Gelsolin Concentration In CerebroSpinal Fluid From Patients With Multiple Sclerosis And Other Neurological Disorders
Kulakowska A, Drozdowski W, Sadzynski A, Bucki R, Janmey PA
Eur J Neurol 2008 Jun;15(6):584-8
Medical University of Bialystok, Department of Neurology, Bialystok, Poland
Gelsolin is a highly conserved IntraCellular Actin-binding protein with an ExtraCellular isoform, plasma Gelsolin, for which there is not yet a clearly defined function.
Materials And Methods
In this study, we determined gelsolin concentrations in blood and CerebroSpinal Fluid (CSF) obtained from 25 subjects using ImmunoBlotting and a functional assay that quantifies Gelsolin's ability to accelerate Actin polymerization.
The Gelsolin concentration in CSF, determined by quantitative ImmunoBlotting was 1.2-15.9 microg/ml (average 5.9 +/- 3.8 mug/ml).
In samples obtained from patients diagnosed with conditions that do not alter standard CSF clinical tests [(idiopathic Cephalgia, Ischialgia due to Discopathy, and idiopathic (Bell's) Facial Nerve Palsy or Entrapment Radial Neuropathy)], the average Gelsolin concentration was 7.2 +/- 4.3 microg/ml.
In contrast, the Gelsolin concentration in samples obtained from patients diagnosed with Multiple Sclerosis was 2.1 +/- 0.7 microg/ml, and a similar low concentration was found in a patient recovering from a SubArachnoid Hemorrhage.
The range of CSF Gelsolin concentrations determined by the Actin polymerization assay was 0.61-9.97 microg/ml (average 3.6 +/- 2.2 microg/ml).
These lower values compared with those obtained from ImmunoBlotting analysis suggest that CSF Gelsolin may bind other CSF molecules leading to a reduction of its Actin-binding activity.
The results presented here show that CSF Gelsolin concentration is significantly altered in certain Neurological conditions, including Multiple Sclerosis, indicating the possible utility of CSF Gelsolin levels for diagnostic purposes.
Exploring Recombinant Human Erythropoietin In Chronic/Progressive Multiple Sclerosis
Ehrenreich H, Fischer B, Norra C, Schellenberger F, Stender N, Stiefel M, Sirén AL, Paulus W, Nave KA, Gold R, Bartels C
Brain 2007 Aug 29
Max Planck Institute of Experimental Medicine, Departments of Radiology and Clinical NeuroPhysiology, Georg-August-University and Hertie Institute of Multiple Sclerosis Research, Göttingen, Germany
The NeuroDegenerative aspects of Chronic Progressive Multiple Sclerosis (MS) have received increasing attention in recent years, since Anti-Inflammatory and ImmunoSuppressive treatment strategies have largely failed.
However, successful NeuroProtection and/or NeuroRegeneration in MS have not been demonstrated yet.
Encouraged by the multifaceted NeuroProtective effects of recombinant human Erythropoietin (rhEPO) in experimental models, we performed an investigator-driven, exploratory open label study (phase I/IIa) in patients with Chronic/Progressive MS.
Main study objectives were:
- Evaluating safety of long-term high-dose intravenous rhEPO treatment in MS, and
- Collecting first evidence of potential efficacy on clinical outcome parameters
Eight MS patients, five randomly assigned to high-dose (48 000 IU), three to low-dose (8000 IU) rhEPO treatment, and, as disease controls, two drug-naďve Parkinson patients (receiving 48 000 IU) were followed over up to 48 weeks:
A 6-week lead-in phase, a 12-week treatment phase with weekly EPO, another 12-week treatment phase with bi-weekly EPO, and a 24-week post-treatment phase.
Clinical and ElectroPhysiological improvement of motor function, reflected by a reduction in Expanded Disability Status Scale (EDSS).
And of Cognitive performance was found upon high-dose EPO treatment in MS patients, persisting for three to six months after cessation of EPO application.
In contrast, low-dose EPO MS patients and drug-naďve Parkinson patients did not improve in any of the parameters tested.
There were no adverse events, no safety concerns and a surprisingly low need of blood-lettings.
This first pilot study demonstrates the necessity and feasibility of controlled trials using high-dose rhEPO in Chronic/Progressive MS.
The Multiple Sclerosis Genetics Group
Gregory SG, Schmidt S, Seth P, Oksenberg JR, Hart J, Prokop A, Caillier SJ, Ban M, Goris A, Barcellos LF, Lincoln R, McCauley JL, Sawcer SJ, Compston DA, Dubois B, Hauser SL, Garcia-Blanco MA, Pericak-Vance MA, Haines JL
Nat Genet 2007 Sep;39(9):1083-91
Duke University Medical Center, Center for Human Genetics, Department of Molecular Genetics and MicroBiology, Durham, North Carolina 27710, USA
Multiple Sclerosis is a DeMyelinating NeuroDegenerative Disease with a strong genetic component.
Previous genetic risk studies have failed to identify consistently linked regions or genes outside of the Major Histocompatibility Complex on Chromosome 6p.
We describe allelic association of a polymorphism in the gene encoding the InterLeukin-7 Receptor alpha chain (IL-7R) as a significant risk factor for Multiple Sclerosis in four independent family-based or case-control data sets (overall P = 2.9 x 10(-7)).
Further, the likely causal SNP, rs6897932, located within the alternatively spliced exon 6 of IL-7R, has a functional effect on gene expression.
The SNP influences the amount of soluble and membrane-bound isoforms of the protein by putatively disrupting an exonic splicing silencer.
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 Disabed 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.
