A limbic-predominant amnestic neurodegenerative syndrome associated with TDP-43 pathology
Authors: Corriveau-Lecavalier Nick , Botha Hugo , Graff-Radford Jonathan , Switzer Aaron R. , Przybelski Scott A. , Wiste Heather J. , Murray Melissa E. , Reichard R. Ross , Dickson Dennis W. , Nguyen Aivi T. , Ramanan Vijay K. , McCarter Stuart J. , Boeve Bradley F. , Machulda Mary M. , Fields Julie A. , Stricker Nikki H. , Nelson Peter T. , Grothe Michel J. , Knopman David S. , Lowe Val J. , Petersen Ronald C. , Jack Clifford R. , Jones David T. 
Published: November 2023

Limbic-predominant age-related TDP-43 encephalopathy (LATE) is a neuropathologically-defined disease that affects 40% of persons in advanced age, but its associated neurological syndrome is not defined. LATE neuropathological changes (LATE-NC) are frequently comorbid with Alzheimer’s disease neuropathologic changes (ADNC). When seen in isolation, LATE-NC have been associated with a predominantly amnestic profile and slow clinical progression. We propose a set of clinical criteria for a limbic-predominant amnestic neurodegenerative syndrome (LANS) that is highly associated with LATE-NC but also other pathologic entities. The LANS criteria incorporate core, standard and advanced features that are measurablein vivo, including older age at evaluation, mild clinical syndrome, disproportionate hippocampal atrophy, impaired semantic memory, limbic hypometabolism, absence of neocortical degenerative patterns and low likelihood of neocortical tau, with degrees of certainty (highest, high, moderate, low). We operationalized this set of criteria using clinical, imaging and biomarker data to validate its associations with clinical and pathologic outcomes. We screened autopsied patients from Mayo Clinic (n = 922) and ADNI (n = 93) cohorts and applied the LANS criteria to those with an antemortem predominant amnestic syndrome (Mayo,n= 165; ADNI,n= 53). ADNC, ADNC/LATE-NC and LATE-NC accounted for 35%, 37% and 4% of cases in the Mayo cohort, respectively, and 30%, 22%, and 9% of cases in the ADNI cohort, respectively. The LANS criteria effectively categorized these cases, with ADNC having the lowest LANS likelihoods, LATE-NC patients having the highest likelihoods, and ADNC/LATE-NC patients having intermediate likelihoods. A logistic regression model using the LANS features as predictors of LATE-NC achieved a balanced accuracy of 74.6% in the Mayo cohort, and out-of-sample predictions in the ADNI cohort achieved a balanced accuracy of 73.3%. Patients with high LANS likelihoods had a milder and slower clinical course and more severe temporo-limbic degeneration compared to those with low likelihoods. Stratifying ADNC/LATE-NC patients from the Mayo cohort according to their LANS likelihood revealed that those with higher likelihoods had more temporo-limbic degeneration and a slower rate of cognitive decline, and those with lower likelihoods had more lateral temporo-parietal degeneration and a faster rate of cognitive decline. The implementation of LANS criteria has implications to disambiguate the different driving etiologies of progressive amnestic presentations in older age and guide prognosis, treatment, and clinical trials. The development ofin vivobiomarkers specific to TDP-43 pathology are needed to refine molecular associations between LANS and LATE-NC and precise antemortem diagnoses of LATE.