FDG‐PET is a sensitive imaging biomarker of the neurodegenerative changes that accompany early neurofibrillary tangle pathology

Abstract

AbstractBackgroundNeurofibrillary tangle pathology in Alzheimer’s disease (AD) is closely related to neurodegeneration, which can be measured in‐vivo using structural MRI or FDG‐PET. However, previous imaging‐pathologic association studies found that gray matter atrophy on structural MRI is relatively insensitive to early stages of neurofibrillary tangle pathology as assessed by the Braak staging scheme. Here we assessed associations between post‐mortem neuropathological Braak staging and ante‐mortem glucose hypometabolism on FDG‐PET, which may be a more sensitive neuroimaging marker of early neurodegenerative changes preceding macrostructural gray matter atrophy.MethodThe study included 64 individuals from the Alzheimer’s Disease Neuroimaging Initiative autopsy cohort who had Braak staging performed at neuropathological examination and had an FDG‐PET scan acquired before death (FDG‐PET to death interval: 3.4±2.3 years). Distribution of Braak stages was N=1/6/9/3/2/33/10 for 0/I/II/III/IV/V/VI. Associations between Braak stages and regional FDG‐PET standard uptake value ratios (SUVR) were assessed in an exploratory brain‐wide Spearman correlation analysis across 52 cortical and subcortical gray matter regions. For brain regions showing a significant association after multiple comparison correction (p<0.05, FDR‐corrected), we then performed pair‐wise comparisons between grouped Braak stages 0/I (N=7), II‐IV (N=14), and V/VI (N=43). For comparison, we conducted analogous analyses for regional gray matter volume assessed on structural MRIs from the same study visit.ResultHigher Braak stages were significantly associated with lower FDG‐PET SUVR in several temporo‐parietal cortical regions typically affected by AD (Fig. 1A). When compared to the Braak 0/I reference group, most of these regions showed significant and pronounced (Cohen’s d>0.9) hypometabolism in grouped Braak stages II‐IV, and severity of hypometabolism further increased in Braak stages V/VI. Although gray matter volume on MRI showed a similar regional association with Braak stages (Fig. 1B), effect sizes were considerably lower and differences to the Braak 0/I reference group were only significant for advanced Braak stages V/VI.ConclusionGlucose hypometabolism as measured by FDG‐PET is a sensitive neuroimaging marker of the neurodegenerative changes that accompany progressive stages of neurofibrillary tangle pathology. Earliest neurodegenerative changes captured by FDG‐PET hypometabolism may precede macrostructural gray matter atrophy as measured by MRI.