Elevated amyloid beta peptides and total tau in cerebrospinal fluid in individuals with Creatine transporter deficiency

Abstract

Background: Creatine transporter deficiency (CTD) is a rare X-linked disorder of creatine transport caused by pathogenic variants in SLC6A8 (Xq28). The disorder is marked by developmental delay, especially speech delay. The biomarkers Aβ40, Aβ42 and total tau are abnormal in Alzheimer disease (AD), a common neurodegenerative disorder pathologically characterized by Aβ peptide containing amyloid plaques and tau neurofibrillary tangles. Although CTD results in neuronal energy deficiency, the pathological processes underlying the CTD phenotype are not fully characterized.

Methods: Cerebral spinal fluid (CSF) was collected as an optional part of a natural history study of CTD. Aβ40, Aβ42 and total tau levels were quantified in CSF from individuals with CTD and from age-appropriate comparison samples. Neuro3-Plex enzyme-linked immunoassay was performed on a Quanterix SR-X instrument. The Vineland Adaptive Behavior Scale, 3rd Edition was used to determine an overall Adaptive Behavior Composite (ABC) standard score.

Results: CSF from 12 individuals with CTD and 23 age appropriate non-CTD comparison samples were analyzed. We found that levels of total tau [t(32) = 4.05, p = 0.0003], Aβ40 [t(31) = 6.11, p < 0.0001], and Aβ42 [t(32) = 3.20, p = 0.003] were elevated in the participants with CTD relative to the comparison group. Additionally, except for one individual that we considered an outlier, all three biomarkers correlated inversely with the adaptive behavior score (total tau: ρ = -0.60 [-0.88, 0.005]; Aβ40: ρ = -0.67 [-0.91, -0.12]; Aβ42: ρ = -0.62 [-0.89, -0.02]).

Conclusion: We describe here the novel finding of elevated protein biomarkers in the CSF of individuals with CTD. Aβ40, Aβ42 and total tau are markedly elevated in individuals with CTD compared to comparison samples, and increased levels of these biomarkers inversely correlated with ABC scores. We hypothesize that elevated CSF levels of Aβ40 and Aβ42 are due to cellular energy deficiency. Elevated CSF total tau levels may indicate ongoing neuronal damage. The observed inverse correlation of Vineland ABC scores with increased biomarker levels needs to be confirmed in a larger CTD cohort; however, our observation of increased Aβ40, Aβ42 and total tau levels in CSF from individuals with CTD may provide insight into pathological mechanisms contributing to the CTD phenotype and may prove useful as supportive data in future therapeutic trials.

Keywords: Amyloid beta peptides; Cerebral energy deficiency; Cerebrospinal fluid; Creatine transporter deficiency; SLC6A8; Tau protein.

Fig. 1

Biomarker levels in 12 males with CTD and a comparison group. Observed concentrations of total Aβ40 (A), Aβ42 (B), Aβ40/ Aβ42 ratio (C) and total tau (D) in CSF from individuals with CTD (n = 12; filled squares) and a comparison sample (open circles = pediatric laboratory controls (PLC), n = 10; filled circles = individuals with Smith-Lemli-Opitz syndrome (SLOS), n = 13). Horizontal line indicates the geometric mean and vertical lines indicate the geometric standard deviation.

Fig. 2

Norm-referenced adaptive behavior scores versus CSF features in 12 males with CTD. Adaptive Behavior Composite (ABC) is a standard score with a population mean and SD of 100 ± 15. Each participant's baseline ABC score is plotted against the corresponding CSF concentration of Aβ40 (A), Aβ42 (B), or total Tau (C). The open circle is the extreme case that was excluded for the sensitivity analysis.