A novel MRI approach for evaluation of microstructural neurodegeneration in early Alzheimer disease

Background Currently, brain tissue atrophy serves as in vivo structural MRI biomarker of neurodegeneration in Alzheimer Disease (AD). However, postmortem histopathological studies show that neuronal loss in AD exceeds volumetric loss of tissue and that AD‐related memory loss begins when neurons are lost. Hence, in vivo detection of neurodegeneration preceding detectable atrophy is essential for early AD diagnosis. Method Our innovative approach to assessing neuronal damage in vivo is based on (a) quantitative Gradient Recalled Echo (qGRE) MRI technique and (b) genetically‐informed relationships between qGRE metrics and major components of brain tissue cellular structure (neurons/neurites and glia) that were obtained using gene expression profiles across the human brain provided by the Allen Human Brain Atlas. Seventy participants were recruited from the Knight Alzheimer Disease Research Center, representing three groups: Healthy controls [Clinical Dementia Rating® (CDR®)=0, amyloid β (Aβ)‐negative), n=34] HC; Preclinical AD (CDR=0, Aβ‐positive, n=19), PC; and mild AD (CDR=0.5 or 1, Aβ‐positive, n=17), AD. Result Preliminary data show that qGRE identified new biomarkers in AD brain characterizing tissues with significantly lower (termed Dark Matter) and relatively preserved (termed Viable Tissue) concentrations of neurons. The fraction of Dark Matter showed clinically important and significant differences between HC and PC groups in hippocampus, middle temporal, fusiform, postcentral, and inferior parietal brain regions. However, no HC vs. PC group difference was detected by the volumetric measurements (Figure 1). Further, measurements of the Dark Matter fraction in the hippocampus showed strong associations with Cerebrospinal fluid (CSF) amyloid Aβ42 (r=‐0.52), CSF ptau (r=0.60), 18 F‐AV1415‐PET tau imaging (r=0.60), and PiB‐PET amyloid imaging (r=0.60). These associations were significantly stronger compared with volumetric measurements: CSF amyloid Aβ42 (r=0.18), CSF ptau (r=‐0.24), PET tau imaging (r=‐0.39), and PiB‐PET amyloid imaging (r=‐0.17)). Importantly, the Dark Matter fraction had a significant inter‐regional association (r=0.87) with neuronal count in the hippocampal subfields obtained from histopathological study of one participant who underwent in vivo qGRE 14 months prior to expiration (Figure 2). Conclusion qGRE‐based measurements identify the microstructural changes in early AD‐related neurodegeneration that are not recognized by structural MRI atrophy measurements, therefore providing new biomarkers for early AD detection.