Regional Brain Atrophy Development Is Related To Specific Aspects Of Clinical Dysfunction In Multiple Sclerosis
Jasperse B, Vrenken H, Sanz-Arigita E, de Groot V, Smith SM, Polman CH, Barkhof F
NeuroImage 2007 Nov 15;38(3):529-37
VU University Medical Center, Department of Neurology, Boelelaan 1117, PO Box 7057, 1007 MB, Amsterdam, The Netherlands
Brain Atrophy in Multiple Sclerosis (MS) is thought to reflect irreversible tissue damage leading to persistent clinical deficit.
Little is known about the rate of Atrophy in specific Brain Regions in relation to specific clinical deficits.
We determined the displacement of the Brain surface between two T1-weighted MRI images obtained at baseline and after a median follow-up time of 2.2 years for 79 recently diagnosed, mildly disabled MS patients.
Voxel- and cluster-wise permutation-based statistics were used to identify Brain Regions in which Atrophy development was significantly related to:
Expanded Disability Status Scale (EDSS), Timed Walk Test (TWT), Paced Auditory Serial Addition Test (PASAT) and 9-Hole Peg Test (HPT). Clusters were considered significant at a corrected cluster-wise p-value of 0.05.
Worse EDSS change-score and worse follow-up EDSS were related to Atrophy development of PeriVentricular and BrainStem regions and right-sided Parietal, Occipital and Temporal regions.
Worse PASAT at follow-up was significantly related to Atrophy of the Ventricles. A worse TWT change-score and worse follow-up TWT were exclusively related to Atrophy around the Ventricles and of the BrainStem.
Worse HPT change-score and worse follow-up HPT of either arm were significantly related to the Atrophy of widely distributed peripheral regions, as well as Atrophy of PeriVentricular and BrainStem regions.
Our findings suggest that decline in ambulatory function is related to Atrophy of Central Brain Regions exclusively.
Whereas decline in Neurologically more complex tasks for coordinated hand function is related to Atrophy of both Central and Peripheral Brain Regions.
Arnon R, Aharoni R
Mol NeuroBiol 2007 Dec;36(3):245-53
The Weizmann Institute of Science, The Department of Immunology, Rehovot, Israel
Multiple Sclerosis (MS) is no longer considered to be simply an Autoimmune Disease.
In addition to inflammation and DeMyelination, Axonal Injury and Neuronal loss underlie the accumulation of disability and the disease progression.
Specific treatment strategies should thus aim to act within the Central Nervous System (CNS) by interfering with both NeuroInflammation and NeuroDegeneration.
Specific treatment strategies to Autoimmune Neurological Disorders should aim to act within the CNS by interfering with both NeuroInflammation and NeuroDegeneration.
The cumulative effect of Glatiramer Acetate (GA; Copaxone(R), Copolymer 1), an approved drug for the treatment of MS:
Reviewed herewith, draws a direct linkage between anti-inflammatory ImmunoModulation, NeuroProtection, NeuroGenesis, and therapeutic activity in the CNS.
GA treatment augmented the three processes characteristic of NeuroGenesis, namely, Neuronal Progenitor Cell proliferation, migration, and differentiation.
The newborn Neurons manifested massive migration through exciting and dormant migratory pathways, into injury sites in Brain regions.
Which do not normally undergo NeuroGenesis, and differentiated to mature Neuronal phenotype, thus, counteracting the NeuroDegenerative course of disease.
The plausible mechanism underlying this multifactorial effect is the induction of GA-reactive T-Cells in the periphery.
And their infiltration into the CNS, where they release ImmunoModulatory Cytokines and Neurotrophic Factors in the injury site.
Migration And Multiple Sclerosis: The French West Indies Experience
J Neurol Sci 2007 Nov 15;262(1-2):117-21
CHU Fort de France, Hôpital Pierre Zobda Quitman, Service de Neurologie, BP 97261, Fort de France, Martinique, France
The French West Indies (FWI), i.e., the islands of Martinique and Guadeloupe, have recently experienced the emergence of Multiple Sclerosis (MS).
