Cerebrospinal fluid β-synuclein as a synaptic biomarker for preclinical Alzheimer’s disease

Barba, Lorenzo; Abu‐Rumeileh, Samir; Bellomo, G.; Paoletti, Federico Paolini; Halbgebauer, Steffen; Oeckl, Patrick; Steinacker, Petra; Massa, Federico; Gaetani, Lorenzo; Parnetti, Lucilla; Otto, Markus

doi:10.1136/jnnp-2022-329124

Cited by 19 publications

(17 citation statements)

References 25 publications

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“…Our previous studies revealed a stage-independent association of CSF β-synuclein with AD because patients at the preclinical, MCI, and dementia stages showed similar elevated values. 11,15,17 CSF β-synuclein might be, thus, associated with the presence of AD pathology but not with clinical progression. Furthermore, the first results obtained in serum encourage investigations on β-synuclein as a peripheral biomarker of synaptic damage in AD and other neurodegenerative disorders, given the selective neuronal expression of the protein.…”

Section: Discussionmentioning

confidence: 96%

CSF Synaptic Biomarkers in AT(N)-Based Subgroups of Lewy Body Disease

et al. 2023

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Background and Objectives.Patients with Lewy body disease (LBD) often show a co-occurring Alzheimer’s disease (AD) pathology. Cerebrospinal fluid (CSF) biomarkers allow the detectionin vivoof AD-related pathological hallmarks included in the AT(N) classification system. Here, we aimed to investigate whether CSF biomarkers of synaptic and neuro-axonal damage are correlated with the presence of AD co-pathology in LBD and can be useful to differentiate LBD patients with different AT(N) profiles.Methods.We retrospectively measured CSF levels of AD core biomarkers (Aβ42/40 ratio, p-tau, t-tau) and of synaptic (β-synuclein, α-synuclein, SNAP-25, neurogranin) and neuro-axonal proteins (NfL) in 28 cognitively unimpaired participants with non-degenerative neurological conditions and 161 participants with a diagnosis of either LBD or AD (at both mild cognitive impairment, AD-MCI, and dementia stages, AD-dem). We compared CSF biomarker levels in clinical and AT(N)-based subgroups.Results.CSF β-synuclein, α-synuclein, SNAP-25, neurogranin and NfL levels did not differ between LBD (n = 101, age = 67.2 ± 7.8 years, 27.7% females) and controls (age = 64.8 ± 8.6 years, 39.3% females) and were increased in AD (AD-MCI n = 30, AD-dem n = 30, age = 72.3 ± 6.0 years, 63.3% females) compared to both groups (p < 0.001 for all comparisons). In LBD, we found increased levels of synaptic and neuro-axonal degeneration biomarkers in patients with A+T+ (LBD/A+T+) than with A-T- profiles (LBD/A-T-) (p < 0.01 for all), and β-synuclein showed the highest discriminative accuracy between the two groups (AUC = 0.938, 95%CI = 0.884 - 0.991). CSF β-synuclein (p = 0.0021), α-synuclein (p = 0.0099) and SNAP-25 concentrations (p = 0.013) were also higher in LBD/A+T+ than in LBD/A+T- cases, which had synaptic biomarkers levels within the normal range. CSF α-synuclein was significantly decreased only in LBD patients with T- profiles compared to controls (p = 0.0448). Moreover, LBD/A+T+ and AD cases did not differ in any biomarker level.Discussion.LBD/A+T+ and AD cases showed significantly increased CSF levels of synaptic and neuro-axonal biomarkers compared to LBD/A-T- and control subjects. LBD patients with AD co-pathology might, thus, experience similar degrees of synaptic dysfunction than pure AD cases.Classification of evidence.This study provides Class II evidence that CSF levels of β-synuclein, α-synuclein, SNAP-25, neurogranin and NfL are higher in patients with AD than in patients with LBD.

