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The relevance of cerebrospinal fluid α-synuclein levels to sporadic and familial Alzheimer’s disease
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 pa...
Autores principales: | , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6260771/ https://www.ncbi.nlm.nih.gov/pubmed/30477568 http://dx.doi.org/10.1186/s40478-018-0624-z |
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author | Twohig, Daniel Rodriguez-Vieitez, Elena Sando, Sigrid B. Berge, Guro Lauridsen, Camilla Møller, Ina Grøntvedt, Gøril R. Bråthen, Geir Patra, Kalicharan Bu, Guojun Benzinger, Tammie L. S. Karch, Celeste M. Fagan, Anne Morris, John C. Bateman, Randall J. Nordberg, Agneta White, Linda R. Nielsen, Henrietta M. |
author_facet | Twohig, Daniel Rodriguez-Vieitez, Elena Sando, Sigrid B. Berge, Guro Lauridsen, Camilla Møller, Ina Grøntvedt, Gøril R. Bråthen, Geir Patra, Kalicharan Bu, Guojun Benzinger, Tammie L. S. Karch, Celeste M. Fagan, Anne Morris, John C. Bateman, Randall J. Nordberg, Agneta White, Linda R. Nielsen, Henrietta M. |
author_sort | Twohig, Daniel |
collection | PubMed |
description | 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 (11)C-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-β(1–40). 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. |
format | Online Article Text |
id | pubmed-6260771 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-62607712018-12-10 The relevance of cerebrospinal fluid α-synuclein levels to sporadic and familial Alzheimer’s disease Twohig, Daniel Rodriguez-Vieitez, Elena Sando, Sigrid B. Berge, Guro Lauridsen, Camilla Møller, Ina Grøntvedt, Gøril R. Bråthen, Geir Patra, Kalicharan Bu, Guojun Benzinger, Tammie L. S. Karch, Celeste M. Fagan, Anne Morris, John C. Bateman, Randall J. Nordberg, Agneta White, Linda R. Nielsen, Henrietta M. Acta Neuropathol Commun Research 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 (11)C-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-β(1–40). 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. BioMed Central 2018-11-26 /pmc/articles/PMC6260771/ /pubmed/30477568 http://dx.doi.org/10.1186/s40478-018-0624-z Text en © The Author(s). 2018 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. |
spellingShingle | Research Twohig, Daniel Rodriguez-Vieitez, Elena Sando, Sigrid B. Berge, Guro Lauridsen, Camilla Møller, Ina Grøntvedt, Gøril R. Bråthen, Geir Patra, Kalicharan Bu, Guojun Benzinger, Tammie L. S. Karch, Celeste M. Fagan, Anne Morris, John C. Bateman, Randall J. Nordberg, Agneta White, Linda R. Nielsen, Henrietta M. The relevance of cerebrospinal fluid α-synuclein levels to sporadic and familial Alzheimer’s disease |
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 | Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6260771/ https://www.ncbi.nlm.nih.gov/pubmed/30477568 http://dx.doi.org/10.1186/s40478-018-0624-z |
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