Early affective changes and increased connectivity in preclinical Alzheimer's disease

Abstract

Introduction: Affective changes precede cognitive decline in mild Alzheimer's disease and may relate to increased connectivity in a "salience network" attuned to emotionally significant stimuli. The trajectory of affective changes in preclinical Alzheimer's disease, and its relationship to this network, is unknown.

Methods: One hundred one cognitively normal older adults received longitudinal assessments of affective symptoms, then amyloid-PET. We hypothesized amyloid-positive individuals would show enhanced emotional reactivity associated with salience network connectivity. We tested whether increased global connectivity in key regions significantly related to affective changes.

Results: In participants later found to be amyloid positive, emotional reactivity increased with age, and interpersonal warmth declined in women. These individuals showed higher global connectivity within the right insula and superior temporal sulcus; higher superior temporal sulcus connectivity predicted increasing emotional reactivity and decreasing interpersonal warmth.

Conclusions: Affective changes should be considered an early preclinical feature of Alzheimer's disease. These changes may relate to higher functional connectivity in regions critical for social-emotional processing.

Keywords: Alzheimer's disease; Amyloid-PET; Functional connectivity; Neuropsychiatric symptoms; Preclinical Alzheimer's disease.

Fig. 1

Flow chart detailing subject selection for the overall analysis and imaging subset analysis. Abbreviation: PiB, [¹¹C]-Pittsburgh compound B; QA, quality assurance testing.

Fig. 2

Visualization of fixed effects modeling emotional reactivity and interpersonal warmth over time by amyloid status. Emotional reactivity increases longitudinally in cognitively normal PiB-positive individuals (β = 0.55, t = 4.0, P < .001) (A), whereas interpersonal warmth decreases over time in all participants, significantly more so in PiB-positive women (β = 0.61, t = 3.3, P = .001) (B). In (A), slopes are specified by the estimate of the fixed effect associated with age (for PiB-negative participants), and this fixed effect plus the fixed effect for the interaction of age by PiB positivity (for PiB-positive participants). Intercepts are specified by β₀ for the model (for PiB-negative participants), and β₀ plus the fixed effect of PiB positivity (for PiB-positive participants). (B) incorporates the fixed effect for sex and its interactions with PiB status and age to specify slopes and intercepts for PiB-negative and PiB-positive men and women. Gray ribbons represent the 95% CI of the fixed effects in the model, not incorporating residual variance or variance due to random effects, and are shown for the range of age values observed for each group. Abbreviation: PiB, [¹¹C]-Pittsburgh compound B.

Fig. 3

Amyloid-positive individuals show increased global connectivity to the insula and superior temporal sulcus (STS). (A) Whole-brain degree analysis reveals clusters in which amyloid-positive cognitively healthy older individuals show greater global connectivity compared with matched amyloid-negative individuals, including the right insula and STS, left hippocampus and parahippocampal gyrus, temporal pole, and bilateral midbrain, midline cerebellum, and pons (including the locus coeruleus and parabrachial nucleus). There were no clusters that showed significantly lower connectivity in PiB-positive individuals. Maps are thresholded at a height by extent threshold of P < .05/.05. (B) We isolated the insula (yellow) and STS (blue) clusters for regional mean whole-brain degree extraction. All images are overlaid on a template MNI152 T1 2-mm brain.