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Abstract
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.
Glossary
- Aβ40=
- amyloid-β1–40;
- Aβ42=
- amyloid-β1–42;
- AD=
- Alzheimer disease;
- AD-dem=
- AD with dementia;
- AD-MCI=
- AD with mild cognitive impairment;
- AT(N)=
- amyloid-tau-neurodegeneration;
- AUC=
- area under the curve;
- Ctrl=
- control;
- CDR=
- Clinical Dementia Rating;
- DLB=
- dementia with Lewy bodies;
- HY=
- Hoehn and Yahr;
- LBD=
- Lewy body disease;
- MMSE=
- Mini-Mental State Examination;
- MoCA=
- Montreal Cognitive Assessment;
- NfL=
- neurofilament light chain protein;
- PD=
- Parkinson disease;
- PDD=
- Parkinson disease with dementia;
- PMCA=
- protein misfolding cyclic amplification;
- p-tau=
- phosphorylated tau protein;
- ROC=
- receiver operating characteristic;
- RT-QuIC=
- real-time quaking-induced conversion;
- SNAP-25=
- synaptosomal-associated protein 25;
- t-tau=
- total tau protein;
- UPDRS-III=
- Unified Parkinson's Disease Rating Scale—part III
Footnotes
Go to Neurology.org/N for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article.
Submitted and externally peer reviewed. The handling editor was Associate Editor Linda Hershey, MD, PhD, FAAN.
Class of Evidence: NPub.org/coe
- Received November 17, 2022.
- Accepted in final form March 17, 2023.
- © 2023 American Academy of Neurology
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