Search

Background and Objectives: Patients with Lewy body disease (LBD) often show a co-occurring Alzheimer disease (AD) pathology. CSF biomarkers allow the detection in vivo of AD-related pathologic hallmarks included in the amyloid-tau-neurodegeneration (AT(N)) classification system. Here, we aimed to investigate whether CSF biomarkers of synaptic and neuroaxonal damage are correlated with the presence of AD copathology in LBD and can be useful to differentiate patients with LBD with different AT(N) profiles., Methods: We retrospectively measured CSF levels of AD core biomarkers (Aβ42/40 ratio, phosphorylated tau protein, and total tau protein) and of synaptic (β-synuclein, α-synuclein, synaptosomal-associated protein 25 [SNAP-25], and neurogranin) and neuroaxonal proteins (neurofilament light chain [NfL]) in 28 cognitively unimpaired participants with nondegenerative neurologic 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 with both groups ( p < 0.001 for all comparisons). In LBD, we found increased levels of synaptic and neuroaxonal 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 2 groups (area under the curve 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 biomarker levels within the normal range. CSF α-synuclein was significantly decreased only in patients with LBD with T- profiles compared with 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 neuroaxonal biomarkers compared with LBD/A-T- and control subjects. Patients with LBD and AT(N)-based AD copathology showed, thus, a distinct signature of synaptic dysfunction from other LBD 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., (© 2023 American Academy of Neurology.)

Parkinson disease (PD) is the second most common neurodegenerative disease, and the most common synucleinopathy, as alpha-synuclein (α-syn), a prion-like protein, plays an important pathophysiologic role in its onset and progression. Although neuropathologic changes begin many years before the onset of motor manifestations, diagnosis still relies on the identification of the motor symptoms, which hinders to formulate an early diagnosis. Because α-syn misfolding and aggregation precede clinical manifestations, the possibility to identify these phenomena in patients with PD would allow us to recognize the disease at the earliest, premotor phases, as a consequence of the transition from a clinical to a molecular diagnosis. Seed amplification assays (SAAs) are a group of techniques that currently support the diagnosis of prion subacute encephalopathies, namely Creutzfeldt-Jakob disease. These techniques enable the detection of minimal amounts of prions in CSF and other matrices of affected patients. Recently, SAAs have been successfully applied to detect misfolded alpha-synuclein (α-syn) in CSF, olfactory mucosa, submandibular gland biopsies, skin, and saliva of patients with Parkinson disease (PD) and other synucleinopathies. In these categories, they can differentiate PD and dementia with Lewy bodies (DLBs) from control subjects, even in the prodromal stages of the disease. In differential diagnosis, SAAs satisfactorily differentiated PD, DLB, and multiple system atrophy (MSA) from nonsynucleinopathy parkinsonisms. The kinetic analysis of the SAA fluorescence profiles allowed the identification of synucleinopathy-dependent α-syn fibrils conformations, commonly referred to as strains, which have demonstrated diagnostic potential in differentiating among synucleinopathies, especially between Lewy body diseases (LBDs) (PD and DLB) and MSA. In front of these highly promising data, which make the α-syn seeding activity detected by SAAs as the most promising diagnostic biomarker for synucleinopathies, there are still preanalytical and analytical issues, mostly related to the assay standardization, which need to be solved. In this review, we discuss the key findings supporting the clinical application of α-syn SAAs to identify PD and other synucleinopathies, the unmet needs, and future perspectives., (© 2022 American Academy of Neurology.)