Levels of cerebrospinal fluid α-synuclein oligomers are increased in Parkinson’s disease with dementia and dementia with Lewy bodies compared to Alzheimer’s disease

Hansson, Oskar; Hall, Sara; Öhrfelt, Annika; Zetterberg, Henrik; Blennow, Kaj; Minthon, Lennart; Nägga, Katarina; Londos, Elisabet; Varghese, Shiji; Majbour, Nour K.; Al-Hayani, Abdulmonem; El‐Agnaf, Omar M. A.

doi:10.1186/alzrt255

Cited by 186 publications

(180 citation statements)

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“…We could confirm previous observations of increased CSF ␣Syn concentrations in CJD (33)(34)(35)(36) and observed also a tendency to elevated concentrations in AD (37)(38)(39). ␣Syn has been suggested as a biomarker for the differential diagnosis of AD and CJD (33) which is supported by our data.…”

Section: Investigation Of Synuclein Origin and Hemolysis As Confoundingsupporting

confidence: 92%

Alpha-, Beta-, and Gamma-synuclein Quantification in Cerebrospinal Fluid by Multiple Reaction Monitoring Reveals Increased Concentrations in Alzheimer′s and Creutzfeldt-Jakob Disease but No Alteration in Synucleinopathies

Oeckl

Metzger

Nagl

et al. 2016

Molecular & Cellular Proteomics

104

144

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␣-Synuclein (␣Syn) is a major constituent of proteinaceous aggregates in neurodegenerative diseases such as Parkinsons disease (PD) and a potential biomarker candidate for diagnosis and treatment effects. However, studies about ␣Syn in cerebrospinal fluid (CSF) in diseases are inconsistent and mainly based on immunological assays. Quantitative information about ␤-synuclein (␤Syn) and ␥-synuclein (␥Syn) in CSF is not available.Here, we present an alternative method for the simultaneous quantification of ␣Syn, ␤Syn and ␥Syn in CSF by multiple reaction monitoring (MRM) with a high sequence coverage (70%) of ␣Syn to validate previous, ELISA-based results and characterize synucleins in CSF in more detail.The MRM has high sensitivity in the low pg/ml range (3-30pg/ml full-length ␣Syn) using 200 l CSF. A high portion of CSF ␣Syn is present in the N-terminally acetylated form and the concentration of unmodified peptides in the nonamyloid component region is about 40% lower than in the N-terminal region. Synuclein concentrations show a high correlation with each other in CSF (r>0.80) and in contrast to ␣Syn and ␥Syn, ␤Syn is not affected by blood contamination. CSF ␣Syn, ␤Syn and ␥Syn concentrations were increased in Alzheimers and CreutzfeldtJakob disease but not altered in PD, PD dementia (PDD), Lewy body dementia and atypical parkinsonian syndromes. The ratio ␤Syn/␣Syn was increased in PDD (1.49 ؎ 0.38, p < 0.05) compared with PD (1.11 ؎ 0.26) and controls (1.15 ؎ 0.28). ␤Syn shows a high correlation with CSF tau concentrations (r ‫؍‬ 0.86, p < 0.0001, n ‫؍‬ 125).In conclusion, we could not confirm previous observations of reduced ␣Syn in PD and our results indicate that CSF synuclein concentrations are rather general markers of synaptic degeneration than specific for synucleinopathies. ␤syn is an attractive biomarker candidate that might be used as an alternative to or in combination with tau in AD and CJD diagnosis and in combination with ␣Syn it is a biomarker candidate for PDD.

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Section: Investigation Of Synuclein Origin and Hemolysis As Confoundingsupporting

confidence: 92%

Alpha-, Beta-, and Gamma-synuclein Quantification in Cerebrospinal Fluid by Multiple Reaction Monitoring Reveals Increased Concentrations in Alzheimer′s and Creutzfeldt-Jakob Disease but No Alteration in Synucleinopathies

Oeckl

Metzger

Nagl

et al. 2016

Molecular & Cellular Proteomics

104

144

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“…The finding of increased CSF oligomeric-a-synuclein in PD and mostly PDD is in keeping with previous reports [8,14,36]. Lack of differences in the oligomeric-total ratio in contrast to two previous reports [8,18] might be due to lack of differences in CSF total-a-synuclein in our cohort.…”

Section: Discussionsupporting

confidence: 81%

“…Finally, our findings have to be taken with caution due to lack of adjust for CSF haemoglobin and technical differences with other studies. However, the CSF, clinical, neuropsychological and MRI associations in our cohort are plausible and partly in keeping with existing evidence [11,14,36,43].…”

