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Background and purpose Olfactory bulb atrophy is associated with cognitive dysfunction in Parkinson's and Alzheimer's disease, and with major depression. It has been suggested that olfactory bulb atrophy or dysfunction is therefore a marker of neurodegeneration. Multiple sclerosis ( MS) is now also recognized as having a significant neurodegenerative component. Thus, the aim of this study was to investigate associations between physical and cognitive disability, depression and olfactory bulb volume in MS. Methods In total, 146 patients with MS (mean age 49.0 ± 10.9 years, disease duration 21.2 ± 9.3 years, median Expanded Disability Status Scale ( EDSS) score 3.0 (range 0-7.5), 103 relapsing−remitting, 35 secondary progressive and eight primary progressive MS) underwent a standardized neurological examination, comprehensive neuropsychological testing and magnetic resonance imaging ( MRI); data of 27 healthy people served as age- and gender-matched control subjects. The olfactory bulb was semi-automatically segmented on high-resolution three-dimensional T1-weighted MRI. Results Mean olfactory bulb volume was lower in MS patients than healthy controls (183.9 ± 40.1 vs. 209.2 ± 59.3 μl; P = 0.018 adjusted to intracranial volume). Olfactory bulb volume was similar across clinical disease subtypes and did not correlate with cognitive performance, EDSS scores or total proton density/T2 white matter lesion volume. However, in progressive MS, the mean olfactory bulb volume correlated with depression scores (Spearman's rho = −0.38, P < 0.05) confirmed using a multivariate linear regression analysis including cognitive fatigue scores. This association was not observed in relapsing−remitting MS. Conclusion Olfactory bulb volume was lower in MS than in healthy controls. Olfactory bulb volume does not seem to mirror cognitive impairment in MS; however, it is associated with higher depression scores in progressive MS. [ABSTRACT FROM AUTHOR]

Multiple sclerosis (MS) is a common neurological disease in North America and Europe. Although most patients develop major locomotor disability over the course of 15-20 years, in approximately one-third of patients the long-term course is favorable, with minimal disability. Although current disease-modifying treatments reduce the relapse rate, their long-term effects are uncertain. MS treatment trials are challenging because of the variable clinical course and typically slow evolution of the disease. Magnetic resonance imaging (MRI) is sensitive in monitoring MS pathology and facilitates evaluation of potential new treatments. MRI measurements of lesion activity have identified new immunomodulatory treatments for preventing relapse. Quantitative measurements of tissue volume and structural integrity, capable of detecting neuroprotection and repair, should facilitate new treatments designed to prevent irreversible disability. Higher-field MR scanners and new positron emission tomography (PET) radioligands are providing new insights into cellular and pathophysiological abnormalities, and should be valuable in future therapeutic trials. Retinal axonal loss measured using optical coherence tomography (OCT) can assess acute neuroprotection in optic neuritis. [ABSTRACT FROM AUTHOR]

Objectives: Using current diagnostic criteria, patients who present with a clinically isolated syndrome (CIS) may develop multiple sclerosis (MS) by subsequently exhibiting dissemination in space and time on clinical (clinically definite (CD) MS) or radiological (MRI) grounds. This study investigated the frequency of radiological without clinical conversion to MS after long term follow-up as this has not previously been defined.Methods: Two cohorts who underwent serial clinical and MRI studies from presentation with a CIS and who were followed-up over a mean of 6 and 20 years were investigated. The distribution and formation of lesions visible on brain MRI were assessed using the revised McDonald criteria (2005). Radiologically defined (RD) MS was determined by fulfilment of the MRI but not the CDMS criteria.Results: 105 people were followed-up for 6 years after a CIS, of whom 51% developed CDMS, 15% RDMS and the remainder were classified as still having had a CIS. 70 people were followed-up at 20 years, of whom 61% and 11% had developed CDMS and RDMS, respectively.Conclusion: About 10-15% of CIS patients may develop MS on MRI criteria only, without further clinical events for up to two decades. [ABSTRACT FROM AUTHOR]

Background In multiple sclerosis, grey matter (GM) damage appears more clinically relevant than either white matter damage or lesion load. Objective We investigated if normal-appearing white matter (NAWM) and grey matter tissue changes assessed by magnetization transfer ratio were associated with long-term disability. Methods Sixty-nine people were assessed 20 years after presentation with a clinically isolated syndrome (CIS) [28 still CIS, 31 relapsing-remitting multiple sclerosis, 10 secondary progressive multiple sclerosis], along with 19 healthy subjects. Mean magnetization transfer ratio, peak height (PH) and peak location of the normalized magnetization transfer ratio histograms were determined in NAWM and grey matter, as well as, white matter and GM Fraction (GMF) and T2-weighted lesion load. Results Median expanded disability status scale for multiple sclerosis patients was 2.5 (range 1-8). GM-PH, and less so, NAWM mean and peak location, were lower in multiple sclerosis patients (P = 0.009) versus controls, relapsing-remitting multiple sclerosis versus CIS (P = 0.008) and secondary progressive multiple sclerosis versus relapsing-remitting multiple sclerosis (P = 0.002). GM-PH (as well as GMF) correlated with expanded disability status scale (rs = -0.49; P = 0.001) and multiple sclerosis functional score (rs = 0.51; P = 0.001). GM-PH independently predicted disability with similar strength to the associations of GMF with clinical measures. Conclusion Grey matter damage was related to long-term disability in multiple sclerosis cohort with a relatively low median expanded disability status scale. Markers of intrinsic grey matter damage (magnetization transfer ratio) and tissue loss offer clinically relevant information in multiple sclerosis. [ABSTRACT FROM AUTHOR]

