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Although described over a century ago, its aetiology, 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.<\/jats:p>\n                  <jats:p>We conducted a retrospective cohort study by reviewing medical records of patients diagnosed with Capgras syndrome at the Mayo Clinic (Rochester, MN) over a 28-year period (January 1995 to December 2022). Clinical, neuropathological and neuroimaging data were analysed.<\/jats:p>\n                  <jats:p>A total of 204 patients were included (median age at onset: 73 years; 44% female). Twelve patients underwent neuropathological examination, all of whom exhibited \u03b1-synuclein pathology, including one patient with a clinical diagnosis of Alzheimer\u2019s 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 aetiologies (\u2018two-hits\u2019) (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-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.<\/jats:p>\n                  <jats:p>Capgras syndrome is associated with DLB and could serve as a potential early diagnostic clue. Recognizing its phenomenological features\u2014the number and type of targeted individuals\u2014can help differentiate between neurodegenerative and psychiatric aetiologies. 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.<\/jats:p>","DOI":"10.1093\/brain\/awaf378","type":"journal-article","created":{"date-parts":[[2025,10,7]],"date-time":"2025-10-07T11:48:51Z","timestamp":1759837731000},"page":"1224-1238","source":"Crossref","is-referenced-by-count":2,"title":["Imposter in the brain: aetiological, clinical and neuroimaging characteristics of Capgras syndrome"],"prefix":"10.1093","volume":"149","author":[{"ORCID":"https:\/\/orcid.org\/0009-0009-1623-6599","authenticated-orcid":false,"given":"Hiroyuki","family":"Watanabe","sequence":"first","affiliation":[{"name":"Department of Neurology, Mayo Clinic , Rochester, MN 55905 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6914-1563","authenticated-orcid":false,"given":"Jennifer L","family":"Whitwell","sequence":"additional","affiliation":[{"name":"Department of Radiology, Mayo Clinic , Rochester, MN 55905 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jerusha G","family":"Bhaskaran","sequence":"additional","affiliation":[{"name":"Department of Radiology, Mayo Clinic , Rochester, MN 55905 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Val J","family":"Lowe","sequence":"additional","affiliation":[{"name":"Department of Radiology, Mayo Clinic , Rochester, MN 55905 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2930-8634","authenticated-orcid":false,"given":"Keith A","family":"Josephs","sequence":"additional","affiliation":[{"name":"Department of Neurology, Mayo Clinic , Rochester, MN 55905 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2025,10,8]]},"reference":[{"key":"2026040804060129500_awaf378-B1","doi-asserted-by":"crossref","first-page":"556","DOI":"10.1192\/bjp.130.6.556","article-title":"The syndrome of Capgras","volume":"130","author":"Christodoulou","year":"1977","journal-title":"Br J Psychiatry"},{"key":"2026040804060129500_awaf378-B2","volume-title":"The delusional misidentification syndromes","author":"Christodoulou","year":"1986"},{"key":"2026040804060129500_awaf378-B3","volume-title":"Neuropsychiatry and behavioral neuroscience","author":"Cummings","year":"2003"},{"key":"2026040804060129500_awaf378-B4","doi-asserted-by":"crossref","first-page":"3955","DOI":"10.1093\/brain\/awad294","article-title":"Capgras syndrome","volume":"146","author":"Carson","year":"2023","journal-title":"Brain"},{"key":"2026040804060129500_awaf378-B5","first-page":"245","article-title":"Delusional misidentification syndromes and cerebral \u201cdysrhythmia\u201d","volume":"14","author":"Christodoulou","year":"1981","journal-title":"Psychiatr Clin (Basel)"},{"key":"2026040804060129500_awaf378-B6","doi-asserted-by":"crossref","first-page":"961","DOI":"10.1097\/JGP.0b013e3180cc1fdf","article-title":"Classification of psychotic symptoms in dementia with Lewy bodies","volume":"15","author":"Nagahama","year":"2007","journal-title":"Am J Geriatr Psychiatry"},{"key":"2026040804060129500_awaf378-B7","doi-asserted-by":"crossref","first-page":"671","DOI":"10.1177\/1533317513506103","article-title":"Delusional misidentification syndromes and dementia: A border zone between neurology and psychiatry","volume":"28","author":"Cipriani","year":"2013","journal-title":"Am J Alzheimers Dis Other Demen"},{"key":"2026040804060129500_awaf378-B8","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1159\/000500474","article-title":"Capgras\u2019 delusion: A systematic review of 255 published 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