Normal-appearing grey and white matter T1 abnormality in early relapsing-remitting multiple sclerosis: a longitudinal study.

OBJECTIVE: To investigate the presence and evolution of T(1) 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 T(1)-weighted data sets (permitting the calculation of a T(1) map) were acquired in all subjects. GM and NAWM T(1) histograms were produced and a hierarchical regression model was used to investigate changes in T(1) 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 T(1) 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 T(1) in early relapsing-remitting MS. Further studies should address whether such T(1) measures have a role in prognosis or therapeutic monitoring.

Relationship of triple dose contrast enhanced lesions with clinical measures and brain atrophy in early relapsing-remitting multiple sclerosis: a two-year longitudinal study.

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, T(2) and T(1) 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.

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.

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

Previous in vivo proton magnetic resonance spectroscopic imaging ((1)H-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 (1)H-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 (1)H-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 (1)H-MRSI may be relatively less sensitive to progressive pathological tissue changes in early RRMS.

Emergence of thalamic magnetization transfer ratio abnormality in early relapsing-remitting multiple sclerosis.

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.

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: (-0.10 pu/year, p=0.001 and -0.18 pu/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.

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 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.

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.

Diffusion tensor imaging of early relapsing-remitting multiple sclerosis with histogram analysis using automated segmentation and brain volume correction.

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 NABT was 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.

Disability in multiple sclerosis is related to normal appearing brain tissue MTR histogram abnormalities.

BACKGROUND: Magnetization transfer ratio (MTR) histogram analysis provides a global measure of disease burden in multiple sclerosis (MS). MTR abnormalities in normal appearing brain tissue (NABT) provide quantitative information on the extent of tissue damage undetected by conventional T2-weighted (T2W) magnetic resonance imaging (MRI). AIMS: 1) To compare the MTR histograms from NABT across a broad spectrum of relapse onset MS patients, including relapsing-remitting (RR) MS (including newly diagnosed and benign subgroups) and secondary progressive (SP) MS. 2) To determine the relationship between clinical disability and NABT MTR histograms. METHODS: 2D spin echo magnetization transfer imaging was performed on 70 RRMS and 25 SPMS patients and compared with 63 controls. MTR histograms were acquired for NABT after extracting lesions and cerebrospinal fluid (CSF). T2W images were used to measure the brain parenchymal fraction (BPF) and T2 lesion load. RESULTS: MS patients had a disease duration ranging from 0.5 to 37 years and an Expanded Disability Status Scale (EDSS) score ranging from 0 to 8.5. There was a significant decrease in NABT mean MTR (+/- standard deviation) compared with controls (33.07 pu +/- 1.06 versus 34.26 pu +/- 0.47; P < 0.001) with an effect size of 2.56. The reduction in NABT mean MTR varied among patient groups from 4.9% for SPMS, 3% for all RRMS, 2.7% for early RRMS and 2.5% for benign MS, compared with controls. NABT mean MTR correlated significantly with T2 lesion load (r = -0.82) and BPF (r = 0.58). EDSS score correlated with NABT mean MTR (r = -0.43), BPF (r = -0.33) and with T2 lesion load (r = 0.59). Multivariate analysis using NABT MTR peak height, T2 lesion load and BPF combined only accounted for 38% of the variance in the EDSS (r = 0.62; P < 0.001). Disease duration accounted for an additional 14% of variance in the EDSS (r = 0.72; P < 0.001). CONCLUSIONS: There is evidence of diffuse abnormalities in NABT in addition to global brain atrophy in relapse onset MS patients, including those with recently diagnosed RRMS and benign MS. The abnormalities are greatest in patients with the more disabling SPMS. Atrophy, NABT and lesion abnormalities are all partly correlated; the processes marked by these MR measures all contribute to disability in MS, providing complementary information relevant to the complex pathological processes that occur in MS.

The longitudinal relation between brain lesion load and atrophy in multiple sclerosis: a 14 year follow up study.

BACKGROUND: Studies have suggested that T2 lesion activity is prominent in early relapsing-remitting multiple sclerosis, whereas brain atrophy, while seen early, appears more evident in later progressive disease. The temporal relation between these processes remains unclear. OBJECTIVE: To explore the association between changing brain lesion loads and subsequent tissue atrophy in multiple sclerosis. METHODS: 28 subjects with clinically probable or definite multiple sclerosis (mean age 46.0 years; 17 female and 11 male) were followed for 14 years after first onset of symptoms. T2 lesion loads were estimated soon after symptom onset and at around five, 10, and 14 years later. Disease related atrophy was estimated at the 14 year follow up by comparing brain tissue volumes (proportional to total intracranial volumes) determined in the multiple sclerosis group with data from 29 normal control subjects (mean age 36.7 years; 16 female, 13 male) using multiple linear regression analyses to allow for differences in age and sex distributions. RESULTS: Change in lesion load in the first five years was more closely correlated to disease related brain atrophy at 14 years than later changes in lesion load, although the correlation was only moderate (Spearman correlation = -0.528, p = 0.004). CONCLUSIONS: From this, it appears that early rather than later focal lesion accumulation relates to subsequent brain atrophy, but factors unconnected directly with lesion formation probably also play a significant role in determining such atrophy.