Gadolinium (Gd) enhancement of lesions indicates inflammatory lesion activity in multiple sclerosis (MS). The question arises whether early inflammatory lesion activity — measured sensitively using triple dose Gd — is related to the future clinical course, or to the development of brain atrophy that is thought to reflect the underlying pathological progression of the disease. In this study, 26 patients with early relapsing-remitting (RR) MS (median disease duration: 1.7 years) were followed up over two years. Associations were explored between their levels of Gd-lesion enhancement in the first six months and later clinical (Expanded Disability Status Scale (EDSS) and MS Functional Composite Score (MSFC)) and magnetic resonance imaging (MRI) (brain volume, T2 and T1 lesion volumes) measures. The extent of Gd-enhancement in the first six months correlated weakly with concurrent relapses (P=0.041), but there was no consistent correlation with clinical and MRI outcomes at two years. More prolonged follow-up is warranted to clarify the relationship between early inflammatory lesions and long-term clinical course. [ABSTRACT FROM AUTHOR]

Objective To investigate the presence and evolution of T1 relaxation time abnormalities in normal-appearing white matter (NAWM) and grey matter (GM), early in the course of relapsing-remitting multiple sclerosis (MS). Methods Twenty-three patients with early relapsing-remitting MS and 14 healthy controls were imaged six monthly for up to three years. Mean follow-up was 26 months for MS patients and 24 months for controls. Dual-echo fast-spin echo and gradient-echo proton-density and T1-weighted data sets (permitting the calculation of a T1 map) were acquired in all subjects. GM and NAWM T1 histograms were produced and a hierarchical regression model was used to investigate changes in T1 over time. Results At baseline, significant patient-control differences were seen, both in NAWM (P<0.001) and in GM (P=0.01). At follow-up, there was no evidence for a serial change in either mean T1 or peak-location for either NAWM or GM. There was weak evidence for a decline in patient NAWM peak-height and also evidence for a decline in control GM peak-height. Conclusion There are significant and persistent abnormalities of NAWM and GM T1 in early relapsing-remitting MS. Further studies should address whether such T1 measures have a role in prognosis or therapeutic monitoring. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Presents the studies included in the tournament for young neurologists. Raise serum nitric oxide metabolites and disease activity in multiple sclerosis; Re-stenosis after carotid stent implantation; Deep brain stimulation for refractory temporal lobe epilepsy; Decreased levels of amyloid beta peptide in the brains of smokers; Nuclear clumps as a myopathological hallmark lesion of myotonic dystrophy.

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. [ABSTRACT FROM AUTHOR]

While there is now evidence for thalamic abnormality in established secondary progressive and relapsing–remitting multiple sclerosis (MS), it remains unclear when such abnormality begins. This study investigated the emergence of thalamic abnormality in relapsing–remitting MS by assessing the thalamic magnetization transfer ratio (MTR) in a cohort with clinically early disease. Twenty-three patients with early relapsing–remitting MS (mean age 37; mean disease duration 1.9 years; Expanded Disability Status Scale (EDSS) range 0–3) and 19 healthy controls (mean age 34) were imaged yearly with a magnetization transfer imaging sequence. Twenty-two MS patients and 14 controls completed two-year follow-up. Regions of interest were placed in both thalami and mean thalamic MTR calculated. At baseline, significant differences between patient and control thalamic MTR were not observed. However, at years one and two, the thalamic MTR in patients was significantly lower than control MTR. Although baseline lesion volume did not correlate with baseline thalamic MTR, at year one, an association between baseline lesion volume and year one thalamic MTR emerged. There was also a significant inverse correlation between EDSS and thalamic MTR (r = -0.47, P = 0.02). The study suggests that thalamic involvement occurs within the first five years of MS onset, when most patients are still minimally disabled. [ABSTRACT FROM AUTHOR]

