2 years (n = 20), a decrease in WMF was seen in the group (n = 10) with the largest decline in Gd volume, whereas WMF increased in the other half (n = 10) concurrent with a net increase in volume of Gd-enhancing lesions (difference between groups: p = 0.034). Conclusions: Increasing gray matter but not white matter (WM) atrophy was observed early in the clinical course of relapsing-remitting multiple sclerosis. Fluctuations in inflammatory WM lesions appear to be related to volume changes in WM over this time period.

Progressive grey matter atrophy in clinically early relapsing-remitting multiple sclerosis.

Brain atrophy appears to occur in patients with multiple sclerosis (MS) in excess of that associated with normal ageing, and may be observed early in the clinical course of the disease. The dynamics and tissue specificity of this process remain unclear. This preliminary study explored the evolution of brain grey matter (GM) and white matter (WM) volume loss (as fractions of total intracranial volumes) in 13 subjects with relapsing-remitting MS (mean disease duration 1.9 years at first scan), compared with nine normal control (NC) subjects. Subjects were scanned every six months for 18 months. In MS compared with NC subjects, significant differences in WM fractional volumes were observed at baseline (mean-5.8%, P/0.008) but no apparent progressive WM tissue loss was detected. In contrast, while no significant differences in GM fractional volumes were observed at baseline, there was significantly greater time-related volume loss in MS compared with NC subjects over the follow-up period (circa-0.0086 per year in MS subjects,-0.0021 per year in the NC subjects, difference 0.010). These results suggest that while both GM and WM atrophy are seen early in the clinical course of MS, they may not occur concurrently and may evolve at different rates.

Abnormalities of cerebral perfusion in multiple sclerosis

Background: Measuring perfusion provides a potential indication of metabolic activity in brain tissue. Studies in multiple sclerosis (MS) have identified areas of decreased perfusion in grey matter (GM) and white matter (WM), but the pattern in clinical subgroups is unclear. Objectives: This study investigated perfusion changes in differing MS clinical subgroups on or off β-interferon therapy using a non-invasive MRI technique (continuous arterial spin labelling) to investigate whether different clinical MS subtypes displayed perfusion changes and whether this could give a further insight into the pathological mechanisms involved. Methods: Sixty patients (21 relapsing remitting, 14 secondary progressive, 12 primary progressive, 13 benign) and 34 healthy controls were compared. Statistical parametric mapping (SPM ’99) was used to investigate regional variations in perfusion in both GM and WM. Global WM perfusion was derived by segmenting WM from images using T1 relaxation times. Results: Regions of lower perfusion in predominantly GM were observed in the primary and secondary progressive cohorts, particularly in the thalamus. Increased WM perfusion was seen in relapsing remitting and secondary progressive cohorts. Conclusions: Low GM perfusion could reflect decreased metabolism secondary to neuronal and axonal loss or dysfunction with a predilection for progressive forms of MS. Increased WM perfusion may indicate increased metabolic activity possibly due to increased cellularity and inflammation. Improved methodology and longitudinal studies may enable further investigation of regional and temporal changes, and their relationship with physical and cognitive impairment.

Association of British Neurologists: revised (2015) guidelines for prescribing disease-modifying treatments in multiple sclerosis

In June 1999, the Association of British Neurologists (ABN) first published guidelines for the use of the licensed multiple sclerosis (MS) disease-modifying treatments (at that time β-interferon and glatiramer acetate). The guidelines were revised in 2001 and have been periodically updated since then. In 2002, following the negative assessment of these treatments by the National Institute for Health and Care Excellence (NICE), the MS risk-sharing scheme started, in which patients eligible according to the 2001 ABN guidelines were provided with treatment funded through the UK National Health Service (NHS), and monitored annually for up to 10 years.1 Recruitment to the risk-sharing scheme cohort is complete. Pending a future final evaluation, the UK Department of Healths instruction to NHS funders remains in place: that patients who fulfil the ABN criteria should continue to receive treatment funded through the NHS. The British neurological community has fully accepted the risk-sharing scheme for prescribing β-interferon and glatiramer acetate. Approximately 70 ‘treating centres’ have recruited >5000 patients between 2002 and 2005, and these have been monitored annually for 10 years; many more patients have received these treatments since 2005. The ABN published revised guidelines in 2007, and then again in 2009, following the licensing of natalizumab and mitoxantrone. This 2015 revised guideline replaces former versions. It includes all newly approved or licensed treatments for MS and represents a consensus concerning their use. These guidelines will require future revision as other treatments receive approval (eg, daclizumab and ocrelizumab): we suggest they are reviewed after an interval of no longer than 12 months. The guideline is not intended to provide a complete description of the possible complications and monitoring of disease-modifying treatments in MS; we refer prescribing neurologists to the relevant summaries of product characteristics. MS is a complex disease. Perhaps uniquely in neurology its clinical course is characterised …

