Article

Metabolite changes in normal-appearing gray and white matter are linked with disability in early primary progressive multiple sclerosis.

Institute of Neurology, London, United Kingdom.
Archives of Neurology (impact factor: 7.58). 04/2005; 62(4):569-73. DOI:10.1001/archneur.62.4.569 pp.569-73
Source: PubMed

ABSTRACT Abnormalities in normal-appearing brain tissues may contribute to disability in primary progressive multiple sclerosis (PPMS), where few lesions are seen on conventional imaging.
To evaluate the mechanisms underlying disease progression in the early phase of PPMS by measuring metabolite concentrations in normal-appearing white matter (NAWM) and cortical gray matter (CGM) and to assess their relationship with clinical outcomes.
Case-control study.
Tertiary referral hospital. Patients Forty-three consecutive patients within 5 years of onset of PPMS and 44 healthy control subjects.
Concentrations of choline-containing compounds, phosphocreatine, myo-inositol, total N-acetyl-aspartate (tNAA), and glutamate-glutamine were estimated using proton magnetic resonance spectroscopic imaging. Brain parenchymal, white matter and gray matter fractions and proton density and gadolinium-enhancing lesion loads were calculated. The Expanded Disability Status Scale and Multiple Sclerosis Functional Composite scores were recorded.
In CGM, concentrations of the tNAA (P<.001) and glutamate-glutamine (P = .005) were lower in patients with PPMS than in controls. In NAWM, myo-inositol levels were higher (P = .002) and tNAA levels were lower (P = .005) in patients with PPMS than in controls. The Expanded Disability Status Scale score correlated with the tNAA concentration in CGM (r = -0.44; P = .03) and with myo-inositol (r = 0.41; P = .01) and glutamate-glutamine concentrations (r = 0.41; P = .01) in NAWM. Proton density lesion load correlated negatively with CGM tNAA concentration and positively with NAWM myo-inositol concentration.
Metabolite changes, which differ in CGM and NAWM, occur in early PPMS and are linked with disability.

