Serum N -acetylaspartate Level in Amyotrophic Lateral Sclerosis (original) (raw)
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American Journal of Neuroradiology, 2007
Proton MR spectroscopy ( 1 H-MR spectroscopy) is a quantitative MR imaging technique often used to complement the sensitivity of conventional MR imaging with specific metabolic information. A key metabolite is the amino acid derivative N-acetylaspartate (NAA), which is almost exclusive to neurons and their processes and is, therefore, an accepted marker of their health and attenuation. Unfortunately, most 1 H-MR spectroscopy studies only account for small 1-to 200-cm volumes of interest (VOI), representing less than 20% of the total brain volume. These VOIs have at least 5 additional restrictions: 1) To avoid contamination from subcutaneous and bone marrow lipids, they must be placed away from the skull, thereby missing most of the cortex. 2) They must be image-guided onto MR imaging-visible pathology, subjecting them to the implicit assumption that metabolic changes occur only there. 3) They encounter misregistration errors in serial studies. 4) The time needed to accumulate sufficient signal-intensity quality is often restrictive, and 5) they incur (unknown) T1-and T2-weighting. All these issues are avoided (at the cost of specific localization) by measuring the nonlocalized average NAA concentration over the entire brain. Indeed, whole-brain NAA quantification has been applied to several diffuse neurodegenerative diseases (where specific localization is less important than the total load of the pathology), and the results are presented in this review.
Biological markers in the diagnosis and treatment of ALS
1999
The care of patients with amyotrophic lateral sclerosis (ALS), which has classically focused on treatment of symptomatology, has now entered an encouraging new era of therapy targeted at the pathophysiology of the disease. However, an objective measure of disease progression and therapeutic response is sorely needed. Quantitative neuromuscular examinations, measurement of pulmonary function, disability scales, and even survival, are limited by variability due to a number of poorly controlled factors. Quantitative electromyography, positron emission tomography scanning, and magnetic cortical stimulation, provide potential objective indicators of disease progression, but require a large number of patients and a long observation period for adequate statistical power. We have examined the role of magnetic resonance spectroscopic imaging in detecting acute changes in motor cortical metabolism in response to riluzole therapy. N-acetylaspartate (NAA), the most prominent signal in proton spectra of normal brain, is a neuron-specific molecule. ALS patients were found to experience a significant increase in the NAA / creatine ratio within 3 weeks of initiation of riluzole therapy. As glutamate can trigger the generation of reactive oxygen species in neurons, we speculate that acute changes in NAA levels may reflect oxidative injury to mitochondria where NAA is synthesised. The advent of a useful test for upper motor neuron metabolic compromise may provide an objective, non-invasive, short duration measure with which to screen the efficacy of potential therapeutic agents for ALS.
Magnetic resonance imaging and 1 H-magnetic resonance spectroscopy in amyotrophic lateral sclerosis
Neuroradiology, 2001
We aimed to increase confidence in the combined use of MRI and proton MR spectroscopy (1H-MRS) in diagnosis of amyotrophic lateral sclerosis (ALS). We investigated 12 patients with ALS, seven definite and five probable, taking into account clinical measures of motor neuron function. On T2-weighted images we found high signal in the corticospinal tract in six and low signal in the primary motor cortex in seven of the 12 patients. Atrophy of the precentral gyrus was apparent in all the patients apart from one with probable ALS. Absolute quantification of cerebral metabolites using 1H-MRS demonstrated a significantly lower mean concentration of N-acetylaspartate (NAA) in the precentral gyrus of patients with probable and definite ALS (8.5 ± 0.62) than in control subjects (10.4 ± 0.71; P < 0.001). NAA concentration in primary motor cortex correlated with Norris scale scores (r = 0.30; P < 0.0001) but not with the ALS Functional Rating Scale score or disease duration. Significantly lower levels of NAA were detected in patients with low signal in the motor cortex than in those without (P < 0.01). Mean choline (Cho) and creatine (Cr) values did not differ between patients with ALS and controls.
