Down syndrome with and without dementia: An in vivo proton Magnetic Resonance Spectroscopy study with implications for Alzheimer's disease

Melissa Lamar,Catherine M.L Foy,Robin G Morris,Michaela Poppe,Nicola Archer,Eileen Daly,Simon Lovestone,Kieran C Murphy,Declan G.M Murphy,Felix Beacher,Vee Prasher,Andrew Simmons

doi:10.1016/j.neuroimage.2011.03.073

Abstract

It is poorly understood why people with Down syndrome (DS) are at extremely high-risk of developing Alzheimer's disease (AD) compared to the general population. One explanation may be related to their extra copy of risk factors modulated by chromosome 21. Myo-inositol (mI), whose transporter gene is located on chromosome 21, has been associated with dementia in the non-DS population; however, nobody has contrasted brain mI in DS with (DS+) and without (DS-) dementia to other non-DS groups. Our primary aim was to compare the hippocampal concentration of mI ([mI]) and other brain metabolites such as N-acetylaspartate (NAA; a proxy measure of neuronal density and mitochondrial function) in DS+, DS-, and age-matched healthy controls using proton Magnetic Resonance Spectroscopy (((1))H-MRS). We compared hippocampal [mI] and other metabolites in 35 individuals with genetically-confirmed DS [DS+ (n=17, age=53±6) and DS- (n=18, age=47±8)] to age-matched healthy controls (n=13, age=51±10) adjusting for proportion of the MRS voxel occupied by cerebrospinal spinal fluid, and gray/white matter. DS+ had a significantly higher [mI] than both DS- and healthy controls. In contrast neither DS+ nor DS- differed significantly from controls in [NAA] (although NAA in DS+ was significantly lower than DS-). Our secondary aim of comparing brain metabolites in DS+ and DS- to Alzheimer's disease (AD; n=39; age=77±5) revealed that the DS+ group had significantly elevated [mI] compared to AD or DS-. [mI] may modify risk for dementia in this vulnerable population.

Highlights

Down syndrome (DS), due to trisomy of chromosome 21, is one of the most common causes of intellectual disability of known genetic etiology
In addition to the composite voxels of interest (VOI) as a covariate, age was added as a covariate in secondary analyses between DS+, DS- and Alzheimer’s disease (AD) groups given the significant difference in age between these groups, F(2,71)=181.1, p
Our results suggest that the hippocampal concentration of mI is significantly elevated in DS+ when compared to all other groups; whereas [NAA] levels were less discriminatory

Summary

Introduction

Down syndrome (DS), due to trisomy of chromosome 21, is one of the most common causes of intellectual disability of known genetic etiology. DS adults have a high prevalence of age-related cognitive decline (Maatta et al, 2006) and Alzheimer’s disease (AD). AD-type neuropathology (i.e., neuritic plaques and neurofibrillary tangles) occurs in the brain of all DS adults over 40 years of age (Wisniewski et al, 1985); with prevalence rates for clinically diagnosed AD increasing from 10% in the fourth decade of life to upwards of 75% in the sixth decade (Coppus et al, 2006; Schupf et al, 1998). It has been suggested that the increased risk for AD in DS results from trisomy of the amyloid precursor protein (APP) gene associated with AD which is located on chromosome 21 (Hardy & Allsop, 1991); other genes on chromosome 21 may be relevant to dementia. We are not aware of any casecontrol studies measuring brain mI in DS adults with (DS+) and without (DS-) dementia as compared to healthy control groups

Methods

Results

Conclusion