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Section: Discussionmentioning

confidence: 96%

CSF Synaptic Biomarkers in AT(N)-Based Subgroups of Lewy Body Disease

et al. 2023

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“…Since there is evidence about the increase of CSF α-syn levels with disease duration 24 , 33 , the relatively low levels of α-syn found both in PD-MCI and in PD-CN in our series might be also due to the short disease duration of the patients included. CSF α-syn increase has been documented in other neurodegenerative disorders unrelated to α-syn pathology, namely AD 38 , Creutzfeldt–Jakob disease 39 and progressive supranuclear palsy 40 . Taken together, these findings indicate that CSF α-syn levels unspecifically reflect the ongoing synaptic damage, as already previously proposed 22 , 41 , 42 .…”

Section: Discussionmentioning

confidence: 99%

CSF neurochemical profile and cognitive changes in Parkinson’s disease with mild cognitive impairment

Paoletti

Gaetani

Bellomo

et al. 2023

npj Parkinsons Dis.

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Pathophysiological substrate(s) and progression of Parkinson’s disease (PD) with mild cognitive impairment (PD-MCI) are still matter of debate. Baseline cerebrospinal fluid (CSF) neurochemical profile and cognitive changes after 2 years were investigated in a retrospective series of PD-MCI (n = 48), cognitively normal PD (PD-CN, n = 40), prodromal Alzheimer’s disease (MCI-AD, n = 25) and cognitively healthy individuals with other neurological diseases (OND, n = 44). CSF biomarkers reflecting amyloidosis (Aβ42/40 ratio, sAPPα, sAPPβ), tauopathy (p-tau), neurodegeneration (t-tau, NfL, p-NfH), synaptic damage (α-syn, neurogranin) and glial activation (sTREM2, YKL-40) were measured. The great majority (88%) of PD-MCI patients was A-/T-/N-. Among all biomarkers considered, only NfL/p-NfH ratio was significantly higher in PD-MCI vs. PD-CN (p = 0.02). After 2 years, one-third of PD-MCI patients worsened; such worsening was associated with higher baseline levels of NfL, p-tau, and sTREM2. PD-MCI is a heterogeneous entity requiring further investigations on larger, longitudinal cohorts with neuropathological verification.

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“…Contrary to α-synuclein, our knowledge about the role of β-synuclein and γ-synuclein in cellular functions and pathology is somewhat limited. Recent findings about β-synuclein point to its role as an important biomarker for the early stages of Alzheimer’s disease (AD) [ 19 ]. The concentration of β-synuclein gradually increases in the cerebrospinal fluid beginning from the preclinical AD phase.…”

Section: Three Members Of the Synuclein Familymentioning

confidence: 99%

“…It may be considered a promising biomarker of synaptic damage in this disease. β-Synuclein may be used as a CSF biomarker for synaptic damage in AD; its level is elevated in both dementia and pre-dementia stages of AD [ 19 , 20 ]. Importantly, higher CSF α-synuclein levels are reported in pre-AD subjects but not in MCI-AD and dementia AD [ 19 ], pointing to its specificity as a biomarker.…”

Section: Three Members Of the Synuclein Familymentioning

confidence: 99%

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Synucleins: New Data on Misfolding, Aggregation and Role in Diseases

Surguchov

Surguchev

2022

Biomedicines

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The synucleins are a family of natively unfolded (or intrinsically unstructured) proteins consisting of α-, β-, and γ-synuclein involved in neurodegenerative diseases and cancer. The current number of publications on synucleins has exceeded 16.000. They remain the subject of constant interest for over 35 years. Two reasons explain this unchanging attention: synuclein’s association with several severe human diseases and the lack of understanding of the functional roles under normal physiological conditions. We analyzed recent publications to look at the main trends and developments in synuclein research and discuss possible future directions. Traditional areas of peak research interest which still remain high among last year’s publications are comparative studies of structural features as well as functional research on of three members of the synuclein family. Another popular research topic in the area is a mechanism of α-synuclein accumulation, aggregation, and fibrillation. Exciting fast-growing area of recent research is α-synuclein and epigenetics. We do not present here a broad and comprehensive review of all directions of studies but summarize only the most significant recent findings relevant to these topics and outline potential future directions.

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Cerebrospinal fluid β-synuclein as a synaptic biomarker for preclinical Alzheimer’s disease

Cited by 19 publications

References 25 publications

CSF Synaptic Biomarkers in AT(N)-Based Subgroups of Lewy Body Disease

CSF Synaptic Biomarkers in AT(N)-Based Subgroups of Lewy Body Disease

CSF neurochemical profile and cognitive changes in Parkinson’s disease with mild cognitive impairment

Synucleins: New Data on Misfolding, Aggregation and Role in Diseases

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