Probing severe cognitive impairment in treatment resistant schizophrenia: a proof-of-concept in vivo study with (18F)-Flutemetamol PET

Treatment-resistant schizophrenia (TRS) affects almost 30% of patients with the disorder. This condition is associated with functional impairment and has been suggested to have a putatively different neurobiology compared to non-treatment-resistant schizophrenia. One striking feature of TRS is the presence of relevant cognitive deficits, which, in many cases, align with a Mild Cognitive Impairment (MCI)‑like clinical profile without implying amyloid-β (Aβ) pathology. Conversely, aspects of MCI partially overlap with the trajectory of schizophrenia, motivating investigation of putative common factors of convergence. Despite its relevance, in vivo data directly addressing this question are lacking. We used ¹⁸(F)-Flutemetamol Positron Emission Tomography (PET) to investigate regional cortical Aβ deposition and its potential association with clinical symptoms in patients with TRS with MCI‑like cognitive impairment (TRS-MCI). TRS-MCI ( n = 12) underwent a PET scan and clinical evaluation, including the Positive and Negative Syndrome Scale (PANSS) and the Brief Assessment of Cognition in Schizophrenia (BACS). PET image analysis was performed using the Diagnosis ORIented ANalysis software, which provides different semiquantitative indices of regional cortical Aβ PET measures. PET data obtained in TRS-MCI were compared with those of amyloid-negative cognitively impaired patients (Aβ- CI) without psychiatric disorders ( n = 12). Group‑level comparisons using expert visual assessment and semi‑automated quantification showed no significant differences. Exploratory correlation within TRS‑MCI revealed a negative association between the regional Aβ composite scores in the Right Parietal Cortex and the PANSS Positive score ( P ≤ 0.01). This pilot study found no evidence of increased cortical Aβ deposition in TRS patients; nevertheless, regional variation in Parietal Cortex ( 18 F)‑Flutemetamol PET signal within the Aβ‑negative range was associated with positive symptoms, warranting confirmation in larger, longitudinal cohorts.