Characterisation of RT-QuIC negative cases from the UK National CJD Research and Surveillance programme.

INTRODUCTION: Incorporation of the real-time quaking-induced conversion (RT-QuIC) assays for diagnosis of sporadic Creutzfeldt-Jakob disease (CJD) has transformed diagnosis largely related to its extremely high specificity. However, the test has a c.10% false-negative result and we aim to characterize the clinical features, investigation profile, and molecular subtype in this cohort of patients. METHODS: 250 individuals diagnosed with definite sporadic CJD were identified from the UK National CJD Research and Surveillance Unit from 2012 to 2023. We compared the clinical features and investigation profile in those with a negative CSF RT-QuIC to those with a positive RT-QuIC. RESULTS: 27 individuals (10.8%) were CSF RT-QuIC negative. Median age of onset was younger (62 years vs 68 years, p = 0.002), median disease duration was longer (4.4 months vs 10.5 months, p < 0.001), and these individuals were less likely to present with gait difficulties (73% vs 93%, p = 0.003) or motor symptoms (62% vs 80%, p = 0.04). The sensitivity of electroencephalography and diffusion-weighted MRI were similar in both groups. In those who were RT-QuIC negative, there was an overrepresentation of the VV1 (32% vs 1%) and MM2 molecular subtypes (21% vs 3%). Co-occurring neurodegenerative disease was found in 33% (9/27) of those who were RT-QuIC negative. CONCLUSIONS: Individuals with sporadic CJD and a negative CSF RT-QuIC present with younger age of onset, different clinical features and are over-represented with the VV1 and MM2 subtypes of sporadic CJD. Further work is required to better understand the biochemical properties contributing to RT-QuIC negative results in these cases.

A General Strategy for N-(Hetero)arylpiperidine Synthesis Using Zincke Imine Intermediates.

Methods to synthesize diverse collections of substituted piperidines are valuable due to the prevalence of this heterocycle in pharmaceutical compounds. Here, we present a general strategy to access N-(hetero)arylpiperidines using a pyridine ring-opening and ring-closing approach via Zincke imine intermediates. This process generates pyridinium salts from a wide variety of substituted pyridines and (heteroaryl)anilines; hydrogenation reactions and nucleophilic additions then access the N-(hetero)arylpiperidine derivatives. We successfully applied high-throughput experimentation (HTE) using pharmaceutically relevant pyridines and (heteroaryl)anilines as inputs and developed a one-pot process using anilines as nucleophiles in the pyridinium salt-forming processes. This strategy is viable for generating piperidine libraries and applications such as the convergent coupling of complex fragments.