Cerebrospinal α-synuclein in α-synuclein Aggregation Disorders: Tau/α-synuclein Ratio As Potential Biomarker for Dementia with Lewy Bodies

Overview

Journal J Neurol

Specialty Neurology

Date 2016 Aug 22

PMID 27544498

Citations 19

Authors

Franc Llorens

Matthias Schmitz

Daniela Varges

Niels Kruse

Nadine Gotzmann

Karin Gmitterova

Brit Mollenhauer

Inga Zerr

Affiliations

Soon will be listed here.

Abstract

Several studies have addressed the utility of cerebrospinal (CSF) α-synuclein levels as a potential biomarker of α-synuclein aggregation disorders. However, its relevance in the differential diagnostic context of neurodegenerative and movement disorders is still a contentious subject. Here, we report total CSF α-synuclein levels in a cohort of clinically diagnosed α-synuclein-related disorders encompassing Parkinson's disease, Parkinson's disease dementia, dementia with Lewy bodies and multiple system atrophy in comparison to essential tremor and neurological control cases. α-synuclein levels in α-synuclein-related disorders were significantly lower than in controls (p < 0.001). However, in the differential diagnostic context, only Parkinson's disease cases presented significant lower α-synuclein levels compared to essential tremor and neurological controls. In cases with clinically diagnosed α-synuclein pathology, CSF α-synuclein levels showed a moderate positive correlation with CSF tau and p-tau, but not with Aβ42 levels. Due to elevated CSF tau levels in dementia with Lewy bodies samples, tau/α-synuclein ratio showed a good clinical accuracy in discriminating controls from dementia with Lewy bodies cases (AUC = 0.8776) compared to single α-synuclein (AUC = 0.7192) and tau (AUC = 0.7739) levels. In conclusion, α-synuclein alone lacks of clinical value as a biomarker of α-synuclein-related disorders, but in combination with total tau, it may improve the diagnosis of dementia with Lewy bodies.

Citing Articles

Cerebrospinal Fluid Total, Phosphorylated and Oligomeric A-Synuclein in Parkinson's Disease: A Systematic Review, Meta-Analysis and Meta-Regression Study.

Kapsali I, Brinia M, Constantinides V Biomedicines. 2024; 12(10).

PMID: 39457579 PMC: 11504870. DOI: 10.3390/biomedicines12102266.

The Role of α-Synuclein in Etiology of Neurodegenerative Diseases.

Krawczuk D, Groblewska M, Mroczko J, Winkel I, Mroczko B Int J Mol Sci. 2024; 25(17).

PMID: 39273146 PMC: 11395629. DOI: 10.3390/ijms25179197.

Dementia with Lewy bodies - a clinicopathological update.

Bencze J, Seo W, Hye A, Aarsland D, Hortobagyi T Free Neuropathol. 2023; 1.

PMID: 37283665 PMC: 10209855. DOI: 10.17879/freeneuropathology-2020-2613.

Signatures of glial activity can be detected in the CSF proteome.

Eninger T, Muller S, Bacioglu M, Schweighauser M, Lambert M, Maia L Proc Natl Acad Sci U S A. 2022; 119(24):e2119804119.

PMID: 35666874 PMC: 9214531. DOI: 10.1073/pnas.2119804119.

Baseline Cerebrospinal Fluid α-Synuclein in Parkinson's Disease Is Associated with Disease Progression and Cognitive Decline.

Emdina A, Hermann P, Varges D, Nuhn S, Goebel S, Bunck T Diagnostics (Basel). 2022; 12(5).

PMID: 35626415 PMC: 9140902. DOI: 10.3390/diagnostics12051259.

References

Galvin J, Lee V, Trojanowski J . Synucleinopathies: clinical and pathological implications. Arch Neurol. 2001; 58(2):186-90. DOI: 10.1001/archneur.58.2.186. View

Hughes A, Daniel S, Kilford L, Lees A . Accuracy of clinical diagnosis of idiopathic Parkinson's disease: a clinico-pathological study of 100 cases. J Neurol Neurosurg Psychiatry. 1992; 55(3):181-4. PMC: 1014720. DOI: 10.1136/jnnp.55.3.181. View

Hall S, Ohrfelt A, Constantinescu R, Andreasson U, Surova Y, Bostrom F . Accuracy of a panel of 5 cerebrospinal fluid biomarkers in the differential diagnosis of patients with dementia and/or parkinsonian disorders. Arch Neurol. 2012; 69(11):1445-52. DOI: 10.1001/archneurol.2012.1654. View

Lim X, Yeo J, Green A, Pal S . The diagnostic utility of cerebrospinal fluid alpha-synuclein analysis in dementia with Lewy bodies - a systematic review and meta-analysis. Parkinsonism Relat Disord. 2013; 19(10):851-8. DOI: 10.1016/j.parkreldis.2013.06.008. View

