BACKGROUND: Alzheime's disease (AD) and Lewy body disease (LBD) are the two most common neurodegenerative dementias, and can occur in combination (AD+LBD). Due to overlapping biomarkers and symptoms, especially at early stages, clinical differentiation of these subtypes could be difficult. Yet it is unclear how the magnitude of diagnostic uncertainty varies across the dementia spectrum and demographic variables. We aimed to compare clinical diagnosis and post-mortem autopsy-confirmed pathological results to assess the clinical subtype diagnosis quality across these various factors.
METHODS: We studied data from the National Alzheimer's Coordinating Center. Selection criteria included an autopsy-based neuropathological assessment for AD and/or LBD, and initial visit with Clinical Dementia Rating CDR Dementia Staging Instrument (CDR) of 0, 0.5, or 1.0 corresponding to normal, mild cognitive impairment, or mild dementia, respectively. Longitudinally, we analyzed first visits at each subsequent CDR stage, and focused on the clinical diagnosis for AD and/or LBD in these visits. This analysis included positive predictive values (PPV), specificity and sensitivity and false negative rates of the clinical diagnosis, as well as disparities in these metrics by sex, race/ethnicity, age and education. If autopsy-confirmed AD, LBD, or AD+LBD was missed, the alternative clinical diagnosis was analyzed.
FINDINGS: Records of 1887 qualified participants from September 1, 2005 to August 20, 2019 were included in the study. Clinical diagnosis of AD+LBD had poor sensitivity from 2.7% (95% CI: 1.2%, 4.8%) at CDR 0.5 to 4.7% (2.1%, 7.8%) at CDR 3.0. Over 60% of participants with autopsy-confirmed AD+LBD were diagnosed clinically as AD. Clinical diagnosis of AD had low sensitivities at early dementia stage (56.8% (95% CI: 52.4%, 61.1%)) and low specificities at all stages. Among participants diagnosed as AD in the clinic, over 33% had concurrent LBD neuropathology at autopsy. Clinical diagnosis of LBD had poor PPVs from mild cognitive impairment (22% (95% CI: 12%, 33%)) to severe dementia (20% (95% CI: 9%, 33%)). Among participants diagnosed as LBD in the clinic, 32% to 54% revealed AD pathology during autopsy. When the three subtypes were missed by clinicians, "No cognitive impairment", "Undecided" and "primary progressive aphasia or behavioral variant frontotemporal dementia" were the leading primary etiologic clinical diagnosis. With increasing dementia stages, the difference in clinical diagnosis accuracy significantly increased between White and Black/African-American participants, and diagnosis quality significantly improved for males but not for females.
INTERPRETATION: Our findings demonstrate that clinical diagnosis of AD, LBD and AD+LBD are inaccurate and harbor significant disparities based on race and sex. These findings have important implications for clinical management, anticipatory guidance, trial enrollment, and applicability of potential disease modifying therapies for AD. They also promote research into better biomarker-based assessment of LBD pathology.
Predicting outcome in mild cognitive impairment: 4-year follow-up study
