Abstract
BackgroundNeuropsychiatric symptoms (NPS) are increasingly recognized as early non-cognitive manifestations in the Alzheimer’s disease (AD) continuum. However, the role of NPS as an early marker of pathophysiological progression in AD remains unclear. Dominantly inherited AD (DIAD) mutation carriers are young individuals who are destined to develop AD in future due to the full penetrance of the genetic mutation. Hence, the study of DIAD mutation carriers enables the evaluation of the associations between pure AD pathophysiology and metabolic correlates of NPS without the confounding effects of co-existing pathologies. In this longitudinal study, we aimed to identify regional brain metabolic dysfunctions associated with NPS in cognitively intact DIAD mutation carriers.MethodsWe stratified 221 cognitively intact participants from the Dominantly Inherited Alzheimer’s Network according to their mutation carrier status. The interactions of NPS measured by the Neuropsychiatric Inventory-Questionnaire (NPI-Q), age, and estimated years to symptom onset (EYO) as a function of metabolism measured by [18F]flurodeoxyglucose ([18F]FDG) positron emission tomography, were evaluated by the mixed-effects regression model with family-level random effects in DIAD mutation carriers and non-carriers. Exploratory factor analysis was performed to identify the neuropsychiatric subsyndromes in DIAD mutation carriers using the NPI-Q sub-components. Then the effects of interactions between specific neuropsychiatric subsyndromes and EYO on metabolism were evaluated with the mixed-effects regression model.ResultsA total of 119 mutation carriers and 102 non-carriers were studied. The interaction of higher NPI-Q and shorter EYO was associated with more rapid declines of global and regional [18F]FDG uptake in the posterior cingulate and ventromedial prefrontal cortices, the bilateral parietal lobes and the right insula in DIAD mutation carriers. The neuropsychiatric subsyndromes of agitation, disinhibition, irritability and depression interacted with the EYO to drive the [18F]FDG uptake decline in the DIAD mutation carriers. The interaction of NPI and EYO was not associated with [18F]FDG uptake in DIAD mutation non-carriers.ConclusionsThe NPS in cognitively intact DIAD mutation carriers may be a clinical indicator of subsequent metabolic decline in brain networks vulnerable to AD, which supports the emerging conceptual framework that NPS represent early manifestations of neuronal injury in AD. Further studies using different methodological approaches to identify NPS in preclinical AD are needed to validate our findings.
Highlights
Neuropsychiatric symptoms (NPS) are increasingly recognized as early non-cognitive manifestations in the Alzheimer’s disease (AD) continuum
The NPS in cognitively intact Dominantly inherited AD (DIAD) mutation carriers may be a clinical indicator of subsequent metabolic decline in brain networks vulnerable to AD, which supports the emerging conceptual framework that NPS represent early manifestations of neuronal injury in AD
We modelled FDG standardized uptake value ratio (SUVR) as a function of the interactions of Neuropsychiatric InventoryQuestionnaire (NPI-Q), age and estimated years to symptom onset (EYO) and covariates, where FDG SUVRij denotes the FDG uptake for the jth person from the ith family, NPI-Qij indicates the severity of NPS, ageij indicates the age of participant at the time of study visit, EYOij indicates the years to estimated age of symptom onset and Xij represents fixed effect covariates for gender, education, APOE ε4 status and family mutation type (APP, PSEN1 and PSEN2): À Á
Summary
Neuropsychiatric symptoms (NPS) are increasingly recognized as early non-cognitive manifestations in the Alzheimer’s disease (AD) continuum. The study of DIAD mutation carriers enables the evaluation of the associations between pure AD pathophysiology and metabolic correlates of NPS without the confounding effects of co-existing pathologies. In this longitudinal study, we aimed to identify regional brain metabolic dysfunctions associated with NPS in cognitively intact DIAD mutation carriers. The roles of NPS as early clinical manifestations of pathophysiological progression of AD in cognitively normal individuals remain unclear.
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