Altered Functional And Structural Connectivities In Patients With MS: A 3-T Study
Rocca MA, Pagani E, Absinta M, Valsasina P, Falini A, Scotti G, Comi G, Filippi M
Neurology 2007 Dec 4;69(23):2136-45
Scientific Institute and University Ospedale San Raffaele,
NeuroImaging Research Unit, Department of Neurology, Via Olgettina, 60, 20132 Milan, Italy
To determine the functional and structural substrates of Motor Network Dysfunction in patients with Relapsing/Remitting Multiple Sclerosis (RRMS).
Using a 3-T scanner, in 12 right-handed RRMS patients and 14 matched controls, we acquired Diffusion Tensor (DT) MRI and functional MRI during the performance of a simple Motor Task with the right (R) hand.
Using DT MRI Tractography, we calculated DT-derived metrics from several Motor and NonMotor White Matter (WM) fiber bundles.
Functional connectivity analysis was performed using SPM2.
Compared with control, MS patients had abnormal DT MRI metrics of all the WM bundles studied.
Compared with controls, MS patients had more significant activations of the left (L) Supplementary Motor Area (SMA), the L primary SensoriMotor Cortex (SMC), and the R Cerebellum.
They also had increased functional connectivity between the R primary SMC and the R Cerebellum (p = 0.01) and the L SMA and the L primary SMC (p = 0.04).
Coefficients of altered connectivity were correlated with structural MRI metrics of tissue damage of the CorticoSpinal and the DentatoRubroThalamic Tract (r values ranging from -0.73 to 0.85).
The correlations found between measures of functional connectivity and structural damage to some of the major Brain Motor White Matter bundles suggest:
An adaptive role of functional connectivity changes in limiting the clinical consequences of structural damage in patients with Relapsing/Remitting Multiple Sclerosis.
Combining measures of altered functional and structural connectivities of specific Brain Networks is a promising tool to elucidate the mechanisms responsible for clinical manifestations of CNS damage.
MicroVascular Abnormality In Relapsing/Remitting Multiple Sclerosis: Perfusion MR Imaging Findings In Normal-Appearing White Matter
Law M, Saindane AM, Ge Y, Babb JS, Johnson G, Mannon LJ, Herbert J, Grossman RI
Radiology 2004 Jun;231(3):645-52
New York University Medical Center, Departments of Radiology and Neurology, MRI Department, Schwartz Building, Basement HCC, 530 First Avenue, New York, NY 10016, USA
To prospectively determine HemoDynamic changes in the Normal-Appearing White Matter (NAWM).
Of patients with Relapsing/Remitting Multiple Sclerosis (RR-MS) by using dynamic susceptibility contrast material-enhanced Perfusion Magnetic Resonance (MR) imaging.
Materials And Methods
Conventional MR imaging (which included acquisition of pre- and postcontrast transverse T1-weighted, Fluid-Attenuated Inversion Recovery.
And T2-weighted images) and dynamic susceptibility contrast-enhanced T2*-weighted MR imaging were performed in 17 patients with RR-MS (five men and 12 women; median age, 38.4 years; age range, 27.6-56.9 years) and 17 control patients (seven men and 10 women; median age, 42.0 years; age range, 18.7-62.5 years).
Absolute Cerebral Blood Volume (CBV), absolute Cerebral Blood Flow (CBF), and Mean Transit Time (MTT).
Referenced to an arterial input function by using an automated method were determined in PeriVentricular, Intermediate, and SubCortical Regions of NAWM at the level of the Lateral Ventricles.
Least-squares regression analysis (controlled for age and sex) was used to compare Perfusion measures in each region between patients with RR-MS and control patients.
Repeated-measures analysis of variance and the Tukey honestly significant difference test were used to perform pairwise comparison of Brain Regions in terms of each Perfusion measure.
Each region of NAWM in patients with RR-MS had significantly decreased CBF (P < .005) and prolonged MTT (P < .001) compared with the corresponding region in control patients.
No significant differences in CBV were found between patients with RR-MS and control patients in any of the corresponding areas of NAWM examined.
In control patients, PeriVentricular NAWM regions had significantly higher CBF (P =.03) and CBV (P =.04) than did Intermediate NAWM regions.
No significant regional differences in CBF, CBV, or MTT were found in patients with RR-MS.
The NAWM of patients with RR-MS shows decreased Perfusion compared with that of controls.
Copyright RSNA, 2004
Cardenas DD, Ditunno J, Graziani V, Jackson AB, Lammertse D, Potter P, Sipski M, Cohen R, Blight AR
Spinal Cord 2007 Feb;45(2):158-68
University of Washington, Department of Rehabilitation Medicine, Seattle, WA, USA
Double-blind, randomized, placebo-controlled, parallel-group clinical trial.