This epidemiological upheaval followed a return migration of the FWI population that had previously migrated to continental France.
The MS prevalence was 14.8/10(5) (95% CI: 11.9-17.7) on Dec. 31, 1999 and its mean annual incidence was 1.4/10(5) (95% CI: 1.0-1.8) for the period July 1997 to June 2002.
The prevalence of MS in Martinique, that received more return migration, is higher than that of Guadeloupe (21.0/10(5) vs. 8.5/10(5)).
This emergence of MS has been accompanied also by an inversion of its clinical spectrum, with recurrent NeuroMyelitis Optica accounting for only 17.8% of cases.
The standardized ratio of the incidence of MS among migrants is 1.71 (95% CI: 1.19-2.38; P < 0.01) and if migration to continental France occurred before the age of 15 it is 4.05 (95% CI: 2.17-6.83; P < 0.0001).
According to recent data, a drastic reduction in exposure to sunlight and to intestinal parasites during childhood, found preferentially among migrants, are possible environmental factors responsible for this emergence.
Cannabinoid Control Of NeuroInflammation Related To Multiple Sclerosis
Baker D, Jackson SJ, Pryce G
Br J Pharmacol 2007 Nov;152(5):649-54
University of London, Institute of Cell and Molecular Sciences, Queen Mary, NeuroImmunology Unit, NeuroScience Centre, London, UK
The Cannabis plant (Cannabis sativa) has been known by many names but the question remains 'Can we call it medicine?'
There has been renewed interest in the value of cannabis for the control of NeuroInflammatory conditions such as Multiple Sclerosis, where it has been shown to have some effect on Spasticity and Pain both experimentally and in clinical trials in humans.
However, in addition to symptom control potential, the question remains whether Cannabinoids can modify the NeuroInflammatory element which drives Relapsing Neurological attacks and the accumulation of progressive disability.
In experimental studies it has been recently shown that synthetic Cannabinoids can affect the Immune Response both:
- Indirectly via CB(1) Receptor-Mediated Signalling Nerve Centres controlling the systemic release of ImmunoSuppressive molecules
- Directly by CB(2) Receptor-Mediated Inhibition of Lymphocyte and Macrophage/Microglial Cell function
However, these ImmunoSuppressive possibilities that would limit the frequency of Relapsing attacks will probably not be realized clinically, following use of medical Cannabis, due to dose constraints.
However, Cannabinoids may still affect the Glial response within the damaged Central Nervous System, which facilitate the slow, Degenerative processes that account for Progressive NeuroDegeneration.
And, therefore may have utility in addition to value of Cannabis-related drugs for symptom control.
British Journal of Pharmacology (2007) 152, 649-654; doi:10.1038/sj.bjp.0707458; published online 24 September 2007.
Lazeron RH, de Sonneville LM, Scheltens P, Polman CH, Barkhof F
Mult Scler 2006 Dec;12(6):760-8
Vrije Universiteit Medical Center, Department of Neurology, P.O. Box 7057, 1007 MB Amsterdam, The Netherlands
In this study, we investigated the influence of in vivo disease pathology (measured as Magnetic Resonance Imaging (MRI) lesion load and Brain Volume reduction) on Cognitive functioning.
Especially the Speed Of Processing, in Multiple Sclerosis (MS) patients.
Since MS is characterized by Cognitive Slowing rather than impaired accuracy, we used the Amsterdam NeuroPsychological Tasks (ANT) program, a computerized test proven to be very sensitive to Cognitive slowing in MS patients.
Thirty-two patients performed the ANT and underwent MRI scanning.
Using the ANT computerized tests, we investigated Focused, Divided, Sustained Attention, Executive function and Psychomotor function.
And, examined associations of speed, speed fluctuation and accuracy of performance of these tests with MRI lesion load and Brain Volume Parameters.
A decrease in the speed of processing and response speed stability, and a decrease in psychomotor accuracy and stability were clearly associated with less Brain Volume.
And, with higher lesion loads, in particular at Frontal and Occipital areas.
Correlations with Brain Volume reduction were found for all domains, except for Visuo-Spatial processing.
