The present study showed that the emergence of NPS heralded metabolic dysfunction in brain regions susceptible to AD pathophysiology in cognitively intact DIAD mutation carriers. In these individuals who were destined to develop AD, the more severe the NPS and the shorter the EYO to AD dementia onset, the greater the metabolic decline in the PCC, vmPFC, bilateral parietal lobes and right insular. We found that the metabolic dysfunctions were driven by the neuropsychiatric subsyndrome of agitation, disinhibition, irritability and depression.
Accumulating evidence have demonstrated the importance of NPS as predictors of cognitive decline in cognitively normal individuals. In the population-based Mayo Clinic Study of Aging, the presence of NPS at baseline increased the risk of incident MCI compared to those without NPS [6]. In the Alzheimer’s Disease Cooperative Study (ADCS) Prevention Instrument Project, anxiety and depression at baseline predicted CDR conversion to ≥ 0.5 in cognitively intact older subjects over a 4-year follow-up [25] while in the National Alzheimer’s Coordinating Center (NACC) cohort, cognitively normal participants who developed CDR > 0 during follow up had a significantly earlier presence of NPS [7]. NPS among cognitively normal individuals may also represent an early manifestation of progressive metabolic dysfunction. In cognitively normal persons aged > 70 years, depressive and anxiety symptoms were associated with decreased FDG uptake in AD-related regions [26]. In a recent study of preclinical sporadic AD individuals, we found that NPS were associated with metabolic dysfunctions in the limbic network and predicted hypometabolism in the PCC [9]. Our present findings in a cohort of preclinical familial AD mutation carriers who are destined to develop AD in future further support the emerging conceptual framework that NPS are early non-cognitive manifestations of AD pathophysiology and herald subsequent metabolic decline.
The default mode network (DMN), which comprises of the PCC, vmPFC and inferior parietal lobes, plays a vital role in episodic memory processing and decreased metabolism in the DMN is observed early in the course of AD [27, 28]. The salience network (SN) which is critical in detecting and integrating behavioural and emotional stimuli, has key nodes in the insular cortex and modulates the switch between the DMN and the central executive network [29, 30]. The impairment of the SN can lead to numerous neuropsychiatric disorders such as psychosis [31] and depression [32]. Brain metabolic dysfunctions within the SN are also related to NPS in AD [33]. Therefore, our finding of NPS heralding greater FDG uptake decline in the PCC, vmPFC, parietal lobes, and right insula in DIAD mutation carriers with shorter EYO to onset of AD dementia supports the link between early NPS, limbic structures and brain regions involved in early AD pathophysiology.
While there is heterogeneity in the neuropsychiatric manifestations in AD, certain NPS tend to co-express. Hence, several neuropsychiatric sub-syndromes have been identified to characterise the clustering of NPS [34] in AD. In our study, an exploratory factor analysis revealed four neuropsychiatric subsyndromes (Table 3) and among them, only the neuropsychiatric subsyndrome “agitation, disinhibition, irritability and depression” was associated with regional metabolic decline in cognitively intact DIAD mutation carriers with shorter EYO to onset of AD dementia. This neuropsychiatric subsyndrome is consistent with findings from a systemic review of behavioural and psychological subsyndromes among elderly individuals with sporadic AD, where 34 different clusters were found and the quartet of agitation/aggression, depression, anxiety and irritability were most commonly clustered together [35]. In addition, delusion and hallucinations, depression and anxiety, agitation and irritability and euphoria and disinhibition tend to be frequently associated symptoms. Hence, our finding is consistent with the current evidence of neuropsychiatric subsyndromes in AD. In addition, given that currently reported subsyndromes are mostly defined among elderly individuals with sporadic AD, our results further advanced the field by identifying specific neuropsychiatric subsyndromes among younger cognitively intact DIAD mutation carriers who are destined to develop AD.
The neurobiology of agitation, disinhibition, irritability and depression is closely linked to dysfunctions within the PCC, vmPFC, bilateral parietal lobes and right insular. The vmPFC enables the use of emotional signals to guide decisions towards the advantageous direction, regulates behavioural responses such as changing reinforcement contingencies and emotional processing and regulation [36, 37]. The manifestation of irritability is linked to abnormal emotional processing associated with vmPFC and PCC, while behavioral disinhibition and prominent emotional lability are linked to lesions in the vmPFC. Dysfunctions within the vmPFC and PCC, which are part of the neural network involved in the modulation of normal emotional behaviour, also lead to affective disorders and depressive symptoms [38]. The insular plays a key role in producing appropriate behavioral responses in a person by integrating affective, homeostatic, and higher-order cognitive processes [39]. Irritability is associated with dysfunctions within the insular [40] while AD patients with agitation also appear to have dysfunctions within the frontal cortex, anterior cingulate cortex (ACC), orbitofrontal cortex, amygdala, and insula [41]. While the neuropsychiatric subsyndrome of agitation, disinhibition, irritability and depression is linked to regional metabolic decline in cognitively normal DIAD mutation carriers, further studies are needed to evaluate if the neuropsychiatric subsyndrome also identifies cognitively normal individuals with an increased risk of pathological progression in sporadic AD.
The main strength of the present longitudinal study is the inclusion of preclinical DIAD mutation carriers who have AD pathology and are destined to develop AD in future. This allows the study of the associations between NPS, metabolism and effects of increasing AD pathology over time (EYO). Furthermore, given that individuals may be susceptible to NPS presentations due to genetic, family and environmental factors, or being at risk for DIAD, studying both DIAD mutation and non-mutation carriers enables the control of these factors.
There are limitations to our study. Firstly, while NPI-Q is commonly used to detect NPS in AD patients, the NPI-Q was not developed for patients with prodromal or preclinical AD. Hence, the sensitivity of NPI-Q in identifying early NPS in cognitively intact individuals remains unclear. In addition, given that the NPI is based on responses from an informed caregiver, the NPI scores may not accurately reflect the NPS of study participants. In this regard, the mild behavioral impairment checklist (MBI-C) [42] which is a 34-item instrument completed by either the patient, close informant, or clinician, has been developed to assess mild behavioral impairment (MBI), a construct that characterises the emergence of sustained and impactful neuropsychiatric symptoms (NPS) in pre-dementia populations as a precursor to cognitive decline and dementia. Given that the MBI-C is sensitive in detecting MBI in people with MCI [43], future studies of NPS in pre-dementia individuals should also include the MBI-C.