Regional multimodal relationships between tau, hypometabolism, atrophy, and fractional anisotropy in atypical Alzheimer's disease

Sintini, Irene; Schwarz, Christopher G.; Martin, Peter R.; Graff‐Radford, Jonathan; Machulda, Mary M.; Senjem, Matthew L.; Reid, Robert I.; Spychalla, Anthony J.; Drubach, Daniel A.; Lowe, Val J.; Jack, Clifford R.; Josephs, Keith A.; Whitwell, Jennifer L.

doi:10.1002/hbm.24473

Cited by 65 publications

(57 citation statements)

References 51 publications

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“…We found that SUVRs in the temporal ( R = −0.530, P = 0.020), parietal ( R = −0.637, P = 0.003), and occipital ( R = −0.567, P = 0.011) lobes correlated negatively between [ 18 F]-APN-1607 and [ 18 F]-FDG uptakes, with a trend toward negative correlation in the frontal lobe ( P = 0.073, R = −0.421). These findings were consistent with results disclosed using other tau tracers [[ 18 F]-AV-1451 ( Gordon et al, 2019 ; Sintini et al, 2019 ) and [ 18 F]-THK5351 ( Baghel et al, 2019 )]. Previous stereological and non-stereological quantitative post-mortem studies of cerebral cortex ( Terry et al, 1981 , 1987 ; Cras et al, 1995 ; Schwab et al, 1998 , 1999 ; Bussiere et al, 2002 ; Kril et al, 2002 ) and clinicopathologic studies ( Giannakopoulos et al, 2003 ) reported a close association between NFT counts and neuron loss.…”

Section: Discussionsupporting

confidence: 92%

“…Positron emission tomography with [ 18 F]-FDG reveals a characteristic pattern of hypometabolism in temporoparietal cortex and posterior cingulate of AD patients ( Minoshima et al, 1995 ; Kato et al, 2016 ; Hsu et al, 2017 ; Rice and Bisdas, 2017 ; Blazhenets et al, 2019 ). Multimodal studies combining A/T/N biomarkers showed tau deposition as measured by [ 18 F]-AV-1451 ( Sintini et al, 2019 ) or [ 18 F]-THK5351 ( Baghel et al, 2019 ) PET, which correlated with hypometabolism to [ 18 F]-FDG PET and with atrophy, as measured by structural magnetic resonance imaging (MRI) ( Sintini et al, 2019 ).…”

Section: Introductionmentioning

confidence: 99%

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Associations of [18F]-APN-1607 Tau PET Binding in the Brain of Alzheimer’s Disease Patients With Cognition and Glucose Metabolism

Bao

et al. 2020

Front. Neurosci.

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Molecular imaging of tauopathies is complicated by the differing specificities and off-target binding properties of available radioligands for positron emission tomography (PET). [ 18 F]-APN-1607 ([ 18 F]-PM-PBB3) is a newly developed PET tracer with promising properties for tau imaging. We aimed to characterize the cerebral binding of [ 18 F]-APN-1607 in Alzheimer’s disease (AD) patients compared to normal control (NC) subjects. Therefore, we obtained static late frame PET recordings with [ 18 F]-APN-1607 and [ 18 F]-FDG in patients with a clinical diagnosis of AD group, along with an age-matched NC group ([ 18 F]-APN-1607 only). Using statistical parametric mapping (SPM) and volume of interest (VOI) analyses of the reference region normalized standardized uptake value ratio maps, we then tested for group differences and relationships between both PET biomarkers, as well as their associations with clinical general cognition. In the AD group, [ 18 F]-APN-1607 binding was elevated in widespread cortical regions ( P < 0.001 for VOI analysis, familywise error-corrected P < 0.01 for SPM analysis). The regional uptake in AD patients correlated negatively with Mini-Mental State Examination score (frontal lobe: R = -0.632, P = 0.004; temporal lobe: R = -0.593, P = 0.008; parietal lobe: R = -0.552, P = 0.014; insula: R = -0.650, P = 0.003; cingulum: R = -0.665, P = 0.002) except occipital lobe ( R = -0.417, P = 0.076). The hypometabolism to [ 18 F]-FDG PET in AD patients also showed negative correlations with regional [ 18 F]-APN-1607 binding in some signature areas of AD (temporal lobe: R = -0.530, P = 0.020; parietal lobe: R = -0.637, P = 0.003; occipital lobe: R = -0.567, P = 0.011). In conclusion, our results suggested that [ 18 F]-APN-1607 PET sensitively detected tau deposition in AD and that individual tauopathy correlated with impaired cerebral glucose metabolism and cognitive function.

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Section: Discussionsupporting

confidence: 92%

Section: Introductionmentioning

confidence: 99%

Associations of [18F]-APN-1607 Tau PET Binding in the Brain of Alzheimer’s Disease Patients With Cognition and Glucose Metabolism

Bao

et al. 2020

Front. Neurosci.

