Whole-brain patterns of 1H-magnetic resonance spectroscopy imaging in Alzheimer's disease and dementia with Lewy bodies

Abstract

Magnetic resonance spectroscopy has demonstrated metabolite changes in neurodegenerative disorders such as Alzheimer's disease (AD) and dementia with Lewy bodies (DLB); however, their pattern and relationship to clinical symptoms is unclear. To determine whether the spatial patterns of brain-metabolite changes in AD and DLB are regional or diffused, and to examine whether the key metabolite levels are associated with cognitive and non-cognitive symptoms, we acquired whole-brain spatially resolved 3T magnetic resonance spectroscopic imaging (MRSI) data from subjects with AD (N=36), DLB (N=35) and similarly aged controls (N=35). Voxel-wise measurement of N-acetylaspartate to creatine (NAA/Cr), choline to Cr (Cho/Cr), myo-inositol to Cr (mI/Cr) as well as glutamate and glutamine to Cr (Glx/Cr) ratios were determined using MRSI. Compared with controls, AD and DLB groups showed a significant decrease in most brain metabolites, with NAA/Cr, Cho/Cr and mI/Cr levels being reduced in posterior cingulate, thalamus, frontotemporal areas and basal ganglia. The Glx/Cr level was more widely decreased in DLB (posterior cingulate, hippocampus, temporal regions and caudate) than in AD (only in posterior cingulate). DLB was also associated with increased levels of Cho/Cr, NAA/Cr and mI/Cr in occipital regions. Changes in metabolism in the brain were correlated with cognitive and non-cognitive symptoms in the DLB but not in the AD group. The different patterns between AD and DLB may have implications for improving diagnosis, better understanding disease-specific neurobiology and targeting therapeutics. In addition, the study raised important questions about the role of occipital neuroinflammation and glial activation as well as the glutamatergic treatment in DLB.

Magnetic resonance imaging in Alzheimer’s disease and mild cognitive impairment

“…NAA/Cr and NAA/mI ratios discriminate AD from VaD, and glutamate/Cr ratios differentiate DLB from AD. Metabolic ratios are substantially lower in AD patients compared to VaD, but higher in widespread brain regions relative to DLB [53, 54]. Whilst MRS is able to study molecular processes in the brain non-invasively without exposure to ionizing radiation, this technique is limited by its low sensitivity [55].…”

Alzheimer’s disease: targeting the glutamatergic system

“…Glutamatergic activity can be measured using proton magnetic resonance spectroscopy ( 1 H MRS) (Hall et al 2012;Bookheimer et al 2000), that is reflective of neuronal integrity. The use of 1 H MRS has also emerged as a promising tool in neurological and psychiatric disorders including the investigation of AD (Wang et al 2015a, b;Su et al 2016) and ALS (Kalra 2019). Age-related changes in selected 1 H MRS biomarkers have been reported, where lower concentrations of Glu recorded in the motor cortex positively correlated with N-acetyl aspartate (NAA) and creatinine (Cr) consistent with neuronal loss/ shrinkage with age (Kaiser et al 2005).…”

Reproducibility of 2DGluCEST in healthy human volunteers at 7 T

“…For example, elevated glutamate likely contributes to “excitotoxic” neuronal cell loss in Alzheimer's disease through overstimulation of glutamatergic receptors . Decreased glutamate is observed in animal model of Alzheimer's disease and in patients with advanced pathology, particularly within the hippocampus, and is positively correlated with the progressive loss of glutamate transporter proteins in brain regions associated with memory and cognitive function …”

“…4,5 For example, elevated glutamate likely contributes to "excitotoxic" neuronal cell loss in Alzheimer's disease through overstimulation of glutamatergic receptors. [6][7][8][9] Decreased glutamate is observed in animal model of Alzheimer's disease and in patients with advanced pathology, [10][11][12][13] particularly within the hippocampus, and is positively correlated with the progressive loss of glutamate transporter proteins in brain regions associated with memory and cognitive function. 14,15 Although altered glutamate levels are implicated in the pathogenesis of neurological and neuropsychiatric diseases, glutamate has also been shown to decrease with age in the neurotypical brain.…”