By Michael T. Lin, MD, PhD
Associate Professor of Neurology and Neuroscience, Weill Cornell Medical College
This is the first comprehensive international study of patients with posterior cortical atrophy, including clinical, biomarker, and pathology data from 1,092 patients. These patients present at a younger age, have a very high prevalence of amyloid positivity on cerebrospinal fluid studies and positron emission tomography, and 94% had autopsy evidence of Alzheimer’s disease.
Chapleau M, La Joie R, Yong K, et al; PCA International Work Group. Demographic, clinical, biomarker, and neuropathological correlates of posterior cortical atrophy: An international cohort study and individual participant data meta-analysis. Lancet Neurol 2024;23:168-177.
The posterior cortical atrophy (PCA) syndrome is characterized by early, prominent, and progressive impairment in visuoperceptual and visuospatial processing, referable to occipital, parietal, and posterior temporal regions. It typically is caused by neurodegenerative diseases, primarily Alzheimer’s disease (AD), and, less commonly, dementia with Lewy bodies (DLB), corticobasal degeneration (CBD), and prion disease. PCA is relatively rare, so previous reports have consisted of small case series from single centers. To remedy this situation, Chapleau and colleagues presented the first large, comprehensive international study of PCA. The authors performed a comprehensive PubMed search from database inception to Aug. 1, 2021, identifying 1,353 papers and 55 research centers, from which 29 centers responded to requests for de-identified individual patient data. An additional seven centers were recruited through the Alzheimer’s Association. In total, data from 1,092 individuals were obtained from 36 research centers in 16 countries. Using a meta-analysis framework, they analyzed the demographic, clinical, biomarker, and neuropathologic features of PCA.
Demographically, PCA presents at younger age (mean age at symptom onset, 59.4 years), with more than 75% of patients developing symptoms before age 65 years. PCA was more common in women (60%). Clinically, there often was a delay to diagnosis (mean age at diagnosis, 63.2 years), with at least mild dementia at time of diagnosis (mean Mini-Mental State Examination score, 20.5 and 62% with global Clinical Dementia Rating ≥ 1). The most common posterior cortical symptoms were constructional dyspraxia (61%), space perception deficit (49%), simultanagnosia (48%), and features of the Gerstmann syndrome (acalculia, 47%; alexia, 43%; agraphia, 42%). As expected, a significant fraction also had clinical features typical of AD at first diagnostic visit, including impairment in memory (47%), executive functions (40%), behavior (33%), and language (32%).
The vast majority of those in whom AD biomarkers were obtained had evidence of amyloid: 81% of 536 subjects had abnormal cerebrospinal fluid (CSF) amyloid-beta, 94% of 299 subjects had positive amyloid positron emission tomography (PET), and 89% of 689 subjects had at least one positive amyloid determination. Out of 689 subjects with a positive amyloid determination, 390 had CSF only, 153 had amyloid PET only, and 146 had both. Of the 146 with both, there were 27 discrepancies: three CSF+/PET- and 24 CSF-/PET+, suggesting that PET was the more reliable marker.
As expected, subjects who were amyloid negative were more likely to have clinical features of other degenerative disorders (such as parkinsonism [DLB] or limb apraxia [CBD]): 20% of amyloid-negative subjects had such features, whereas only 5% of amyloid-positive subjects had such features (P < 0.0001). Age at symptom onset and diagnosis, sex, and other clinical features did not differ by amyloid status.
There also were several differences in AD biomarkers compared to AD patients with the typical amnestic presentation. Only 43% of 451 PCA subjects carried an APOE4 allele, compared to ~60% in AD cases overall.1 CSF p-tau was positive in only 65% of 503 subjects, although tau PET was positive in 97% of 170 subjects. This matches a previous smaller study in which an atypical AD CSF profile (amyloid+, tau-) occurred in one-third of PCA subjects.2
Autopsy data was available for 145 subjects. The primary neuropathologic diagnosis was AD in 94%, most of whom had one or more co-pathologies: cerebral amyloid angiopathy (71%), DLB (44%), and cerebrovascular injury (42%). Only 10 cases had a primary neuropathologic diagnosis other than AD: four cases of DLB (all of whom also had significant levels of AD neuropathologic changes), four cases of frontotemporal degeneration (two CBD, one Pick’s disease, one TDP43), and two cases of brain infarct with minimal AD co-pathology. There were no cases of prion disease.
COMMENTARY
This is the first large, comprehensive, international meta-analytic study of PCA. There may have been some selection bias, as illustrated by the lack of prion disease cases. However, it reaffirms the young age at onset and extremely high correlation with AD biomarkers and AD pathology seen in previous smaller studies. PCA may be the presentation that is most highly correlated with AD at ~90%; in contrast, only ~70% of amnestic or aphasia presentations correlate with AD pathology. This is particularly crucial because the young age at onset may be an impediment to diagnosis, and there is now disease-modifying treatment for AD in the form of anti-amyloid antibodies.
Moreover, PCA subjects tend to have lower frequencies of APOE4 and may, therefore, be at lower risk for amyloid-related imaging abnormalities as a side effect of anti-amyloid antibodies. Thus, all subjects with a PCA presentation should be tested for AD biomarkers by CSF or amyloid PET. The study also raises interesting questions about how the pathophysiology of PCA-AD differs from that of more typical presentations, in terms of the roles of APOE4, phosphor-tau, sex, age, and brain connectivity.
REFERENCES
- Crean S, Ward A, Mercaldi CJ, et al. Apolipoprotein E ε4 prevalence in Alzheimer’s disease patients varies across global populations: A systematic literature review and meta-analysis. Dement Geriatr Cogn Disord 2011;31:20-30.
- Montembeault M, Brambati SM, Lamari F, et al. Atrophy, metabolism and cognition in the posterior cortical atrophy spectrum based on Alzheimer’s disease cerebrospinal fluid biomarkers. Neuroimage Clin 2018;20:1018-1025.