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“…Prior voxel‐level analyses have found different regional patterns of cortical volume loss 42–44 and flortaucipir uptake in the cortex 45–48 between PCA and LPA. The aim of our study was not to identify regional differences between PCA and LPA, and hence we did not repeat these studies.…”

Section: Discussionmentioning

confidence: 99%

MRI and flortaucipir relationships in Alzheimer's phenotypes are heterogeneous

Josephs

Tosakulwong

Graff‐Radford

et al. 2020

Ann Clin Transl Neurol

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Objective: To assess the relationships between MRI volumetry and [ 18 F]flortaucipir PET of typical and atypical clinical phenotypes of Alzheimer's disease, by genarian (age by decade). Methods: Five-hundred and sixty-four participants including those with typical (n = 86) or atypical (n = 80) Alzheimer's dementia and normal controls (n = 398) underwent apolipoprotein E genotyping, MRI, flortaucipir, and 11 C-PiB; all 166 Alzheimer's participants were beta-amyloid positive and all controls were beta-amyloid negative. Grey matter volume and flortaucipir standard uptake value ratios were calculated for hippocampus, entorhinal cortex, and neocortex. Ratios of hippocampal-to-neocortical and entorhinal-to-neocortical volume and flortaucipir uptake were also calculated. Linear regression models assessed relationships among regional volume, flortaucipir uptake, and ratios and phenotypes, within three genarians (50-59, 60-69, and 70+). Voxel-level analyses were also performed. Results: For 50-59 greater medial temporal atrophy and flortaucipir uptake was observed in the typical compared with atypical phenotype. The typical phenotype also showed greater frontal neocortex uptake with the voxel-level analysis. For 60-69 and 70+ there was greater hippocampal volume loss in the typical compared with atypical phenotype while only the 60-69, but not the 70+ group, showed a difference in hippocampal flortaucipir uptake. We also observed a pattern for higher neocortical flortaucipir uptake to correlate with younger age decade for both phenotypes. Interpretation: MRI volumetry versus flortaucipir PET relationships differ across Alzheimer's clinical phenotypes, and also within phenotype across age decades. This suggests that there is potential risk of masked effects by not accounting for genarian in participants with beta-amyloid and tau-positive biomarker defined Alzheimer's disease.

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“…Cross-sectional studies have demonstrated striking [ 18 F]AV-1451 uptake in patients with AD, with patterns differing with age (Lowe et al, 2018; Pontecorvo et al, 2017; Tetzloff et al, 2018) and across clinical variants (Ossenkoppele et al, 2016; Scholl et al, 2017). Studies have also shown close spatial relationships between tau-PET uptake and grey matter volume in typical and atypical clinical variants of AD (Dronse et al, 2017; Iaccarino et al, 2018; Ossenkoppele et al, 2016; Sintini et al, 2018; Whitwell et al, 2018; Xia et al, 2017) and demonstrated that tau uptake is also related to antecedent rates of volume loss (Das et al, 2018; Gordon et al, 2018). Two studies have investigated longitudinal regional changes in [ 18 F]AV-1451 uptake in AD patients (Harrison et al, 2018; Jack et al, 2018).…”

Section: Introductionmentioning

confidence: 91%

Longitudinal tau-PET uptake and atrophy in atypical Alzheimer's disease

Sintini

Martin

Graff‐Radford

et al. 2019

NeuroImage: Clinical

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The aims of this study were: to examine regional rates of change in tau-PET uptake and grey matter volume in atypical Alzheimer's disease (AD); to investigate the role of age in such changes; to describe multimodal regional relationships between tau accumulation and atrophy. Thirty atypical AD patients underwent baseline and one-year follow-up MRI, [ 18 F]AV-1451 PET and PiB PET. Region- and voxel-level rates of tau accumulation and grey matter atrophy relative to cognitively unimpaired individuals, and the influence of age on such rates, were assessed. Univariate and multivariate analyses were performed between baseline measurements and rates of change, between baseline tau and atrophy, and between the two rates of change. Regional patterns of change in tau and volume differed, with highest rates of tau accumulation in frontal lobe and highest rates of atrophy in temporoparietal regions. Age had a negative effect on disease progression, predominantly on tau, with younger patients having a more rapid accumulation. Baseline tau uptake and regions of tau accumulation were disconnected, with high baseline tau uptake across the cortex correlated with high rates of tau accumulation in frontal and sensorimotor regions. In contrast, baseline volume and atrophy were locally related in the occipitoparietal regions. Higher tau uptake at baseline was locally related to higher rates of atrophy in frontal and occipital lobes. Tau accumulation rates positively correlated with rates of atrophy. In summary, our study showed that tau accumulation and atrophy presented different regional patterns in atypical AD, with tau spreading into the frontal lobes while atrophy remains in temporoparietal and occipital cortex, suggesting a temporal disconnect between protein deposition and neurodegeneration.

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Regional multimodal relationships between tau, hypometabolism, atrophy, and fractional anisotropy in atypical Alzheimer's disease

Cited by 65 publications

References 51 publications

Associations of [18F]-APN-1607 Tau PET Binding in the Brain of Alzheimer’s Disease Patients With Cognition and Glucose Metabolism

Associations of [18F]-APN-1607 Tau PET Binding in the Brain of Alzheimer’s Disease Patients With Cognition and Glucose Metabolism

MRI and flortaucipir relationships in Alzheimer's phenotypes are heterogeneous

Longitudinal tau-PET uptake and atrophy in atypical Alzheimer's disease

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