The Peripheral Benzodiazepine Binding Site In The Brain In Multiple Sclerosis: Quantitative In Vivo Imaging Of Microglia As A Measure Of Disease Activity
Banati RB, Newcombe J, Gunn RN, Cagnin A, Turkheimer F, Heppner F, Price G, Wegner F, Giovannoni G, Miller DH, Perkin GD, Smith T, Hewson AK, Bydder G, Kreutzberg GW, Jones T, Cuzner ML, Myers R
Brain 2000 Nov;123(Pt 11):2321-2337
MRC Cyclotron Unit and Robert Steiner Magnetic Resonance Imaging Unit, Imperial College School of Medicine, Hammersmith Hospital, Dept of NeuroScience, Imperial College School of Medicine, Charing Cross Hospital, NeuroInflammation Group and NMR Research Unit, Institute of Neurology, Univ, College London, Eisai London Research Laboratories, Univ, College London, London, Dept of NeuroScience Research, SmithKline-Beecham Pharmaceuticals, Harlow, Dept of Physiology, Univ of Cambridge, Cambridge, UK, Paul Flechsig Institute, Leipzig, Dept of Neuromorphology,Max-Planck-Institute of NeuroBiology, Munich, Germany and Dept of Neuropathology, Univ of Zurich, Switzerland
PMID# 11050032; UI# 20504122
This study identifies by MicroAutoRadiography activated Microglia/Macrophages as the main cell type expressing the Peripheral Benzodiazepine Binding Site (PBBS) at sites of active CNS pathology.
Quantitative measurements of PBBS expression in vivo obtained by PET and [(11)C](R:)-PK11195 are shown to correspond to animal experimental and human post-mortem data on the distribution pattern of activated Microglia in Inflammatory Brain Disease.
Film AutoRadiography with [(3)H](R:)-PK11195, a specific Ligand for the PBBS, showed minimal binding in normal control CNS, whereas maximal binding to MonoNuclear Cells was found in Multiple Sclerosis plaques.
However, there was also significantly increased [(3)H](R:)-PK11195 binding on activated Microglia outside the HistoPathologically defined borders of Multiple Sclerosis plaques.
And in areas, such as the Cerebral Central Gray Matter, that are not normally reported as sites of pathology in Multiple Sclerosis.
A similar pattern of [(3)H](R:)-PK11195 binding in areas containing activated Microglia was seen in the CNS of animals with Experimental Allergic EncephaloMyelitis (EAE).
In areas without identifiable focal pathology, ImmunoCytoChemical staining combined with high-resolution emulsion AutoRadiography demonstrated that the Cellular source of [(3)H](R:)-PK11195 binding is activated Microglia, which frequently retains a ramified morphology.
Furthermore, in vitro RadioLigand Binding studies confirmed that Microglial activation leads to a rise in the number of PBBS and not a change in binding affinity.
Quantitative [(11)C](R:)-PK11195 PET in Multiple Sclerosis patients demonstrated increased PBBS expression in areas of focal pathology identified by T1- and T2-weighted MRI and, importantly, also in Normal-Appearing Anatomical Structures, including Cerebral Central Gray Matter.
The additional binding frequently delineated Neuronal projection areas, such as the Lateral Geniculate Bodies in patients with a history of Optic Neuritis. In summary, [(11)C](R:)-PK11195 PET provides a cellular marker of disease activity in vivo in the human Brain.
Evidence For Adaptive Functional Changes In The Cerebral Cortex With Axonal Injury From Multiple Sclerosis
Reddy H, Narayanan S, Arnoutelis R, Jenkinson M, Antel J, Matthews PM, Arnold DL
Brain 2000 Nov;123(Pt 11):2314-2320
Centre for Functional Magnetic Resonance Imaging of the Brain, Dept of Clinical Neurology, and Univ of Oxford, John Radcliffe Hospital, Oxford, UK and Montreal Neurological Institute, McGill University, Dept of Neurology and NeuroSurgery, Montreal, Canada
PMID# 11050031; UI# 20504121
Axonal injury occurs even in the earliest stages of Multiple Sclerosis.
Magnetic Resonance Spectroscopic Imaging (MRSI) measurements of Brain N:-AcetylAspartate (NAA), a marker of Axonal integrity, show that this Axonal injury can occur even in the absence of clinically evident functional impairments.
To test whether Cortical adaptive responses contribute to the maintenance of normal Motor Function in patients with Multiple Sclerosis, we performed MRSI and functional MRI (fMRI) examinations of nine Multiple Sclerosis patients who had unimpaired hand function.
We found that activation of the IpsiLateral SensoriMotor Cortex with simple hand movements was increased by a mean of fivefold relative to normal controls (n = 8) and that the extent of this increase was strongly correlated (sigma = -0.93, P: = 0.001) with decreases in Brain NAA.
These results suggest that compensatory Cortical adaptive responses may help to account for the limited relationship between conventional MRI measures of lesion burden and clinical measures of disability.
And that therapies directed towards promoting Cortical reorganization in response to Brain injury could enhance recovery from relapses of Multiple Sclerosis.
The Effect Of Interferon-ß-1b treatment on MRI Measures Of Cerebral Atrophy In Secondary/Progressive Multiple Sclerosis
Molyneux PD, Kappos L, Polman C, Pozzilli C, Barkhof F, Filippi M, Yousry T, Hahn D, Wagner K, Ghazi M, Beckmann K, Dahlke F, Losseff N, Barker GJ, Thompson AJ, Miller DH
Brain 2000 Nov;123(Pt 11):2256-2263
Institue of Neurology, NMR Research Unit, National Hospital, Queen Square, London WC1N 3BG, UK
PMID# 11050025; UI# 20504115
The recently completed European trial of Interferon-ß-1b (IFN-ß-1b) in patients with Secondary/Progressive Multiple Sclerosis (SP Multiple Sclerosis) has given an opportunity to assess the impact of treatment on Cerebral Atrophy using serial MRI.
Unenhanced T1-weighted Brain imaging was acquired in a subgroup of 95 patients from five of the European centers; imaging was performed at 6-month intervals from month 0 to month 36.
A blinded observer measured Cerebral volume on four contiguous 5 mm Cerebral Hemisphere slices at each time point, using an algorithm with a high level of reproducibility and automation.
There was a significant and progressive reduction in Cerebral volume in both placebo and treated groups, with a mean reduction of 3.9 and 2.9%, respectively, by month 36 (P: = 0.34 between groups).
Exploratory subgroup analyzes indicated that patients without Gadolinium (Gd) enhancement at the baseline had a greater reduction of Cerebral volume in the placebo group (mean reduction at month 36: placebo 5.1%, IFN-ß-1b 1.8%, P: < 0.05).
Whereas those with Gd-enhancing lesions showed a trend to greater reduction of Cerebral volume if the patient was on IFN-ß-1b (placebo 2.6%, IFN-ß-1b 3.7%; P: > 0.05).
These results are consistent with ongoing tissue loss in both arms of this study of Secondary/Progressive Multiple Sclerosis. This finding is concordant with previous observations that disease progression, although delayed, is not halted by IFN-ß.
The different pattern seen in patients with and without baseline Gadolinium enhancement suggests that part of the Cerebral volume reduction observed in IFN-ß-treated patients may be due to the AntiInflammatory/AntiEdematous effect of the drug.
Longer periods of observation and larger groups of patients may be needed to detect the effects of treatment on Cerebral Atrophy in this population of patients with advanced disease