DAT-SPECT profiling for biological definition of two prospective Parkinson's disease cohorts

BackgroundThere is a need for simplified classification systems capable of effectively stratifying Parkinsons disease (PD) in routine clinical practice. ObjectivesIdentification of PD subtypes integrating neuroimaging and clinical features, widely used to support clinical diagnosis. MethodsWe included, from Parkinsons Progression Markers Initiative (PPMI), 249 de novo early diagnosed PD patients. Two step clustering analysis was run on 123I-FP-CIT-SPECT striatal uptake [D+/D] and motor impairment [M+/M]. The emerging subgroups were evaluated for demographic, clinical, cerebrospinal fluid biomarkers, brain morphometry and longitudinal clinical progression. Mediation analysis evaluated the effect of biomarkers on the relationship between subgroups and cognitive decline. We validated the proposed classification algorithm through an independent validation cohort (n=84). ResultsFour distinct subtypes emerged: [D+/M+]: poorer memory performance, greater A{beta}1-42 and -synuclein pathology and atrophy in the inferior temporo-occipital cortex. At follow-up D+/M+ showed faster progression of motor disability, motor complications and cognitive decline. [D/M]: higher levels of anxiety and gray matter volume reductions in the precuneus, fusiform gyrus and the precentral gyrus. [D/M+]: marked by pronounced rigidity and apathy, atrophy in motor and sensorimotor areas, and a more rapid progression of rigidity. [D+/M]: severe impulsiveness, lower working memory performance and thalamic atrophy. A{beta}1-42 showed significant mediational effect on the relationship between D+/M+ and cognitive decline. The validation cohort supported the clinical findings observed in the PPMI cohort. ConclusionsPD can be categorized into distinct subgroups using information widely available in clinical and research settings. These data offer valuable insights into the underlying co-pathology, disease progression and severity. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=102 SRC="FIGDIR/small/25323734v1_ufig1.gif" ALT="Figure 1"> View larger version (31K): org.highwire.dtl.DTLVardef@6ea5e1org.highwire.dtl.DTLVardef@4c6a7dorg.highwire.dtl.DTLVardef@e34a3corg.highwire.dtl.DTLVardef@1eea38_HPS_FORMAT_FIGEXP M_FIG C_FIG