Section: Discussionsupporting

confidence: 81%

Correlates of cerebrospinal fluid levels of oligomeric- and total-α-synuclein in premotor, motor and dementia stages of Parkinson’s disease

et al. 2014

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High-oligomeric and low-total-α-synuclein cerebrospinal fluid (CSF) levels have been found in Parkinson's disease (PD), but with inconsistent or limited data, particularly on their clinical and structural correlates in earliest (premotor) or latest (dementia) PD stages. We determined CSF oligomeric- and total-α-synuclein in 77 subjects: 23 with idiopathic REM-sleep behaviour disorder (iRBD, a condition likely to include a remarkable proportion of subjects in the premotor stage of PD) and 41 with PD [21 non-demented (PDND) + 20 demented (PDD)], intended to reflect the premotor-motor-dementia PD continuum, along with 13 healthy controls. The study protocol also included the Unified PD Rating Scale motor-section (UPDRS-III), mini mental state examination (MMSE), neuropsychological cognitive testing, 3T brain MRI for cortical-thickness analyses, CSF τ and CSF Aβ. CSF oligomeric-α-synuclein was higher in PDND than iRBD and in PDD than iRBD and controls, and correlated with UPDRS-III, MMSE, semantic fluency and visuo-perceptive scores across the proposed premotor-motor-dementia PD continuum (iRBD + PDND + PDD). CSF total-α-synuclein positively correlated with age, CSF Aβ, and, particularly, CSF τ, tending towards lower levels in PD (but not iRBD) vs. controls only when controlling for CSF τ. Low CSF total-α-synuclein was associated with dysfunction in phonetic-fluency (a frontal-lobe function) in PD and with frontal cortical thinning in iRBD and PDND independently of CSF τ. Conversely, the associations of high (instead of low) CSF total-α-synuclein with posterior-cortical neuropsychological deficits in PD and with posterior cortical thinning in PDD were driven by high CSF τ. These findings suggest that CSF oligomeric- and total-α-synuclein have different clinical, neuropsychological and MRI correlates across the proposed premotor-motor-dementia PD continuum. CSF total-α-synuclein correlations with CSF τ and Aβ support the hypothesis of an interaction among these proteins in PD, with CSF τ probably influencing the presence of high (instead of low) CSF total-α-synuclein and its correlates mostly in the setting of PD-related dementia.

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“…Furthermore, several studies have described elevated levels of oligomeric α-synuclein in cerebrospinal fluid (CSF) in PD patients compared to control subjects (Tokuda et al, 2006; Park et al, 2011; Aasly et al, 2014; Hansson et al, 2014; Parnetti et al, 2014). All of the CSF studies have adopted an ELISA based on the monoclonal α-synuclein antibody 211 as capture antibody and its biotinylated version as reporter antibody.…”

Section: Alpha-synuclein Oligomersmentioning

confidence: 99%

Alpha-Synuclein Oligomers—Neurotoxic Molecules in Parkinson's Disease and Other Lewy Body Disorders

2016

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Adverse intra- and extracellular effects of toxic α-synuclein are believed to be central to the pathogenesis in Parkinson's disease and other disorders with Lewy body pathology in the nervous system. One of the physiological roles of α-synuclein relates to the regulation of neurotransmitter release at the presynapse, although it is still unclear whether this mechanism depends on the action of monomers or smaller oligomers. As for the pathogenicity, accumulating evidence suggest that prefibrillar species, rather than the deposits per se, are responsible for the toxicity in affected cells. In particular, larger oligomers or protofibrils of α-synuclein have been shown to impair protein degradation as well as the function of several organelles, such as the mitochondria and the endoplasmic reticulum. Accumulating evidence further suggest that oligomers/protofibrils may have a toxic effect on the synapse, which may lead to disrupted electrophysiological properties. In addition, recent data indicate that oligomeric α-synuclein species can spread between cells, either as free-floating proteins or via extracellular vesicles, and thereby act as seeds to propagate disease between interconnected brain regions. Taken together, several lines of evidence suggest that α-synuclein have neurotoxic properties and therefore should be an appropriate molecular target for therapeutic intervention in Parkinson's disease and other disorders with Lewy pathology. In this context, immunotherapy with monoclonal antibodies against α-synuclein oligomers/protofibrils should be a particularly attractive treatment option.

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Levels of cerebrospinal fluid α-synuclein oligomers are increased in Parkinson’s disease with dementia and dementia with Lewy bodies compared to Alzheimer’s disease

Cited by 186 publications

References 40 publications

Alpha-, Beta-, and Gamma-synuclein Quantification in Cerebrospinal Fluid by Multiple Reaction Monitoring Reveals Increased Concentrations in Alzheimer′s and Creutzfeldt-Jakob Disease but No Alteration in Synucleinopathies

Alpha-, Beta-, and Gamma-synuclein Quantification in Cerebrospinal Fluid by Multiple Reaction Monitoring Reveals Increased Concentrations in Alzheimer′s and Creutzfeldt-Jakob Disease but No Alteration in Synucleinopathies

Correlates of cerebrospinal fluid levels of oligomeric- and total-α-synuclein in premotor, motor and dementia stages of Parkinson’s disease

Alpha-Synuclein Oligomers—Neurotoxic Molecules in Parkinson's Disease and Other Lewy Body Disorders

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