Davis, Albert A

AbstractObjectiveTau hyperphosphorylation at threonine 217 (pT217) in cerebrospinal fluid (CSF) has recently been linked to early amyloidosis and could serve as a highly sensitive biomarker for Alzheimer’s disease (AD). However, it remains unclear whether other tauopathies induce pT217 modifications. To determine if pT217 modification is specific to AD, CSF pT217 was measured in AD and other tauopathies.MethodsUsing immunoprecipitation and mass spectrometry methods, we compared CSF T217 phosphorylation occupancy (pT217/T217) and amyloid‐beta (Aβ) 42/40 ratio in cognitively normal individuals and those with symptomatic AD, progressive supranuclear palsy, corticobasal syndrome, and sporadic and familial frontotemporal dementia.ResultsIndividuals with AD had high CSF pT217/T217 and low Aβ42/40. In contrast, cognitively normal individuals and the majority of those with 4R tauopathies had low CSF pT217/T217 and normal Aβ 42/40. We identified a subgroup of individuals with increased CSF pT217/T217 and normal Aβ 42/40 ratio, most of whom were MAPT R406W mutation carriers. Diagnostic accuracies of CSF Aβ 42/40 and CSF pT217/T217, alone and in combination were compared. We show that CSF pT217/T217 × CSF Aβ 42/40 is a sensitive composite biomarker that can separate MAPT R406W carriers from cognitively normal individuals and those with other tauopathies.InterpretationMAPT R406W is a tau mutation that leads to 3R+4R tauopathy similar to AD, but without amyloid neuropathology. These findings suggest that change in CSF pT217/T217 ratio is not specific to AD and might reflect common downstream tau pathophysiology common to 3R+4R tauopathies.

Abstract Background The clinical diagnosis of Parkinson's disease (PD) requires the presence of parkinsonism and supportive criteria that include a clear and dramatic beneficial response to dopaminergic therapy. Our aim was to test the diagnostic criterion of dopaminergic response by evaluating its association with pathologically confirmed diagnoses in a large population of parkinsonian patients. Methods We reviewed clinical data maintained in an electronic medical record from all patients with autopsy data who had been seen in the Movement Disorders Center at Washington University, St. Louis, between 1996 and 2018. All patients with parkinsonism who underwent postmortem neuropathologic examination were included in this analysis. Results There were 257 unique parkinsonian patients with autopsy‐based diagnoses who had received dopaminergic therapy. Marked or moderate response to dopaminergic therapy occurred in 91.2% (166/182) of those with autopsy‐confirmed PD, 52.0% (13/25) of those with autopsy‐confirmed multiple systems atrophy, 44.4% (8/18) of those with autopsy‐confirmed progressive supranuclear palsy, and 1 (1/8) with autopsy‐confirmed corticobasal degeneration. Other diagnoses were responsible for the remaining 24 individuals, 9 of whom had a moderate response to dopaminergic therapy. Conclusion A substantial response to dopaminergic therapy is frequent but not universal in PD. An absent response does not exclude PD. In other neurodegenerative disorders associated with parkinsonism, a prominent response may also be evident, but this occurs less frequently than in PD. © 2020 International Parkinson and Movement Disorder Society