title: Myo-inositol changes precede amyloid pathology and relate to APOE genotype in Alzheimer disease.
abstract: OBJECTIVE
  We aimed to test whether in vivo levels of magnetic resonance spectroscopy (MRS) metabolites myo-inositol (mI), N-acetylaspartate (NAA), and choline are abnormal already during preclinical Alzheimer disease (AD), relating these changes to amyloid or tau pathology, and functional connectivity.
  
  
  METHODS
  In this cross-sectional multicenter study (a subset of the prospective Swedish BioFINDER study), we included 4 groups, representing the different stages of predementia AD: (1) cognitively healthy elderly with normal CSF β-amyloid 42 (Aβ42), (2) cognitively healthy elderly with abnormal CSF Aβ42, (3) patients with subjective cognitive decline and abnormal CSF Aβ42, (4) patients with mild cognitive decline and abnormal CSF Aβ42 (Ntotal = 352). Spectroscopic markers measured in the posterior cingulate/precuneus were considered alongside known disease biomarkers: CSF Aβ42, phosphorylated tau, total tau, [(18)F]-flutemetamol PET, f-MRI, and the genetic risk factor APOE.
  
  
  RESULTS
  Amyloid-positive cognitively healthy participants showed a significant increase in mI/creatine and mI/NAA levels compared to amyloid-negative healthy elderly (p < 0.05). In amyloid-positive healthy elderly, mI/creatine and mI/NAA correlated with cortical retention of [(18)F] flutemetamol tracer ([Formula: see text] = 0.44, p = 0.02 and [Formula: see text] = 0.51, p = 0.01, respectively). Healthy elderly APOE ε4 carriers with normal CSF Aβ42 levels had significantly higher mI/creatine levels (p < 0.001) than ε4 noncarriers. Finally, elevated mI/creatine was associated with decreased functional connectivity within the default mode network (rpearson = -0.16, p = 0.02), independently of amyloid pathology.
  
