title: Neuropsychiatric symptoms predict hypometabolism in preclinical Alzheimer disease.
abstract: OBJECTIVE
  To identify regional brain metabolic dysfunctions associated with neuropsychiatric symptoms (NPS) in preclinical Alzheimer disease (AD).
  
  
  METHODS
  We stratified 115 cognitively normal individuals into preclinical AD (both amyloid and tau pathologies present), asymptomatic at risk for AD (either amyloid or tau pathology present), or healthy controls (no amyloid or tau pathology present) using [18F]florbetapir PET and CSF phosphorylated tau biomarkers. Regression and voxel-based regression models evaluated the relationships between baseline NPS measured by the Neuropsychiatric Inventory (NPI) and baseline and 2-year change in metabolism measured by [18F]fluorodeoxyglucose (FDG) PET.
  
  
  RESULTS
  Individuals with preclinical AD with higher NPI scores had higher [18F]FDG uptake in the posterior cingulate cortex (PCC), ventromedial prefrontal cortex, and right anterior insula at baseline. High NPI scores predicted subsequent hypometabolism in the PCC over 2 years only in individuals with preclinical AD. Sleep/nighttime behavior disorders and irritability and lability were the components of the NPI that drove this metabolic dysfunction.
  
  
  CONCLUSIONS
  The magnitude of NPS in preclinical cases, driven by sleep behavior and irritability domains, is linked to transitory metabolic dysfunctions within limbic networks vulnerable to the AD process and predicts subsequent PCC hypometabolism. These findings support an emerging conceptual framework in which NPS constitute an early clinical manifestation of AD pathophysiology.
authors.affiliation: From the Translational Neuroimaging Laboratory (K.P.N., T.A.P., S.M., C.-O.C., A.L.B., M.S., M.S.K., P.R.-N.) and Alzheimer's Disease Research Unit (K.P.N., X.L., M.B., P.R.-N., S.G.), McGill University Research Centre for Studies in Aging, Montreal, Quebec, Canada; Department of Neurology (K.P.N., N.K.), National Neuroscience Institute, Singapore; Montreal Neurological Institute (P.R.-N.); Department of Neurology and Neurosurgery (P.R.-N.), McGill University, Montreal, Quebec, Canada; Department of Neurology (X.L.), The Second Affiliated Hospital of Chongqing Medical University, Chongqing; and Department of Neurology (M.B.), Yantai Yuhuangding Hospital Affiliated to Qingdao Medical University, Shandong, PR China.
authors.forename: Kok Pin
authors.initials: KP
authors.lastname: Ng
authors.affiliation: From the Translational Neuroimaging Laboratory (K.P.N., T.A.P., S.M., C.-O.C., A.L.B., M.S., M.S.K., P.R.-N.) and Alzheimer's Disease Research Unit (K.P.N., X.L., M.B., P.R.-N., S.G.), McGill University Research Centre for Studies in Aging, Montreal, Quebec, Canada; Department of Neurology (K.P.N., N.K.), National Neuroscience Institute, Singapore; Montreal Neurological Institute (P.R.-N.); Department of Neurology and Neurosurgery (P.R.-N.), McGill University, Montreal, Quebec, Canada; Department of Neurology (X.L.), The Second Affiliated Hospital of Chongqing Medical University, Chongqing; and Department of Neurology (M.B.), Yantai Yuhuangding Hospital Affiliated to Qingdao Medical University, Shandong, PR China.
authors.forename: Tharick A
authors.initials: TA
authors.lastname: Pascoal
authors.affiliation: From the Translational Neuroimaging Laboratory (K.P.N., T.A.P., S.M., C.-O.C., A.L.B., M.S., M.S.K., P.R.-N.) and Alzheimer's Disease Research Unit (K.P.N., X.L., M.B., P.R.-N., S.G.), McGill University Research Centre for Studies in Aging, Montreal, Quebec, Canada; Department of Neurology (K.P.N., N.K.), National Neuroscience Institute, Singapore; Montreal Neurological Institute (P.R.-N.); Department of Neurology and Neurosurgery (P.R.-N.), McGill University, Montreal, Quebec, Canada; Department of Neurology (X.L.), The Second Affiliated Hospital of Chongqing Medical University, Chongqing; and Department of Neurology (M.B.), Yantai Yuhuangding Hospital Affiliated to Qingdao Medical University, Shandong, PR China.
