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Additional file 1: Table S1. Clinical features and results of indicative biomarkers in the DLB group. Table S2. CSF NfL, GFAP, and AD core biomarker values across diagnostic groups. Table S3. Plasma NfL, GFAP, and p-tau181 values across diagnostic groups. Table S4. CSF and plasma NfL, GFAP, and p-tau181 across FTD phenotypic continuum. Table S5. CSF and plasma NfL, GFAP, and p-tau181 in genetic and sporadic FTD. Fig. S1. Plasma NfL levels in the SNAP group according to the clinical presentation. Fig. S2. Accuracy of plasma NfL, p-tau181, and GFAP in discriminating between healthy controls and disease groups. Fig. S3. CSF and plasma diagnostic accuracies for each biomarker across disease groups. Fig. S4. Plasma biomarker levels in CBS and DLB according to the amyloid status (left) and ROC curves after excluding A+ cases in non-AD disease groups (right).

Additional file 1: Table S1. Summary of evaluations in the included cohorts. Table S2. Demographic data and summary of α-syn RT-QuIC results in the CJD cohort. Table S3. Summary of demographic and clinical features and results of indicative biomarkers of DLB individuals. Table S4. Baseline clinical features of the Bologna PRO-HYDRO cohort and comparisons between α-synLB + and α-syn-LB -. Table S5. Comparisons between Aß + vs. Aß– subgroups of patients from the Bologna PRO-HYDRO cohort. Table S6. Comparisons between responders and non-responders 6 months after surgery.

Background Idiopathic normal pressure hydrocephalus (iNPH) is a clinico-radiological syndrome of elderly individuals likely sustained by different neurodegenerative changes as copathologies. Since iNPH is a potentially reversible condition, assessing neurodegenerative pathologies in vitam through CSF biomarkers and their influence on clinical features and surgical outcome represents crucial steps. Methods We measured α-synuclein seeding activity related to Lewy body (LB) pathology by the real-time quaking-induced conversion assay (RT-QuIC) and Alzheimer disease core biomarkers (proteins total-tau, phospho-tau, and amyloid-beta) by immunoassays in the cerebrospinal fluid (CSF) of 293 iNPH patients from two independent cohorts. To compare the prevalence of LB copathology between iNPH participants and a control group representative of the general population, we searched for α-synuclein seeding activity in 89 age-matched individuals who died of Creutzfeldt-Jakob disease (CJD). Finally, in one of the iNPH cohorts, we also measured the CSF levels of neurofilament light chain protein (NfL) and evaluated the association between all CSF biomarkers, baseline clinical features, and surgery outcome at 6 months. Results Sixty (20.5%) iNPH patients showed α-synuclein seeding activity with no significant difference between cohorts. In contrast, the prevalence observed in CJD was only 6.7% (p = 0.002). Overall, 24.0% of iNPH participants showed an amyloid-positive (A+) status, indicating a brain co-pathology related to Aβ deposition. At baseline, in the Italian cohort, α-synuclein RT-QuIC positivity was associated with higher scores on axial and upper limb rigidity (p = 0.003 and p = 0.011, respectively) and lower MMSEc scores (p = 0.003). A+ patients showed lower scores on the MMSEc (p = 0.037) than A- patients. Higher NfL levels were also associated with lower scores on the MMSEc (rho = -0.213; p = 0.021). There were no significant associations between CSF biomarkers and surgical outcome at 6 months (i.e. responders defined by decrease of 1 point on the mRankin scale). Conclusions Prevalent LB- and AD-related neurodegenerative pathologies affect a significant proportion of iNPH patients and contribute to cognitive decline (both) and motor impairment (only LB pathology) but do not significantly influence the surgical outcome at 6 months. Their effect on the clinical benefit after surgery over a more extended period remains to be determined.