  
  CONCLUSIONS
  mI levels are elevated already at asymptomatic stages of AD. Moreover, mI/creatine concentrations were increased in healthy APOE ε4 carriers with normal CSF Aβ42 levels, suggesting that mI levels may reveal regional brain consequences of APOE ε4 before detectable amyloid pathology.
authors.affiliation: From Clinical Geriatrics (O.V., L.-O.W., E.W.), Department of Neurobiology, Care Sciences and Society, Karolinska Institute, Stockholm; Department of Diagnostic Radiology (P.C.S., O.S.), Lund University; Clinical Neurochemistry Laboratory (H.Z., K.B.), Institute of Neuroscience and Physiology, the Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden; UCL Institute of Neurology (H.Z.), Queen Square, London, UK; Memory Clinic (L.M., O.H.), Skåne University Hospital; and Clinical Memory Research Unit (L.M., O.H.), Department of Clinical Sciences, Malmö, Lund University, Sweden. olga.voevodskaya@ki.se oskar.hansson@med.lu.se.
authors.forename: Olga
authors.initials: O
authors.lastname: Voevodskaya
authors.affiliation: From Clinical Geriatrics (O.V., L.-O.W., E.W.), Department of Neurobiology, Care Sciences and Society, Karolinska Institute, Stockholm; Department of Diagnostic Radiology (P.C.S., O.S.), Lund University; Clinical Neurochemistry Laboratory (H.Z., K.B.), Institute of Neuroscience and Physiology, the Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden; UCL Institute of Neurology (H.Z.), Queen Square, London, UK; Memory Clinic (L.M., O.H.), Skåne University Hospital; and Clinical Memory Research Unit (L.M., O.H.), Department of Clinical Sciences, Malmö, Lund University, Sweden.
authors.forename: Pia C
authors.initials: PC
authors.lastname: Sundgren
authors.affiliation: From Clinical Geriatrics (O.V., L.-O.W., E.W.), Department of Neurobiology, Care Sciences and Society, Karolinska Institute, Stockholm; Department of Diagnostic Radiology (P.C.S., O.S.), Lund University; Clinical Neurochemistry Laboratory (H.Z., K.B.), Institute of Neuroscience and Physiology, the Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden; UCL Institute of Neurology (H.Z.), Queen Square, London, UK; Memory Clinic (L.M., O.H.), Skåne University Hospital; and Clinical Memory Research Unit (L.M., O.H.), Department of Clinical Sciences, Malmö, Lund University, Sweden.
authors.forename: Olof
authors.initials: O
authors.lastname: Strandberg
authors.affiliation: From Clinical Geriatrics (O.V., L.-O.W., E.W.), Department of Neurobiology, Care Sciences and Society, Karolinska Institute, Stockholm; Department of Diagnostic Radiology (P.C.S., O.S.), Lund University; Clinical Neurochemistry Laboratory (H.Z., K.B.), Institute of Neuroscience and Physiology, the Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden; UCL Institute of Neurology (H.Z.), Queen Square, London, UK; Memory Clinic (L.M., O.H.), Skåne University Hospital; and Clinical Memory Research Unit (L.M., O.H.), Department of Clinical Sciences, Malmö, Lund University, Sweden.
authors.forename: Henrik
authors.initials: H
authors.lastname: Zetterberg
authors.affiliation: From Clinical Geriatrics (O.V., L.-O.W., E.W.), Department of Neurobiology, Care Sciences and Society, Karolinska Institute, Stockholm; Department of Diagnostic Radiology (P.C.S., O.S.), Lund University; Clinical Neurochemistry Laboratory (H.Z., K.B.), Institute of Neuroscience and Physiology, the Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden; UCL Institute of Neurology (H.Z.), Queen Square, London, UK; Memory Clinic (L.M., O.H.), Skåne University Hospital; and Clinical Memory Research Unit (L.M., O.H.), Department of Clinical Sciences, Malmö, Lund University, Sweden.
authors.forename: Lennart
authors.initials: L
authors.lastname: Minthon
authors.affiliation: From Clinical Geriatrics (O.V., L.-O.W., E.W.), Department of Neurobiology, Care Sciences and Society, Karolinska Institute, Stockholm; Department of Diagnostic Radiology (P.C.S., O.S.), Lund University; Clinical Neurochemistry Laboratory (H.Z., K.B.), Institute of Neuroscience and Physiology, the Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden; UCL Institute of Neurology (H.Z.), Queen Square, London, UK; Memory Clinic (L.M., O.H.), Skåne University Hospital; and Clinical Memory Research Unit (L.M., O.H.), Department of Clinical Sciences, Malmö, Lund University, Sweden.
authors.forename: Kaj
authors.initials: K
authors.lastname: Blennow
authors.affiliation: From Clinical Geriatrics (O.V., L.-O.W., E.W.), Department of Neurobiology, Care Sciences and Society, Karolinska Institute, Stockholm; Department of Diagnostic Radiology (P.C.S., O.S.), Lund University; Clinical Neurochemistry Laboratory (H.Z., K.B.), Institute of Neuroscience and Physiology, the Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden; UCL Institute of Neurology (H.Z.), Queen Square, London, UK; Memory Clinic (L.M., O.H.), Skåne University Hospital; and Clinical Memory Research Unit (L.M., O.H.), Department of Clinical Sciences, Malmö, Lund University, Sweden.
authors.forename: Lars-Olof
authors.initials: LO
authors.lastname: Wahlund
authors.affiliation: From Clinical Geriatrics (O.V., L.-O.W., E.W.), Department of Neurobiology, Care Sciences and Society, Karolinska Institute, Stockholm; Department of Diagnostic Radiology (P.C.S., O.S.), Lund University; Clinical Neurochemistry Laboratory (H.Z., K.B.), Institute of Neuroscience and Physiology, the Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden; UCL Institute of Neurology (H.Z.), Queen Square, London, UK; Memory Clinic (L.M., O.H.), Skåne University Hospital; and Clinical Memory Research Unit (L.M., O.H.), Department of Clinical Sciences, Malmö, Lund University, Sweden.
authors.forename: Eric
authors.initials: E
authors.lastname: Westman
authors.affiliation: From Clinical Geriatrics (O.V., L.-O.W., E.W.), Department of Neurobiology, Care Sciences and Society, Karolinska Institute, Stockholm; Department of Diagnostic Radiology (P.C.S., O.S.), Lund University; Clinical Neurochemistry Laboratory (H.Z., K.B.), Institute of Neuroscience and Physiology, the Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden; UCL Institute of Neurology (H.Z.), Queen Square, London, UK; Memory Clinic (L.M., O.H.), Skåne University Hospital; and Clinical Memory Research Unit (L.M., O.H.), Department of Clinical Sciences, Malmö, Lund University, Sweden. olga.voevodskaya@ki.se oskar.hansson@med.lu.se.
authors.forename: Oskar
authors.initials: O
authors.lastname: Hansson
mesh_terms: D000368:Aged; D000544:Alzheimer Disease / Q000000981:diagnostic imaging / Q000453:epidemiology / Q000235:genetics / Q000378:metabolism; D058227:Amyloidogenic Proteins / Q000378:metabolism*; D053327:Apolipoprotein E4 / Q000235:genetics*; D001224:Aspartic Acid / Q000031:analogs & derivatives / Q000378:metabolism; D001921:Brain / Q000000981:diagnostic imaging* / Q000378:metabolism; D001931:Brain Mapping; D002794:Choline / Q000378:metabolism; D003072:Cognition Disorders / Q000000981:diagnostic imaging* / Q000453:epidemiology / Q000235:genetics* / Q000378:metabolism; D003430:Cross-Sectional Studies; D005260:Female; D006801:Humans; D007294:Inositol / Q000378:metabolism*; D008137:Longitudinal Studies; D008279:Magnetic Resonance Imaging; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D049268:Positron-Emission Tomography; D062706:Prodromal Symptoms; D011446:Prospective Studies; D013548:Sweden / Q000453:epidemiology; D016875:tau Proteins / Q000134:cerebrospinal fluid
chemical_list: D058227:Amyloidogenic Proteins; D053327:Apolipoprotein E4; C054369:MAPT protein, human; D016875:tau Proteins; D001224:Aspartic Acid; D007294:Inositol; C000179:N-acetylaspartate; D002794:Choline