Brain Metabolic Dysfunction in Early Neuropsychiatric Symptoms of Dementia

Abstract

Neuropsychiatric symptoms (NPS) including behavioral and psychiatric symptoms are common in the dementia stages of Alzheimer's disease (AD) and are associated with poorer outcomes in cognition, functional states, quality of life, and accelerated progression to severe dementia or death. NPS are also increasingly observed in the mild cognitive impairment stage of AD and may predict incipient dementia. As such, there is an emerging conceptual framework, which support NPS as early non-cognitive symptoms of dementia. [18F]fluorodeoxyglucosepositron emission tomography is a technique that is sensitive in detecting resting metabolism associated with NPS in neuropsychiatric conditions, and there is a growing body of literature evaluating the role of NPS as early indicators of brain metabolic dysfunctions in AD. In this mini-review, we examine the frequency and associations of NPS with metabolic dysfunction in the AD continuum, including preclinical, prodromal, and dementia stages of AD. We will also present the validated neurobehavioral syndrome, mild behavioral impairment describes the later life emergence of sustained NPS as an at-risk state for incident cognitive decline and dementia, and an early presentation of neurodegenerative diseases in some. Lastly, we will discuss future directions in the field so as to better understand the neurobiological basis of NPS in the early stages of the AD continuum, and their role in predicting AD pathophysiological progression and incident dementia.

Chronic subsyndromal depression and risk of dementia in older adults

“…Among these trajectories, only the increasing trajectory was associated with a higher risk of dementia compared to the low trajectory. The high risk of dementia observed only during the increasing trajectory of depression in our study and in the Rotterdam study further supports the prodromal hypothesis, which suggests that depressive symptoms during old age possibly represent a prodrome or an early stage of dementia (Mirza et al, 2016;Ng et al, 2019). However, previous studies showed that chronic SSD is associated with the atrophy rates in the frontal and anterior cingulate cortices but not with the atrophy rates in typical AD-related regions such as the hippocampus and entorhinal cortex.…”

Associations of AT(N) biomarkers with neuropsychiatric symptoms in preclinical Alzheimer’s disease and cognitively unimpaired individuals

“…The evidence for the associations between neurodegeneration and NPS in preclinical AD is inconsistent, which may be due to the small number of studies and the variability of biomarkers studied. However, studies have extensively evaluated the neuroanatomical and metabolic correlates of NPS in the MCI and dementia stages of AD, suggesting that the NPS are associated with neurodegeneration of specific neural networks in AD [69][70][71]. Therefore, it may not be surprising to observe a lack of an association between NPS and neurodegeneration in preclinical AD.…”

“…The development of AD biomarkers and neuroimaging methods has further advanced the understanding of the mechanisms leading to NPS in AD. In these reviews, brain networks/circuits that are involved in agitation, apathy and delusions [71], neuropathology, neurotransmitter, neuroimaging, ApoE genotype, inflammation, and clusterin biomarkers associated with agitation and aggression in AD [79], and metabolic dysfunctions associated with NPS in the AD continuum [70], have been discussed. Most recently, a systematic review has further shown inconsistent associations between AT(N) biomarkers and NPS such as depression, anxiety, apathy, agitation, irritability and night-time behavioral disturbances in MCI and AD dementia [44].…”

Prevalence of mild behavioural impairment domains: a meta‐analysis

“…The pathophysiological process of AD begins years before the diagnosis of clinical dementia 3 . Recent research shows that neuropsychiatric symptoms (NPS) or mild behavioural impairment (MBI) could be early manifestations of neurodegenerative disease 4–12 …”