Distinct involvement of the cranial and spinal nerves in progressive supranuclear palsy

Abstract

The most frequent neurodegenerative proteinopathies include diseases with deposition of misfolded tau or α-synuclein in the brain. Pathological protein aggregates in the peripheral nervous system (PNS) are well-recognized in α-synucleinopathies and have recently attracted attention as a diagnostic biomarker. However, there is a paucity of observations in tauopathies. To characterize the involvement of the PNS in tauopathies, we investigated tau pathology in cranial and spinal nerves (PNS-tau) in 54 tauopathy cases (progressive supranuclear palsy: PSP, n = 15; Alzheimer’s disease: AD, n = 18; chronic traumatic encephalopathy: CTE, n = 5; and corticobasal degeneration: CBD, n = 6; Pick’s disease, n = 9; limbic-predominant neuronal inclusion body 4-repeat tauopathy, LNT, n = 1) using immunohistochemistry, Gallyas silver staining, biochemistry, and seeding assays. Most PSP cases revealed phosphorylated and 4-repeat tau immunoreactive tau deposits in the PNS as follows: (number of tau-positive cases/available cases) cranial nerves III: 7/8 (88 %), IX/X: 10/11 (91 %), XII: 6/6 (100 %); anterior spinal roots: 10/10 (100 %). The tau-positive inclusions in PSP often showed structures with fibrillary (neurofibrillary tangle-like) morphology in the axon that were also recognized with Gallyas silver staining. CBD cases rarely showed fine granular non-argyrophilic tau deposits. In contrast, tau pathology in the PNS was not evident in AD, CTE, and Pick’s disease cases. The single LNT case also showed tau pathology in the PNS. In PSP, the severity of PNS-tau involvement correlated with that of the corresponding nuclei, although, occasionally, p-tau deposits were present in the cranial nerves but not in the related brainstem nuclei. Not surprisingly, most of the PSP cases presented with eye movement disorder and bulbar symptoms, and some cases also showed lower-motor neuron signs. Using tau biosensor cells, for the first time we demonstrated seeding capacity of tau in the PNS. In conclusion, prominent PNS-tau distinguishes PSP from other tauopathies. The morphological differences of PNS-tau between PSP and CBD suggest that the tau pathology in PNS could reflect that in the central nervous system. The high frequency and early presence of tau lesions in PSP suggest that PNS-tau may have clinical and biomarker relevance.

Tau seeding activity in skin biopsy differentiates tauopathies from synucleinopathies

“…The expression level of substrates can amplify the pathogenic seed and contribute to the selected vulnerability of different neuronal populations 24,25 , and we previously showed higher concentrations of tau protein and higher levels of 4R tau transcripts in skin lysates of PSP and CBD vs synucleinopathies and HC 22 . In support of these results, another recent study has shown the presence of phosphorylated and 4R deposits in autoptic peripheral nerves, namely cranial and anterior spinal root nerves, of patients with PSP 26 . Nevertheless, few works in literature have explored the diagnostic capacities of 4R substrates in PSP and CBD in brain, and no one in skin.…”

The Irony of Iron: The Element with Diverse Influence on Neurodegenerative Diseases

“…Interestingly, iron accumulation has also been observed along the oculomotor nerve of six PSP brains, which has not been observed in aged controls [88]. A recent study by Tanaka et al [89] demonstrates the PSP-specific involvement of tau deposition in the cranial and spinal nerves, including the oculomotor nerve, supporting a tight association between iron and tau in PSP. Accordingly, the correlations between susceptibility and flortaucipir uptake were shown to be significantly positive in the putamen, pallidum, subthalamic nucleus, RN, and the dentate nucleus of PSP patients, and it was suggested that susceptibility measures may mediate or explain the levels of flortaucipir uptake [87].…”