Prevalence and clinical effects of Lewy Body pathology in non-prion rapidly progressive dementias: a retrospective cohort study

Knowledge on the prevalence and clinical effects of Lewy body (LB) pathology in patients with rapidly progressive dementia (RPD) has been limited by the lack of a pathology-specific marker. The introduction of the alpha-synuclein (α-syn) seed amplification assay (SAA) has recently provided the first accurate in vivo biomarker of LB pathology. Based on data from limited neuropathological cohorts, we hypothesised that LB pathology is frequent in non-prion RPD and often clinically unrecognised. We studied 171 consecutively referred clinically well-characterised patients with RPD, defined as those reaching the stage of major neurocognitive disorder within one year of symptom onset. Patients diagnosed with Creutzfeldt-Jakob disease or a treatable form of RPD were excluded. Records on specific clinical features were retrospectively reviewed. We tested all patients with a validated α-syn CSF SAA to evaluate the prevalence and clinical correlates of LB pathology. Moreover, CSF biomarkers of Alzheimer’s disease (AD) pathology were measured in all cases. In the cohort, 39.2% (67/171) tested positive by α-syn SAA. α-syn SAA positivity was more frequently detected alone than in combination with biomarkers of AD pathology (25.1% vs. 14.0%). α-syn SAA+ status was independently associated with higher odds of fluctuating cognition (OR 2.99, 95%CI 1.46–6.25, p = 0.012), visual hallucinations (OR 2.41, 95%CI 1.24–4.75, p = 0.027), extrapyramidal signs (OR 4.57, 95%CI 2.35–9.11, p < 0.001) and akinetic mutism (OR 3.77, 95%CI 1.22–12.82, p = 0.038). The presence of at least two core features of the diagnostic criteria for Dementia with Lewy bodies yielded high specificity (83.6%, 95%CI 75.4–89.5), but low sensitivity (55.2%, 95%CI 43.4–66.5) and overall low performance (AUC 0.69, 95%CI 0.61–0.78) in discriminating α-syn+ from α-syn- participants. The presence of at least one core feature showed higher sensitivity (88.1%, 95%CI 78.2–93.8) but lower specificity (44.2%, 95%CI 35.1–53.8), also resulting in limited diagnostic accuracy (AUC 0.66, 95%CI 0.58–0.74). LB pathology is prevalent among patients with non-prion RPD but not adequately predicted by clinical features. Our findings support the use of biomarkers of LB pathology in the diagnostic workup of RPD, helping clinicians provide biologically based diagnoses.