Pahwa R, Koller W . Is there a relationship between Parkinson's disease and essential tremor?. Clin Neuropharmacol. 1993; 16(1):30-5. DOI: 10.1097/00002826-199302000-00003. View

Jimenez-Jimenez F, Alonso-Navarro H, Garcia-Martin E, Agundez J . The relationship between Parkinson's disease and essential tremor: review of clinical, epidemiologic, genetic, neuroimaging and neuropathological data, and data on the presence of cardinal signs of parkinsonism in essential tremor. Tremor Other Hyperkinet Mov (N Y). 2013; 2. PMC: 3572635. DOI: 10.7916/D8FN14Z6. View

Llorens F, Schmitz M, Karch A, Cramm M, Lange P, Gherib K . Comparative analysis of cerebrospinal fluid biomarkers in the differential diagnosis of neurodegenerative dementia. Alzheimers Dement. 2016; 12(5):577-89. DOI: 10.1016/j.jalz.2015.10.009. View

Gilman S, Wenning G, Low P, Brooks D, Mathias C, Trojanowski J . Second consensus statement on the diagnosis of multiple system atrophy. Neurology. 2008; 71(9):670-6. PMC: 2676993. DOI: 10.1212/01.wnl.0000324625.00404.15. View

Spies P, Melis R, Sjogren M, Olde Rikkert M, Verbeek M . Cerebrospinal fluid alpha-synuclein does not discriminate between dementia disorders. J Alzheimers Dis. 2009; 16(2):363-9. DOI: 10.3233/JAD-2009-0955. View

10.

Halliday G, Leverenz J, Schneider J, Adler C . The neurobiological basis of cognitive impairment in Parkinson's disease. Mov Disord. 2014; 29(5):634-50. PMC: 4049032. DOI: 10.1002/mds.25857. View

11.

McKeith I . Consensus guidelines for the clinical and pathologic diagnosis of dementia with Lewy bodies (DLB): report of the Consortium on DLB International Workshop. J Alzheimers Dis. 2006; 9(3 Suppl):417-23. DOI: 10.3233/jad-2006-9s347. View

12.

Sako W, Murakami N, Izumi Y, Kaji R . Reduced alpha-synuclein in cerebrospinal fluid in synucleinopathies: evidence from a meta-analysis. Mov Disord. 2014; 29(13):1599-605. DOI: 10.1002/mds.26036. View

13.

Mollenhauer B, Cullen V, Kahn I, Krastins B, Outeiro T, Pepivani I . Direct quantification of CSF alpha-synuclein by ELISA and first cross-sectional study in patients with neurodegeneration. Exp Neurol. 2008; 213(2):315-25. DOI: 10.1016/j.expneurol.2008.06.004. View

14.

Vann Jones S, OBrien J . The prevalence and incidence of dementia with Lewy bodies: a systematic review of population and clinical studies. Psychol Med. 2013; 44(4):673-83. DOI: 10.1017/S0033291713000494. View

15.

Emre M, Aarsland D, Brown R, Burn D, Duyckaerts C, Mizuno Y . Clinical diagnostic criteria for dementia associated with Parkinson's disease. Mov Disord. 2007; 22(12):1689-707. DOI: 10.1002/mds.21507. View

16.

Youden W . Index for rating diagnostic tests. Cancer. 1950; 3(1):32-5. DOI: 10.1002/1097-0142(1950)3:1<32::aid-cncr2820030106>3.0.co;2-3. View

17.

Schoonenboom N, Reesink F, Verwey N, Kester M, Teunissen C, van de Ven P . Cerebrospinal fluid markers for differential dementia diagnosis in a large memory clinic cohort. Neurology. 2011; 78(1):47-54. DOI: 10.1212/WNL.0b013e31823ed0f0. View

18.

Schade S, Mollenhauer B . Biomarkers in biological fluids for dementia with Lewy bodies. Alzheimers Res Ther. 2014; 6(5-8):72. PMC: 4255553. DOI: 10.1186/s13195-014-0072-3. View

19.

Gao L, Tang H, Nie K, Wang L, Zhao J, Gan R . Cerebrospinal fluid alpha-synuclein as a biomarker for Parkinson's disease diagnosis: a systematic review and meta-analysis. Int J Neurosci. 2014; 125(9):645-54. DOI: 10.3109/00207454.2014.961454. View

20.

Kaerst L, Kuhlmann A, Wedekind D, Stoeck K, Lange P, Zerr I . Using cerebrospinal fluid marker profiles in clinical diagnosis of dementia with Lewy bodies, Parkinson's disease, and Alzheimer's disease. J Alzheimers Dis. 2013; 38(1):63-73. DOI: 10.3233/JAD-130995. View