authors.forename: Sulantha
authors.initials: S
authors.lastname: Mathotaarachchi
authors.affiliation: From the Translational Neuroimaging Laboratory (K.P.N., T.A.P., S.M., C.-O.C., A.L.B., M.S., M.S.K., P.R.-N.) and Alzheimer's Disease Research Unit (K.P.N., X.L., M.B., P.R.-N., S.G.), McGill University Research Centre for Studies in Aging, Montreal, Quebec, Canada; Department of Neurology (K.P.N., N.K.), National Neuroscience Institute, Singapore; Montreal Neurological Institute (P.R.-N.); Department of Neurology and Neurosurgery (P.R.-N.), McGill University, Montreal, Quebec, Canada; Department of Neurology (X.L.), The Second Affiliated Hospital of Chongqing Medical University, Chongqing; and Department of Neurology (M.B.), Yantai Yuhuangding Hospital Affiliated to Qingdao Medical University, Shandong, PR China.
authors.forename: Chang-Oh
authors.initials: CO
authors.lastname: Chung
authors.affiliation: From the Translational Neuroimaging Laboratory (K.P.N., T.A.P., S.M., C.-O.C., A.L.B., M.S., M.S.K., P.R.-N.) and Alzheimer's Disease Research Unit (K.P.N., X.L., M.B., P.R.-N., S.G.), McGill University Research Centre for Studies in Aging, Montreal, Quebec, Canada; Department of Neurology (K.P.N., N.K.), National Neuroscience Institute, Singapore; Montreal Neurological Institute (P.R.-N.); Department of Neurology and Neurosurgery (P.R.-N.), McGill University, Montreal, Quebec, Canada; Department of Neurology (X.L.), The Second Affiliated Hospital of Chongqing Medical University, Chongqing; and Department of Neurology (M.B.), Yantai Yuhuangding Hospital Affiliated to Qingdao Medical University, Shandong, PR China.
authors.forename: Andréa L
authors.initials: AL
authors.lastname: Benedet
authors.affiliation: From the Translational Neuroimaging Laboratory (K.P.N., T.A.P., S.M., C.-O.C., A.L.B., M.S., M.S.K., P.R.-N.) and Alzheimer's Disease Research Unit (K.P.N., X.L., M.B., P.R.-N., S.G.), McGill University Research Centre for Studies in Aging, Montreal, Quebec, Canada; Department of Neurology (K.P.N., N.K.), National Neuroscience Institute, Singapore; Montreal Neurological Institute (P.R.-N.); Department of Neurology and Neurosurgery (P.R.-N.), McGill University, Montreal, Quebec, Canada; Department of Neurology (X.L.), The Second Affiliated Hospital of Chongqing Medical University, Chongqing; and Department of Neurology (M.B.), Yantai Yuhuangding Hospital Affiliated to Qingdao Medical University, Shandong, PR China.
authors.forename: Monica
authors.initials: M
authors.lastname: Shin
authors.affiliation: From the Translational Neuroimaging Laboratory (K.P.N., T.A.P., S.M., C.-O.C., A.L.B., M.S., M.S.K., P.R.-N.) and Alzheimer's Disease Research Unit (K.P.N., X.L., M.B., P.R.-N., S.G.), McGill University Research Centre for Studies in Aging, Montreal, Quebec, Canada; Department of Neurology (K.P.N., N.K.), National Neuroscience Institute, Singapore; Montreal Neurological Institute (P.R.-N.); Department of Neurology and Neurosurgery (P.R.-N.), McGill University, Montreal, Quebec, Canada; Department of Neurology (X.L.), The Second Affiliated Hospital of Chongqing Medical University, Chongqing; and Department of Neurology (M.B.), Yantai Yuhuangding Hospital Affiliated to Qingdao Medical University, Shandong, PR China.
authors.forename: Min Su
authors.initials: MS
authors.lastname: Kang
authors.affiliation: From the Translational Neuroimaging Laboratory (K.P.N., T.A.P., S.M., C.-O.C., A.L.B., M.S., M.S.K., P.R.-N.) and Alzheimer's Disease Research Unit (K.P.N., X.L., M.B., P.R.-N., S.G.), McGill University Research Centre for Studies in Aging, Montreal, Quebec, Canada; Department of Neurology (K.P.N., N.K.), National Neuroscience Institute, Singapore; Montreal Neurological Institute (P.R.-N.); Department of Neurology and Neurosurgery (P.R.-N.), McGill University, Montreal, Quebec, Canada; Department of Neurology (X.L.), The Second Affiliated Hospital of Chongqing Medical University, Chongqing; and Department of Neurology (M.B.), Yantai Yuhuangding Hospital Affiliated to Qingdao Medical University, Shandong, PR China.
