Diffuse Axonal and Tissue Injury in Patients With Multiple Sclerosis With Low Cerebral Lesion Load and No Disability

Stefano, Nicola De; Narayanan, Sridar; Francis, Simon J.; Smith, Stephen M.; Mortilla, M.; Tartaglia, Maria Carmela; Bartolozzi, Maria Letizia; Guidi, Leonello; Federico, Antonio; Arnold, Douglas L.

doi:10.1001/archneur.59.10.1565

Cited by 173 publications

(111 citation statements)

References 71 publications

(79 reference statements)

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“…Axonal injury begins early in multiple sclerosis (De Stefano et al, 2002), and cumulative axon loss results in progressive disability. However, the disease often goes through phases of remission and relapse, and white matter plaques visible in magnetic resonance images can wane with remission of symptoms.…”

Section: Magnetic Resonance Spectroscopy and Imaging Of Naamentioning

confidence: 99%

N-Acetylaspartate in the CNS: From neurodiagnostics to neurobiology

Moffett

Ross

Arun

et al. 2007

Progress in Neurobiology

1,179

1,094

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The brain is unique among organs in many respects, including its mechanisms of lipid synthesis and energy production. The nervous system-specific metabolite N-acetylaspartate (NAA), which is synthesized from aspartate and acetyl-coenzyme A in neurons, appears to be a key link in these distinct biochemical features of CNS metabolism. During early postnatal CNS development, the expression of lipogenic enzymes in oligodendrocytes, including the NAA-degrading enzyme aspartoacylase (ASPA), is increased along with increased NAA production in neurons. NAA is transported from neurons to the cytoplasm of oligodendrocytes, where ASPA cleaves the acetate moiety for use in fatty acid and steroid synthesis. The fatty acids and steroids produced then go on to be used as building blocks for myelin lipid synthesis. Mutations in the gene for ASPA result in the fatal leukodystrophy Canavan disease, for which there is currently no effective treatment. Once postnatal myelination is completed, NAA may continue to be involved in myelin lipid turnover in adults, but it also appears to adopt other roles, including a bioenergetic role in neuronal mitochondria. NAA and ATP metabolism appear to be linked indirectly, whereby acetylation of aspartate may facilitate its removal from neuronal mitochondria, thus favoring conversion of glutamate to alpha ketoglutarate which can enter the tricarboxylic acid cycle for energy production. In its role as a mechanism for enhancing mitochondrial energy production from glutamate, NAA is in a key position to act as a magnetic resonance spectroscopy marker for neuronal health, viability and number. Evidence suggests that NAA is a direct precursor for the enzymatic synthesis of the neuron specific dipeptide N-acetylaspartylglutamate, the most concentrated neuropeptide in the human brain. Other proposed roles for NAA include neuronal osmoregulation and axon-glial signaling. We propose that NAA may also be involved in brain nitrogen balance. Further research will be required to more fully understand the biochemical functions served by NAA in CNS development and activity, and additional functions are likely to be discovered.

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Section: Magnetic Resonance Spectroscopy and Imaging Of Naamentioning

confidence: 99%

N-Acetylaspartate in the CNS: From neurodiagnostics to neurobiology

Moffett

Ross

Arun

et al. 2007

Progress in Neurobiology

1,179

1,094

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“…However, following characteristics of the NAWM of CIS and R R M S p a t i e n t s c o u l d b e i d e n t i f i e d ( t a b l e 2 , r e f e r e n c e s a r e l i s t e d c h r o n o l o g i c a l l y b y publication date). Twenty-four MRS studies were published with decreased ratios of NAA to Cr or Cho, or decreased NAA absolute concentrations in the NAWM in a total of 56 CIS or 418 RRMS patients (Davie et al, 1994;Husted et al, 1994;Peters et al, 1995;Fu et al, 1998;Schiepers et al, 1997;Foong J et al, 1999;Sarchielli et al, 1999;van Walderveen et al, 1999;Suhy et al, 2000;de Stefano et al, 2001;Tedeschi et al, 2001;Kapeller et al, 2001;Chard et al, 2002;de Stefano et al, 2002;Casanova et al 2003;Inglese et al, 2004;Adalsteinsson et al, 2004;He et al, 2005;Staffen et al, 2005;Tiberio et al, 2006;Sijens et al, 2006;Pascual et al, 2007;.…”

