Objective:

To compare the clinicopathological characteristics of largest clinically and pathologically studied kindred with MAPT N279K mutation, known as the pallidopontonigral degeneration (PPND), with progressive supranuclear palsy (PSP) patients. 

Background:

Design/Methods:

This study includes 17 patients from the PPND Family, 18 patients with early-onset PSP (EPSP), and 19 patients with classical-onset PSP (CPSP). Diagnosis was confirmed through postmortem pathological examination. We performed a retrospective analysis of clinical and pathological data from these autopsied patients. 

Results:

Balance disturbances occurred later in PPND than in CPSP (2.7±1.6 vs. 1.5±1.3 years; p=0.0200). Unprovoked falls presented later in PPND than in EPSP and CPSP (4.1±1. vs. 2.7±1.2 vs. 1.5±0.7 years; p<0.001), and PPND patients were wheelchair- bound later (6.0±1.9 vs. 4.9±1.3 vs. 4.1±1.0 years; p=0.008). PPND patients were more likely to exhibit pyramidal signs (47.1 vs. 5.6 vs. 0%; p=<0.001), olfactory disturbances (41.2 vs. 11.1 vs. 5.3%, p=0.013) and benefits from dopaminergic treatment were more frequent (56.9 vs. 16.7 vs. 5.3%; p=0.0015). Neuropathological findings revealed lower brain weight in PPND compared to EPSP (1100±90 vs. 1240±160g; p=0.0024), with a lower Braak neurofibrillary tangle stage in PPND (0 [0,I]) compared to EPSP (II [I,III]; p=0.007) and CPSP (III [II,III]; p<0.001). Tau severity in neuronal and glial cells was comparable between EPSP and CPSP; however, it was more severe in PPND compared to both EPSP and CPSP in the temporal cortex, frontal cortex, and basal ganglia. 

Conclusions:

Clinically, PPND differs significantly from sporadic PSP, early symptoms may be indicative of Parkinson's disease, with PSP-like symptoms developing as the disease progresses. Pathologically, while both diseases share tau pathology, PPND exhibits more severe tau pathology in the cortices and basal ganglia.