The relevance of cerebrospinal fluid α-synuclein levels to sporadic and familial Alzheimer’s disease
Abstract Accumulating evidence demonstrating higher cerebrospinal fluid (CSF) α-synuclein (αSyn) levels and αSyn pathology in the brains of Alzheimer’s disease (AD) patients suggests that αSyn is involved in the pathophysiology of AD. To investigate whether αSyn could be related to specific aspects...
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BMC
2018-11-01
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| Series: | Acta Neuropathologica Communications |
| Subjects: | |
| Online Access: | http://link.springer.com/article/10.1186/s40478-018-0624-z |
| _version_ | 1818926075245232128 |
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| author | Daniel Twohig Elena Rodriguez-Vieitez Sigrid B. Sando Guro Berge Camilla Lauridsen Ina Møller Gøril R. Grøntvedt Geir Bråthen Kalicharan Patra Guojun Bu Tammie L. S. Benzinger Celeste M. Karch Anne Fagan John C. Morris Randall J. Bateman Agneta Nordberg Linda R. White Henrietta M. Nielsen for the Dominantly Inherited Alzheimer Network (DIAN) |
| author_facet | Daniel Twohig Elena Rodriguez-Vieitez Sigrid B. Sando Guro Berge Camilla Lauridsen Ina Møller Gøril R. Grøntvedt Geir Bråthen Kalicharan Patra Guojun Bu Tammie L. S. Benzinger Celeste M. Karch Anne Fagan John C. Morris Randall J. Bateman Agneta Nordberg Linda R. White Henrietta M. Nielsen for the Dominantly Inherited Alzheimer Network (DIAN) |
| author_sort | Daniel Twohig |
| collection | DOAJ |
| description | Abstract Accumulating evidence demonstrating higher cerebrospinal fluid (CSF) α-synuclein (αSyn) levels and αSyn pathology in the brains of Alzheimer’s disease (AD) patients suggests that αSyn is involved in the pathophysiology of AD. To investigate whether αSyn could be related to specific aspects of the pathophysiology present in both sporadic and familial disease, we quantified CSF levels of αSyn and assessed links to various disease parameters in a longitudinally followed cohort (n = 136) including patients with sporadic mild cognitive impairment (MCI) and AD, and in a cross-sectional sample from the Dominantly Inherited Alzheimer’s Network (n = 142) including participants carrying autosomal dominant AD (ADAD) gene mutations and their non-mutation carrying family members. Our results show that sporadic MCI patients that developed AD over a period of two years exhibited higher baseline αSyn levels (p = 0.03), which inversely correlated to their Mini-Mental State Examination scores, compared to cognitively normal controls (p = 0.02). In the same patients, there was a dose-dependent positive association between CSF αSyn and the APOEε4 allele. Further, CSF αSyn levels were higher in symptomatic ADAD mutation carriers versus non-mutation carriers (p = 0.03), and positively correlated to the estimated years from symptom onset (p = 0.05) across all mutation carriers. In asymptomatic (Clinical Dementia Rating < 0.5) PET amyloid-positive ADAD mutation carriers CSF αSyn was positively correlated to 11C-Pittsburgh Compound-B (PiB) retention in several brain regions including the posterior cingulate, superior temporal and frontal cortical areas. Importantly, APOEε4-positive ADAD mutation carriers exhibited an association between CSF αSyn levels and mean cortical PiB retention (p = 0.032). In both the sporadic AD and ADAD cohorts we found several associations predominantly between CSF levels of αSyn, tau and amyloid-β1–40. Our results suggest that higher CSF αSyn levels are linked to AD pathophysiology at the early stages of disease development and to the onset of cognitive symptoms in both sporadic and autosomal dominant AD. We conclude that APOEε4 may promote the processes driven by αSyn, which in turn may reflect on molecular mechanisms linked to the asymptomatic build-up of amyloid plaque burden in brain regions involved in the early stages of AD development. |
| first_indexed | 2024-12-20T02:51:21Z |
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| institution | Directory Open Access Journal |
| issn | 2051-5960 |
| language | English |
| last_indexed | 2024-12-20T02:51:21Z |
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| series | Acta Neuropathologica Communications |
| spelling | doaj.art-78c6795fc8e748bc9fe1342825c85d622022-12-21T19:56:01ZengBMCActa Neuropathologica Communications2051-59602018-11-016111910.1186/s40478-018-0624-zThe relevance of cerebrospinal fluid α-synuclein levels to sporadic and familial Alzheimer’s diseaseDaniel Twohig0Elena Rodriguez-Vieitez1Sigrid B. Sando2Guro Berge3Camilla Lauridsen4Ina Møller5Gøril R. Grøntvedt6Geir Bråthen7Kalicharan Patra8Guojun Bu9Tammie L. S. Benzinger10Celeste M. Karch11Anne Fagan12John C. Morris13Randall J. Bateman14Agneta Nordberg15Linda R. White16Henrietta M. Nielsen17for the Dominantly Inherited Alzheimer Network (DIAN)Department of Biochemistry and Biophysics, Stockholm UniversityDepartment of Neurobiology, Care Sciences and Society, Karolinska InstitutetDepartment of