Alzheimer's Disease Research Unit, McGill Centre for Studies in Aging, McGill University, Montréal, Québec, Canada.
Translational Neuroimaging Laboratory, The McGill University Research Centre for Studies in Aging, Montreal, Canada.
Transl Neurodegener. 2021 Jan 4;10(1):1. doi: 10.1186/s40035-020-00225-y.
Neuropsychiatric 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.
We 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 [F]flurodeoxyglucose ([F]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.
A 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 [F]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 [F]FDG uptake decline in the DIAD mutation carriers. The interaction of NPI and EYO was not associated with [F]FDG uptake in DIAD mutation non-carriers.
The 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.
神经精神症状（NPS）越来越被认为是阿尔茨海默病（AD）连续体中的早期非认知表现。然而，NPS 作为 AD 病理生理进展的早期标志物的作用尚不清楚。显性遗传性 AD（DIAD）突变携带者是年轻个体，由于遗传突变的完全外显，他们注定会在未来患上 AD。因此，对 DIAD 突变携带者的研究可以评估纯 AD 病理生理学与 NPS 的代谢相关性之间的关联，而不会受到共存病理的混杂影响。在这项纵向研究中，我们旨在确定与认知正常的 DIAD 突变携带者的 NPS 相关的区域性脑代谢功能障碍。
我们根据突变携带者状态对来自显性遗传性阿尔茨海默病网络的 221 名认知正常的参与者进行分层。通过混合效应回归模型，以家族水平的随机效应评估由神经精神病学问卷（NPI-Q）测量的 NPS 与[F]氟脱氧葡萄糖（[F]FDG）正电子发射断层扫描测量的代谢之间的相互作用，考虑了 NPS 的交互作用、年龄和估计的症状出现年限（EYO）。在 DIAD 突变携带者和非携带者中进行了探索性因子分析，以使用 NPI-Q 亚成分确定 DIAD 突变携带者的神经精神亚综合征。然后，通过混合效应回归模型评估特定神经精神亚综合征与 EYO 之间的相互作用对代谢的影响。
共研究了 119 名突变携带者和 102 名非携带者。较高的 NPI-Q 和较短的 EYO 的相互作用与 DIAD 突变携带者的后扣带回和腹内侧前额叶皮质、双侧顶叶和右侧岛叶的全局和区域性[F]FDG 摄取的更快下降有关。激越、抑制障碍、易怒和抑郁的神经精神亚综合征与 EYO 相互作用，导致 DIAD 突变携带者的[F]FDG 摄取下降。NPI 和 EYO 的相互作用与 DIAD 突变非携带者的[F]FDG 摄取无关。
认知正常的 DIAD 突变携带者的 NPS 可能是 AD 易损脑网络中随后代谢下降的临床指标，这支持了 NPS 代表 AD 中神经元损伤的早期表现的新兴概念框架。需要使用不同的方法学方法来识别临床前 AD 中的 NPS，以验证我们的发现。
