Medial amygdalar tau is associated with anxiety symptoms in preclinical Alzheimer's disease

Abstract

Background: While the amygdala receives early tau deposition in Alzheimer's disease (AD) and is involved in social and emotional processing, the relationship between amygdalar tau and early neuropsychiatric symptoms in AD is unknown. We sought to determine whether focal tau binding in the amygdala and abnormal amygdalar connectivity were detectable in a preclinical AD cohort and identify relationships between these and self-reported mood symptoms.

Methods: We examined n=598 individuals (n=347 amyloid-positive (58% female), n=251 amyloid-negative (62% female); subset into tau PET and fMRI cohorts) from the A4 Study. In our tau PET cohort, we used amygdalar segmentations to examine representative nuclei from three functional divisions of the amygdala. We analyzed between-group differences in division-specific tau binding in the amygdala in preclinical AD. We conducted seed-based functional connectivity analyses from each division in the fMRI cohort. Finally, we conducted exploratory post-hoc correlation analyses between neuroimaging biomarkers of interest and anxiety and depression scores.

Results: Amyloid-positive individuals demonstrated increased tau binding in medial and lateral amygdala (F(4,442)=14.61, p=0.00045; F(4,442)=5.83, p=0.024, respectively). Across amygdalar divisions, amyloid-positive individuals had relatively increased regional connectivity from amygdala to other temporal regions, insula, and orbitofrontal cortex. There was an interaction by amyloid group between tau binding in the medial and lateral amygdala and anxiety. Medial amygdala to retrosplenial connectivity negatively correlated with anxiety symptoms (r_s=-0.103, p=0.015).

Conclusions: Our findings suggest that preclinical tau deposition in the amygdala may result in meaningful changes in functional connectivity which may predispose patients to mood symptoms.

Keywords: amygdala; anxiety; default mode network; functional networks; preclinical Alzheimer’s disease; tau.

Figure 1.. Functional networks overlaid on amygdala tau deposition.

Three major functional subdivisions of the amygdala defined by neuroimaging (24) overlaid on a pathologic cross-section through the amygdala showing the major nuclei (based on Saygin et al. 2017 (37)). Red shading indicates nuclei with the heaviest burden of tau pathology (12), while green shading indicates nuclei with relatively less tau burden.

Figure 2.. Between-group differences in global and amygdalar region-specific tau binding.

(A) Global amygdalar tau binding was greater in the amyloid-positive group. (B) Amygdalar tau uptake was greater in amyloid-positive individuals in the medial (CTA) and lateral (lateral nuclei) amygdala, but not in the dorsal (central nucleus) amygdala. T- or F-statistics reported when appropriate. Results are controlled for age, ICV, and entorhinal tau binding. * p < 0.05, ** p< 0.001, *** p<0.0001. CTA = Cortico-amygdaloid Transition Area; SUVR = Standardized Uptake Value Ratio.

Figure 3.. Functional connectivity from amygdalar seeds to the whole brain (amyloid-positive > amyloid-negative control).

Across the three seeds, amyloid-positive subjects had greater connectivity from the (A) dorsal network, (B) medial network, and (C) lateral network seeds, to bilateral medial temporal lobes and temporal poles relative to amyloid-negative controls, with variable connectivity to retrosplenial cortex and decreased connectivity to insula, basal ganglia (including accumbens), and superior parietal and dorsolateral prefrontal cortex. Color bars represent T-values. CTA = Cortico-amygdaloid Transition Area.

Figure 4.. Connectivity to the retrosplenial cortex cluster across the three amygdalar nuclei seeds between amyloid-positive and amyloid-negative groups.

(A) Representation of the retrosplenial cluster identified from the CTA seed. (B) Relatively decreased connectivity to the retrosplenial cortex between amyloid groups was only observed from the medial (CTA) seed. Error bars represent standard error of the mean. CTA = Cortico-amygdaloid Transition Area; RSC = Retrosplenial Cortex.

Figure 5.. Relationship between medial-, dorsal-, and lateral-group amygdalar tau uptake and depression or anxiety score.

Data plotted for amyloid-positive (coral) and amyloid-negative (light blue) individuals. Depression did not significantly associate with (A) dorsal-group (central nucleus), (B) medial-group (CTA), or (C) lateral-group (lateral nucleus) tau binding in the left hemisphere. Anxiety was significantly correlated with (F) left lateral-group tau but was not correlated with (D) dorsal-group or (E) medial-group tau uptake. Shaded area represents 95% confidence. CTA = Cortico-amygdaloid Transition Area; SUVR = Standardized Uptake Value Ratio; GDS = Geriatric Depression Scale score; r_s = Spearman Correlation Coefficient; STAI = short-form State-Trait Anxiety Inventory score.

Figure 6.. Correlations between clusters of interest and neurocognitive scores.

(A) Clusters identified from conjunction analysis of functional connectivity maps from the three amygdalar seeds. Red = right insula cluster; green = left temporal cluster; blue = right temporal cluster. (B) Partial correlation results to neuropsychiatric measures from the dorsal-, medial-, and lateral-groups respectively, to a given cluster. Aβ+ = Amyloid-positive; Aβ− = Amyloid-negative; CTA = Corticoamygdaloid Transition Area; GDS = Geriatric Depression Scale score; NP = Neuropsychiatric Test; RSC = Retrosplenial Cortex; STAI = short-form State-Trait Anxiety Inventory score.