Brain metabolite changes in cortical grey and normal-appearing white matter in clinically early relapsing-remitting multiple sclerosis.

While much work has concentrated on focal white matter (WM) lesions in multiple sclerosis, there is growing evidence to suggest that normal-appearing WM (NAWM) and grey matter (GM) are also involved in the disease process. This study investigated multiple sclerosis disease effects on NAWM and cortical GM (CGM) metabolite concentrations, and the relationships between these metabolite concentrations and clinical impairment. Proton magnetic resonance spectroscopic imaging ((1)H-MRSI) data acquired using point resolved spectroscopic (PRESS) localization (echo time 30 ms, repetition time 3000 ms, nominal voxel volume 2.3 ml) from 27 relapsing-remitting multiple sclerosis and 29 normal control (NC) subjects were processed using LCModel to estimate metabolite concentrations in millimoles per litre. (1)H-MRSI voxel tissue contents were estimated using SPM99 tissue and semi-automatic lesion segmentations of three-dimensional fast spoiled gradient recall scans acquired during the same scanning session. NAWM and CGM metabolite concentrations estimated were: choline-containing compounds (Cho); creatine and phosphocreatine (Cr); myo-inositol (Ins); N-acetyl-aspartate plus N-acetyl-aspartyl-glutamate (tNAA); and glutamate plus glutamine (Glx). CGM data came from 24 of the multiple sclerosis (mean age 35.2 years, mean disease duration 1.7 years) and 25 of the NC (mean age 34.9 years) subjects. NAWM data came from 25 of the multiple sclerosis (mean age 35.0 years, mean disease duration 1.7 years) and 28 of the NC (mean age 36.7 years) subjects. Metabolite concentrations were compared between multiple sclerosis and NC subjects using multiple (linear) regression models allowing for age, gender, (1)H-MRSI voxel tissue and CSF contents, and brain parenchymal volume. At a significance level of P < 0.05, CGM Cho, CGM and NAWM tNAA, and CGM Glx were all significantly reduced, and NAWM Ins was significantly elevated. Spearman correlations of multiple sclerosis functional composite scores with tissue metabolite concentrations were significant for the following: CGM Cr (r(s) = 0.524, P = 0.009), CGM Glx (r(s) = 0.580, P = 0.003) and NAWM Ins (r(s) = -0.559, P = 0.004). These results indicate that metabolite changes in NAWM and CGM can be detected early in the clinical course of multiple sclerosis, and that some of these changes relate to clinical status. The correlation of clinical impairment with CGM Cr and Glx but not tNAA suggests that it is more closely associated with neuronal metabolic dysfunction rather than loss in clinically early relapsing-remitting multiple sclerosis. The correlation of clinical impairment with a raised NAWM Ins may indicate that glial proliferation also relates to function at this stage of the disease.

Quantitative 1H MRS imaging 14 years after presenting with a clinically isolated syndrome suggestive of multiple sclerosis.

clinically isolated syndromes (CIS) are events suggestive for emerging multiple sclerosis (MS). A majority of patients develop MS within months or years whilst others remain clinically isolated. The goal of this study was to investigate whether biochemical metabolites detectable by 'H magnetic resonance spectroscopy (MRS) may serve to distinguish between these two groups. We investigated 41 patients 14 years after presentation with a CIS and 21 controls with combined quantitative short echo 'H MRS and magnetic resonance imaging (MRI) and assessed disability according to the Expanded Disability Status Scale (EDSS). At follow-up, 32 had developed MS, and 9 still had CIS. Compared with controls, MS patients demonstrated significantly higher concentrations of myo-inositol (Ins) in normal appearing white matter (NAWM) and lesions. Lesions also demonstrated a reduced N-acetyl-aspartate (NAA) level and an increase in choline-containing compounds (Cho). The NAWM Ins concentration was correlated with EDSS (r = 0.48, p = 0.005). MS normal appearing cortical grey matter (CGM) exhibited a decreased NAA. Patients who remained CIS did not differ significantly from controls in any MRS measure. Metabolite changes in normal appearing white and grey matter in MS indicate diffuse involvement of the entire MS brain, which was not seen in the persisting CIS patients. Elevated Ins in MS NAWM appeared functionally relevant It may indicate glial cell proliferation or gliosis.

