FDG-PET hypermetabolism is associated with higher tau-PET in mild cognitive impairment at low amyloid-PET levels

Rubinski, Anna; Franzmeier, Nicolai; Neitzel, Julia; Ewers, Michael

doi:10.1186/s13195-020-00702-6

Cited by 35 publications

(38 citation statements)

References 58 publications

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“…Interestingly, we found that the early cognitive benefit associated with the ε4 allele is mainly in executive function (reasoning, phonemic fluency), while no difference was observed for memory or semantic tasks which involve temporal and temporal intern area. This is consistent with several metabolic PET imaging studies which have found that APOE ε4 allele in the normal population is associated with a decrease in metabolism in the posterior regions of the brain (parietal, posterior cingulate), but also with an increase of metabolism in the anterior frontal area [42,43]. A recent meta-analysis of studies on the age range from 2 to 40 years did not find differences in cognitive performance between APOE ε4 carriers and noncarriers, with the authors concluding that there was no support for the antagonistic pleiotropic hypothesis [20].…”

Section: Discussionsupporting

confidence: 92%

The association of APOE ε4 with cognitive function over the adult life course and incidence of dementia: 20 years follow-up of the Whitehall II study

et al. 2021

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Background Approximately 25% of the general population carries at least one ε4 allele of the Apolipoprotein E (APOE ε4), the strongest genetic risk factor for late onset Alzheimer’s disease. Beyond its association with late-onset dementia, the association between APOE ε4 and change in cognition over the adult life course remains uncertain. This study aims to examine whether the association between Apolipoprotein E (APOE) ε4 zygosity and cognition function is modified between midlife and old age. Methods A cohort study of 5561 participants (mean age 55.5 (SD = 5.9) years, 27.1% women) with APOE genotyping and repeated cognitive tests for reasoning, memory, and semantic and phonemic fluency, during a mean (SD) follow-up of 20.2 (2.8) years (the Whitehall II study). We used joint models to examine the association of APOE genotype with cognitive function trajectories between 45 and 85 years taking drop-out, dementia, and death into account and Fine and Gray models to examine associations with dementia. Results Compared to non-carriers, heterozygote (prevalence 25%) and homozygote (prevalence 2%) APOE ε4 carriers had increased risk of dementia, sub-distribution hazard ratios 2.19 (95% CI 1.73, 2.77) and 5.97 (95% CI 3.85, 9.28) respectively. Using data spanning 45–85 years with non-ε4 carriers as the reference, ε4 homozygotes had poorer global cognitive score starting from 65 years; ε4 heterozygotes had better scores between 45 and 55 years, then no difference until poorer cognitive scores from 75 years onwards. In analysis of individual cognitive tests, better cognitive performance in the younger ε4 heterozygotes was primarily attributable to executive function. Conclusions Both heterozygous and homozygous ε4 carriers had poorer cognition and greater risk of dementia at older ages. Our findings show some support for a complex antagonist pleiotropic effect of APOE ε4 heterozygosity over the adult life course, characterized by cognitive advantage in midlife.

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Section: Discussionsupporting

confidence: 92%

The association of APOE ε4 with cognitive function over the adult life course and incidence of dementia: 20 years follow-up of the Whitehall II study

et al. 2021

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“…A recent study including subjects with mild cognitive impairment showed that higher tau-PET uptake was associated with higher glucose metabolism in patients with lower levels of amyloid-PET uptake. This finding resulted to be associated with lower memory performance [ 30 ]. A study focused on the identification of a brain 18 F-FDG-PET Parkinson’s disease–related pattern (PDRP) showed that the typical PDRP topography was characterized by relative hypermetabolism in the thalamus, putamen/pallidum, pons, cerebellum, and motor cortex.…”

Section: Discussionmentioning

confidence: 99%

Amyotrophic lateral sclerosis with SOD1 mutations shows distinct brain metabolic changes

