Elevated amyloid beta peptides and total tau in cerebrospinal fluid in individuals with Creatine transporter deficiency
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),...
| Main Authors: | , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2023-12-01
|
| Series: | Molecular Genetics and Metabolism Reports |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2214426923000472 |
| _version_ | 1827687046512115712 |
|---|---|
| author | Samar Rahhal Cristan Farmer Audrey Thurm Christopher A. Wassif Niamh X. Cawley John Perreault An Dang Do Simona Bianconi Fady Hannah-Shmouni Whitney Guthrie Laura S. Cubit Judith S. Miller V. Reid Sutton Dwight Koeberl Forbes D. Porter |
| author_facet | Samar Rahhal Cristan Farmer Audrey Thurm Christopher A. Wassif Niamh X. Cawley John Perreault An Dang Do Simona Bianconi Fady Hannah-Shmouni Whitney Guthrie Laura S. Cubit Judith S. Miller V. Reid Sutton Dwight Koeberl Forbes D. Porter |
| author_sort | Samar Rahhal |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-10T09:27:10Z |
| format | Article |
| id | doaj.art-f3fb51c11aca47f49c9ed8fa1ae4f882 |
| institution | Directory Open Access Journal |
| issn | 2214-4269 |
| language | English |
| last_indexed | 2024-03-10T09:27:10Z |
| publishDate | 2023-12-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Molecular Genetics and Metabolism Reports |
| spelling | doaj.art-f3fb51c11aca47f49c9ed8fa1ae4f8822023-11-22T04:47:26ZengElsevierMolecular Genetics and Metabolism Reports2214-42692023-12-0137101001Elevated amyloid beta peptides and total tau in cerebrospinal fluid in individuals with Creatine transporter deficiencySamar Rahhal0Cristan Farmer1Audrey Thurm2Christopher A. Wassif3Niamh X. Cawley4John Perreault5An Dang Do6Simona Bianconi7Fady Hannah-Shmouni8Whitney Guthrie9Laura S. Cubit10Judith S. Miller11V. Reid Sutton12Dwight Koeberl13Forbes D. Porter14Division of Translational Medicine, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health (NIH), Bethesda, MD, USA; Corresponding author at: 10 Center Dr, Bethesda, MD 20892, USA.Neurodevelopmental and Behavioral Phenotyping Service, National Institute of Mental Health, National Institutes of Health (NIH), Bethesda, MD, USANeurodevelopmental and Behavioral Phenotyping Service, National Institute of Mental Health, National Institutes of Health (NIH), Bethesda, MD, USADivision of Translational Medicine, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health (NIH), Bethesda, MD, USADivision of Translational Medicine, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health (NIH), Bethesda, MD, USADivision of Translational Medicine, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health (NIH), Bethesda, MD, USADivision of Translational Medicine, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health (NIH), Bethesda, MD, USADivision of Translational Medicine, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health (NIH), Bethesda, MD, USADivision of Translational Medicine, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health (NIH), Bethesda, MD, USACenter for Autism Research, Children's Hospital of Philadelphia, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Division of Developmental and Behavioral Pediatrics, Children's Hospital of Philadelphia, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USACenter for Autism Research, Children's Hospital of Philadelphia, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USACenter for Autism Research, Children's Hospital of Philadelphia, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Division of Developmental and Behavioral Pediatrics, Children's Hospital of Philadelphia, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USADepartment of Molecular & Human Genetics, Baylor College of Medicine & Texas Children's Hospital, USADepartment of Pediatrics, Duke University School of Medicine, Durham, NC, USADivision of Translational Medicine, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health (NIH), Bethesda, MD, USABackground: 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.http://www.sciencedirect.com/science/article/pii/S2214426923000472Creatine transporter deficiencySLC6A8Amyloid beta peptidesTau proteinCerebrospinal fluidCerebral energy deficiency |