Increasing normal–appearing grey and white matter magnetisation transfer ratio abnormality in early relapsing–remitting multiple sclerosis

Abnormalities within normal–appearing grey and white matter (NAGM and NAWM) occur early in the clinical course of multiple sclerosis (MS) and can be detected in–vivo using the magnetisation transfer ratio (MTR). To better characterize the rates of change in both tissues and to ascertain when such changes begin, we serially studied a cohort of minimally disabled, early relapsing–remitting MS patients, using NAGM and NAWM MTR histograms. Twenty–three patients with clinically definite early relapsing–remitting MS (mean disease duration at baseline 1.9 years), and 19 healthy controls were studied. A magnetisation transfer imaging sequence was acquired yearly for two years. Twenty–one patients and 10 controls completed followup. NAWM and NAGM MTR histograms were derived and mean MTR calculated. A hierarchical regression analysis, adjusting for brain parenchymal fraction,was used to assess MTR change over time. MS NAWM and NAGM MTR were significantly reduced in comparison with controls at baseline and, in patients, both measures decreased further during follow–up: (–0.10pu/year, p = 0.001 and –0.18pu/year, p < 0.001 respectively). The rate of MTR decrease was significantly greater in NAGM than NAWM (p = 0.004). Under the assumption that such changes are linear, backward extrapolation of the observed rates of change suggested that NAWM abnormality began before symptom onset. We conclude that increasing MTR abnormalities in NAWM and NAGM are observed early in the course of relapsing–remitting MS. It is now important to investigate whether these measures are predictive of future disability, and consequently, whether MTR could be used as a surrogate marker in therapeutic trials.

Cord atrophy separates early primary progressive and relapsing remitting multiple sclerosis.

Background and objective: The onset of multiple sclerosis is relapsing remitting or primary progressive. An improved understanding of the causes of early progressive disability in primary progressive multiple sclerosis (PPMS) could provide mechanistic targets for therapeutic intervention. Methods: Five magnetic resonance imaging (MRI) parameters that could potentially cause progressive disability were investigated in 43 patients with early PPMS and in 37 patients with early relapsing remitting multiple sclerosis (RRMS): atrophy in brain, both grey matter and white matter; intrinsic abnormality in brain, both grey matter and white matter (measured by the magnetisation transfer ratio (MTR)); and atrophy of the upper cervical spinal cord. Both groups were also compared with controls. Results: Patients with PPMS were older and more likely to be men. Both patient groups had atrophy of brain grey matter and white matter, and intrinsic abnormality in MTR of normal-appearing grey matter and white matter. Cord atrophy was present only in the PPMS (mean cord area: PPMS, 67.8 mm2; RRMS, 72.7 mm2; controls, 73.4 mm2; p = 0.007). This was confirmed by multivariate analysis of all five MRI parameters, age and sex. Conclusion: Grey matter and white matter of the brain are abnormal in both early RRMS and PPMS, but cord atrophy is present only in PPMS. This is concordant with myelopathy being the usual clinical presentation of PPMS. Measurement of cord atrophy seems to be clinically relevant in PPMS treatment trials.