authors.forename: Xiaofeng
authors.initials: X
authors.lastname: Li
authors.affiliation: From the Translational Neuroimaging Laboratory (K.P.N., T.A.P., S.M., C.-O.C., A.L.B., M.S., M.S.K., P.R.-N.) and Alzheimer's Disease Research Unit (K.P.N., X.L., M.B., P.R.-N., S.G.), McGill University Research Centre for Studies in Aging, Montreal, Quebec, Canada; Department of Neurology (K.P.N., N.K.), National Neuroscience Institute, Singapore; Montreal Neurological Institute (P.R.-N.); Department of Neurology and Neurosurgery (P.R.-N.), McGill University, Montreal, Quebec, Canada; Department of Neurology (X.L.), The Second Affiliated Hospital of Chongqing Medical University, Chongqing; and Department of Neurology (M.B.), Yantai Yuhuangding Hospital Affiliated to Qingdao Medical University, Shandong, PR China.
authors.forename: Maowen
authors.initials: M
authors.lastname: Ba
authors.affiliation: From the Translational Neuroimaging Laboratory (K.P.N., T.A.P., S.M., C.-O.C., A.L.B., M.S., M.S.K., P.R.-N.) and Alzheimer's Disease Research Unit (K.P.N., X.L., M.B., P.R.-N., S.G.), McGill University Research Centre for Studies in Aging, Montreal, Quebec, Canada; Department of Neurology (K.P.N., N.K.), National Neuroscience Institute, Singapore; Montreal Neurological Institute (P.R.-N.); Department of Neurology and Neurosurgery (P.R.-N.), McGill University, Montreal, Quebec, Canada; Department of Neurology (X.L.), The Second Affiliated Hospital of Chongqing Medical University, Chongqing; and Department of Neurology (M.B.), Yantai Yuhuangding Hospital Affiliated to Qingdao Medical University, Shandong, PR China.
authors.forename: Nagaendran
authors.initials: N
authors.lastname: Kandiah
authors.affiliation: From the Translational Neuroimaging Laboratory (K.P.N., T.A.P., S.M., C.-O.C., A.L.B., M.S., M.S.K., P.R.-N.) and Alzheimer's Disease Research Unit (K.P.N., X.L., M.B., P.R.-N., S.G.), McGill University Research Centre for Studies in Aging, Montreal, Quebec, Canada; Department of Neurology (K.P.N., N.K.), National Neuroscience Institute, Singapore; Montreal Neurological Institute (P.R.-N.); Department of Neurology and Neurosurgery (P.R.-N.), McGill University, Montreal, Quebec, Canada; Department of Neurology (X.L.), The Second Affiliated Hospital of Chongqing Medical University, Chongqing; and Department of Neurology (M.B.), Yantai Yuhuangding Hospital Affiliated to Qingdao Medical University, Shandong, PR China.
authors.forename: Pedro
authors.initials: P
authors.lastname: Rosa-Neto
authors.affiliation: From the Translational Neuroimaging Laboratory (K.P.N., T.A.P., S.M., C.-O.C., A.L.B., M.S., M.S.K., P.R.-N.) and Alzheimer's Disease Research Unit (K.P.N., X.L., M.B., P.R.-N., S.G.), McGill University Research Centre for Studies in Aging, Montreal, Quebec, Canada; Department of Neurology (K.P.N., N.K.), National Neuroscience Institute, Singapore; Montreal Neurological Institute (P.R.-N.); Department of Neurology and Neurosurgery (P.R.-N.), McGill University, Montreal, Quebec, Canada; Department of Neurology (X.L.), The Second Affiliated Hospital of Chongqing Medical University, Chongqing; and Department of Neurology (M.B.), Yantai Yuhuangding Hospital Affiliated to Qingdao Medical University, Shandong, PR China. serge.gauthier@mcgill.ca.
authors.forename: Serge
authors.initials: S
authors.lastname: Gauthier
mesh_terms: D000368:Aged; D000544:Alzheimer Disease / Q000000981:diagnostic imaging / Q000235:genetics / Q000378:metabolism* / Q000523:psychology*; D000814:Aniline Compounds; D053327:Apolipoprotein E4 / Q000235:genetics; D015415:Biomarkers / Q000134:cerebrospinal fluid; D001921:Brain / Q000000981:diagnostic imaging / Q000378:metabolism*; D001931:Brain Mapping; D005026:Ethylene Glycols; D005260:Female; D019788:Fluorodeoxyglucose F18; D005500:Follow-Up Studies; D006801:Humans; D007508:Irritable Mood; D008279:Magnetic Resonance Imaging; D008297:Male; D009483:Neuropsychological Tests; D049268:Positron-Emission Tomography; D062706:Prodromal Symptoms; D011379:Prognosis; D019275:Radiopharmaceuticals; D012890:Sleep; D016875:tau Proteins / Q000134:cerebrospinal fluid
chemical_list: D000814:Aniline Compounds; D053327:Apolipoprotein E4; D015415:Biomarkers; D005026:Ethylene Glycols; C054369:MAPT protein, human; D019275:Radiopharmaceuticals; D016875:tau Proteins; D019788:Fluorodeoxyglucose F18; C545186:florbetapir