In Alzheimer's disease, brain amyloid deposition has a distinct topography that correlates with aerobic glycolysis (AG), that is, the use of glucose beyond that predicted by oxygen consumption. The causes for this relationship remain unclear but might provide crucialinsight into how amyloid deposition begins. Here we develop methods to study the earliest topography of amyloid deposition based on amyloid imaging and investigate its spatiotemporal evolution with respect to the topography of AG in adults. We find that the spatiotemporal dynamics of amyloid deposition are largely explained by 1 factor, defined here as the amyloid topography dissimilarity index (ATDI). ATDI is bimodal, more highly dynamic during early amyloid accumulation, and predicts which individuals will cross a conservative quantitative threshold at least 3-5 years in advance. Using ATDI, we demonstrate that subthreshold amyloid accumulates primarily in regions that have high AG during early adulthood. Our findings suggest that early on-target subthreshold amyloid deposition mirrors its later regional pattern, which best corresponds to the topography of young adult brain AG. (C) 2020 Elsevier Inc. All rights reserved.

Sex differences influence brain morphology and physiology during both development and aging. Here we apply a machine learning algorithm to a multiparametric brain PET imaging dataset acquired in a cohort of 20- to 82-year-old, cognitively normal adults (n = 205) to define their metabolic brain age. We find that throughout the adult life span the female brain has a persistently lower metabolic brain age-relative to their chronological age-compared with the male brain. The persistence of relatively younger metabolic brain age in females throughout adulthood suggests that development might in part influence sex differences in brain aging. Our results also demonstrate that trajectories of natural brain aging vary significantly among individuals and provide a method to measure this.

Prior work has shown that the regional topography of PIB-binding in humans with Alzheimer's disease (AD) closely matches that of aerobic glycolysis (AG) in a separate group of typical young adults. Here we extend these findings by comparing the regional topography of PIB-binding from over 600 individuals, with and without preclinical or symptomatic AD, to various brain metabolism patterns in both young and older adults, including brain oxygen (CMRO2) and glucose (CMRGlc) metabolism, blood flow (CBF), and AG. 1024 PIB-PET scans were obtained in 622 individuals, processed including partial volume correction, and summarized as SUVR (relative to cerebellum) for 42 FreeSurfer-defined gray matter regions of interest. CMRO2, CMRGlc, CBF, and AG values were also obtained for the same regions in a separate cohort as previously published. Penalized regression (LASSO) was used to compare PIB topography in PIB+ individuals (as defined when their mean cortical SUVR > 1.42) with the various metabolic patterns in young and older adults. Individual PIB scans from all 1024 scans were then correlated with mean young adult AG. LASSO regression revealed that PIB+ topography is best predicted by only two metabolic factors: young adult AG and older adult CBF (linear model comparing PIB+ to young AG and older CBF: p=0.002 and p=0.016, respectively). In contrast to the long-tail unimodal distribution of mean cortical SUVR across all of the 1024 individual PIB scans (Hartigan's Dip Test, d=0.006, p>0.99), correlation of individual PIB scans to young adult AG demonstrates a bimodal distribution (d=0.017, p<0.05). Individual PIB+ scans largely correlate with young adult AG (mean r=0.31, 95%CI [0.28, 0.33], peaking at approximately r=0.6).

Research of the human brain metabolism in vivo has largely focused on total glucose use (via fluorodeoxyglucose positron emission tomography) and, until recently, did not examine the use of glucose outside oxidative phosphorylation, which is known as aerobic glycolysis (AG). AG supports important functions including biosynthesis and neuroprotection but decreases dramatically with aging. This multitracer positron emission tomography study evaluated the relationship between AG, total glucose use (CMRGlc), oxygen metabolism (CMRO2), tau, and amyloid deposition in 42 individuals, including those at preclinical and symptomatic stages of Alzheimer's disease. Our findings demonstrate that in individuals with amyloid burden, lower AG is associated with higher tau deposition. No such correlation was observed for CMRGlc or CMRO2. We suggest that aging-related loss of AG leading to decreased synaptic plasticity and neuroprotection may accelerate tauopathy in individuals with amyloid burden. Longitudinal AG and Alzheimer's disease pathology studies are needed to verify causality.

