Cerebrospinal fluid profile of NPTX2 supports role of Alzheimer’s disease-related inhibitory circuit dysfunction in adults with Down syndrome
Abstract Background Alzheimer’s disease (AD) is the major cause of death in adults with Down syndrome (DS). There is an urgent need for objective markers of AD in the DS population to improve early diagnosis and monitor disease progression. NPTX2 has recently emerged as a promising cerebrospinal flu...
| Main Authors: | , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2020-08-01
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| Series: | Molecular Neurodegeneration |
| Subjects: | |
| Online Access: | http://link.springer.com/article/10.1186/s13024-020-00398-0 |
| _version_ | 1818870018450915328 |
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| author | Olivia Belbin Mei-Fang Xiao Desheng Xu Maria Carmona-Iragui Jordi Pegueroles Bessy Benejam Laura Videla Susana Fernández Isabel Barroeta Raúl Nuñez-Llaves Victor Montal Eduard Vilaplana Miren Altuna Jordi Clarimón Daniel Alcolea Rafael Blesa Alberto Lleó Paul F. Worley Juan Fortea |
| author_facet | Olivia Belbin Mei-Fang Xiao Desheng Xu Maria Carmona-Iragui Jordi Pegueroles Bessy Benejam Laura Videla Susana Fernández Isabel Barroeta Raúl Nuñez-Llaves Victor Montal Eduard Vilaplana Miren Altuna Jordi Clarimón Daniel Alcolea Rafael Blesa Alberto Lleó Paul F. Worley Juan Fortea |
| author_sort | Olivia Belbin |
| collection | DOAJ |
| description | Abstract Background Alzheimer’s disease (AD) is the major cause of death in adults with Down syndrome (DS). There is an urgent need for objective markers of AD in the DS population to improve early diagnosis and monitor disease progression. NPTX2 has recently emerged as a promising cerebrospinal fluid (CSF) biomarker of Alzheimer-related inhibitory circuit dysfunction in sporadic AD patients. The objective of this study was to evaluate NPTX2 in the CSF of adults with DS and to explore the relationship of NPTX2 to CSF levels of the PV interneuron receptor, GluA4, and existing AD biomarkers (CSF and neuroimaging). Methods This is a cross-sectional, retrospective study of adults with DS with asymptomatic AD (aDS, n = 49), prodromal AD (pDS, n = 18) and AD dementia (dDS, n = 27). Non-trisomic controls (n = 34) and patients with sporadic AD dementia (sAD, n = 40) were included for comparison. We compared group differences in CSF NPTX2 according to clinical diagnosis and degree of intellectual disability. We determined the relationship of CSF NPTX2 levels to age, cognitive performance (CAMCOG, free and cued selective reminding, semantic verbal fluency), CSF levels of a PV-interneuron marker (GluA4) and core AD biomarkers; CSF Aβ1–42, CSF t-tau, cortical atrophy (magnetic resonance imaging) and glucose metabolism ([18F]-fluorodeoxyglucose positron emission tomography). Results Compared to controls, mean CSF NPTX2 levels were lower in DS at all AD stages; aDS (0.6-fold, adj.p < 0.0001), pDS (0.5-fold, adj.p < 0.0001) and dDS (0.3-fold, adj.p < 0.0001). This reduction was similar to that observed in sporadic AD (0.5-fold, adj.p < 0.0001). CSF NPTX2 levels were not associated with age (p = 0.6), intellectual disability (p = 0.7) or cognitive performance (all p > 0.07). Low CSF NPTX2 levels were associated with low GluA4 in all clinical groups; controls (r 2 = 0.2, p = 0.003), adults with DS (r 2 = 0.4, p < 0.0001) and sporadic AD (r 2 = 0.4, p < 0.0001). In adults with DS, low CSF NPTX2 levels were associated with low CSF Aβ1–42 (r 2 > 0.3, p < 0.006), low CSF t-tau (r 2 > 0.3, p < 0.001), increased cortical atrophy (p < 0.05) and reduced glucose metabolism (p < 0.05). Conclusions Low levels of CSF NPTX2, a protein implicated in inhibitory circuit function, is common to sporadic and genetic forms of AD. CSF NPTX2 represents a promising CSF surrogate marker of early AD-related changes in adults with DS. |