Evidence for grey matter MTR abnormality in minimally disabled patients with early relapsing-remitting multiple sclerosis

Objectives: To establish whether magnetisation transfer ratio (MTR) histograms are sensitive to change in normal appearing grey matter (NAGM) in early relapsing-remitting multiple sclerosis (RRMS) in the absence of significant disability; and to assess whether grey or white matter MTR measures are associated with clinical measures of impairment in early RRMS Methods: 38 patients were studied (mean disease duration 1.9 years (range 0.5 to 3.7); median expanded disability status scale (EDSS) 1.5 (0 to 3)), along with 35 healthy controls. MTR was determined from proton density weighted images with and without MT presaturation. SPM99 was used to generate normal appearing white matter (NAWM) and NAGM segments of the MTR map, and partial voxels were minimised with a 10 pu threshold and voxel erosions. Mean MTR was calculated from the tissue segments. Atrophy measures were determined using a 3D fast spoiled gradient recall sequence from 37 patients and 17 controls. Results: Mean NAGM and NAWM MTR were both reduced in early RRMS (NAGM MTR: 31.9 pu in patients v 32.2 pu in controls; p<0.001; NAWM MTR: 37.9 v 38.3 pu, p = 0.001). Brain parenchymal fraction (BPF) correlated with NAGM MTR, but when BPF was included as a covariate NAGM MTR was still lower in the patients (p = 0.009). EDSS correlated with NAGM MTR (r = 0.446 p = 0.005). Conclusions: In early RRMS, grey matter MTR abnormality is apparent. The correlation with mild clinical impairment (in this essentially non-disabled cohort) suggests that NAGM MTR could be a clinically relevant surrogate marker in therapeutic trials.

Metabolite changes in early relapsing- remitting multiple sclerosis : A two year follow-up study

Previous in vivo proton magnetic resonance spectroscopic imaging (1H–MRSI) studies have found reduced levels of N–acetyl–aspartate (NAA) in multiple sclerosis (MS) lesions, the surrounding normal–appearing white matter (NAWM) and cortical grey matter (CGM), suggesting neuronal and axonal dysfunction and loss. Other metabolites, such as myoinositol (Ins), creatine (Cr), choline (Cho), and glutamate plus glutamine (Glx), can also be quantified by 1H–MRSI, and studies have indicated that concentrations of these metabolites may also be altered in MS. Relatively little is known about the time course of such metabolite changes. This preliminary study aimed to characterise changes in total NAA (tNAA, the sum of NAA and N–acetyl–aspartyl–glutamate), Cr, Cho, Ins and Glx concentrations in NAWM and in CGM, and their relationship with clinical outcome, in subjects with clinically early relapsing–remitting MS (RRMS). Twenty RRMS subjects and 10 healthy control subjects underwent 1H–MRSI examinations yearly for two years. Using the LCModel, tNAA, Cr, Cho, Ins and Glx concentrations were estimated both in NAWM and CGM.At baseline, the concentration of tNAA was significantly reduced in the NAWM of the MS patients compared to the control group (–7%, p = 0.003), as well as in the CGM (–8.7%, p = 0.009). NAWM tNAA concentrations tended to recover from baseline, but otherwise tissue metabolite profiles did not significantly change in the MS subjects, or relatively between MS and healthy control subjects. While neuronal and axonal damage is apparent from the early clinical stages of MS, this study suggests that initially it may be partly reversible. Compared with other MR imaging measures, serial 1H–MRSI may be relatively less sensitive to progressive pathological tissue changes in early RRMS.

Increasing cord atrophy in early relapsing-remitting multiple sclerosis: a 3 year study

Objectives: Previous studies have shown that upper cervical cord atrophy (UCCA) occurs in multiple sclerosis (MS), particularly in those disabled and with primary or secondary progressive disease. It is less clear how early it can be detected in relapsing-remitting (RR) MS, and whether early cord atrophy relates to the concurrent or future clinical course. Methods: Twenty seven RR MS patients (median disease duration 1.7 years, in all cases <3 years from onset) were recruited along with 20 controls. They were followed for up to 3 years with a yearly assessment of UCCA and clinical function measured by the Expanded Disability Status Scale (EDSS) and MS Functional Composite Score (MSFC). Clinical and MRI correlations were investigated. Statistical models adjusted for covariates including total intracranial volume. Results: Longitudinal analysis showed a significant decrease in UCCA in patients both within the patient cohort (p<0.001) and in comparison with controls (p = 0.001). There was a significant increase in EDSS (p = 0.008) but no significant change in MSFC. The rate of UCCA loss did not correlate with clinical change or with change in brain volume. Conclusions: In summary, serial UCCA measurement detects the development of spinal cord atrophy in clinically early RR MS.