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Myo-inositol changes precede amyloid pathology and relate to APOE genotype in Alzheimer disease

2016; Lippincott Williams & Wilkins; Volume: 86; Issue: 19 Linguagem: Inglês

10.1212/wnl.0000000000002672

1526-632X

Olga Voevodskaya, Pia C. Sundgren, Olof Strandberg, Henrik Zetterberg, Lennart Minthon, Kaj Blennow, Lars‐Olof Wahlund, Eric Westman, Oskar Hansson, Oskar Hansson, Lennart Minthon, Håkan Toresson, Katarina Nägga, Sebastian Palmqvist, Erik Stomrud, Per Johansson, Christer Nilsson, Maria H Nilsson, Niklas Mattsson, Daniel Lindqvist, Susanna Vestberg, Shorena Janelidze, Henrik Zetterberg, Kaj Blennow, Ulf Andréasson, Danielle van Westen, Jimmy Lätt, Peter Mannfolk, Markus Nilsson, Olof Strandberg, Pia C. Sundgren, Freddy Ståhlberg, Olof Lindberg, Eric Westman, Lars‐Olof Wahlund, Per Wollmer, Ruben Smith, Tomas Olsson,

Dementia and Cognitive Impairment Research

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 (N total = 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 ( = 0.44, p = 0.02 and = 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 ( r pearson = −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.