In vivo tracking of tau pathology using positron emission tomography (PET) molecular imaging in small animals

Hyperphosphorylation of the tau protein leading to the formation of neurofibrillary tangles(NFTs)is a common feature in a wide range of neurodegenerative diseases known as tauopathies,which include Alzheimer’s disease(AD)and the frontotemporal dementias(FTDs).Although heavily investigated,the mechanisms underlying the pathogenesis and progression of tauopathies have yet to be fully understood.In this context,several rodent models have been developed that successfully recapitulate the behavioral and neurochemical features of tau pathology,aiming to achieve a better understanding of the link between tau and neurodegeneration.To date,behavioral and biochemical parameters assessed using these models have been conducted using a combination of memory tasks and invasive methods such as cerebrospinal fluid(CSF)sampling or post-mortem analysis.Recently,several novel positron emission tomography(PET)radiopharmaceuticals targeting tau tangles have been developed,allowing for non-invasive in vivo quantification of tau pathology.Combined with tau transgenic models and micro-PET,these tracers hold the promise of advancing the development of theoretical models and advancing our understanding of the natural history of AD and non-AD tauopathies.In this review,we briefly describe some of the most important insights for understanding the biological basis of tau pathology,and shed light on the opportunity for improved modeling of tau pathology using a combination of tau-radiopharmaceuticals and animal models.

Neuropsychiatric symptoms are early indicators of an upcoming metabolic decline in Alzheimer's disease

Background: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.Methods: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[^(18)F]flurodeoxyglucose([^(18)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 subcomponents.Then the effects of interactions between specific neuropsychiatric subsyndromes and EYO on metabolism were evaluated with the mixed-effects regression model.Results: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[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[^(18)F]FDG uptake decline in the DIAD mutation carriers.The interaction of NPI and EYO was not associated with[^(18)F]FDG uptake in DIAD mutation non-carriers.Conclusions: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 predinical AD are needed to validate our findings.