Longitudinal Evolution of Posterior Cortical Atrophy Diagnostic Delays, Overlapping Phenotypes, and Clinical Outcomes

Abstract

Background and Objectives Although several large studies have evaluated individuals with posterior cortical atrophy (PCA) cross-sectionally, its longitudinal progression remains poorly characterized. The objectives of this study were to determine the longitudinal trajectory of PCA, encompassing the temporal aspects of diagnosis, the spectrum of clinical manifestations, and patient outcomes. Methods This retrospective study included participants evaluated and diagnosed with PCA at the Mayo Clinic, between 1995 and 2023. Clinical data (demographics, neurologic evaluations, and cognitive tests at initial presentation and late stage) were extracted from medical records. Initial clinical diagnoses during previous medical evaluations, including ophthalmologic assessments after onset of neurologic symptoms, were documented. Participants were retrospectively classified as PCA-pure if they solely met PCA criteria or as PCA-plus if they exhibited complex phenotypes also meeting criteria for other neurodegenerative syndromes. CSF analyses and neuropathology findings were documented. Results The cohort of 558 participants (65% female) had a mean age at symptom onset of 61 ± 8 years, with 68% meeting early-onset criteria (younger than 65 years). The mean duration from symptom onset to diagnosis was 3.6 ± 2.5 years. Ophthalmologic/optometric evaluations (49%) and completion of ophthalmologic procedures (16%) were common before PCA diagnosis. Psychiatric diagnoses were made in 23% of participants before PCA diagnosis, particularly among younger women. Common initial symptoms included misplacement of items, difficulties with reading and driving, and concerns pertaining to basic visual processing. Notable signs were constructional apraxia, dyscalculia, simultanagnosia, and space perception deficits. CSF biomarkers were consistent with Alzheimer disease in 139 of 158 individuals (88%). Superimposed features of non-PCA clinical syndromes were observed in a quarter of the participants at presentation, with frequency of PCA-plus cases increasing longitudinally. Longitudinal analysis of Short Test of Mental Status scores predicted an initial rapid decline in cognitive function, with the rate of decline gradually slowing over 0-10 years (time coefficient [SE] = −4.20 [0.29], p < 0.001). Discussion This study highlights the protracted time from symptom onset and frequent misdiagnoses/misattribution of symptoms in PCA. Ophthalmologic evaluations often preceded neurologic assessments. Psychiatric diagnoses were more frequent among younger women. These observations highlight the need to improve diagnostic processes and earlier recognition of PCA, which may enhance the effectiveness of emerging disease-modifying therapies.