Contribution of Pathological Alpha-synuclein as a Diagnostic Biomarker for Dementia With Lewy Bodies

Summary

Alzheimer's disease and dementia with Lewy bodies (DLB) are the two main age-related neurodegenerative cognitive disorders. Differential diagnosis between these conditions is challenging, both at the prodromal and dementia stages. The lack of a precise diagnosis can be particularly harmful for patients with DLB, as up to 80% of them show severe adverse reactions to antipsychotic medications, including falls, confusion, and even death. The diagnosis of Alzheimer's disease has improved with cerebrospinal fluid (CSF) biomarkers such as Tau, phosphorylated Tau (P-Tau), and the Aβ42/Aβ40 ratio (Lehmann et al., 2018). However, differentiating Alzheimer's disease from DLB remains difficult: 1 to 3 Alzheimer's biomarkers are frequently positive in the CSF of patients with DLB: in 49% of cases at the prodromal stage and up to 72% at the dementia stage. Moreover, total α-synuclein measurement in CSF has not proven to be diagnostically reliable. The DAT-scan, sometimes used as a supportive tool, is an expensive technique and lacks sensitivity, with detection rates of only 78% in dementia-stage DLB and 54% in prodromal DLB.

Given these limitations, identifying specific biomarkers for DLB, particularly pathological α-synuclein, is a critical objective. α-synuclein is the main protein component of Lewy bodies, whose abnormal β-sheet conformation promotes aggregation and prion-like propagation. Conventional measurements of total α-synuclein in CSF have failed to achieve sufficient diagnostic specificity. In contrast, detecting aggregated or pathological forms of α-synuclein in CSF appears to be a promising approach for improving the diagnosis of synucleinopathies. New techniques based on α-synuclein aggregation amplification have shown encouraging results in retrospective studies including neuropathologically confirmed cases (Bargar et al., 2021; Rossi et al., 2020). However, prospective evaluation of these methods in real-world clinical settings is still lacking. We hypothesize that a specific assay targeting pathological α-synuclein in CSF could reliably distinguish patients with DLB from those with Alzheimer's disease.

Conditions

• Dementia With Lewy Bodies (DLB)
• Alzheimer's Disease (AD)

Interventions

OTHER

Biological : blood sampling

will be collected from the patient

OTHER

nasopharyngeal swab

will be collected from the patient

OTHER

Procedure : Lumbar puncture

will be collected from the patient

OTHER

Behavioral : clinical, functional, cognitive and psychiatric evaluations

will be collected from the patient

OTHER

MRI

will be done on the patient

Sponsors & Collaborators

• University Hospital, Strasbourg, France

  lead OTHER

Study Design

Allocation

NON_RANDOMIZED

Purpose

DIAGNOSTIC

Masking

NONE

Model

PARALLEL

Eligibility

Min Age

18 Years

Sex

ALL

Healthy Volunteers

No

Timeline & Regulatory

Start

2026-01-01

Primary Completion

2032-01-01

Completion

2032-01-01