T1 histograms of normal-appearing brain tissue are abnormal in early relapsing-remitting multiple sclerosis.

OBJECTIVE: To use both whole-brain and normal-appearing brain tissue (NABT) T1 relaxation time histograms to investigate abnormalities in early relapsing-remitting (RR) multiple sclerosis (MS). BACKGROUND: In patients with established MS, both lesions and NABT exhibit an increase in T1 relaxation time. By using T1 histogram analysis, it is hoped that such changes in early disease can be detected. METHOD: Twenty-seven patients and 14 age- and sex-matched controls underwent magnetic resonance imaging (MRI) of the brain, which included the following sequences: 1) proton density (PD)- and T2-weighted fast spin echo (FSE) to measure T2 lesion load, 2) PD- and T1-weighted gradient echos from which T1 relaxation was calculated, and 3) T1-weighted SE imaging pre- and post-triple dose (0.3 mmol/kg) gadolinium (Gd-DTPA) to measure T1 hypointense and gadolinium-enhancing lesion loads, respectively. All patients had RR MS with disease duration <3 years (median 1.7 years). Statistical parametric mapping (SPM) 99 was used to segment brain from cerebrospinal fluid (CSF), and lesions were segmented using a local thresholding technique. RESULTS: Both whole-brain and NABT histograms were abnormal for all six T1 histogram parameters that were measured. For NABT, the mean T1 was 1,027 (+/- 74) ms in patients and 969 (+/- 41) ms in controls (p=0.003). There was little difference between the global and NABT histograms, which indicates that most of the whole-brain histogram abnormality derives from normal-appearing tissues. There was a correlation between the Nine-Hole Peg Test and NABT T1 measures. CONCLUSION: There are widespread abnormalities of NABT in early RR MS, which were sensitively detected by T1 relaxation time histogram analysis. As such, T1 histogram analysis appears promising for studying the natural history of early RR MS, and in the monitoring of response to treatment

Brain atrophy in clinically early relapsing-remitting multiple sclerosis.

Brain atrophy measured by MRI is a potentially useful tool for monitoring disease progression in multiple sclerosis. The location, extent and mechanisms of brain atrophy in early disease are not well documented. Using quantitative MRI, this study investigated whole brain, grey and white matter atrophy in clinically early relapsing-remitting multiple sclerosis and its relationship to lesion measures. Data came from 27 normal control subjects (14 females and 13 males, mean age 36.1 years) and 26 subjects with clinically definite multiple sclerosis (18 females and eight males, mean age 35.1 years, mean delay from first symptom to scan 1.8 years, median Expanded Disability Status Scale score 1.0). All had three-dimensional fast spoiled gradient recall (3D FSPGR), T(1)-weighted pre- and post-gadolinium-enhanced and T(2)-weighted scans. The 3D FSPGR images were automatically segmented into grey and white matter and cerebrospinal fluid using SPM99. 3D FSPGR hypo-intense, T(2) hyper-intense, T(1) hypo-intense and T(1) post-gadolinium-enhancing lesion volumes were determined by semi-automatic lesion segmentation. The SPM99 output was combined with the 3D FSPGR lesion segmentations to quantify tissue volumes as fractions of total intracranial volumes, producing values for the brain parenchymal fraction (BPF), white matter fraction (WMF) and grey matter fraction (GMF). Comparing multiple sclerosis with control subjects, BPF, GMF and WMF were significantly reduced (P < 0.001 for all tissue fractions). Using Pearson correlations, T(2) hyper-intense and T(1) hypo-intense lesion volumes were inversely related to BPF (T(2) r = -0.78, P < 0.001; T(1) r = -0.59, P = 0.002) and GMF (T(2) r = -0.73, P < 0.001; T(1) r = -0.53, P = 0.006), but not WMF (T(2) r = -0.30, P = 0.134; T(1) r = -0.26, P = 0.199). T(1) post-gadolinium-enhancing lesion volumes were not correlated with any fractional volumes. These results indicate that significant brain atrophy, affecting both grey and white matter, occurs early in the clinical course of multiple sclerosis. The lack of correlation between lesion load measures and WMF suggests that pathological changes in white matter may occur by mechanisms which are at least partly independent from overt lesion genesis in early multiple sclerosis.

Diffusion tensor imaging in early relapsing-remitting multiple sclerosis.