For the AFFIRM and SENTINEL Investigators
Calabresi PA, Giovannoni G, Confavreux C, Galetta SL, Havrdova E, Hutchinson M, Kappos L, Miller DH, O'connor PW, Phillips JT, Polman CH, Radue EW, Rudick RA, Stuart WH, Lublin FD, Wajgt A, Weinstock-Guttman B, Wynn DR, Lynn F, Panzara MA
Neurology 2007 Oct 2;69(14):1391-403
Johns Hopkins Multiple Sclerosis Center, Baltimore, MD, USA
To determine the incidence and clinical effects of AntiBodies that develop during treatment with Natalizumab.
In two randomized, double-blind, placebo-controlled studies (Natalizumab safety and efficacy in Relapsing/Remitting Multiple Sclerosis [MS, AFFIRM].
And safety and efficacy of Natalizumab in combination with Interferon-beta-1a [INF-ß-1a] in patients with Relapsing/Remitting MS [SENTINEL]) of patients with Relapsing Multiple Sclerosis.
Blood samples were obtained at baseline and every 12 weeks to determine the presence of AntiBodies against Natalizumab. AntiBodies to Natalizumab were measured using an ELISA.
Patients were categorized as "transiently positive" if they had detectable AntiBodies (>/=0.5 microg/mL) at a single time point or "persistently positive" if they had AntiBodies at two or more time points >/=6 weeks apart.
In the AFFIRM study, AntiBodies were detected in 57 of 625 (9%) of Natalizumab-treated patients: Twenty (3%) were transiently positive and 37 (6%) were persistently positive.
Persistently positive patients showed a loss of clinical efficacy as measured by disability progression (p < /= 0.05), relapse rate (p = 0.009), and MRI (p < /= 0.05) compared with AntiBody-negative patients.
In transiently positive patients, full efficacy was achieved after approximately 6 months of treatment, the time when patients were becoming AntiBody negative.
The incidence of infusion-related adverse events was significantly higher in persistently positive patients.
Results of SENTINEL were similar to AFFIRM, except with regard to sustained disability progression; differences between persistently positive and AntiBody-negative patients were not statistically significant.
The incidence of persistent AntiBody positivity associated with Natalizumab is 6%.
Reduced clinical efficacy is apparent in persistently positive patients.
Patients with a suboptimal clinical response or persistent infusion-related adverse events should be considered for AntiBody testing.
Schurch B, Denys P, Kozma CM, Reese PR, Slaton T, Barron RL
Eur Urol 2007 Sep;52(3):850-9
University Hospital Balgrist, Spinal Cord Injury Center, Zurich, Switzerland
To evaluate the impact of Botulinum Toxin Type A (BoNTA) on health-related quality of life in patients with Neurogenic Urinary Incontinence (UI) using the Incontinence Quality of Life questionnaire (I-QOL).
Randomized, double-blind, multicenter, placebo-controlled study involving eight centers across Belgium, France, and Switzerland.
Patients (n=59) with UI due to Neurogenic Detrusor OverActivity (Spinal Cord Injury, n=53; Multiple Sclerosis, n=6) who were inadequately managed on oral AntiCholinergics received a single dose of BoNTA (200U or 300U, Botox((R))) or placebo.
I-QOL scores at screening and after treatment at weeks 2, 6, 12, 18, and 24 were recorded.
Median total and subscale I-QOL scores increased significantly from screening with BoNTA 300U compared with placebo at all time points (p < 0.05) and with BoNTA 200U compared with placebo at all time points for total score.
And the Avoidance Limiting Behavior subscale (p < 0.05), and at weeks 2, 6, 12, and 18 (p < 0.05), but not 24 for the Psychosocial Impact and Social Embarrassment subscales.
Approximately twice as many BoNTA recipients as placebo recipients achieved at least a minimal important difference in total I-QOL score at 2, 6, 12, and 24 wk.
BoNTA significantly improves UI-associated health-related quality of life in patients with Neurogenic UI.
Wattjes MP, Harzheim M, Lutterbey GG, Bogdanow M, Schmidt S, Schild HH, Träber F
NeuroRadiology 2008 Feb;50(2):123-9
University of Bonn, Department of Radiology/NeuroRadiology, Bonn, Germany
The aim of this study was to determine the prognostic value of metabolic alterations in the Normal-Appearing White Matter (NAWM).
Of patients presenting with Clinically Isolated Syndromes (CIS) suggestive of Multiple Sclerosis (MS) with special regard to the prediction of conversion to definite MS.
Using a 3T whole-body MR system, a multi-sequence conventional MRI protocol and single-voxel Proton MR Spectroscopy (PRESS, repetition time 2000 ms, echo times 38 ms and 140 ms) of the Parietal NAWM were performed in 25 patients presenting with CIS at baseline and in 20 controls.
Absolute concentrations of N-Acetyl-Aspartate (tNAA), myo-Inositol (Ins), Choline (Cho) and Creatine (tCr) as well as metabolite ratios were determined.
Follow-up including Neurological assessment and conventional MRI was performed 3-4 and 6-7 months after the initial event.
Nine patients converted to definite MS during the follow-up period.
Compared to controls, those patients who converted to MS also showed significantly lower tNAA concentrations in the NAWM (-13.4%, P = 0.002) whereas nonconverters (-6.5%, P = 0.052) did not.
The Ins concentration was 20.2% higher in the converter group and 1.9% higher in the nonconverter group, but these differences did not reach significance.
No significant differences could be observed for tCr and Cho in either patient group.
Axonal Damage at baseline in patients presenting with CIS was more prominent in those who subsequently converted to definite MS in the short term follow-up, indicating that tNAA might be a sufficient prognostic marker for patients with a higher risk of conversion to early definite MS.