Uncovering distinct spatial‐temporal trajectories of Lewy‐type α‐synuclein pathology: a Subtype and Stage Inference model analysis
Authors: Mastenbroek Sophie E , Vogel Jacob W , Collij Lyduine E. , Serrano Geidy E , Young Alexandra L. , Barkhof Frederik , Ossenkoppele Rik , Beach Thomas G , Hansson Oskar 
Published: December 2023

AbstractBackgrounda‐synuclein aggregation is a pathologic hallmark of several Lewy body disorders with differing symptoms. This symptom heterogeneity may be due to varying underlying disease trajectories. Here, we use a data‐driven approach to identify and characterize distinct spatial‐temporal progression patterns of α‐synuclein deposition.MethodThe Subtype and Stage Inference (SuStaIn) model evaluates the optimal grouping of individuals into subtypes with distinct orderings of events/stages. We applied Ordinal SuStaIn to post‐mortem Lewy‐type α‐synuclein (LTS) density scores measured in 10 regions (including olfactory bulb and tract [OBT], limbic, brainstem, and cortical regions) of 814 subjects from the Sun Health Research Institute Brain Donation Program (Table‐1). The optimal SuStaIn model was selected according to the Cross‐Validation Information Criteria. We selected 781 subjects with stage>0 (n
excluded = 13) and subtype probability>50% (n
excluded = 20) to assess differences in subtypes. Hierarchical multinomial logistic regressions were performed to compare subtypes on (1) age at death, sex, APOE‐e4 copies, and post‐mortem interval; (2) total amyloid plaque load; and (3) total tau tangle load. In a subset of individuals (n = 355), we additionally compared subtypes on MMSE scores and the motor section of the Unified Parkinson Disease Rating Scale (UPDRS). All models were adjusted for SuStaIn stage and significant predictors of preceding models.ResultSuStaIn identified three subtypes with distinct LTS trajectories, which we termed “OBT/Limbic‐first”, “OBT/Brainstem‐first”, and “OBT‐sparing/Brainstem‐first” based on the first regions to show deposition (Figure‐1). The majority of individuals were assigned to OBT/Limbic‐first (N = 475,60.8%), followed by OBT/Brainstem‐first (N = 165,21.1%), and OBT‐sparing/Brainstem‐first (N = 141,18.1%) subtypes (Table‐1). We observed a higher frequency of homozygous APOE‐e4 carriers and amyloid and tau burden in the OBT/Limbic‐first subtype compared to the OBT/Brainstem‐first (ßAPOE

‐e4 = 0.82±0.40, pAPOE‐e4 = .042; ßamyloid= 0.08±0.42, pamyloid<.001; ßtau= 0.17±0.03, ptau<.001) and OBT‐sparing/Brainstem‐first (ßAPOE‐e4 = 0.98±0.48, pAPOE‐e4 = .042; ßamyloid= 0.14±0.27, pamyloid<.001; ßtau= 0.18±0.03, ptau<.001) subtypes. In addition, the OBT/Brainstem‐first subtype showed a higher amyloid burden (ß = 0.06±0.02, p = .012) and higher MMSE (ß = 0.08±0.04, p = 0.030) compared to the OBT‐sparing/Brainstem‐first (Table‐1, Figure‐2).ConclusionIn this large post‐mortem SuStaIn study, we identified three subtypes of α‐synuclein deposition, possibly reflecting different epicenters and spreading trajectories of misfolded α‐synuclein, where OBT/Limbic‐first was associated with Alzheimer’s co‐pathology. Follow‐up work will study how these subtypes differ in clinical diagnosis and symptomatology.