Reductions in acidic amino acids andN-acetylaspartylglutamate in amyotrophic lateral sclerosis CNS
Brain Research, 1991
Acidic excitatory amino acids have been implicated in the pathogenesis of amyotrophic lateral sclerosis (ALS). We now report that, in addition to selective regional reductions in endogenous aspartate and glutamate, N-acetylaspartate (NAA), and N-acetylaspartylgiutamate (NAAG) are also decreased in the CNS, whereas the activity of N-acetylated-a-linked-amino dipeptidase (NAALADase) is increased. In cervical cord, the concentrations of aspartate and glutamate were decreased significantly in the ventral horn; NAb, was decreased in the ventral horn, dorsal horn and ventral column, whereas NAAG was decreased in all regions of the cord examined, except the posterior column. NAALADase activity was increased in the ventral column. In motor cortex of ALS patients, aspartate and glutamate were decreased and NAALADase activity was increased in both gray and white matter; whereas NAAG was decreased in gray matter alone. None of these parameters was affected in the cerebral cortex of the Huntington's patients. Of the markers examined, the alterations in the levels of NAAG most closely parallel the cellular neuropathology in ALS. Recently, we demonstrated that the concentrations of Asp, Glu, NAAG and NAA are significantly elevated by
Journal of Alzheimer's disease : JAD, 2015
Mild cognitive impairment (MCI) is an intermediary state on the way to Alzheimer's disease (AD). Little is known about whole brain concentration of the neuronal marker, N-acetylaspartate (NAA) in MCI patients. To test the hypothesis that since MCI and AD are both neurodegenerative, quantification of the NAA in their whole brain (WBNAA) could differentiate them from cognitively-intact matched controls. Proton MR spectroscopy to quantify the WBNAA was applied to 197 subjects (86 females) 72.6 ± 8.4 years old (mean ± standard deviation). Of these, 102 were cognitively intact, 42 diagnosed as MCI, and 53 as probable AD. Their WBNAA amounts were converted into absolute concentration by dividing with the brain volume segmented from the MRI that also yielded the fractional brain volume (fBPV), an atrophy metric. WBNAA concentration of MCI and AD patients (10.5 ± 3.0 and 10.1 ± 2.9 mM) were not significantly different (p = 0.85). They were, however, highly significantly 25-29% lower tha...
European Journal of Radiology, 2013
Background and objective: To examine whether clinically benign multiple sclerosis patients (BMS) show similar losses of their global N-acetylaspartate (NAA) neuronal marker relative to more clinically disabled patients of similar disease duration. Methods: The whole-brain NAA concentration (WBNAA) was acquired with whole-head non-localizing proton MR spectroscopy. Fractional brain parenchymal volume (fBPV), T 2 and T 1 lesion loads, were obtained from the MRI in: (i) 24 BMS patients: 23.1 ± 7.2 years disease duration, median Expanded Disability Status Scale (EDSS) score of 2.0 (range: 0-3); (ii) 26 non-benign MS patients (non-BMS), 24.5 ± 7.4 years disease duration, median EDSS of 4.0 (range: 3.5-6.5); (iii) 15 healthy controls. Results: Controls' 12.4 ± 2.3 mM WBNAA was significantly higher than the BMS's and non-BMS's 10.5 ± 2.4 and 9.9 ± 2.1 mM (both p < 0.02), but the difference between the patients' groups was not (p > 0.4). Likewise, the controls' 81.2 ± 4.5% fBPV exceeded the BMS and non-BMS's 77.0 ± 5.8% and 76.3 ± 8.6% (p < 0.03), which were also not different from one another (p > 0.7). BMS patients' T 1-hypointense lesion load, 2.1 ± 2.2 cm 3 , was not significantly different than the non-BMS's 4.1 ± 5.4 cm 3 (p > 0.08) and T 2hyperintense loads: 6.0 ± 5.7 cm 3 and 8.7 ± 7.8 cm 3 , were also not different (p > 0.1). Conclusions: WBNAA differentiates normal controls from MS patients but does not distinguish BMS from more disabled MS patients of similar disease duration. Nevertheless, all MS patients who remain RR for 15+ years suffered WBNAA loss similar to the average RR MS population at fourfold shorter disease duration suggesting relative global neuronal sparing or leveling-off of the neurodegeneration rate.