| spellingShingle | Samar Rahhal Cristan Farmer Audrey Thurm Christopher A. Wassif Niamh X. Cawley John Perreault An Dang Do Simona Bianconi Fady Hannah-Shmouni Whitney Guthrie Laura S. Cubit Judith S. Miller V. Reid Sutton Dwight Koeberl Forbes D. Porter Elevated amyloid beta peptides and total tau in cerebrospinal fluid in individuals with Creatine transporter deficiency Molecular Genetics and Metabolism Reports Creatine transporter deficiency SLC6A8 Amyloid beta peptides Tau protein Cerebrospinal fluid Cerebral energy deficiency |
| title | Elevated amyloid beta peptides and total tau in cerebrospinal fluid in individuals with Creatine transporter deficiency |
| title_full | Elevated amyloid beta peptides and total tau in cerebrospinal fluid in individuals with Creatine transporter deficiency |
| title_fullStr | Elevated amyloid beta peptides and total tau in cerebrospinal fluid in individuals with Creatine transporter deficiency |
| title_full_unstemmed | Elevated amyloid beta peptides and total tau in cerebrospinal fluid in individuals with Creatine transporter deficiency |
| title_short | Elevated amyloid beta peptides and total tau in cerebrospinal fluid in individuals with Creatine transporter deficiency |
| title_sort | elevated amyloid beta peptides and total tau in cerebrospinal fluid in individuals with creatine transporter deficiency |
| topic | Creatine transporter deficiency SLC6A8 Amyloid beta peptides Tau protein Cerebrospinal fluid Cerebral energy deficiency |
| url | http://www.sciencedirect.com/science/article/pii/S2214426923000472 |
| work_keys_str_mv | AT samarrahhal elevatedamyloidbetapeptidesandtotaltauincerebrospinalfluidinindividualswithcreatinetransporterdeficiency AT cristanfarmer elevatedamyloidbetapeptidesandtotaltauincerebrospinalfluidinindividualswithcreatinetransporterdeficiency AT audreythurm elevatedamyloidbetapeptidesandtotaltauincerebrospinalfluidinindividualswithcreatinetransporterdeficiency AT christopherawassif elevatedamyloidbetapeptidesandtotaltauincerebrospinalfluidinindividualswithcreatinetransporterdeficiency AT niamhxcawley elevatedamyloidbetapeptidesandtotaltauincerebrospinalfluidinindividualswithcreatinetransporterdeficiency AT johnperreault elevatedamyloidbetapeptidesandtotaltauincerebrospinalfluidinindividualswithcreatinetransporterdeficiency AT andangdo elevatedamyloidbetapeptidesandtotaltauincerebrospinalfluidinindividualswithcreatinetransporterdeficiency AT simonabianconi elevatedamyloidbetapeptidesandtotaltauincerebrospinalfluidinindividualswithcreatinetransporterdeficiency AT fadyhannahshmouni elevatedamyloidbetapeptidesandtotaltauincerebrospinalfluidinindividualswithcreatinetransporterdeficiency AT whitneyguthrie elevatedamyloidbetapeptidesandtotaltauincerebrospinalfluidinindividualswithcreatinetransporterdeficiency AT laurascubit elevatedamyloidbetapeptidesandtotaltauincerebrospinalfluidinindividualswithcreatinetransporterdeficiency AT judithsmiller elevatedamyloidbetapeptidesandtotaltauincerebrospinalfluidinindividualswithcreatinetransporterdeficiency AT vreidsutton elevatedamyloidbetapeptidesandtotaltauincerebrospinalfluidinindividualswithcreatinetransporterdeficiency AT dwightkoeberl elevatedamyloidbetapeptidesandtotaltauincerebrospinalfluidinindividualswithcreatinetransporterdeficiency AT forbesdporter elevatedamyloidbetapeptidesandtotaltauincerebrospinalfluidinindividualswithcreatinetransporterdeficiency |