Assess safety and efficacy of Sustained-Release Fampridine in subjects with Chronic Spinal Cord Injury.
A total of 11 academic rehabilitation research centers in the United States.
A total of 91 subjects with Motor-incomplete Spinal Cord Injury (SCI), randomized to three arms:
Fampridine, sustained release, 25 mg b.i.d. (Group I), 40 mg b.i.d. (Group II), and placebo (Group III) for 8 weeks.
Patient diary questionnaire, Ashworth score, American Spinal Cord Injury Association International Standards, International Index of Erectile Function, Bladder and Bowel Management Questionnaires, and Clinician and Subject Global Impressions (Clinician Global Impression of change, Subject Global Impression (SGI)).
Safety was evaluated from adverse events, physical examinations, vital signs, ElectroCardiograms, and laboratory tests.
In total, 78% of the subjects completed the study. More (13/30) discontinued from Group II than Group I (4/30) and Group III (3/31).
The most frequent adverse events across groups were Hypertonia, Generalized Spasm, Insomnia, Dizziness, Asthenia, Pain, Constipation, and Headache.
One subject in Group II experienced a Seizure. SCI changed significantly in favor of Group I (P = 0.02).
Subgroup analysis of subjects with baseline Ashworth scores > 1 showed significant improvement in Spasticity in Group I versus III (P = 0.02).
Group I showed significant improvement in SGI, and potential benefit on Spasticity.
The drug was well tolerated. Group II showed more adverse events and discontinuations.
Systemic And Nasal Delivery Of Orexin-A (Hypocretin-1) Reduces The Effects Of Sleep Deprivation On Cognitive Performance In Nonhuman Primates
Deadwyler SA, Porrino L, Siegel JM, Hampson RE
J NeuroSci 2007 Dec 26;27(52):14239-47
Wake Forest University Health Sciences, Department of Physiology and Pharmacology, Winston-Salem, North Carolina 27157, Veterans Administration Greater Los Angeles Healthcare System/Sepulveda, and University of California, Department of Psychiatry and BioBehavioral Sciences, Los Angeles, California North Hills, California 91343
Hypocretin-1 (Orexin-A) was administered to sleep-deprived (30–36 h) rhesus monkeys immediately preceding testing on a multi-image Delayed Match-To-Sample (DMS) Short-Term Memory task.
The DMS task used multiple delays and stimulus images and effectively measures Cognitive Deficits produced by sleep deprivation (Porrino et al., 2005).
Two methods of administration of Orexin-A were tested, IntraVenous injections (2.5–10.0 µg/kg, i.v.) and a novel method developed for nasal delivery via an atomizer spray mist to the nostrils (dose estimated 1.0 µg/kg).
Results showed that Orexin-A delivered via the IntraVenous and nasal routes significantly improved performance in sleep-deprived monkeys
However, the Nasal delivery method was significantly more effective than the highest dose (10 µg/kg) of IntraVenous Orexin-A tested.
The improvement in performance by Orexin-A was specific to trials classified as high versus low Cognitive Load as determined by performance difficulty under normal testing conditions.
Except for the maximum IntraVenous dose (10 µg/kg), neither delivery method affected task performance in alert non-sleep-deprived animals.
The improved performance in sleep-deprived animals was accompanied by Orexin-A related alterations in local Cerebral Glucose metabolism (CMRglc).
In specific Brain Regions shown previously to be engaged by the task and impaired by sleep deprivation (Porrino et al., 2005).
Consistent with the differential effects on performance, Nasal delivered Orexin-A produced a more pronounced reversal of sleep deprivation induced changes in Brain metabolic activity (CMRglc) than IntraVenous Orexin-A.
These findings provide strong evidence for the effectiveness of IntraNasal Orexin-A in alleviating Cognitive Deficits produced by loss of sleep.
Meier DS, Weiner HL, Guttmann CR
AJNR Am J NeuroRadiol 2007 Nov-Dec;28(10):1956-63
Center for Neurological Imaging, Multiple Sclerosis Center, Harvard Medical School, Brigham and Women's Hospital, Department of Radiology, Boston MA 02115, USA
Background And Purpose
Formation of lesions in Multiple Sclerosis (MS) shows pronounced short-term fluctuation of MR imaging HyperIntensity and size, a qualitatively known but poorly characterized phenomenon.
With the use of time-series modeling of MR imaging intensity, our study relates the short-term dynamics of new T2 lesion formation to those of contrast enhancement and markers of long-term progression of disease.