Canosa

Calvo

Moglia

et al. 2022

Eur J Nucl Med Mol Imaging

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Purpose Neuropathological data suggest that ALS with SOD1 mutations (SOD1-ALS) is a distinct form of ALS. We evaluated brain metabolic changes characterizing SOD1-ALS as compared to sporadic ALS (sALS), employing 18fluorodeoxyglucose-positron-emission tomography (18F-FDG-PET). Methods We included 18 SOD1-ALS patients, 40 healthy controls (HC), and 46 sALS patients without mutations in SOD1, TARDBP, FUS, and C9ORF72, randomly selected from 665 subjects who underwent brain 18F-FDG-PET at diagnosis between 2008 and 2019 at the ALS Centre of Turin. We excluded patients with frontotemporal dementia. We used the full factorial design in SPM12 to evaluate whether differences among groups exist overall. In case the hypothesis was confirmed, group comparisons were performed through the two-sample t-test model of SPM12. In all the analyses, the height threshold was P < 0.001 (P < 0.05 FWE-corrected at cluster level). Results The full factorial design resulted in a significant main effect of groups. We identified a relative hypometabolism in sALS patients compared to SOD1-ALS cases in the right precentral and medial frontal gyrus, right paracentral lobule, and bilateral postcentral gyrus. SOD1 patients showed a relative hypermetabolism as compared to HC in the right precentral gyrus and paracentral lobule. As compared to HC, sALS patients showed relative hypometabolism in frontal, temporal, and occipital cortices. Conclusion SOD1-ALS was characterized by a relative hypermetabolism in the motor cortex as compared to sALS and HC. Since promising, targeted, therapeutic strategies are upcoming for SOD1-ALS, our data support the use of PET to study disease pathogenesis and to track its course in clinical trials, in both asymptomatic and symptomatic mutation carriers.

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“…In addition, the inclusion of the amyloid-negative subjects in this study might interfere with the exploration of FDG cascade. The conflicting relationship between tau and glucose metabolism has been reported in amyloid negative MCI, where FDG hypermetabolism was associated with higher tau PET [ 34 ]. However, apart from results indicated by logistic regression, [ 18 F]FDG SUVr decreases in late pseudo-time , as illustrated in Fig.…”

Section: Discussionmentioning

confidence: 99%

Image-level trajectory inference of tau pathology using variational autoencoder for Flortaucipir PET

Hong

Kang

Alberts

et al. 2022

Eur J Nucl Med Mol Imaging

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Purpose Alzheimer’s disease (AD) studies revealed that abnormal deposition of tau spreads in a specific spatial pattern, namely Braak stage. However, Braak staging is based on post mortem brains, each of which represents the cross section of the tau trajectory in disease progression, and numerous studies were reported that do not conform to that model. This study thus aimed to identify the tau trajectory and quantify the tau progression in a data-driven approach with the continuous latent space learned by variational autoencoder (VAE). Methods A total of 1080 [18F]Flortaucipir brain positron emission tomography (PET) images were collected from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database. VAE was built to compress the hidden features from tau images in latent space. Hierarchical agglomerative clustering and minimum spanning tree (MST) were applied to organize the features and calibrate them to the tau progression, thus deriving pseudo-time. The image-level tau trajectory was inferred by continuously sampling across the calibrated latent features. We assessed the pseudo-time with regard to tau standardized uptake value ratio (SUVr) in AD-vulnerable regions, amyloid deposit, glucose metabolism, cognitive scores, and clinical diagnosis. Results We identified four clusters that plausibly capture certain stages of AD and organized the clusters in the latent space. The inferred tau trajectory agreed with the Braak staging. According to the derived pseudo-time, tau first deposits in the parahippocampal and amygdala, and then spreads to the fusiform, inferior temporal lobe, and posterior cingulate. Prior to the regional tau deposition, amyloid accumulates first. Conclusion The spatiotemporal trajectory of tau progression inferred in this study was consistent with Braak staging. The profile of other biomarkers in disease progression agreed well with previous findings. We addressed that this approach additionally has the potential to quantify tau progression as a continuous variable by taking a whole-brain tau image into account.

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FDG-PET hypermetabolism is associated with higher tau-PET in mild cognitive impairment at low amyloid-PET levels

Cited by 35 publications

References 58 publications

The association of APOE ε4 with cognitive function over the adult life course and incidence of dementia: 20 years follow-up of the Whitehall II study

The association of APOE ε4 with cognitive function over the adult life course and incidence of dementia: 20 years follow-up of the Whitehall II study

Amyotrophic lateral sclerosis with SOD1 mutations shows distinct brain metabolic changes

Image-level trajectory inference of tau pathology using variational autoencoder for Flortaucipir PET

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