Axonal Dysfunction And Disability In A Relapse Of Multiple Sclerosis: Longitudinal Study Of A Patient
De Stefano N, Matthews PM, Narayanan S, Francis GS, Antel JP, Arnold DL
Neurology 1997 Oct;49(4):1138-41
Montreal Neurological Institute and Hospital, Dept of Neurology and NeuroSurgery, PQ, Canada
PMID# 9339704; UI# 97479623
In a 6-year longitudinal study of a patient with Progressive/Relapsing Multiple Sclerosis (MS), we used Proton Magnetic Resonance Spectroscopy to assess N-AcetylAspartate (NAA).
From a large central Brain Volume to evaluate the relationship between this marker of Neuronal integrity and clinical disability.
During the follow-up period, there was one major relapse and its subsequent partial remission.
Changes in the Brain NAA to Creatine ratio correlated strongly with clinical disability (Spearman rank coefficient = -0.73, p < 0.001). We interpret this as evidence that Axonal dysfunction or loss contributes to functional impairment of patients with MS.
Because the NAA signal in the large volume of interest originated predominantly from White Matter that appeared normal on conventional MRI, these results also suggest that some degree of Axonal dysfunction may be widespread in acute, severe relapses.
Mews I, Bergmann M, Bunkowski S, Gullotta F, Bruck W
Mult Scler 1998 Apr;4(2):55-62
Univ of Gottingen, Dept of NeuroPathology, Germany
PMID# 9599334; UI# 98261700
Oligodendrocyte and Axon pathology was studied in 11 autopsy cases of clinically silent Multiple Sclerosis.
A total of 54 lesions, either DeMyelinated or late ReMyelinated, were distributed through the whole Brain and Spinal Cord with 39% of the lesions located in PeriVentricular areas.
Determination of Axon density revealed an average reduction of 64% and 59% in DeMyelinated and ReMyelinated Lesions with an extreme variation between different plaques and cases.
Oligodendrocytes were identified by ImmunoCytoChemistry for Myelin Oligodendrocyte Glycoprotein (MOG) and in situ hybridization for ProteoLipid Protein (PLP) mRNA.
Oligodendrocytes were almost completely lost in DeMyelinated lesions; ReMyelinated lesions revealed preservation of a considerable number of Oligodendrocytes within the lesions.
At the border between plaques and the PeriPlaque White Matter, similar Oligodendrocyte numbers as in ReMyelinated lesions were found.
Different factors including Lesion site, Axonal preservation and ReMyelination may thus contribute to the Clinical NonAppearance of Multiple Sclerosis Lesions.
Axonal Damage In Acute Multiple Sclerosis Lesions
Ferguson B, Matyszak MK, Esiri MM, Perry VH
Brain 1997 Mar;120 ( Pt 3):393-9
Oxford University, Dept of Pharmacology, UK
PMID# 9126051; UI# 97271100
One of the histological hallmarks of early Multiple Sclerosis lesions is primary DeMyelination, with Myelin destruction and relative sparing of Axons.
On the other hand, it is widely accepted that Axonal loss occurs in, and is responsible for, the permanent Disability characterizing the later Chronic Progressive stage of the disease.
In this study, we have used an AntiBody against Amyloid Precursor Protein, known to be a sensitive marker of Axonal Damage in a number of other contexts, in ImmunoCytoChemical experiments on paraffin embedded Multiple Sclerosis Lesions of varying ages.
In order to see at which stage of the disease Axonal damage, in addition to DeMyelination, occurs and may thus contribute to the development of disability in patients.
The results show the expression of Amyloid Precursor Protein in damaged Axons within acute Multiple Sclerosis lesions, and in the active borders of less acute Lesions.
This observation may have implications for the design and timing of therapeutic intervention, one of the most important aims of which must be the reduction of permanent Disability.
N-AcetylAspartate Is An Axon-Specific Marker Of Mature White Matter In Vivo: A Biochemical And ImmunoHistoChemical Study On The Rat Optic Nerve
Bjartmar C, Battistuta J, Terada N, Dupree E, Trapp BD
Ann Neurol 2002 Jan;51(1):51-8
Lerner Research Institute, Cleveland Clinic Foundation, Department of NeuroSciences, Cleveland, OH 44195, USA
Axonal pathology is a major cause of Neurological disability in Multiple Sclerosis. Axonal transection begins at disease onset but remains clinically silent because of compensatory Brain mechanisms.
Noninvasive surrogate markers for Axonal Injury are therefore essential to monitor cumulative disease burden in vivo.
The Neuronal compound N-AcetylAspartate, as measured by Magnetic Resonance Spectroscopy, is currently the best and most specific noninvasive marker of Axonal pathology in Multiple Sclerosis.
The possibility has been raised, however, that N-AcetylAspartate is expressed also by OligodendroGlial Lineage Cells. In order to investigate N-AcetylAspartate specificity for White Matter Axons, transected rat Optic Nerves were analyzed by high-performance liquid Chromatography and ImmunoHistoChemistry.
In transected adult Nerves, N-AcetylAspartate and N-Acetyl AspartylGlutamate decreased in concordance with Axonal Degeneration and were undetectable 24 days PostTransection.
Nonproliferating Oligodendrocyte Progenitor Cells, Oligodendrocytes, and Myelin were abundant in these Axon-free Nerves. At 24 days PostTransection, N-AcetylAspartate was increased (42%; p = 0.02) in nontransected ContraLateral Nerves.
After transection at postnatal day 4, total N-AcetylAspartate decreased by 80% (P14; p = 0.002) and 94% (P20; p = 0.003). In these developing Axon-free Nerves, 25 to 33% of Oligodendrocyte Progenitor Cells were proliferating.