| first_indexed | 2024-12-19T12:00:21Z |
| format | Article |
| id | doaj.art-0c1c43d3ccb644e492a07268b4f71135 |
| institution | Directory Open Access Journal |
| issn | 1750-1326 |
| language | English |
| last_indexed | 2024-12-19T12:00:21Z |
| publishDate | 2020-08-01 |
| publisher | BMC |
| record_format | Article |
| series | Molecular Neurodegeneration |
| spelling | doaj.art-0c1c43d3ccb644e492a07268b4f711352022-12-21T20:22:29ZengBMCMolecular Neurodegeneration1750-13262020-08-0115111010.1186/s13024-020-00398-0Cerebrospinal fluid profile of NPTX2 supports role of Alzheimer’s disease-related inhibitory circuit dysfunction in adults with Down syndromeOlivia Belbin0Mei-Fang Xiao1Desheng Xu2Maria Carmona-Iragui3Jordi Pegueroles4Bessy Benejam5Laura Videla6Susana Fernández7Isabel Barroeta8Raúl Nuñez-Llaves9Victor Montal10Eduard Vilaplana11Miren Altuna12Jordi Clarimón13Daniel Alcolea14Rafael Blesa15Alberto Lleó16Paul F. Worley17Juan Fortea18Memory Unit and Biomedical Research Institute Sant Pau (IIB Sant Pau), Neurology Department, Hospital de la Santa Creu i Sant PauSolomon H. Snyder Department of Neuroscience, Johns Hopkins University School of MedicineSolomon H. Snyder Department of Neuroscience, Johns Hopkins University School of MedicineMemory Unit and Biomedical Research Institute Sant Pau (IIB Sant Pau), Neurology Department, Hospital de la Santa Creu i Sant PauMemory Unit and Biomedical Research Institute Sant Pau (IIB Sant Pau), Neurology Department, Hospital de la Santa Creu i Sant PauMemory Unit and Biomedical Research Institute Sant Pau (IIB Sant Pau), Neurology Department, Hospital de la Santa Creu i Sant PauMemory Unit and Biomedical Research Institute Sant Pau (IIB Sant Pau), Neurology Department, Hospital de la Santa Creu i Sant PauBarcelona Down Medical Center, Fundació Catalana Síndrome de DownMemory Unit and Biomedical Research Institute Sant Pau (IIB Sant Pau), Neurology Department, Hospital de la Santa Creu i Sant PauMemory Unit and Biomedical Research Institute Sant Pau (IIB Sant Pau), Neurology Department, Hospital de la Santa Creu i Sant PauMemory Unit and Biomedical Research Institute Sant Pau (IIB Sant Pau), Neurology Department, Hospital de la Santa Creu i Sant PauMemory Unit and Biomedical Research Institute Sant Pau (IIB Sant Pau), Neurology Department, Hospital de la Santa Creu i Sant PauMemory Unit and Biomedical Research Institute Sant Pau (IIB Sant Pau), Neurology Department, Hospital de la Santa Creu i Sant PauMemory Unit and Biomedical Research Institute Sant Pau (IIB Sant Pau), Neurology Department, Hospital de la Santa Creu i Sant PauMemory Unit and Biomedical Research Institute Sant Pau (IIB Sant Pau), Neurology Department, Hospital de la Santa Creu i Sant PauMemory Unit and Biomedical Research Institute Sant Pau (IIB Sant Pau), Neurology Department, Hospital de la Santa Creu i Sant PauMemory Unit and Biomedical Research Institute Sant Pau (IIB Sant Pau), Neurology Department, Hospital de la Santa Creu i Sant PauSolomon H. Snyder Department of Neuroscience, Johns Hopkins University School of MedicineMemory Unit and Biomedical Research Institute Sant Pau (IIB Sant Pau), Neurology Department, Hospital de la Santa Creu i Sant PauAbstract Background Alzheimer’s disease (AD) is the major cause of death in adults with Down syndrome (DS). There is an urgent need for objective markers of AD in the DS population to improve early diagnosis and monitor disease progression. NPTX2 has recently emerged as a promising cerebrospinal fluid (CSF) biomarker of Alzheimer-related inhibitory circuit dysfunction in sporadic AD patients. The objective of this study was to evaluate NPTX2 in the CSF of adults with DS and to explore the relationship of NPTX2 to CSF levels of the PV