Diffusion tensor magnetic resonance imaging (DTI) indices are abnormal in patients with established multiple sclerosis (MS). The objective of this study was to examine the diffusion characteristics of MS lesions, normal appearing white matter (NAWM) and normal appearing grey matter (NAGM) in MS patients with early relapsing-remitting disease. A further objective was to investigate the relationship between three DTI parameters (fractional anisotropy (FA), mean diffusivity (MD) and volume ratio (VR)) and clinical outcome measures (Kurtzke expanded disability status scale (EDSS) and MS Functional Composite Measure) in early disease. DTI was performed in 28 patients and 27 controls. Analysis was carried out using a region of interest (ROI) approach. ROIs were placed in 12 NAWM and nine NAGM regions. Significant differences were found in FA, MD and VR between lesions and NAWM (P< 0.001 for all three DTI parameters). No significant differences were found between patients and controls when examining NAWM or NAGM, although there was a trend for abnormal NAWM FA and VR in some regions. No correlation was found between DTI parameters in lesions, NAWM or NAGM and the clinical outcome measures. The lack of significant DTI abnormality in the NAWM and NAGM may reflect a lack of pathological change or a limited sensitivity of DTI using ROI methodology. Previous studies have shown abnormalities in TI relaxation time, magnetisation transfer ratio (MTR) and N-Acetyl aspartate (NM) in this cohort of patients, and as such, DTI using a region of interest (ROI) approach may not be as sensitive as other MR techniques in detecting subtle changes in normal appearing brain

Preliminary evidence for neuronal damage in cortical grey matter and normal appearing white matter in short duration relapsing-remitting multiple sclerosis: a quantitative MR spectroscopic imaging study.

Neuronal damage and loss is likely to underlie irreversible disability in multiple sclerosis (MS). The time of onset, location and extent of neuronal damage in early disease are all uncertain. To explore this issue 16 patients with short duration, mild relapsing-remitting disease (mean disease duration 1.8 years, median EDSS 1) were studied using short echo time proton magnetic resonance spectroscopic imaging (1H-MRSI) to quantify the concentration of the neuronal marker N-acetyl-aspartate (NAA). The data were compared with those from 12 age-matched controls. 1H-MRSI was obtained from a 1.5-cm-thick slice just above the lateral ventricles. The Linear Combination (LC) Model combined with locally developed software allowed automated measurement of absolute metabolite concentrations from lesions, normal-appearing white matter (NAWM) and cortical grey matter (CGM). MS CGM exhibited significantly lower NAA (P = 0.01) and myo-inositol (P = 0.04) than control CGM. MS NAWM exhibited a lower concentration of NAA (P = 0.01) and increased myo-inositol (P = 0.03) than control white matter. More marked reductions in NAA and increases in myo-inositol were seen in lesions. The reduced NAA in MS CGM and NAWM suggest that mild but widespread neuronal dysfunction or loss occurs early in the course of relapsing-remitting MS. This preliminary finding should be confirmed in a larger cohort, and follow-up studies are also needed to determine the prognostic and pathophysiological significance of these early changes.

Comprehensive primary care follow-up for premature infants.

Advances in perinatal and neonatal care have led to an increased incidence of survival of premature infants. Although most premature infants have normal outcomes, they are at increased risk for morbidity and mortality and require comprehensive primary care follow-up after they are discharged from the hospital. This article will review guidelines for general follow-up of premature infants and the associated problems related to prematurity. General follow-up is performed by the pediatric nurse practitioner, with subspecialty consultant referrals as needed. Knowledge of the problems of prematurity and treatment regimes will assist the pediatric nurse practitioner in providing high-quality care to these high-risk infants.

MTR and T1 provide complementary information in MS NAWM, but not in lesions.

MTR and T1 relaxation times are abnormal in MS lesions and NAWM, and may reflect tissue damage such as demyelination and axonal loss. Their relationship and potential to provide complementary information in tissue characterisation is explored. The aim of this study was to document the relationship between magnetisation transfer ratio (MTR) and T1 relaxation time in Multiple Sclerosis (MS) lesions and normal appearing white matter (NAWM) in order to determine whether the combination provides a more comprehensive tissue characterisation than either parameter in isolation. Ten patients with relapsing remitting MS and 10 age matched healthy controls underwent imaging using a protocol which included the measurement of both MTR and T1 relaxation times. The MTR and T1 values were compared statistically using a commonly adopted correlation approach and a mixed-model regression approach. There was a strong correlation between MTR and T1 in MS lesions (r=0.74). The correlation was seen equally in T1 hypointense and isointense lesions. The relationship was much weaker in MS NAWM (r=0.24) and no correlation was found in control white matter (r=0.06). Mixed-model regression analysis confirmed that the relationship between T1 and MTR is strongly dependent upon tissue type (MS lesion, MS NAWM, or control white matter). The relationship between MTR and T1 relaxation time measurements varies markedly between pathological and normal tissue types. In MS, the complementary information obtained from MTR and T1 is most apparent in NAWM. The results emphasise the potential for combinations of MR parameters to improve tissue characterisation, which in turn should improve understanding of disease pathology and treatment monitoring. Multiple Sclerosis (2000) 6 327 - 331