Our previous studies demonstrated that the aerobic glycolysis (AG, non-oxidative part of brain glucose metabolism), a marker of metabolic functions involved in synaptic plasticity and neuroprotection, declines with age on the whole brain level. This decline is greatest in regions known to accumulate a high density of beta-amyloid plaques in Alzheimer's disease (AD). These observations suggest that there is a substantial age-related loss in metabolic brain reserve supporting synaptic plasticity and neuroprotection that may introduce a selective vulnerability to processes leading to AD pathology and cognitive decline. Neurofibrillary tau pathology is a marker of cell death and dysfunction but little is known about the relationship between regional AG and tau pathology in the human brain in vivo. Our previous tau PET imaging studies with AV-1451 demonstrated tau deposition in several brain regions, including enthorhinal, temporal, lateral occipital, and parietal cortex. Here we present our preliminary evaluation of the relationship between AG, metabolism, blood flow and tau deposition. Thirty five individuals (32 cognitively normal, 15 females, 53–88 years old) underwent PET studies using inhalation of 15O-CO and 15O-O2, and injection of 15O-water, 18F-fluorodeoxyglucose, and [18F]-AV-1451. AG, cerebral metabolic rate of glucose (CMRGlu) and oxygen (CMRO2), cerebral blood flow (CBF), and tau deposition were calculated and corrected for partial volume effects in regions of interest defined using FreeSurfer. Association between AG, CMRGlu, CMRO2, CBF and AV-1451 deposition was evaluated using linear regression models, both unadjusted and adjusted for age and gender. A negative correlation was demonstrated between tau deposition and AG in lateral occipital, inferior and superior parietal cortices, suggesting that higher AG levels are associated with less tau deposition. This association remained significant after adjusting for age and gender for lateral occipital (F1,31=8.632, p=0.006) and superior parietal (F1,31=12.367, p=0.001). Tau deposition correlated to CMRGlu in superior parietal cortex (F1,31=4.856; p=0.035). No correlation was demonstrated between tau deposition and CMRO2 and CBF. Our findings support the hypothesis that in regions known to accumulate AD pathology, higher levels of AG are associated with lower pathological burden, suggesting that high AG promotes resilience to progression of AD pathology.

The normal aging human brain experiences global decreases in metabolism, but whether this affects the topography of brain metabolism is unknown. Here we describe PET-based measurements of brain glucose uptake, oxygen utilization, and blood flow in cognitively normal adults from 20 to 82 years of age. Age-related decreases in brain glucose uptake exceed that of oxygen use, resulting in loss of brain aerobic glycolysis (AG). Whereas the topographies of total brain glucose uptake, oxygen utilization, and blood flow remain largely stable with age, brain AG topography changes significantly. Brain regions with high AG in young adults show the greatest change, as do regions with prolonged developmental transcriptional features (i.e., neoteny). The normal aging human brain thus undergoes characteristic metabolic changes, largely driven by global loss and topographic changes in brain AG.

Positron emission tomography (PET) with 15O-tracers is commonly used to measure brain hemodynamic parameters such as cerebral blood flow, cerebral blood volume, and cerebral metabolic rate of oxygen. Conventionally, the absolute quantification of these parameters requires an arterial input function that is obtained invasively by sampling blood from an artery. In this work, we developed and validated an image-derived arterial input function technique that avoids the unreliable and burdensome arterial sampling procedure for full quantitative 15O-PET imaging. We then compared hemodynamic PET imaging performed on a PET/MR hybrid scanner against a conventional PET only scanner. We demonstrated the proposed imaging-based technique was able to generate brain hemodynamic parameter measurements in strong agreement with the traditional arterial sampling based approach. We also demonstrated that quantitative 15O-PET imaging can be successfully implemented on a PET/MR hybrid scanner.

Objectives. Glucose metabolism outside of oxidative phosphorylation, or aerobic glycolysis (AG), is a hallmark of active cancer cells that is not directly measured with standard 18 F-fluorodeoxyglucose (FDG) positron emission tomography (PET). In this study, we characterized tumor regions with elevated AG defined based on PET measurements of glucose and oxygen metabolism. Methods. Fourteen individuals with high-grade brain tumors underwent structural MR scans and PET measurements of cerebral blood flow (CBF), oxygen (CMRO 2 ) and glucose (CMRGlu) metabolism, and AG, using 15 O-labeled CO, O 2 and H 2 O, and FDG, and were compared to a normative cohort of 20 age-matched individuals. Results. Elevated AG was observed in most high-grade brain tumors and it was associated with decreased CMRO 2 and CBF, but not with significant changes in CMRGlu. Elevated AG was a dramatic and early sign of tumor growth associated with decreased survival. AG changes associated with tumor growth were differentiated from the effects of nonneoplastic processes such as epileptic seizures. Conclusions. Our findings demonstrate that high-grade brain tumors exhibit elevated AG as a marker of tumor growth and aggressiveness. AG may detect areas of active tumor growth that are not evident on conventional FDG PET.

