Reduced NAA in motor and non‐motor brain regions in amyotrophic lateral sclerosis: a cross‐sectional and longitudinal study

Rule, Randall R.; Suhy, Joyce; Schuff, Norbert; Gelinas, Deborah; Miller, Robert G.; Weiner, Michael W.

doi:10.1080/14660820410017109

Cited by 76 publications

(57 citation statements)

References 29 publications

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“…55, 97 A serial 1 H-MR spectroscopy study indicated that a significant decrease of the NAA level also occurs in brain extramotor regions after 9 months. 99 However, in 1 prospective study of 30 patients with ALS, no significant 1 H-MR spectroscopy and DTI changes were observed.…”

Section: Mr Imaging To Monitor Disease Evolutionmentioning

confidence: 99%

“…To date, only a few studies have attempted to assess quantitatively the dynamics of nonconventional brain structural changes in patients with ALS, and they provided conflicting results. Some studies have demonstrated a significant decrease of the NAA level in the motor cortex 55,[97][98][99] or the FA in the brain WM 97 and cervical cord 47 during Ͻ1 year. Changes of metabolite ratios and diffusivity abnormalities were significantly correlated with progression of disease severity.…”

Section: Mr Imaging To Monitor Disease Evolutionmentioning

confidence: 99%

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The Present and the Future of Neuroimaging in Amyotrophic Lateral Sclerosis

Agosta¹,

Chiò²,

Cosottini³

et al. 2010

AJNR Am J Neuroradiol

117

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SUMMARY:In patients with ALS, conventional MR imaging is frequently noninformative, and its use has been restricted to excluding other conditions that can mimic ALS. Conversely, the extensive application of modern MR imagingϪbased techniques to the study of ALS has undoubtedly improved our understanding of disease pathophysiology and is likely to have a role in the identification of potential biomarkers of disease progression. This review summarizes how new MR imaging technology is changing dramatically our understanding of the factors associated with ALS evolution and highlights the reasons why it should be used more extensively in studies of disease progression, including clinical trials.ABBREVIATIONS: ALS ϭ amyotrophic lateral sclerosis; ALSFRS ϭ ALS Functional Rating Scale; Cho ϭ choline; Cr ϭ creatine; CST ϭ corticospinal tract; DTI ϭ diffusion tensor imaging; FA ϭ fractional anisotropy; FLAIR ϭ fluid-attenuated inversion recovery; fMRI ϭ functional MR imaging; FTD ϭ frontotemporal dementia; FUS/TLS ϭ fused in sarcoma/translocated in liposarcoma gene; GM ϭ gray matter; 1 H-MR spectroscopy ϭ proton MR spectroscopy; L ϭ left; LMN ϭ lower motor neuron; MD ϭ mean diffusivity; mIns ϭ myo-inositol; MT ϭ magnetization transfer; MTR ϭ MT ratio; NAA ϭ N-acetylaspartate; ns ϭ not significant; PD ϭ proton density; R ϭ right; SOD1 ϭ superoxide dismutase 1; SPM ϭ statistical parametric mapping; TDP-43 ϭ TAR DNA-binding protein gene; UMN ϭ upper motor neuron; VBM ϭ voxel-based morphometry; WM ϭ white matter A LS, also known as motor neuron disease, is a neurodegenerative disorder characterized by a progressive muscular paralysis reflecting degeneration of motor neurons in the primary motor cortex, brain stem, and spinal cord. The phenotypic expression of ALS is highly heterogeneous and determined by 4 elements: 1) body region of onset, 2) relative mix of UMN and LMN involvement, 3) rate of progression, and 4) cognitive impairment.1 In approximately 5%-10% of patients, the disease is inherited; 20% of these individuals have a mutation of the SOD1 gene; approximately 2%-5%, of the TARDBP (TDP-43) gene; and 2%-4%, of the FUS/TLS gene. 2Most patients with ALS, however, have no obvious family history and have sporadic ALS.2 To date, the only specific marker of sporadic ALS is the presence of inclusions staining positively for ubiquitin and TDP-43 in degenerating motor neurons. 3Despite technical advances in medicine in the last century, the diagnosis of sporadic ALS relies on the interpretation of clinical symptoms and signs (ie, signs suggestive of combined UMN and LMN degeneration, together with disease progression compatible with a neurodegenerative disorder). Paraclinical and laboratory tests are used only to exclude "ALS-mimic" syndromes. 4,5 In ALS, the absence of a disease marker for UMN and LMN involvement has 2 main negative consequences. First, the delay from onset of the disease to diagnosis of ALS can vary between 13 and 18 months 6,7

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Section: Mr Imaging To Monitor Disease Evolutionmentioning

confidence: 99%

Section: Mr Imaging To Monitor Disease Evolutionmentioning

confidence: 99%

The Present and the Future of Neuroimaging in Amyotrophic Lateral Sclerosis

Agosta¹,

Chiò²,

Cosottini³

et al. 2010

AJNR Am J Neuroradiol

117

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“…A number of studies have demonstrated a reduction in N-acetylaspartate (NAA), a marker of neuronal loss, in patients with ALS compared to controls expressed as absolute concentrations, 11,12 or as ratios of other metabolites like choline (Cho) and creatine (Cr) 10,[13][14][15][16][17][18][19][20][21][22][23][24] in the primary motor cortex, 13,17,19,23,25,26 centrum semiovale, internal capsule, corticospinal tract, cervical spine, 10,12,23 medulla, 5 and brainstem. Whether similar findings might be evident in people at risk for developing ALS, however, remains an unanswered question.…”

