Parkinsonism of uncertain clinical significance (PUCS): A proposed new diagnostic entity

Diagnosis of neurologic disorders can be very challenging when different diseases share similar clinical features. Patients with parkinsonism can present with considerable phenotypic variability with various combinations of tremor, rigidity, bradykinesia and postural instability [ [1] Halliday G.M. et al. Neuropathology underlying clinical variability in patients with synucleinopathies. Acta Neuropathol. 2011; 122: 187-204 Crossref PubMed Scopus (313) Google Scholar ]. There is a broad spectrum of parkinsonian disorders, neurodegenerative or non-degenerative (e.g. vascular or drug-induced parkinsonism). There may be phenomenological overlap or a paucity of clinical features leading to an extensive differential diagnosis, especially at early disease stages [ [2] Postuma R.B. et al. MDS clinical diagnostic criteria for Parkinson’s disease. Mov. Disord. 2015; 30: 1591-1601 Crossref PubMed Scopus (3332) Google Scholar , [3] Marsili L. Rizzo G. Colosimo C. Diagnostic criteria for Parkinson’s disease: from James Parkinson to the concept of prodromal disease. Front. Neurol. 2018; 9: 156 Crossref PubMed Scopus (120) Google Scholar ]. Further difficulty in clinical diagnosis occurs when diseases coexist (dual pathology), including comorbid synucleinopathies and tauopathies [ [4] Uchikado H. et al. Coexistence of PSP and MSA: a case report and review of the literature. Acta Neuropathol. 2006; 111: 186-192 Crossref PubMed Scopus (31) Google Scholar , [5] Ozawa T. et al. The spectrum of pathological involvement of the striatonigral and olivopontocerebellar systems in multiple system atrophy: clinicopathological correlations. Brain. 2004; 127: 2657-2671 Crossref PubMed Scopus (395) Google Scholar ]. Synucleinopathies are characterized by the deposition of abnormal alpha-synuclein, including Parkinson's disease (PD), Dementia with Lewy bodies (DLB) and Multiple System Atrophy (MSA). Tauopathies are characterized by abnormal tau protein deposition, including Progressive Supranuclear Palsy (PSP), corticobasal degeneration, argyrophilic grain disease and many types of fronto-temporal dementias, which also commonly cause parkinsonism. Heterogeneity also comes from the existence of different α-synuclein and tau strains [ [6] Candelise N. et al. Seeding variability of different alpha synuclein strains in synucleinopathies. Ann. Neurol. 2019; 85: 691-703 Crossref PubMed Scopus (72) Google Scholar ].