Increased neural activity relates to greater neuropsychiatric symptoms and beta‐amyloid plaque load in cognitively normal older adults

Abstract

AbstractBackgroundEpidemiological studies have shown that individuals predisposed to experiencing psychological stress, and those affected with diseases associated with chronic stress such as depression and anxiety have an increased risk of developing Alzheimer’s disease (AD). These findings may imply that poor resilience to psychological stress is not simply a characteristic of dementia, but may reflect mechanisms involved in disease etiology. In this study, we examined the level of neural activity as a potential mechanism of linking individual susceptibility to psychological stress and AD‐related neuropathology across the spectrum of AD.MethodsA total of 166 participants (mean age = 74.21; 90 Females) spanning diagnostic spectrums along cognitively normal (CN) individuals and AD patients was selected for analysis from the ADNI2 database based on the availability of resting state fMRI and AV45 PET data. Neural activity was quantified by applying the amplitude of low frequency fluctuations (ALFF) method to time series of fMRI blood oxygenation‐level‐dependent signals (in the frequency range of 0.01‐0.08 Hz) obtained during resting‐state fMRI (rsfMRI) scan. Amyloid pathology was quantified by AV45‐SUVR measures that were normalized to the cerebellum. Mini‐Mental State Exam (MMSE) and the total Neuropsychiatric Inventory Questionnaire (NPI‐Q) scores were used as cognitive and stress susceptibility measures.ResultsBehavioral measures of stress were significantly associated with brain Aβ indices and neural activity across the entire cohort, spanning from CN older adults to AD patients (ps<0.05). Relationships between the neural activity, stress responses, and Aβ deposition, however, differ by diagnostic groups. As stress indicators increased, CN subjects exhibited increased activity in several brain regions including the regions within the default mode network (DMN), while AD participants exhibited decreased activity across the brain. Moreover, as brain Aβ load increased, CN participants experienced DMN hyperactivity, while AD participants experienced hypoactivity.ConclusionThese results indicate a potential link between heightened stress responses and increased susceptibility to the development of AD pathologies through neuronal hyperactivity, especially in the preclinical stage of AD. Alleviating stress and regulating stress responses may be important modifiable factors and intervention strategies that could help prevent and intervene the development of AD pathology.