Toward Localizing Psychosis in Pathologically Confirmed Neurodegenerative Disease

Psychosis is a common symptom in neurodegenerative diseases that contributes to significant patient and caregiver burden. While neuroimaging studies have implicated various brain regions in psychosis, findings have been inconsistent across different disease entities and psychosis subtypes. This study aimed to identify structural neuroanatomic changes associated with specific patterns of psychotic content across pathologically confirmed neurodegenerative diseases. We examined 283 autopsy-confirmed neurodegenerative disease cases (70 with psychosis) at a tertiary medical center, representing diverse clinical syndromes and pathologies. Psychotic content was systematically classified using standardized criteria. Voxel-based morphometry analyses of MRI were conducted to identify structural correlates of psychotic features across all syndromes, within specific clinical syndromes, and within pathological subtypes. Overall, delusions were associated with atrophy in the right temporal lobe and bilateral frontal lobes, particularly when the delusions were persecutory or paranoid. Together, these regions support processing of external stimuli, reward, emotion, self-awareness, and executive function. By contrast, misidentification delusions correlated with right ventral temporal-occipital atrophy, implicating selective disruption of ventral visual stream processing. No consistent patterns of atrophy were found with hallucinations. Our findings suggest that damage to temporal and frontal subregions predisposes individuals with neurodegeneration to develop delusions across clinical syndromes and pathologies. This study provides support for the theory that dysfunction in brain circuits supporting reward, emotion, self-awareness, processing of external sensory signals, and executive functioning can lead to new-onset delusional beliefs in neurodegenerative disease. These insights suggest shared mechanisms between "neurologic" and "psychiatric" disorders that could inform future prognostic and therapeutic approaches.