These data validate Magnetic Resonance Spectroscopy measurements of N-AcetylAspartate as an Axon-specific monitor of Central Nervous System White Matter in vivo.
In addition, the results indicate that Neuronal adaptation can increase N-AcetylAspartate levels, and that 5 to 20% of the N-AcetylAspartate in developing White Matter is synthesized by proliferating Oligodendrocyte Progenitor Cells.
Patients With Progressive Multiple Sclerosis Have Elevated AntiBodies To NeuroFilament Subunit
Silber E, Semra YK, Gregson NA, Sharief MK
Neurology 2002 May 14;58(9):1372-81
King's College, Guy's, King's, and St. Thomas' School of Medicine, Department of NeuroImmunology, London, United Kingdom
The cause of Axonal Loss, an important contributor to disability in MS, is poorly understood.
This study investigated whether progression in MS is associated with CSF AntiBodies to the 68-kd light NeuroFilament subunit (NF-L), an Axonal Cytoskeletal protein, and compared this with AntiBodies against Tubulin and the heavy NeuroFilament subunit (NF-H).
IgG to NF-L, Tubulin, and NF-H was measured by ImmunoAssay in matched CSF and Serum samples from patients with Relapsing/Remitting MS (RRMS; n = 39), Primary/Progressive MS (PPMS; n = 10), and Secondary/Progressive MS (SPMS; n = 18); patients with Other Inflammatory (n = 21) and NonInflammatory (n = 40) Neurologic Diseases; and healthy controls (n = 12).
ImmunoCytoChemistry was performed to assess AntiBody binding to human Brain sections, and IsoElectric Focusing with ImmunoBlotting was performed to assess OligoClonal Anti-NF-L production.
Intrathecal production of Anti-NF-L AntiBodies was significantly elevated in PPMS and SPMS.
In contrast, there were no significant differences in CSF levels of AntiBodies to Tubulin or NF-H between the groups.
Anti-NF-L, AntiTubulin, and anti-NF-H levels correlated with the duration of disease before Lumbar Puncture and Expanded Disability Status Scale levels.
ImmunoCytoChemistry demonstrated binding of CSF or Serum AntiBodies to Axonal or Neuronal components in six of seven RRMS patients, seven of seven PPMS patients, and eight of 10 SPMS patients tested.
IsoElectric Focusing demonstrated independent CSF OligoClonal Bands reactive with NF-L in six of 13 specimens tested.
Anti-NF-L AntiBodies seem to be raised in Progressive MS and may serve as a marker for Axonal Loss and disease progression. They may contribute to Axonal Loss and the accumulation of disability.
Normalized Regional Brain Atrophy Measurements In Multiple Sclerosis
Zivadinov R, Locatelli L, Stival B, Bratina A, Grop A, Nasuelli D, Brnabic-Razmilic O, Zorzon M
NeuroRadiology 2003 Nov;45(11):793-8
Cattinara Hospital, University of Trieste, Department of Clinical Medicine and Neurology, Strada di Fiume, 447-34149 Trieste, Italy
There is still a controversy regarding the best Regional Brain Atrophy measurements in Multiple Sclerosis (MS) studies.
The aim of this study was to establish whether, in a Cross-Sectional Study, the Normalized measurements of Regional Brain Atrophy correlate better with the MRI-defined regional Brain lesions than the Absolute measurements of Regional Brain Atrophy.
We assessed 45 patients with Clinically Definite Relapsing/Remitting (RR) MS (median disease duration 12 years), and measured T1-lesion load (LL) and T2-LL of Frontal Lobes and Pons, using a reproducible semi-automated technique.
The Regional Brain Parenchymal Volume (RBPV) of Frontal Lobes and Pons was obtained by use of a computerized interactive program, which incorporates semi-automated and automated segmentation processes.
A normalized measurement, the Regional Brain Parenchymal Fraction (RBPF), was calculated as the ratio of RBPV to the total Volume of the Parenchyma and the CerebroSpinal Fluid (CSF) in the Frontal Lobes and in the region of the Pons.
The Total Regional Brain Volume Fraction (TRBVF) was obtained after we had corrected for the Total Volume of the Parenchyma and the CSF in the Frontal Lobes and in the region of the Pons for the Total IntraCranial Volume.
The mean Coefficient of Variation (CV) for RBPF of the Pons was 1% for intra-observer reproducibility and 1.4% for inter-observer reproducibility.
Generally, the Normalized measurements of Regional Brain Atrophy correlated with Regional Brain Volumes and disability better than did the Absolute measurements.
RBPF and TRBVF correlated with T2-LL of the Pons (r=-0.37, P=0.011, and r= -0.40, P=0.0005 respectively) and with T1-LL of the Pons (r=-0.27, P=0.046, and r=-0.31, P=0.04, respectively).
Whereas RBPV did not (r=-0.18, P = NS). T1-LL of the Frontal Lobes was related to RBPF (r=-0.32, P=0.033) and TRBVF (r=-0.29, P=0.05), but not to RBPV (R=-0.27, P= NS).
There was only a trend of correlation between T2-LL of the Frontal Lobes and RBPF (r=-0.27, P=0.06) and TRBVF (r=-0.28, P=0.057), and no correlation with RBPV (r=-0.23, P= NS).
The magnitude of correlation between the Expanded Disability Status Scale (EDSS) and Pontine and Frontal Lobe RBPF and TRBVF was more than twice as high as the correlation between EDSS and RBPV of the same regions.
These data suggest that Normalized Regional Brain Atrophy measurements are preferable to Absolute Regional measurements in Cross-Sectional Studies.