Academic centers utilize sequential clinical and neuroimaging assessments, including morphometric ratios, to obtain an unequivocal diagnosis of the non-synucleinopathic forms of Parkinsonism, such as progressive supranuclear palsy (PSP), however, a 1–2 year follow-up is required. The on-going long-lasting trials using anti-tau antibodies for PSP patients might therefore be biased by the incorrect enrollment of Parkinson’s disease (PD) patients manifesting early axial signs. This perspective study aimed at achieving two major goals: first, to summarize the established biomarker candidates found in cerebrospinal fluid (CSF) in probable PSP patients, including low p-tau and altered neurofilaments. Second, we share our recent data, from CSF samples of well-selected PSP subjects, attributable to both main variants (and revisited in light of MDS criteria), who were followed for 1 year before and 2 years after lumbar puncture. We found a significantly high level of noradrenaline (NE) in these patients, similar to controls, when compared to PD patients. In contrast, CSF samples, in PD, showed a significant reduction in CSF NE and its major metabolite, which confirmed that PD is a multi-system disease involving several endogenous pathways. The NE axis impairments were prominent in PSP featuring worse NPI. It might represent a counterpart to the early and peculiar psycho-pathological profiles that are observed in tauopathies. In conclusion, we highlight that CSF biomarkers, which are easy to collect, can provide rapid insights as diagnostic tools. Early alterations in endogenous NE machinery in atypical Parkinsonism may represent a specific risk trait in forms characterized by a worse prognosis.

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