Biomarkers.

Background: About 20-30% of clinically diagnosed AD dementia patients do not meet pathologic criteria for AD and this proportion is even higher in amnestic MCI. Among tau-negative amnestic patients, limbic-predominant age-related TDP-43 encephalopathy (LATE) has been described as a principal diagnostic alternative, especially at advanced age. LATE is characterized by a specific temporo-limbic hypometabolic signature on FDG-PET that may aid in differential diagnosis. However, little is known about the prevalence of this and other hypometabolism patterns among tau-negative amnestic patients.

Method: 360 cognitively impaired subjects (261 aMCI, 99 ADD) from the ADNI study who underwent F-Flortaucipir Tau-PET and F-FDG-PET were divided into Tau+ and Tau- using a visual read method. After screening Tau- patients for regional hypometabolism, LATE-like hypometabolism patterns were identified using an automated pattern-matching approach based on pathology-specific FDG-PET signatures derived from autopsy-confirmed cases. FDG-PET patterns among Tau- patients not fitting the LATE-specific pattern were further examined using a hierarchical clustering approach. Group differences in age, hippocampal volume, and cognitive variables were studied.

Result: 185 patients (162 aMCI, 23 ADD) were visually rated as Tau-. Among those presenting any regional hypometabolism (N=95), 37 patients (39%) had a LATE-like hypometabolism pattern (Figure 1). Hierarchical clustering of the remaining individuals revealed 3 different clusters suggestive of other neurodegenerative conditions, including a left-lateralized temporal pole pattern reminiscent of semantic dementia (C1, 18%), a posterior-occipital pattern characteristic for DLB (C2, 24%), and a more diffuse frontal pattern (C3, 19%). Compared to the other Tau- groups, the LATE-like group was significantly older (p=0.02) and had more pronounced memory impairment (p=0.02) and hippocampal atrophy (p=0.03) (Figure 2). When initially screening Tau- patients for older age (>75y) and hippocampal atrophy, the majority of patients showed a LATE-like FDG-PET pattern (59%), but other patterns remained to be present in this population at smaller proportions (19%, 9%, and 13%, for C1, C2, and C3, respectively).

Conclusion: FDG-PET provides valuable diagnostic information after a negative Tau-PET scan. Among older tau-negative patients with hippocampal atrophy, temporo-limbic hypometabolism suggestive of LATE is the most prevalent pattern, but distinct hypometabolic patterns suggestive of other neurodegenerative conditions are also present in non-negligible proportions.