Characterizing Individuals Fulfilling Clinical Criteria for Limbic-Predominant Age-Related TDP-43 Encephalopathy in a Tertiary Memory Clinic

Abstract

Background and objectives: Limbic-predominant age-related TDP-43 encephalopathy (LATE) is characterized by an amnestic- and limbic-predominant phenotype, which can mimic Alzheimer disease (AD). In a memory clinic cohort, we tested whether clinical criteria for LATE can detect a clinical profile of LATE that is distinct from AD. Methods: In this retrospective examination of a longitudinal memory clinic cohort from the Alzheimer Center Amsterdam, we included individuals with mild cognitive impairment (MCI) and dementia (aged >50 years). We classified individuals based on baseline data on cognition, atrophy, amyloid-status, and tau-status into Probable- and Possible-LATE, co-occurring LATE and AD (LATE-AD), and AD (without LATE). Next, we compared these groups on demographics, clinical features, cognition, and atrophy. Results: Of 3,606 individuals (mean age at baseline 66 [SD 6], 49.2% female) available for classification, we classified 56 (1.6%) as Probable-LATE, 115 (3.2%) as Possible-LATE, 127 (3.5%) as LATE-AD, and 1,675 (46.5%) as AD. Individuals with Probable-LATE progressed slower than AD on mini-mental state examination (MMSE) (sβ [SE] = 0.12 [0.05], p = 0.02), memory (sβ [SE] = 0.11 [0.5], p = 0.01), attention (sβ [SE] = 0.12 [0.16], p = 0.05), executive functioning (sβ [SE] = 0.09 [0.04], p = 0.03), and visuospatial functioning (sβ [SE] = 0.10 [0.05], p = 0.05). Individuals with LATE-AD progressed faster than AD on MMSE (sβ [SE] = -0.12 [0.05], p = 0.01), attention (sβ [SE] = -0.13 [0.06], p = 0.04), and executive functioning (sβ [SE] = -0.10 [0.05], p = 0.03). Mortality risk, compared to AD, was lower in individuals with Probable-LATE (hazard ratio [HR] 0.70 [0.49-0.99], p = 0.04) and higher in Possible LATE-AD (HR 1.25 [1.01-1.53], p = 0.04). Compared to AD, at baseline, individuals with Probable-LATE and Possible-LATE had higher inferior temporal-to-hippocampus ratios (indicating limbic-predominant atrophy; sβ [SE] = 0.59 [0.16], p < 0.01; sβ [SE] = 0.40 [0.13], p < 0.01), and Probable-LATE, Possible-LATE, and LATE-AD all showed smaller amygdalar volumes at baseline than AD (sβ [SE] = -0.55 [0.15], p < 0.01; sβ [SE] = -0.43 [0.12], p < 0.01; sβ [SE] = -0.62 [0.11], p < 0.01). Individuals with LATE-AD had thinner cortex at baseline in an "AD-signature" composite region compared to AD (sβ [SE] = -0.73 [0.11], p < 0.01). Discussion: Using an operationalization of clinical criteria for LATE, 8.2% of participants with MCI or dementia from our tertiary memory clinic were classified as Possible-LATE, Probable-LATE, or LATE-AD. Probable-LATE was characterized by a milder disease course than AD, whereas LATE-AD was characterized by a more aggressive disease course. This underscores the value of the proposed clinical criteria in identifying individuals with suspected LATE, who have distinct clinical trajectories from AD. Our findings, therefore, support the use of these criteria to improve diagnostic and prognostic accuracy in the memory clinic.