In particular, speed and speed fluctuation scores correlated with Brain Volume reduction, while accuracy of performance, in general, did not correlate.
Only some test speed scores and speed fluctuation scores correlated with lesion load measurements.
This study shows that, in MS patients, accuracy of processing is not compromised unless high Working Memory demands are involved.
Problems in NeuroCognitive functioning in MS are mainly modulated by speed and stability of speed processing, in particular when Attention-demanding controlled information processing is required.
Abnormalities in these domains are most strongly associated with Brain Volume Loss, confirming that pathology beyond focal lesions is important in MS.
Lerdal A, Gulowsen Celius E, Krupp L, Dahl AA
Eur J Neurol 2007 Dec;14(12):1338-43
Buskerud University College, Department of Health, Drammen, Norway
We sought to identify clinical characteristics and socio-demographic variables associated with longitudinal patterns of Fatigue in Multiple Sclerosis (MS) patients.
A questionnaire including the Fatigue Severity Scale (FSS) was mailed to a community sample of 502 MS patients three times 1 year apart.
Three patterns of Fatigue were defined: persistent Fatigue (PF) (mean FSS score >/=5 at all time-points), Sporadic Fatigue (SF) (mean FSS score >/=5 at one or two time-points) and No Fatigue (mean FSS score < 5 at all time-points).
Among the 267 (53%) patients who responded at all time-points, 101 [38%, 95% confidence intervals (CI) 32-44] had persistent, 98 (37%, 95% CI 31-43) sporadic and 68 (25%, 95% CI 20-31) no fatigue.
Persistent and sporadic Fatigue were more common in patients with, increased Neurological Impairment (P < 0.001):
Primary /Progressive MS (P = 0.01), Insomnia (P < 0.001), Heat Sensitivity (P < 0.001), sudden-onset Fatigue (P < 0.001) or mood disturbance (P < 0.001) compared with patients Without Fatigue.
Multivariable analysis showed that Depression (PF P = 0.02, SF P < 0.001), Heat Sensitivity (PF P = 0.04, SF P = 0.02) and Physical Impairment (PF P = 0.004, SF P = 0.01) were associated with both sporadic and persistent Fatigue.
About 75% of the patients had persistent or sporadic Fatigue over a 2 years observation period.
Multivariable analyses confirmed a significant association between levels of Depression, Physical Impairment and persistent Fatigue.
Flachenecker P, Bihler I, Weber F, Gottschalk M, Toyka KV, Rieckmann P
Mult Scler 2004 Apr;10(2):165-9
Julius-Maximilians University of Würzburg, Department of Neurology, Josef-Schneider-Strasse 11, D-97080 Würzburg, Germany
Fatigue is one of the most common disabling symptoms in patients with Multiple Sclerosis (MS), but the putative role of ProInflammatory Cytokines remains to be elucidated.
Thirty-seven patients (27 women, 10 men) with Relapsing/Remitting (n = 29) and Secondary/Progressive (n = 8) MS, aged 41.0 +/- 10.2 years, were studied.
Fatigue was assessed by Krupp's Fatigue Severity Scale (FSS). Cytokine mRNA expression for Interferon-gamma (IFN-γ) Tumor Necrosis Factor-alpha (TNF-) and InterLeukin-10 (IL-10) were measured by real time RT PCR.
Autonomic function was evaluated by standard tests for ParaSympathetic and Sympathetic function, as well as by Serum levels of NorEpinephrine and Epinephrine.
Median levels of TNF- mRNA expression were significantly higher in MS patients with (FSS > or = 4.0 and > or = 5.0, n = 26 and n = 14, respectively).
Than in those Without Fatigue (FSS < 4.0, n = 11). No differences were seen for IFN-gamma and IL-10 mRNA expression.
Cytokine levels were not correlated to autonomic tests or to Serum Catecholamine levels.
These results suggest that TNF-, as a principal ProInflammatory mediator, is associated with MS-related Fatigue.
This is in support of a pathogenic role of the MS-related inflammatory process in the development of Fatigue.