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confidence: 99%

Presymptomatic spinal cord neurometabolic findings in SOD1 -positive people at risk for familial ALS

Carew¹,

Nair²,

Andersen³

et al. 2011

Neurology

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Objective: It has been speculated that amyotrophic lateral sclerosis (ALS) is characterized by a premanifest period during which neurodegeneration precedes the appearance of clinical manifestations. Magnetic resonance spectroscopy (MRS) was used to measure ratios of neurometabolites in the cervical spine of asymptomatic individuals with a mutation in the SOD1 gene (SOD1ϩ) and compare their neurometabolic ratios to patients with ALS and healthy controls. Methods:A cross-sectional study of 1 H-MRS of the cervical spine was performed on 24 presymptomatic SOD1ϩ volunteers, 29 healthy controls, and 23 patients with ALS. All presymptomatic subjects had no symptoms of disease, normal forced vital capacity, and normal electromyographic examination. Relative concentrations of choline (Cho), creatine (Cr), myo-inositol (Myo), and N-acetylaspartate (NAA) were determined.Results: NAA/Cr and NAA/Myo ratios are reduced in both SOD1ϩ subjects (39.7%, p ϭ 0.001 and 18.0%, p ϭ 0.02) and patients with ALS (41.2%, p Ͻ 0.001 and 24.0%, p ϭ 0.01) compared to controls. Myo/Cr is reduced (10.3%, p ϭ 0.02) in SOD1ϩ subjects compared to controls, but no difference was found between patients with ALS and controls. By contrast, NAA/Cho is reduced in patients with ALS (24.0%, p ϭ 0.002), but not in presymptomatic SOD1ϩ subjects compared to controls. It has been speculated that amyotrophic lateral sclerosis (ALS) is characterized by a premanifest period during which neuronal degeneration precedes the appearance of clinical symptoms. Some evidence of this premanifest period has been derived from the superoxide dismutase (SOD1) mouse model of ALS in which there is a decline in the estimated motor unit number in advance of the appearance of symptoms. Conclusions:1 Limited data from a number of healthy individuals at risk for ALS by virtue of their carrying a mutation in the SOD1 gene (SOD1ϩ) suggest a decline in motor unit numbers several months in advance of the appearance of symptoms.

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“…In another study, chemical shift imaging follow-up measurements in ALS patients after a three months period exhibited a decline of concentrations of NAA, Cr and Cho in the most affected motor cortex areas of ALS in comparison to healthy controls [22]. In an investigation on 1 H MRS measurements at different time points of follow-up, trends in metabolite concentration levels were reported [19], and in a further MRS study in samples of possible/suspected and probable/definite patients, no clear pattern of progressive change over time was found [23]. In summary, 1 H MRS could not be established as a longitudinal biomarker in ALS in these studies.…”

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confidence: 89%

Brain metabolites in definite amyotrophic lateral sclerosis

2007

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Biomarkers beyond clinical assessment are needed in patients who suffer from amyotrophic lateral sclerosis (ALS). Here, single-voxel proton magnetic resonance spectroscopy ((1)H MRS) of the gray matter of the motor cortex and the white matter including the pyramidal tracts was used to investigate concentrations of N-acetylaspartate (NAA), creatine (Cr), choline (Cho), myoinositol, glutamate, and glutamine in patients with definite ALS in a longitudinal design (three measurements at study inclusion, after 3 and 6 months). A volume-corrected analysis of gray and white matter fractions within the volumes of interest (VOI) was performed for the identification of the absolute metabolite concentrations. The patient group showed a significant decline of the compound NAA over time in the motor cortex areas both of the clinically more and less affected hemisphere between first measurement and month 6 and for the less affected side additionally between first measurement and month 3. For the NAA/(Cr + Cho) ratio, significant decline in the less affected hemisphere was observed from the first measurement to month 3 and to month 6 as well as from month 3 to month 6. In contrast, neither NAA nor the NAA/(Cr + Cho) ratios in the white matter areas showed any significant alterations. All other compounds showed no significant changes over time. In summary, the longitudinal changes of cortical metabolite concentrations in the course of ALS could be assessed by optimized (1)H MRS techniques at group level, so that (1)H MRS parameters, in particular volume-corrected values of NAA in the clinically less affected hemisphere, seem to have the potential to serve as a surrogate marker for monitoring ALS disease progression.

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Reduced NAA in motor and non‐motor brain regions in amyotrophic lateral sclerosis: a cross‐sectional and longitudinal study

Cited by 76 publications

References 29 publications

The Present and the Future of Neuroimaging in Amyotrophic Lateral Sclerosis

The Present and the Future of Neuroimaging in Amyotrophic Lateral Sclerosis

Presymptomatic spinal cord neurometabolic findings in SOD1 -positive people at risk for familial ALS

Brain metabolites in definite amyotrophic lateral sclerosis

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