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Circulating N-Acetylaspartate does not track brain NAA concentrations, cognitive function or features of small vessel disease in humans.

ABSTRACT: N-acetylaspartate (NAA) is the second most abundant metabolite in the human brain; although it is assumed to be a proxy for a neuronal marker, its function is not fully elucidated. NAA is also detectable in plasma, but its relation to cerebral NAA levels, cognitive performance, or features of cerebral disease has not been investigated. To study whether circulating NAA tracks cerebral NAA levels, and whether circulating NAA correlates with cognitive function and features of cerebral small vessel disease (SVD). Two datasets were analyzed. In dataset 1, structural MRI was acquired in 533 subjects to assess four features of cerebral SVD. Cognitive function was evaluated with standardized test scores (N = 824). In dataset 2, brain ¹H-MRS from the occipital region was acquired (N = 49). In all subjects, fasting circulating NAA was measured with mass spectrometry. Dataset 1: in univariate and adjusted for confounders models, we found no correlation between circulating NAA and the examined features of cerebral SVD. In univariate analysis, circulating NAA levels were associated inversely with the speed in information processing and the executive function score, however these associations were lost after accounting for confounders. In line with the negative findings of dataset 1, in dataset 2 there was no correlation between circulating and central NAA or total NAA levels. This study indicates that circulating NAA levels do not reflect central (occipital) NAA levels, cognitive function, or cerebral small vessel disease in man.

SUBMITTER: Rebelos E

PROVIDER: S-EPMC9262942 | biostudies-literature | 2022 Jul

REPOSITORIES: biostudies-literature

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Circulating N-Acetylaspartate does not track brain NAA concentrations, cognitive function or features of small vessel disease in humans.

Rebelos Eleni E Daniele Giuseppe G Campi Beatrice B Saba Alessandro A Koskensalo Kalle K Ihalainen Jukka J Saukko Ekaterina E Nuutila Pirjo P Backes Walter H WH Jansen Jacobus F A JFA Dagnelie Pieter C PC Köhler Sebastian S de Galan Bastiaan E BE van Sloten Thomas T TT Stehouwer Coen D A CDA Ferrannini Ele E

Scientific reports 20220707 1

N-acetylaspartate (NAA) is the second most abundant metabolite in the human brain; although it is assumed to be a proxy for a neuronal marker, its function is not fully elucidated. NAA is also detectable in plasma, but its relation to cerebral NAA levels, cognitive performance, or features of cerebral disease has not been investigated. To study whether circulating NAA tracks cerebral NAA levels, and whether circulating NAA correlates with cognitive function and features of cerebral small vessel ...[more]

PMID: 35798828

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Project description:Age-related cerebral small vessel disease involves heterogeneous pathogenesis, such as arteriosclerosis/lipohyalinosis and cerebral amyloid angiopathy. MRI can visualize the brain lesions attributable to small vessel disease pathologies, including white-matter hyperintensities, lacune and cerebral microbleeds. However, these MRI markers usually coexist in small vessel disease of different aetiologies. Currently, there is no available classification integrating these neuroimaging markers for differentiating clinical and neuroanatomic features of small vessel disease yet. In this study, we tested whether our proposed stratification scheme could characterize specific clinical, neuroanatomic and potentially pathogenesis/aetiologies in classified small vessel disease subtypes. Cross-sectional analyses from a community-based non-demented non-stroke cohort consisting of ≥50 years old individuals were conducted. All participants were scanned 3T brain MRI for small vessel disease detection and neuroanatomic measurements and underwent physical and cognitive assessments. Study population were classified into robust and four small vessel disease groups based on imaging markers indicating (i) bleeding or non-bleeding; (ii) specific location of cerebral microbleeds; and (iii) the severity and combination of white-matter hyperintensities and lacune. We used whole-brain voxel-based morphometry analyses and tract-based spatial statistics to evaluate the regional grey-matter volume and white-matter microstructure integrity for comparisons among groups. Among the 735 participants with eligible brain MRI images, quality screening qualified 670 for grey-matter volume analyses and 617 for white-matter microstructural analyses. Common and distinct patterns of the clinical and neuroimaging manifestations were found in the stratified four small vessel disease subgroups. Hierarchical clustering analysis revealed that small vessel disease type 4 had features distinct from the small vessel disease types 1, 2 and 3. Abnormal white-matter microstructures and cognitive function but preserved physical function and grey-matter volume were found in small vessel disease type 4. Among small vessel disease types 1, 2 and 3, there were similar characteristics but different severity; the clinical features showed both physical frail and cognitive impairment and the neuroanatomic features revealed frontal-subcortical white-matter microstructures and remote, diffuse cortical abnormalities. This novel stratification scheme highlights the distinct clinical and neuroanatomic features of small vessel disease and the possible underlying pathogenesis. It could have potential application in research and clinical settings.

