Neurofibrillary tangle maturation in nodding syndrome of Uganda

Nodding syndrome is an African neurologic disorder with epilepsy and tau pathology that presents in childhood. We report the distribution of tau pathology and neurofibrillary tangle maturation in the brains of four cases of nodding syndrome with long duration. The tau epitopes in nodding syndrome spanned the primary sequence of tau and included phosphorylation sites and three- and four-repeat isoforms. In the brainstem, tau pathology preferentially occurred in the major nuclei of the ascending monoaminergic system (locus coeruleus, dorsal raphe nucleus, and substantia nigra) and pre-cerebellar nuclei (mostly the pontine nuclei). The late stages of tangle maturation represented by extraneuronal ghost tangles, and tangle-associated neuritic clusters were present in all regions of the brain with tau pathology. In the cerebral cortex, the tau pathology was most apparent in the neocortex with relative sparing of the medial temporal lobe and hippocampus. The late stages of neurofibrillary tangle maturation in the substantia nigra were not associated with marked extraneuronal neuromelanin extravasation, likely indicating that the key pathogenic neuronal insult occurred in early life, before the accumulation of cytoplasmic neuromelanin. We conclude that tau pathology in these cases of nodding syndrome involves both the neocortex and the neurons of the isodendritic core of the brainstem and display neurofibrillary tangle maturation that likely relates to a cerebral insult in early life.