3rd Edition of Dementia World Conference 2026

Abstract

Creutzfeldt-Jakob disease (CJD) is a rare and fatal neurodegenerative disorder characterized by rapidly progressive cognitive decline accompanied by various neurological manifestations, including myoclonus, cerebellar dysfunction, parkinsonism, and behavioral or psychiatric symptoms. Genetic prion diseases caused by pathogenic variants in the prion protein gene (PRNP) account for a minority of CJD cases and may show distinct clinical and radiological features depending on the genotype. Among these variants, the V180I mutation is rare and has been associated with relatively late onset, prominent cortical dysfunction, characteristic magnetic resonance imaging (MRI) abnormalities, and the frequent absence of periodic sharp wave complexes (PSWCs) on electroencephalography (EEG). We report a patient with CJD associated with a V180I PRNP mutation whose initial manifestation was prominent depression. A previously healthy 64-year-old woman without a history of psychiatric illness developed progressive emotional lability, irritability, frequent crying, loss of motivation, and recurrent suicidal thoughts approximately six months before neurological evaluation. She was initially diagnosed with major depressive disorder and received psychiatric treatment, but her symptoms failed to improve significantly. One month later, rapidly progressive memory impairment, psychomotor slowing, inappropriate speech, and repetitive verbal behavior became evident. Her condition subsequently deteriorated, with severe cognitive dysfunction, mutism, reduced spontaneous activity, and bilateral hand tremor. Neurological examination revealed marked disorientation, akinetic mutism, mild symmetric resting tremor, bradykinesia, and rigidity. Diffusion-weighted and FLAIR MRI demonstrated extensive high-signal abnormalities involving the bilateral frontal, temporal, and parietal cortices and basal ganglia, with relative sparing of the occipital lobes and cerebellum. Brain ¹⁸F-FDG PET showed marked hypometabolism in the bilateral cerebral cortices, together with moderate hypometabolism in the basal ganglia, thalami, and cerebellum. MR spectroscopy demonstrated decreased N-acetylaspartate and increased choline peaks in the affected cortical and basal ganglia regions. Cerebrospinal fluid analysis revealed no pleocytosis and normal glucose and protein levels, while the 14-3-3 protein was positive. Serial EEG examinations demonstrated diffuse intermittent theta-to-delta slowing without PSWCs. Genetic analysis of PRNP identified a heterozygous V180I substitution, together with methionine homozygosity at codon 129 and glutamate homozygosity at codon 219. These findings supported the diagnosis of genetic CJD associated with the V180I mutation. This case illustrates that genetic CJD associated with the V180I PRNP mutation may initially present predominantly with psychiatric symptoms, including depression, before the emergence of rapidly progressive cognitive and neurological deterioration. In patients with late-onset depressive symptoms followed by rapidly progressive dementia, CJD should be considered even in the absence of a family history or typical PSWCs on EEG. Early recognition of characteristic cortical and basal ganglia abnormalities on diffusion-weighted MRI and subsequent PRNP genetic testing may facilitate timely diagnosis.