Section: Of What Could Be Found With Mrs In Early Stages Of Rrms or Ementioning

confidence: 99%

“…Twenty-nine MRS studies were published with no significant Cho changes in the NAWM in a total of 190 CIS or 513 RRMS patients (Husted et al, 1994;Peters et al, 1995;Schiepers et al, 1997;Davie et al, 1997;Sarchielli et al, 1999;Foong J et al, 1999;Sarchielli et al, 1999;Brex et al, 1999;van Walderveen et al, 1999;Suhy et al, 2000;de Stefano et al, 2001;Kapeller et al, 2001;Chard et al, 2002;de Stefano et al, 2002;Kapeller et al, 2002;Casanova et al 2003;Inglese et al, 2004;Adalsteinsson et al, 2004;Fernando et al, 2004;Ruiz-Pena et al, 2004;Vrenken et al, 2005;Mathiesen et al, 2005;Khan et al, 2005;Sijens et al, 2006;Khan et al, 2008;Bellmann-Strobl et al, 2009;AboulEnein et al, 2010).…”

Section: No Significant Changes Of Cho Ratios or Cho Concentrationsmentioning

confidence: 99%

MR Spectroscopy in Multiple Sclerosis - A New Piece of the Puzzle or Just a New Puzzle

Aboul‐Enein¹

2012

Magnetic Resonance Spectroscopy

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“…11 They must, therefore, be imageguided, introducing 2 implicit assumptions: 1) changes occur only at MRI abnormalities and 2) they are representative of the entire brain. 12 They must also avoid most of the cortex, are sensitive to (unknown) T1 and T2 relaxation times, and are subject to misregistration errors.…”

mentioning

confidence: 99%

Two-year serial whole-brain N -acetyl- l -aspartate in patients with relapsing-remitting multiple sclerosis

Rigotti

Inglese²,

Kirov³

et al. 2012

Neurology

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Objectives:To test the hypotheses that 1) patients with relapsing-remitting multiple sclerosis (RR-MS) exhibit a quantifiable decline in their whole-brain concentration of the neural marker N-acetyl-L-aspartate (WBNAA), that is 2) more sensitive than clinical changes and 3) may provide a practical outcome measure for proof-of-concept and larger phase III clinical trials.Methods: Nineteen patients (5 men and 14 women) with clinically definite RR-MS, who were 33 Ϯ 5 years old (mean Ϯ SD), had a disease duration of 47 Ϯ 28 months, and had a median Expanded Disability Status Scale (EDSS) score of 1.0 (range 0-5.5), underwent MRI and proton magnetic resonance spectroscopy ( 1 H-MRS) semiannually for 2 years (5 time points). Eight matched control subjects underwent the protocol annually (3 time points). Their global N-acetyl-L-aspartate 1 H-MRS signal was converted into absolute amounts by phantom replacement and into WBNAA by dividing with the brain parenchymal volume, V B , from MRI segmentation. Results:The baseline WBNAA of the patients (10.5 Ϯ 1.7 mM) was significantly lower than that of the controls (12.3 Ϯ 1.3 mM; p Ͻ 0.002) and declined significantly (5%/year, p Ͻ 0.002) vs that for the controls who did not show a decline (0.4%/year, p Ͼ 0.7). Likewise, V B values of the patients also declined significantly (0.5%/year, p Ͻ 0.0001), whereas those of the controls did not (0.2%/year, p ϭ 0.08). The mean EDSS score of the patients increased insignificantly from 1.0 to 1.5 (range 0-6.0) and did not correlate with V B or WBNAA.Conclusions: WBNAA of patients with RR-MS declined significantly at both the group and individual levels over a 2-year time period common in clinical trials. Because of the small sample sizes required to establish power, WBNAA can be incorporated into future studies. Neurology ® 2012;78:1383-1389 GLOSSARY EDSS ϭ Expanded Disability Status Scale; 1 H-MRS ϭ proton magnetic resonance spectroscopy; MP-RAGE ϭ magnetization-prepared rapid acquisition gradient echo; MS ϭ multiple sclerosis; NAA ϭ N-acetyl-L-aspartate; RR ϭ relapsing-remitting; TE ϭ echo time; TI ϭ inversion time; TR ϭ repetition time; WBNAA ϭ whole-brain concentration of the neural marker N-acetyl-L-aspartate.

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Diffuse Axonal and Tissue Injury in Patients With Multiple Sclerosis With Low Cerebral Lesion Load and No Disability

Cited by 173 publications

References 71 publications

N-Acetylaspartate in the CNS: From neurodiagnostics to neurobiology

N-Acetylaspartate in the CNS: From neurodiagnostics to neurobiology

MR Spectroscopy in Multiple Sclerosis - A New Piece of the Puzzle or Just a New Puzzle

Two-year serial whole-brain N -acetyl- l -aspartate in patients with relapsing-remitting multiple sclerosis

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