Background Abnormalities in normal-appearing brain tissues may contribute to disability in primary progressive multiple sclerosis (PPMS), where few lesions are seen on conventional imaging. Objectives To evaluate the mechanisms underlying disease progression in the early phase of PPMS by measuring metabolite concentrations in normal-appearing white matter (NAWM) and cortical gray matter (CGM) and to assess their relationship with clinical outcomes. Design Case-control study. Setting Tertiary referral hospital. Patients Forty-three consecutive patients within 5 years of onset of PPMS and 44 healthy control subjects. Main Outcome Measures Concentrations of choline-containing compounds, phosphocreatine, myo-inositol, total N-acetyl-aspartate (tNAA), and glutamate-glutamine were estimated using proton magnetic resonance spectroscopic imaging. Brain parenchymal, white matter and gray matter fractions and proton density and gadolinium-enhancing lesion loads were calculated. The Expanded Disability Status Scale and Multiple Sclerosis Functional Composite scores were recorded. Results In CGM, concentrations of the tNAA (P<.001) and glutamate-glutamine (P = .005) were lower in patients with PPMS than in controls. In NAWM, myo-inositol levels were higher (P = .002) and tNAA levels were lower (P = .005) in patients with PPMS than in controls. The Expanded Disability Status Scale score correlated with the tNAA concentration in CGM (r = -0.44; P = .03) and with myo-inositol (r = 0.41; P = .01) and glutamate-glutamine concentrations (r = 0.41; P = .01) in NAWM. Proton density lesion load correlated negatively with CGM tNAA concentration and positively with NAWM myo-inositol concentration. Conclusion Metabolite changes, which differ in CGM and NAWM, occur in early PPMS and are linked with disability. [ABSTRACT FROM AUTHOR]

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 beta-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 T(1) 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. [ABSTRACT FROM AUTHOR]

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 P = 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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Diffusion tensor magnetic resonance imaging (DTI) reveals measurable abnormalities in normal-appearing brain tissue (NABT) in established multiple sclerosis (MS). However, it is unclear how early this occurs. Recent studies have employed whole brain histogram analysis to improve sensitivity, but concern exists regarding reliability of tissue/cerebrospinal fluid segmentation and possible intersubject brain volume differences, which can introduce partial volume error. To address this, 28 early relapsing-remitting MS subjects [median disease duration 1.6 years; median Expanded Disability Status Scale (EDSS) score 1.5] and 20 controls were compared with whole brain histogram analysis using an automated segmentation algorithm to improve reproducibility. Brain parenchymal volumes (BPV) were estimated for each subject in the analysis. The mean, peak height and peak location were calculated for DTI parameters [fractional anisotropy (FA), mean diffusivity and volume ratio]. An increased FA peak height in MS subject NABTwas observed (P=0.02) accounting for age, gender and BPV. Removing BPV revealed additional abnormalities in NABT. The main conclusions are i) FA peak height is increased in NABT in early MS, ii) partial volume edge effects may contribute to apparent NABT histogram abnormalities, and iii) correction for brain volume differences should reduce potential partial volume edge effects. [ABSTRACT FROM AUTHOR]

Background: In 10–15 % of patients with multiple sclerosis (MS), the clinical course is characterized by slow progression in disability without relapses (primary progressive (PP) MS). The mechanism of disability in this form of MS is poorly understood. Using magnetization transfer ratio (MTR) imaging, we investigated normal appearing white matter (NAWM) and normal appearing grey matter (NAGM) in PPMS and explored the relationship of MTR measures with disability. Methods: Thirty patients with PPMS and 30 age matched controls had spin echo based MTR imaging to study lesions and normal appearing tissues. The brain was segmented into NAWM and NAGM using SPM99 with lesions segmented using a semiautomated local thresholding technique. A 75 % probability threshold for classification of NAWM and NAGM was used to diminish partial volume effects. From normalized histograms of MTR intensity values, six MTR parameters were measured. Mean lesion MTR and T2 lesion volume were also measured. Disability was assessed using Kurtzke's expanded disability status scale (EDSS). Results: Compared with controls, patients exhibited a significant reduction in mean NAWM (p = 0.001) and NAGM (p = 0.004) MTR. Spearman's rank correlation of EDSS with the six MTR parameters in NAWM and NAGM, mean lesion MTR, and T2 lesion volume, was only significant with mean NAGM MTR (r = -0.41, p = 0.02), the 25th percentile of NAGM MTR intensity (r = -0.37, p = 0.05), and T2 lesion volume (r = 0.39, p = 0.04). Multiple regression analysis of the relationship between EDSS and 4 MR parameters representing each tissue type (mean NAWM MTR, mean NAGM MTR, mean lesion MTR, T2 lesion volume) showed that the association of EDSS with mean NAGM MTR remained significant. Conclusions: There appear to be significant abnormalities in the NAGM in PP MS. Further investigation of the pathological basis and functional significance of grey matter abnormality in PPMS is warranted. [ABSTRACT FROM AUTHOR]

Focuses on a study which assessed the disability resulting from multiple sclerosis (MS) 14 years after the presentation of clinically isolated syndromes. Patients and methods; Physiological manifestations of MS; Measurement of metabolites; Level of myo-inositol in MS patients.