0 0
 · 
0 Bookmarks
 · 
23 Views
  • Source
    Article: (1)H-MRSI evidence for cortical gray matter pathology that is independent of cerebral white matter lesion load in patients with secondary progressive multiple sclerosis.
    Zografos Caramanos, Salvatore DiMaio, Sridar Narayanan, Yves Lapierre, Douglas L Arnold
    [show abstract] [hide abstract]
    ABSTRACT: We examined: (i) neuro-axonal disturbance (as indicated by (1)H-MRSI NA/Cr values) in the cortical grey matter (cGM) of 10 untreated patients with relapsing-remitting (RR) and 10 with secondary-progressive (SP) multiple sclerosis (MS), and (ii) the relationships between cGM-NA/Cr values and the degree of EDSS-measured clinical disability and cerebral white-matter (WM) lesion load (LL) in these patients. Whereas mean and median cGM-NA/Cr values in our RR group were similar to those in 18 age-matched normal controls (NC), large statistically-significant decreases (between 14.3% and 18.5%) were found in our SP group relative to both our RR and NC groups. When data from all patients was combined, we found: (i) a large negative correlation between EDSS scores and cGM-NA/Cr values (r=-0.55); and (ii) a larger negative correlation of cGM-NA/Cr values with cerebral T1-hypointese WM-LL (T1-LL, r=-0.73) than with cerebral T2-hyperintense-LL (T2-LL, r=-0.63). Importantly, (i) correlations of WM-LL with cGM-NA/Cr were larger in the RR group than in the SP group (T1-LL: r=-0.79 vs. -0.54; T2-LL: r=-0.63 vs. -0.51), and (ii) cerebral WM-LL values could not fully account for the extent of the decrease in mean cGM-NA/Cr that was seen in our SP group relative to our NC group. Our observations are consistent with the possibilities that: (i) in patients with RR-MS, (1)H-MRSI-measured cGM neuro-axonal disturbances are strongly related to the effects of axonal transection that are associated with cerebral WM lesions; and (ii) in patients with SP-MS, such cGM neuro-axonal disturbances are more severe and are associated with a more-widespread degenerative process (which probably includes a considerable degree of cortical demyelination).
    Journal of the neurological sciences 03/2009; 282(1-2):72-9. · 2.32 Impact Factor
  • Source
    Article: Neuropsychiatric manifestations of depression in multiple sclerosis: neuroinflammatory, neuroendocrine, and neurotrophic mechanisms in the pathogenesis of immune-mediated depression.
    Michele L Pucak, Katherine A L Carroll, Douglas A Kerr, Adam I Kaplin
    [show abstract] [hide abstract]
    ABSTRACT: Evidence suggests that depression in multiple sclerosis (MS) is largely biologically mediated by some of the same processes involved in the immunopathogenesis of this neurologic disease. In particular, the increase in proinflammatory cytokines, activation of the hypothalamic-pituitary-adrenal (HPA) axis, and reduction in neurotrophic factors that occur in MS may each account for the increased rate of depression seen in MS. The possible contributions of these neuroinflammatory, neuroendocrine, and neurotrophic mechanisms suggest a diverse array of novel treatment strategies for depression, both in the context of inflammatory conditions as well as in idiopathic depression. Furthermore, if such processes in MS play a causative role in the pathogenesis of depression, and depression in turn has affects on neurophysiological processes related to immune function, then treatment of depression might have a positive effect on MS disease progression. This makes treating MS depression a neuropsychiatric imperative.
    Dialogues in clinical neuroscience 02/2007; 9(2):125-39.
  • Source
    Article: Glutamate-stimulated peroxynitrite production in a brain-derived endothelial cell line is dependent on N-methyl-D-aspartate (NMDA) receptor activation.
    G S Scott, S R Bowman, T Smith, R J Flower, C Bolton
    [show abstract] [hide abstract]
    ABSTRACT: There is accumulating and convincing evidence indicating a role for glutamate in the pathogenesis of the human demyelinating disease multiple sclerosis (MS). Studies in experimental autoimmune encephalomyelitis (EAE), the animal model of MS, demonstrate that pharmacological inhibition of specific glutamate receptors suppresses neurological symptoms and prevents blood-brain barrier (BBB) breakdown. The mechanisms through which glutamate influences BBB function during EAE remain unclear. Glutamate triggers the production of nitric oxide and superoxide, which can lead to the formation of peroxynitrite (ONOO(-)). Recent studies have implicated ONOO(-) in the loss of neurovascular integrity during EAE. We propose that glutamate contributes to BBB breakdown via the actions of ONOO(-). The present investigation examined glutamate-induced ONOO(-) formation in the b.End3 brain-derived endothelial cell line. b.End3 cells were incubated with a concentration range of glutamate and ONOO(-) production was assessed over time. Results showed a concentration- and time-dependent increase in ONOO(-) levels in glutamate-treated cells that were suppressed by selective and non-selective inhibitors of ONOO(-)-mediated reactions. Specific activation of b.End3-associated NMDA receptors also resulted in a concentration-dependent increase in ONOO(-) production. The ability of b.End3 cells to respond to the presence of glutamate was confirmed through the detection of NMDA receptor immnuoreactivity in cell extracts. In addition, the use of the NMDA receptor antagonists MK-801 and memantine reduced glutamate-mediated ONOO(-) generation from b.End3 cells. The data reinforce the important relationship between glutamate and the NMDA receptor, positioned at neurovascular sites, which may be of particular relevance to the pathogenesis of demyelinating disease.
    Biochemical Pharmacology 02/2007; 73(2):228-36. · 4.70 Impact Factor
Data provided are for informational purposes only. Although carefully collected, accuracy cannot be guaranteed. The impact factor represents a rough estimation of the journal's impact factor and does not reflect the actual current impact factor. Publisher conditions are provided by RoMEO. Differing provisions from the publisher's actual policy or licence agreement may be applicable.

Keywords

Brain parenchymal
 
conventional imaging
 
cortical gray matter
 
disease progression
 
Expanded Disability Status Scale
 
Expanded Disability Status Scale score correlated
 
gadolinium-enhancing lesion loads
 
glutamate-glutamine concentrations
 
gray matter fractions
 
metabolite concentrations
 
Multiple Sclerosis Functional Composite scores
 
NAWM myo-inositol concentration
 
normal-appearing brain tissues
 
normal-appearing white matter
 
primary progressive multiple sclerosis
 
proton density
 
proton magnetic resonance spectroscopic imaging
 
Tertiary referral hospital
 
total N-acetyl-aspartate
 
white matter