interneuron receptor, GluA4, and existing AD biomarkers (CSF and neuroimaging). Methods This is a cross-sectional, retrospective study of adults with DS with asymptomatic AD (aDS, n = 49), prodromal AD (pDS, n = 18) and AD dementia (dDS, n = 27). Non-trisomic controls (n = 34) and patients with sporadic AD dementia (sAD, n = 40) were included for comparison. We compared group differences in CSF NPTX2 according to clinical diagnosis and degree of intellectual disability. We determined the relationship of CSF NPTX2 levels to age, cognitive performance (CAMCOG, free and cued selective reminding, semantic verbal fluency), CSF levels of a PV-interneuron marker (GluA4) and core AD biomarkers; CSF Aβ1–42, CSF t-tau, cortical atrophy (magnetic resonance imaging) and glucose metabolism ([18F]-fluorodeoxyglucose positron emission tomography). Results Compared to controls, mean CSF NPTX2 levels were lower in DS at all AD stages; aDS (0.6-fold, adj.p < 0.0001), pDS (0.5-fold, adj.p < 0.0001) and dDS (0.3-fold, adj.p < 0.0001). This reduction was similar to that observed in sporadic AD (0.5-fold, adj.p < 0.0001). CSF NPTX2 levels were not associated with age (p = 0.6), intellectual disability (p = 0.7) or cognitive performance (all p > 0.07). Low CSF NPTX2 levels were associated with low GluA4 in all clinical groups; controls (r 2 = 0.2, p = 0.003), adults with DS (r 2 = 0.4, p < 0.0001) and sporadic AD (r 2 = 0.4, p < 0.0001). In adults with DS, low CSF NPTX2 levels were associated with low CSF Aβ1–42 (r 2 > 0.3, p < 0.006), low CSF t-tau (r 2 > 0.3, p < 0.001), increased cortical atrophy (p < 0.05) and reduced glucose metabolism (p < 0.05). Conclusions Low levels of CSF NPTX2, a protein implicated in inhibitory circuit function, is common to sporadic and genetic forms of AD. CSF NPTX2 represents a promising CSF surrogate marker of early AD-related changes in adults with DS.http://link.springer.com/article/10.1186/s13024-020-00398-0Neuronal Pentraxin-2Alzheimer’s diseaseDown syndromeInhibitory circuitsCerebrospinal fluidBiomarker |
| spellingShingle | Olivia Belbin Mei-Fang Xiao Desheng Xu Maria Carmona-Iragui Jordi Pegueroles Bessy Benejam Laura Videla Susana Fernández Isabel Barroeta Raúl Nuñez-Llaves Victor Montal Eduard Vilaplana Miren Altuna Jordi Clarimón Daniel Alcolea Rafael Blesa Alberto Lleó Paul F. Worley Juan Fortea Cerebrospinal fluid profile of NPTX2 supports role of Alzheimer’s disease-related inhibitory circuit dysfunction in adults with Down syndrome Molecular Neurodegeneration Neuronal Pentraxin-2 Alzheimer’s disease Down syndrome Inhibitory circuits Cerebrospinal fluid Biomarker |
| title | Cerebrospinal fluid profile of NPTX2 supports role of Alzheimer’s disease-related inhibitory circuit dysfunction in adults with Down syndrome |
| title_full | Cerebrospinal fluid profile of NPTX2 supports role of Alzheimer’s disease-related inhibitory circuit dysfunction in adults with Down syndrome |
| title_fullStr | Cerebrospinal fluid profile of NPTX2 supports role of Alzheimer’s disease-related inhibitory circuit dysfunction in adults with Down syndrome |
| title_full_unstemmed | Cerebrospinal fluid profile of NPTX2 supports role of Alzheimer’s disease-related inhibitory circuit dysfunction in adults with Down syndrome |
| title_short | Cerebrospinal fluid profile of NPTX2 supports role of Alzheimer’s disease-related inhibitory circuit dysfunction in adults with Down syndrome |
| title_sort | cerebrospinal fluid profile of nptx2 supports role of alzheimer s disease related inhibitory circuit dysfunction in adults with down syndrome |
| topic | Neuronal Pentraxin-2 Alzheimer’s disease Down syndrome Inhibitory circuits Cerebrospinal fluid Biomarker |
| url | http://link.springer.com/article/10.1186/s13024-020-00398-0 |
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