Neurology, University Hospital of TrondheimDepartment of Neuroscience, Norwegian University of Science and TechnologyDepartment of Neuroscience, Norwegian University of Science and TechnologyDepartment of Neurology, University Hospital of TrondheimDepartment of Neurology, University Hospital of TrondheimDepartment of Neurology, University Hospital of TrondheimDepartment of Biochemistry and Biophysics, Stockholm UniversityDepartment of Neuroscience, Mayo Clinic College of MedicineDepartment of Radiology, Washington University School of MedicineDepartment of Psychiatry, Washington University School of MedicineDepartment of Neurology, Washington University School of MedicineDepartment of Neurology, Washington University School of MedicineDepartment of Neurology, Washington University School of MedicineDepartment of Neurobiology, Care Sciences and Society, Karolinska InstitutetDepartment of Neurology, University Hospital of TrondheimDepartment of Biochemistry and Biophysics, Stockholm UniversityAbstract Accumulating evidence demonstrating higher cerebrospinal fluid (CSF) α-synuclein (αSyn) levels and αSyn pathology in the brains of Alzheimer’s disease (AD) patients suggests that αSyn is involved in the pathophysiology of AD. To investigate whether αSyn could be related to specific aspects of the pathophysiology present in both sporadic and familial disease, we quantified CSF levels of αSyn and assessed links to various disease parameters in a longitudinally followed cohort (n = 136) including patients with sporadic mild cognitive impairment (MCI) and AD, and in a cross-sectional sample from the Dominantly Inherited Alzheimer’s Network (n = 142) including participants carrying autosomal dominant AD (ADAD) gene mutations and their non-mutation carrying family members. Our results show that sporadic MCI patients that developed AD over a period of two years exhibited higher baseline αSyn levels (p = 0.03), which inversely correlated to their Mini-Mental State Examination scores, compared to cognitively normal controls (p = 0.02). In the same patients, there was a dose-dependent positive association between CSF αSyn and the APOEε4 allele. Further, CSF αSyn levels were higher in symptomatic ADAD mutation carriers versus non-mutation carriers (p = 0.03), and positively correlated to the estimated years from symptom onset (p = 0.05) across all mutation carriers. In asymptomatic (Clinical Dementia Rating < 0.5) PET amyloid-positive ADAD mutation carriers CSF αSyn was positively correlated to 11C-Pittsburgh Compound-B (PiB) retention in several brain regions including the posterior cingulate, superior temporal and frontal cortical areas. Importantly, APOEε4-positive ADAD mutation carriers exhibited an association between CSF αSyn levels and mean cortical PiB retention (p = 0.032). In both the sporadic AD and ADAD cohorts we found several associations predominantly between CSF levels of αSyn, tau and amyloid-β1–40. Our results suggest that higher CSF αSyn levels are linked to AD pathophysiology at the early stages of disease development and to the onset of cognitive symptoms in both sporadic and autosomal dominant AD. We conclude that APOEε4 may promote the processes driven by αSyn, which in turn may reflect on molecular mechanisms linked to the asymptomatic build-up of amyloid plaque burden in brain regions involved in the early stages of AD development.http://link.springer.com/article/10.1186/s40478-018-0624-zAlzheimer’s diseaseMild cognitive impairmentalpha-synucleinBiomarkersAPOEε4 |
| spellingShingle | Daniel Twohig Elena Rodriguez-Vieitez Sigrid B. Sando Guro Berge Camilla Lauridsen Ina Møller Gøril R. Grøntvedt Geir Bråthen Kalicharan Patra Guojun Bu Tammie L. S. Benzinger Celeste M. Karch Anne Fagan John C. Morris Randall J. Bateman Agneta Nordberg Linda R. White Henrietta M. Nielsen for the Dominantly Inherited Alzheimer Network (DIAN) The relevance of cerebrospinal fluid α-synuclein levels to sporadic and familial Alzheimer’s disease Acta Neuropathologica Communications Alzheimer’s disease Mild cognitive impairment alpha-synuclein Biomarkers APOEε4 |
| title | The relevance of cerebrospinal fluid α-synuclein levels to sporadic and familial Alzheimer’s disease |
| title_full | The relevance of cerebrospinal fluid α-synuclein levels to sporadic and familial Alzheimer’s disease |
| title_fullStr | The relevance of cerebrospinal fluid α-synuclein levels to sporadic and familial Alzheimer’s disease |
| title_full_unstemmed | The relevance of cerebrospinal fluid α-synuclein levels to sporadic and familial Alzheimer’s disease |
| title_short | The relevance of cerebrospinal fluid α-synuclein levels to sporadic and familial Alzheimer’s disease |
| title_sort | relevance of cerebrospinal fluid α synuclein levels to sporadic and familial alzheimer s disease |
| topic | Alzheimer’s disease Mild cognitive impairment alpha-synuclein Biomarkers APOEε4 |
| url | http://link.springer.com/article/10.1186/s40478-018-0624-z |
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