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

Voevodskaya, Olga; Sundgren, Pia C. LU ; Strandberg, Olof LU ; Zetterberg, Henrik LU ; Minthon, Lennart LU ; Blennow, Kaj LU ; Wahlund, Lars Olof; Westman, Eric and Hansson, Oskar LU (2016) In Neurology 86(19). p.1754-1761
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 (N... (More)

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.

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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Neurology
volume
86
issue
19
pages
8 pages
publisher
American Academy of Neurology
external identifiers
  • scopus:84978396743
ISSN
0028-3878
DOI
10.1212/WNL.0000000000002672
language
English
LU publication?
yes
id
b584cf5f-19fc-48bb-9cbb-e9bf173b8399
date added to LUP
2016-08-02 14:16:06
date last changed
2017-07-02 04:53:10
@article{b584cf5f-19fc-48bb-9cbb-e9bf173b8399,
  abstract     = {<p>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 &lt;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 &lt;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.</p>},
  author       = {Voevodskaya, Olga and Sundgren, Pia C. and Strandberg, Olof and Zetterberg, Henrik and Minthon, Lennart and Blennow, Kaj and Wahlund, Lars Olof and Westman, Eric and Hansson, Oskar},
  issn         = {0028-3878},
  language     = {eng},
  month        = {05},
  number       = {19},
  pages        = {1754--1761},
  publisher    = {American Academy of Neurology},
  series       = {Neurology},
  title        = {Myo-inositol changes precede amyloid pathology and relate to APOE genotype in Alzheimer disease},
  url          = {http://dx.doi.org/10.1212/WNL.0000000000002672},
  volume       = {86},
  year         = {2016},
}