Biomarkers characterizing Alzheimer's disease (AD) can estimate brain amyloid, tau accumulation, cerebral glucose metabolism decrease, and atrophy. In autosomal dominant AD similar biomarker changes have been observed (Bateman et al, 2012). Cerebral blood flow (CBF) may also change with the disease severity (Alsop et al, 2010). Cerebral glucose metabolism measured by 18F-fluorodeoxyglucose (FDG)-PET is linked to CBF. Many studies have recently used early frames of 11C-Pittsburgh Compound B (PiB)-PET (ePiB) as a proxy of CBF and have investigated associations with FDG (Rostomian et al, 2011). We evaluated in an autosomal dominant AD cohort the perfusion components of ePiB and FDG in comparison to a gold standard estimate of CBF, 15O-H2O. Thirty participants, including 11 mutation carriers (MC), underwent FDG, full dynamic PiB, 15O-H2O PET and structural MRI scans. The PET images of each participant were registered with their structural MRI. The ePiB images were created using 1 to 9 min time frames, as best correlation with FDG. For each participant, voxel-wise spatial correlations were performed between FDG and 15O-H2O, and between ePiB and 15O-H2O images. The Pearson's correlation coefficient was used to assess the association between the different modalities for the whole brain and gray matter cortex, in PiB-positive and negative MC and non-carriers. PiB-positivity was defined with a threshold of >0.18 in mean cortical binding potential. The FDG and ePiB images were visually similar and they displayed similar correlations for the whole brain and the cortex (0.8±0.01 and 0.7±0.01, respectively). Both FDG and ePiB had similar correlations with the 15O-H2O, reaching an average of 0.6±0.01 and 0.4±0.01 for the whole brain and cortex, respectively. The same associations were observed in MC and non-carriers, and in the PiB-positive and PiB-negative participants from the MC group. Our results show that cerebral metabolism and early PiB perfusion frames are correlated to CBF irrespective of the level of AD pathology or mutation status. Evaluation of how these related phenomena evolve with the disease may give insight into the sequence of AD neuropathology. More studies are needed to determine whether these associations are maintained through the course of the disease.

Cerebral hypoperfusion has been suggested as a biomarker for preclinical Alzheimer's disease (AD) and can be used to complement other imaging biomarkers, such as Pittsburgh compound B (PiB)-PET. Arterial spin labelling (ASL) MR is quickly becoming a viable alternative to O15-water PET for measuring cerebral blood flow (CBF) non-invasively and without use of radiotracers. However, many direct comparisons show only moderate agreement between these two methodologies at the regional level, possibly due to small sample sizes. The goal of the current study is to evaluate correlation between ASL and O15-water in a large cohort including both healthy aging and risk for developing AD. Sixty-one cognitively normal (CDR=0) individuals from the Adult Children Study (ACS) at the Knight Alzheimer Disease Research Center underwent ASL, PiB-PET, and O15-water PET imaging. Images were processed using 84 cortical/subcortical regions of interest from the FreeSurfer automated brain segmentation software. Half of the participants had positive PiB scans (mean cortical binding potential over 0.18). Regional CBF estimates for ASL and O15-water PET, referenced to cerebellar gray matter, were compared for each subject. Also, student's t-tests were performed in each region to determine if ASL perfusion measures predicted a positive PiB scan. Average Pearson's correlation within subject between methods was 0.35 ± 0.15 and was primarily driven by several regions. The superior parietal, isthmus cingulate, precuneus, and paracentral regions had the highest inter-method correlation. Though no regions significantly predicted amyloid burden, the left entorhinal, left inferior temporal, and both parahippocampal regions showed trends. The same comparison in 015-PET showed no significant results, but trends were observed in the right rostral middle frontal and both anterior cingulate regions. Our results show the strongest correlations in a group of regions associated with changes in preclinical AD. Also, the results from our large cohort support smaller studies finding moderate correlation between O15-PET and ASL. For both modalities, no clear regional differences were seen between high and low amyloid groups. Further analyses are needed to determine how changes in CBF measures can be useful in assessing risk for development of AD.

Amyloid-β (Aβ) plaque deposition can precede the clinical manifestations of dementia of the Alzheimer type (DAT) by many years and can be associated with changes in brain metabolism. Both the Aβ plaque deposition and the changes in metabolism appear to be concentrated in the brain's default-mode network. In contrast to prior studies of brain metabolism which viewed brain metabolism from a unitary perspective that equated glucose utilization with oxygen consumption, we here report on regional glucose use apart from that entering oxidative phosphorylation (so-called "aerobic glycolysis"). Using PET, we found that the spatial distribution of aerobic glycolysis in normal young adults correlates spatially with Aβ deposition in individuals with DAT and cognitively normal participants with elevated Aβ, suggesting a possible link between regional aerobic glycolysis in young adulthood and later development of Alzheimer pathology.