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

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 (1H-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.

Research highlights► Down syndrome (DS) with dementia (DS+) had significantly higher [mI] than DS no dementia (DS−) and HC. ► Neither DS+ nor DS− differed significantly from controls in [NAA] ► DS+ had significantly elevated [mI] compared to AD or DS-(DS+ > DS− > AD). ► DS+ and AD had significantly less hippocampal [NAA] than the DS− group. ► The in vivo biology of dementia in DS is different from non-DS dementia (i.e., AD).