Watanabe_2025_Brain__

Capgras syndrome is a delusional misidentification syndrome characterized by the recurrent belief that someone, usually a family member, has been replaced by an impostor. Although described over a century ago, its etiology, clinical features, and neuroimaging characteristics remain poorly understood due to its rarity. This study aimed to clarify these aspects through the analysis of a large cohort and to explore its clinical implications and underlying mechanisms. We conducted a retrospective cohort study by reviewing medical records of patients diagnosed with Capgras syndrome at the Mayo Clinic (Rochester, Minnesota) over a 28-year period (January 1995-December 2022). Clinical, neuropathological, and neuroimaging data were analyzed. A total of 204 patients were included (median age at onset: 73 years; 44% female). Twelve patients underwent neuropathological examination, all of whom exhibited alpha-synuclein pathology, including one patient with a clinical diagnosis of Alzheimer's disease (AD). Regarding clinical diagnoses, neurodegenerative diseases were the most common (69%, n=140), with dementia with Lewy bodies (DLB) being predominant (58%, n=118), followed by mixed etiologies ("two-hits") (18%, n=36) and AD (10%, n=21). Psychotic disorders accounted for 9% (n=18) of cases. No case was attributed to a single stroke, although 9% (n=19) involved coexisting cerebrovascular disease in the context of AD or DLB. In DLB, the timing of Capgras syndrome onset varied: it occurred later than cognitive decline and core clinical features (e.g., visual hallucinations, fluctuating cognition, parkinsonism) in both DLB and mild cognitive impairment (MCI)-onset prodromal DLB, but earlier in psychiatric-onset prodromal DLB. In both DLB and AD, Capgras syndrome typically targeted a single spouse, whereas in psychotic disorders, it often involved multiple, non-spousal targets. Depression or anxiety was present in 55% (n=112). Capgras syndrome worsened in the evening or at night (87%, n=45/52), suggesting a link to negative affective states. Among 82 patients with DLB and AD treated with cholinesterase inhibitors, 15% (n=12) showed symptomatic improvement. Neuroimaging with MRI and 18F-fluorodeoxyglucose-PET revealed widespread bilateral cortical involvement and prominent right frontal dysfunction in DLB and AD. Capgras syndrome is associated with DLB and could serve as a potential early diagnostic clue. Recognizing its phenomenological features-the number and type of targeted individuals-can help differentiate between neurodegenerative and psychiatric etiologies. In neurodegenerative diseases, Capgras syndrome may reflect a multifactorial, dynamic process, driven by widespread bilateral cortical dysfunction (particularly involving the right frontal lobe), and psychological factors. Thus, a combined approach involving pharmacological and non-pharmacological interventions may offer effective management strategies.