Project description:BackgroundPlasma cholesterol is one of the strongest risk factors associated with the development of atherosclerotic cardiovascular disease (ASCVD) and myocardial infarction. Human studies suggest that elevated plasma β-carotene is associated with reductions in circulating cholesterol and the risk of myocardial infarction. The molecular mechanisms underlying these observations are unknown.ObjectiveThe objective of this study was to determine the impact of dietary β-carotene and the activity of β-carotene oxygenase 1 (BCO1), which is the enzyme responsible for the conversion of β-carotene to vitamin A, on circulating cholesterol concentration.MethodsIn our preclinical study, we compared the effects of a 10-d intervention with a diet containing 50 mg/kg of β-carotene on plasma cholesterol in 5-wk-old male and female C57 Black 6 wild-type and congenic BCO1-deficient mice. In our clinical study, we aimed to determine whether 5 common small nucleotide polymorphisms located in the BCO1 locus affected serum cholesterol concentrations in a population of young Mexican adults from the Universities of San Luis Potosí and Illinois: A Multidisciplinary Investigation on Genetics, Obesity, and Social-Environment (UP AMIGOS) cohort.ResultsUpon β-carotene feeding, Bco1-/- mice accumulated >20-fold greater plasma β-carotene and had ∼30 mg/dL increased circulating total cholesterol (P < 0.01) and non-HDL cholesterol (P < 0.01) than wild-type congenic mice. Our results in the UP AMIGOS cohort show that the rs6564851 allele of BCO1, which has been linked to BCO1 enzymatic activity, was associated with a reduction in 10 mg/dL total cholesterol concentrations (P = 0.009) when adjusted for vitamin A and carotenoid intakes. Non-HDL-cholesterol concentration was also reduced by 10 mg/dL when the data were adjusted for vitamin A and total carotenoid intakes (P = 0.002), or vitamin A and β-carotene intakes (P = 0.002).ConclusionsOverall, our results in mice and young adults show that BCO1 activity impacts circulating cholesterol concentration, linking vitamin A formation with the risk of developing ASCVD.

Project description:BackgroundThe association between platelet endothelial cell adhesion molecule-1 (PECAM-1) with cerebral small-vessel disease and cognition in dementia-free subjects remains uninvestigated.Methods and resultsA prospective cohort of dementia-free subjects was recruited from memory clinics and followed up for 5 years. Annual neurocognitive assessments and twice-yearly brain magnetic resonance imaging scans were performed. Associations of baseline plasma PECAM-1 levels with cerebral small-vessel disease, cognitive decline (Montreal Cognitive Assessment scores and executive function Z scores), and incident dementia were evaluated. Of 213 subjects (aged 70.2±7.7 years, 51.2% men), median PECAM-1 levels were 0.790 (interquartile range, 0.645-0.955 ng/mL). Compared with the highest tertile, subjects within the lowest PECAM-1 tertile had greater cross-sectional white matter hyperintensity volume (β=4.84 [95% CI, 0.67-9.01]; P=0.023), age-related white matter change scores (β=1.39 [95% CI, 0.12-2.67]; P=0.033), and cerebral microbleeds (Adjusted risk ratio, 2.59 [95% CI, 1.19-5.62]; P=0.016). Of the 204 participants with follow-up data (median, 60.0 [interquartile range, 60.0-60.0] months), 24 (11.8%) developed incident dementia. Compared with the highest tertile, subjects within the lower tertiles of PECAM-1 had a higher risk of incident dementia (first tertile: adjusted hazard ratio [AHR], 4.52 [95% CI, 1.35-15.13]; P=0.024; second tertile: AHR, 3.28 [95% CI, 1.02-10.60]; P=0.047). The lowest PECAM-1 tertile was associated with greater progression of white matter hyperintensity volume (β=4.15 [95% CI, 0.06-8.24]; P=0.047), cerebral microbleeds (incident relative risk [IRR], 2.21 [95% CI, 1.05-4.65]; P=0.036), and decline in executive function (β=-0.45 [95% CI, -0.76 to -0.14]; P=0.004), and Montreal Cognitive Assessment (β=-1.32 [95% CI, -2.30 to -0.35]; P=0.008) scores.ConclusionsIn dementia-free subjects, lower circulating PECAM-1 levels are associated with greater cerebral small-vessel disease progression and cognitive decline, thus warranting future study as a potential therapeutic target.

Dataset Information

Circulating N-Acetylaspartate does not track brain NAA concentrations, cognitive function or features of small vessel disease in humans.

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Circulating N-Acetylaspartate does not track brain NAA concentrations, cognitive function or features of small vessel disease in humans.

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