Objective: To elucidate the structure of clinical heterogeneity and longitudinal transition patterns in a prodromal Lewy body disease (LBD) screening cohort using a data-driven approach.

Background: Screening cohorts for prodromal LBD capture clinically heterogeneous populations through questionnaire-based assessments. However, the latent structure underlying this heterogeneity and how individuals transition between clinical states over time remain poorly understood.

Method: We applied a Hidden Markov Model to 102 participants from the NaT-PROBE cohort, a community-based cohort of individuals at risk of Lewy body disease identified through prodromal symptom screening (median follow-up: 192 weeks). Twenty-nine subdomains across seven clinical domains were compressed into 14 variables via hierarchical block principal component analysis and used as model inputs. The optimal number of latent states was determined by cross-validation.

Results: Three clinically distinct states were identified: a stable state (S1, 48%), a subjective symptom-predominant state (S2, 42%), and a neurodegenerative state (S3, 10%). S3 showed the lowest MIBG heart-to-mediastinum ratio (H/M: 2.39), with approximately half of the cases falling below the abnormal threshold; olfactory function (OSIT-J: 5.0) and motor function were also significantly impaired. Transition analysis revealed that S3 was a fully absorbing state with zero probability of recovery. Transitions into S3 occurred predominantly from S1 directly, bypassing S2, while transitions from S2 to S3 were rare. Notably, at the group level, S2 showed the best objective markers (MIBG H/M: 3.00; OSIT-J: 8.4) despite the most prominent subjective complaints, indicating a dissociation between subjective symptoms and objective neurodegeneration. Bidirectional transitions between S1 and S2 indicated that subjective symptom burden was reversible for a subset of S2, while others persisted. Individual cases with abnormal MIBG or DaT-SPECT findings were also observed within S2, suggesting internal heterogeneity.

Conclusion: Irreversible progression toward neurodegeneration was confirmed in this prodromal LBD cohort; however, the state with the most prominent subjective symptoms showed milder objective degeneration, and subjective symptom severity did not predict progression. Objective markers are essential for monitoring disease progression in prodromal LBD.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/latent-clinical-states-and-longitudinal-transitions-in-prodromal-lewy-body-disease-a-data-driven-analysis-from-the-nat-probe-study/