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

Abstract

Alzheimer’s disease (AD) features a dynamic sequence of amyloid deposition, neurodegeneration, and cognitive impairment. A significant fraction of AD brains also displays Lewy body pathology, suggesting that addition of classically Parkinson’s disease-related proteins to the AD biomarker panel may be of value. To determine whether addition of cerebrospinal fluid (CSF) total α-synuclein and its form phosphorylated at S129 (pS129) to the AD biomarker panel [Amyloid-β1-42 (Aβ42), tau, and phosphorylated tau (p-tau181)] improves its performance, we examined CSF samples collected longitudinally up to 7 years as part of the Alzheimer’s Disease Neuroimaging Initiative. From 87 AD, 177 mild cognitive impairment (MCI), and 104 age-matched healthy controls, 792 baseline and longitudinal CSF samples were tested for total α-synuclein, pS129, Aβ42, tau, and p-tau181. pS129, but not total α-synuclein, was weakly associated with diagnosis at baseline when t-tau/Aβ42 was included in the statistical model (β=0.0026, p=0.041, 95% CI [(0.0001)–(0.005)]). CSF α-synuclein predicted Alzheimer’s Disease Assessment Scale-Cognitive (β=−0.59, p=0.0015, 95% CI [(−0.96)–(−0.23)]), memory (β=0.4, p=0.00025, 95% CI [(0.16)–(0.59)]) and executive (0.62, <0.0001, 95% CI [(0.31)–(0.93)]) function composite scores, and progression from MCI to AD (β=0.019, p=0.0011, 95% CI [(0.002)–(0.20)]). pS129 was associated with executive function (β=−2.55, p=0.0085, 95% CI [(−4.45)–(−0.66)]). Lower values in the mismatch between α-synuclein and p-tau181 predicted faster cognitive decline (β=0.64, p=0.0012, 95% CI [(0.48)–(0.84)]). Longitudinal biomarker changes did not differ between groups, and may not reflect AD progression. The α-synuclein-p-tau181-Mismatch could better predict longitudinal cognitive changes than classical AD markers alone, and its pathological correlates should be investigated further.

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

“…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 ).…”

Cerebrospinal fluid levels of synaptic and neuronal integrity correlate with gray matter volume and amyloid load in the precuneus of cognitively intact older adults

“…; Wang et al . ). This study revealed the latent structure within a set of CSF biomarkers involved in pathophysiological processes of AD by means of a factor analysis, a statistical method that assesses the underlying structure in a dataset based on its variance.…”

“…Others have recently suggested that the longitudinal progression of α‐synuclein levels in CSF remains unchanged over the different clinical stage of AD (Wang et al . ). In addition, one should not exclude the importance of comorbidities of pathology, which are reflected in biomarker levels.…”

“…integrity, and amylodoigenic processing using standard statistical correlational methods (Barao et al 2013;Luo et al 2013;De Vos et al 2016;Wang et al 2018). This study revealed the latent structure within a set of CSF biomarkers involved in pathophysiological processes of AD by means of a factor analysis, a statistical method that assesses the underlying structure in a dataset based on its variance.…”

“…Furthermore, certain biomarkers such as VILIP-1 or YKL-40 might have different rates of change depending on the disease stage and disease progression (Kester et al 2015b). Others have recently suggested that the longitudinal progression of a-synuclein levels in CSF remains unchanged over the different clinical stage of AD (Wang et al 2018). In addition, one should not exclude the importance of comorbidities of pathology, which are reflected in biomarker levels.…”