Longitudinal Whole-Brain N-Acetylaspartate Concentration in Healthy Adults
American Journal of Neuroradiology, 2011
BACKGROUND AND PURPOSE: Although NAA is often used as a marker of neural integrity and health in different neurologic disorders, the temporal behavior of WBNAA is not well characterized. Our goal therefore was to establish its normal variations in a cohort of healthy adults over typical clinical trial periods. MATERIALS AND METHODS: Baseline amount of brain NAA, Q NAA , was obtained with nonlocalizing proton MR spectroscopy from 9 subjects (7 women, 2 men; 31.2 Ϯ 5.6 years old). Q NAA was converted into absolute millimole amount by using phantom-replacement. The WBNAA concentration was derived by dividing Q NAA with the brain parenchyma volume, V B , segmented from MR imaging. Temporal variations were determined with 4 annual scans of each participant. RESULTS: The distribution of WBNAA levels was not different among time points with respect to the mean, 12.1 Ϯ 1.5 mmol/L (P Ͼ .6), nor was its intrasubject change (coefficient of variation ϭ 8.6%) significant between any 2 scans (P Ͼ .5). There was a small (0.2 mL) but significant (P ϭ .05) annual V B decline. CONCLUSIONS: WBNAA is stable over a 3-year period in healthy adults. It qualifies therefore as a biomarker for global neuronal loss and dysfunction in diffuse neurologic disorders that may be well worth considering as a secondary outcome measure candidate for clinical trials. ABBREVIATIONS: CV ϭ coefficient of variation; GM ϭ gray matter; 1 H-MRS ϭ proton MR spectroscopy; MPRAGE ϭ magnetization-prepared rapid acquisition of gradient echo; NAA ϭ Nacetylaspartate; Q NAA ϭ absolute amount of NAA (millimoles); SNR ϭ signal intensity-to-noise ratio; S R ϭ reference NAA peak area; S S ϭ subject NAA peak area; VOI ϭ volume of interest; V R 180°ϭ reference transmitter voltage; V S 180°ϭ subject transmitter voltage; WBNAA ϭ whole-brain NAA concentration; WM ϭ white matter
AJNR. American journal of neuroradiology, 2002
The T2-weighted MR imaging total lesion volume and Expanded Disability Status Scale (EDSS) score are two common measures of relapsing-remitting multiple sclerosis disability and pathologic abnormality. Because the whole-brain N-acetylaspartate concentration is considered to be a new marker of the disease burden, the purpose of this study was to evaluate the relationship among these three measures. The whole-brain N-acetylaspartate concentration and T2-weighted lesion volume were quantified by using MR imaging and proton MR spectroscopy in 49 patients with relapsing-remitting multiple sclerosis (36 female and 13 male patients; average age, 39 years; age range, 24-55 years; average EDSS score, 2; range of EDSS scores, 0-6). Correlations among whole-brain N-acetylaspartate concentrations, T2-weighted lesion volumes, and EDSS scores were obtained. No correlation was found between whole-brain N-acetylaspartate levels and either T2-weighted lesion volumes or EDSS scores. A weak correlatio...
Journal of Neurology, 2014
Background and purpose: Primary and secondary progressive forms of multiple sclerosis (PPMS and SPMS) have different pathological characteristics. However, it is unknown whether neurodegenerative mechanisms are shared. Methods: We measured cerebrospinal fluid (CSF) levels of neurofilament (Nf) light and heavy isoforms and N-acetylaspartic acid (NAA) in 21 PP, 10 SPMS patients and 15 non-inflammatory neurological disease controls (NINDC). Biomarkers were related to EDSS (Expanded Disability Status Scale) and MSSS (Multiple Sclerosis Severity Score) over a long period of follow-up (median (interquartile range) 9 (5.5-12.5) years) in 19 PPMS and 4 SPMS patients, and to T2 lesion load (T2LL), T1 lesion load (T1LL), and brain parenchymal fraction (BPF) at time of lumbar puncture. Results: Nf light was higher in PPMS (p<0.005) and Nf heavy was increased in both SPMS and PPMS (p<0.05 and p<0.01) compared to NINDC, but were comparable between the two MS subtypes. Nf heavy was a predictor of the ongoing disability
Ultra high-field (7tesla) magnetic resonance spectroscopy in Amyotrophic Lateral Sclerosis
PLOS ONE, 2017
The main objective of this study was to utilize high field (7T) in vivo proton magnetic resonance imaging to increase the ability to detect metabolite changes in people with ALS, specifically, to quantify levels of glutamine and glutamine separately. The second objective of this study was to correlate metabolic markers with clinical outcomes of disease progression. 13 ALS participants and 12 age-matched healthy controls (HC) underwent 7 Tesla MRI and MRS. Single voxel MR spectra were acquired from the left precentral gyrus using a very short echo time (TE = 5 ms) STEAM sequence. MRS data was quantified using LCModel and correlated to clinical outcome markers. N-acetylaspartate (NAA) and total NAA (tNA, NAA + NAAG) were decreased by 17% in people with ALS compared to HC (P = 0.004 and P = 0.005, respectively) indicating neuronal injury and/or loss in the precentral gyrus. tNA correlated with disease progression as measured by forced vital capacity (FVC) (P = 0.014; R ρ = 0.66) and tNA/tCr correlated with overall functional decline as measured by worsening of the ALS Functional Rating Scale-Revised (ALSFRS-R) (P = 0.004; R ρ =-0.74). These findings underscore the importance of NAA as a reliable biomarker for neuronal injury and disease progression in ALS. Glutamate (Glu) was 15% decreased in people with ALS compared to HC (P = 0.02) while glutamine (Gln) concentrations were similar between the two groups. Furthermore, the decrease in Glu correlated with the decrease in FVC (P = 0.013; R ρ = 0.66), a clinical marker of disease progression. The decrease in Glu is most likely driven by intracellular Glu loss due to neuronal loss and degeneration. Neither choline containing components (Cho), a marker for cell membrane turnover, nor myo-Inositol (mI), a suspected marker for neuroinflammation, showed significant differences between the two