Alpha-synuclein measured in cerebrospinal fluid from patients with Alzheimer’s disease, mild cognitive impairment, or healthy controls: a two year follow-up study

Abstract

Backgroundα-Synuclein has been proposed as a potential biomarker for Alzheimer’s disease (AD) and amnestic mild cognitive impairment (aMCI). However, results from α-synuclein measurements in cerebrospinal fluid (CSF) have been inconclusive, and to our knowledge, longitudinal studies of changes prior to the AD diagnosis have not been investigated.MethodsLevels of α-synuclein at baseline and after one and two years were measured in CSF, by enzyme-linked immunosorbent assay. Twenty-six patients with early AD (AD-AD), 48 patients with aMCI, subdivided as 23 that developed AD during follow-up (MCI-AD), and 25 that did not (MCI-MCI), and 25 healthy control individuals, were included. One-way ANOVA was applied to compare mean α-synuclein baseline values between all four study groups, and a linear mixed model was used to compare mean change over time between the three patient groups. Linear associations between α-synuclein and amyloid-β 1–42 (Aβ42), amyloid-β 1–40 (Aβ40), total tau and phosphorylated tau were also examined.ResultsA large variation in individual α-synuclein CSF levels was observed, particularly in the MCI-AD group. No significant differences were found in mean α-synuclein levels between all the study groups at baseline. When using a linear mixed model, no significant differences were found at follow-up for estimated mean changes between the patient groups. MCI-AD patients with short duration of symptoms prior to inclusion in the study (≤2 years) had considerably higher mean CSF α-synuclein levels compared to patients with a longer symptom duration (802.2 vs. 442.8 pg/mL, p = 0.01). No such difference was seen in the MCI-MCI or AD-AD groups. Significant linear associations (p < 0.0005) between α-synuclein and Aβ40, total tau and phosphorylated tau were found.ConclusionThe observed difference in mean CSF α-synuclein level according to duration of symptoms in the MCI-AD group, may be an indication of changes related to disease progression. However, the lack of significant differences between groups, as well as the large individual variation in CSF levels of α-synuclein in the present study, suggest that α-synuclein is not a useful biomarker for AD.Electronic supplementary materialThe online version of this article (doi:10.1186/s12883-016-0706-0) contains supplementary material, which is available to authorized users.

A Longitudinal Study of Total and Phosphorylated α-Synuclein with Other Biomarkers in Cerebrospinal Fluid of Alzheimer’s Disease and Mild Cognitive Impairment

“…Patients with AD or MCI show increased CSF levels of α-syn[12, 17, 18], perhaps due to release from damaged neurons[40, 41], as has been hypothesized for the increased levels of CSF tau in AD. Fewer studies have examined α-syn across the transition from MCI to AD dementia; however, in one longitudinal study, CSF α-syn was higher in MCI subjects with a shorter duration of symptoms, but did not differ across diagnostic groups[42]. Here, we also find a significant difference in CSF α-syn levels between CN, AD and MCI.…”

Correlation of Plasma EGF with Striatal Dopamine Transporter Availability in Healthy Subjects

“…Especially in PD, α-synuclein interacts with tubulin, parkin, dopamine receptor, synphilin-1, phospholipase, and small ubiquitin related modifiers 20 . Previous studies showed that α-synuclein was not different between Apo e4 carriers and Apo e4 non-carriers in normal subjects, MCI, and AD, consistent with this study 22 , 23 . However, molecular linkage between Apo E and α-synuclein was demonstrated in one study using A30P and A53T transgenic mice.…”

Measurement of CSF α‐synuclein improves early differential diagnosis of mild cognitive impairment due to Alzheimer’s disease

“…The controversial results published in previous reports regarding the potential of CSF α‐syn as a diagnostic biomarker for AD and/or LBD (Spies et al ; Reesink et al ; Kapaki et al ; Berge et al ; Oeckl et al ) may be because of various factors like sample size, uncertain diagnosis and/ or uncontrolled follow‐up of patients or controls, patients enrolled at different stages of the disease, differences between the age of the groups, no control for blood contamination, and others. Analytical and methodological differences can also contribute to the mentioned discrepancies between reports, particularly derived from handling of the samples and lack of validated CSF α‐syn kits.…”

“…Cerebrospinal fluid (CSF) α‐syn levels have been studied in MCI and dementia disorders, but there is no consensus as to whether α‐syn is consistently affected (Spies et al ; Reesink et al ; Kapaki et al ; Toledo et al ; Korff et al ; Slaets et al ; Mackin et al ; Hansson et al ; Majbour et al ; Llorens et al ; Berge et al ; Oeckl et al ; Chiasserini et al ; Shi et al ; Wang et al ). Most published results indicated that CSF α‐syn, in combination with the ‘central core’ CSF biomarkers of AD, have clinical value in the differential diagnosis of AD and LBD at the stage of dementia (Slaets et al ; Shi et al ); and can be useful in diagnosing MCI due to AD (Korff et al ; Mackin et al ).…”

“…Most published results indicated that CSF α‐syn, in combination with the ‘central core’ CSF biomarkers of AD, have clinical value in the differential diagnosis of AD and LBD at the stage of dementia (Slaets et al ; Shi et al ); and can be useful in diagnosing MCI due to AD (Korff et al ; Mackin et al ). Finally, a few authors have not found a role of CSF α‐syn as a useful biomarker for AD or MCI (Berge et al ).…”