Materials And Methods
We analyzed 915 examinations from weekly to monthly MR imaging in 40 patients with MS using a time-series model, emulating 2 opposing processes of T2 prolongation and shortening, respectively.
Patterns of activity, duration, and residual HyperIntensity within new T2 lesions were measured and evaluated for relationships to disability, Atrophy, and clinical phenotype in long-term follow-up.
Significant T2 activity was observed for 8 to 10 weeks beyond contrast enhancement.
Which suggests that T2 MR imaging is sensitive to NonInflammatory processes such as Degeneration and repair.
Larger lesions showed longer subacute phases but disproportionally more recovery.
Patients with smaller average peak lesion size showed trends toward greater disability and proportional residual damage.
Higher rates of disability or Atrophy were associated with subjects whose lesions showed greater residual HyperIntensity.
Smaller lesions appeared disproportionally more damaging than larger lesions, with lesions in Progressive MS smaller and of shorter activity than in Relapsing/Remitting MS.
Associations of lesion dynamics with rates of Atrophy and disability and clinical subtype suggest that changes in lesion dynamics may represent a shift from inflammatory toward Degenerative Disease activity.
And greater proximity to a Progressive stage, possibly allowing staging of the progression of MS earlier, before Atrophy or disability develops.
Optic Neuritis And Multiple Sclerosis
Curr Opin Neurol 2008 Feb;21(1):16-21
The National Hospital for Neurology and NeuroSurgery, Moorfields Eye Hospital and St Thomasʼ Hospital, London, UK
Purpose Of Review
To discuss recent Neuro-Ophthalmic advances relevant to the management of Optic Neuritis and Multiple Sclerosis
Major advances have occurred in the fields of Autoimmunity in Optic Neuritis, and in imaging the Retinal Nerve Fiber layer in both Optic Neuritis and Multiple Sclerosis
A proportion of cases of Optic Neuritis occur in patients who do not develop Multiple Sclerosis; the Optic Neuritis may be monophasic illness or recurrent.
In many recurrent cases who also have Myelitis (NeuroMyelitis Optica) a Serum AntiBody to Aquaporin-4 water channels has been detected.
It remains to be seen how many cases of recurrent Non-Multiple Sclerosis Optic Neuritis without Myelitis will be shown to be associated with this AutoAntiBody.
Optical Coherence Tomography has been shown to detect Axonal Loss in the Retina in both recovered Optic Neuritis and in Multiple Sclerosis without a past history of Optic Neuritis.
This is not a novel observation, but the technique may provide a quantitative measure of the loss of Optic Nerve Axons following the acute insult in Optic Neuritis, and chronically in Primary and Secondary/Progressive Multiple Sclerosis.
This is of particular interest in view of the evidence that it is Axonal Loss, rather than DeMyelination with preservation of Axons, that underlies disability in Multiple Sclerosis.
The Fibrin-derived gamma377-395 Peptide Inhibits Microglia Activation And Suppresses Relapsing Paralysis In Central Nervous System Autoimmune Disease
Adams RA, Bauer J, Flick MJ, Sikorski SL, Nuriel T, Lassmann H, Degen JL, Akassoglou K
J Exp Med 2007 Mar 19;204(3):571-82
University of California, Department of Pharmacology, San Diego, La Jolla, CA 92093, USA
PeriVascular Microglia activation is a hallmark of inflammatory DeMyelination in Multiple Sclerosis (MS), but the mechanisms underlying Microglia activation and specific strategies to attenuate their activation remain elusive.
Here, we identify Fibrinogen as a novel regulator of Microglia activation and show that targeting of the interaction of Fibrinogen with the Microglia Integrin Receptor Mac-1 (alpha(M)beta(2).
CD11b/CD18) is sufficient to suppress Experimental Autoimmune Encephalomyelitis in mice that retain full Coagulation function.
We show that Fibrinogen, which is deposited PeriVascularly in MS plaques, signals through Mac-1 and induces the differentiation of Microglia to Phagocytes via activation of Akt and Rho.
Genetic disruption of Fibrinogen-Mac-1 interaction in Fibrinogen-gamma(390-396A) knock-in mice.
Or pharmacologically impeding Fibrinogen-Mac-1 interaction through IntraNasal delivery of a Fibrinogen-derived inhibitory Peptide (gamma(377-395)) attenuates Microglia activation and suppresses Relapsing Paralysis.
Because blocking Fibrinogen-Mac-1 interactions affects the ProInflammatory but not the ProCoagulant properties of Fibrinogen.
Targeting the gamma(377-395) Fibrinogen Epitope could represent a potential therapeutic strategy for MS and other NeuroInflammatory Diseases associated with Blood-Brain Barrier disruption and Microglia activation.