47. α-SYNUCLEIN SKIN BOPSY AS A DIAGNOSTIC TOOL FOR PRODROMAL DEMENTIA WITH LEWY BODIES

Introduction

The International DLB Consortium's criteria for diagnosing probable Dementia with Lewy Bodies (DLB) require the presence of major neurocognitive disorder along with either two core clinical features or one core feature plus a supportive biomarker. Separate from these criteria, however, two prodromal forms of DLB (pDLB) have also been described: Mild Cognitive Impairment (MCI)-onset pDLB, characterized by cognitive impairment on neuropsychological testing that does not meet criteria for major neurocognitive disorder (NCD), and psychiatric-onset pDLB, characterized by new or worsening psychiatric symptoms, such as hallucinations, anxiety, or depression, which precede cognitive decline, often by several years.

Since cognitive decline, as well as the core features of DLB—fluctuating cognition, REM sleep behavior disorder (RBD), parkinsonian symptoms, and visual hallucinations (VH)— can be absent or milder in psychiatric-onset pDLB, patients may experience a delayed diagnosis or be misdiagnosed with a primary psychiatric disorder.

Psychiatric-onset pDLB also appears to exhibit a female predominance, and women are more likely to present with milder or absent parkinsonism and a lower incidence of RBD. This can render women particularly vulnerable to delayed diagnoses or misdiagnoses.

An accessible and reliable diagnostic biomarker is crucial for diagnosing psychiatric-onset pDLB. The detection of phosphorylated α-synuclein deposits in peripheral nerves by skin biopsy has emerged as a promising tool, demonstrating excellent accuracy for in vivo diagnosis of α-synucleinopathies.

Methods

A retrospective chart review was conducted on UNC Neurology Clinic patients who underwent α -synuclein skin biopsies based on clinical suspicion for pDLB. A total of 104 patients (61 men, 43 women) aged 50-90 with suspected pDLB were analyzed. Cognitive function was assessed via Montreal Cognitive Assessment (MoCA), Mini Mental State Exam (MMSE), or comprehensive neuropsychological testing.

Presentations were classified as psychiatric-onset if psychiatric symptoms had emerged, or previously stable symptoms worsened, within five years prior to a cognitive decline. Presentations were classified as MCI-onset if patients had cognitive impairment not meeting criteria for major NCD. Clinical diagnosis of DLB was based on the 2017 revised consensus criteria from the International DLB Consortium.

3mm punch biopsies were taken from cervical spine, distal thigh, and distal leg skin sites per the Syn-One Test (CND Life Sciences, Scottsdale, AZ) protocol. Biopsies were immunostained and analyzed for phosphorylated α-synuclein by CND Life Sciences.

Results

Of the 104 patients biopsied, 56 were positive for α-synuclein in skin. Among these 56 patients, there was a statistically significant association between female sex and psychiatric-onset pDLB (p = .024). Patients with psychiatric-onset pDLB were also younger than those with MCI-onset pDLB (p = .047) and trended towards less cognitive impairment.

Conclusions

α-synuclein skin biopsy testing proved clinically useful as a diagnostic biomarker for psychiatric-onset and MCI-onset pDLB. This tool can aid in earlier and more accurate detection and treatment of DLB. Additionally, psychiatric-onset pDLB showed a female predominance. Delays in diagnosis of DLB, or misdiagnosis, may occur due to a reliance on cognitive-based diagnostic criteria. These findings underscore the need for more inclusive diagnostic criteria that account for non-cognitive symptoms, particularly in women.