Comparison of [11C]UCB-J and [18F]FDG PET in Alzheimer’s disease: A tracer kinetic modeling study

[11C]UCB-J PET for synaptic vesicle glycoprotein 2 A (SV2A) has been proposed as a suitable marker for synaptic density in Alzheimer’s disease (AD). We compared [11C]UCB-J binding for synaptic density and [18F]FDG uptake for metabolism (correlated with neuronal activity) in 14 AD and 11 cognitively normal (CN) participants. We assessed both absolute and relative outcome measures in brain regions of interest, i.e., K1 or R1 for [11C]UCB-J perfusion, VT (volume of distribution) or DVR to cerebellum for [11C]UCB-J binding to SV2A; and Ki or Ki R to cerebellum for [18F]FDG metabolism. [11C]UCB-J binding and [18F]FDG metabolism showed a similar magnitude of reduction in the medial temporal lobe of AD –compared to CN participants. However, the magnitude of reduction of [11C]UCB-J binding in neocortical regions was less than that observed with [18F]FDG metabolism. Inter-tracer correlations were also higher in the medial temporal regions between synaptic density and metabolism, with lower correlations in neocortical regions. [11C]UCB-J perfusion showed a similar pattern to [18F]FDG metabolism, with high inter-tracer regional correlations. In summary, we conducted the first in vivo PET imaging of synaptic density and metabolism in the same AD participants and reported a concordant reduction in medial temporal regions but a discordant reduction in neocortical regions.

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In vivo synaptic density relates to glucose metabolism at rest in healthy subjects, but is strongly modulated by regional differences

Journal of Cerebral Blood Flow & Metabolism ◽

10.1177/0271678x20981502 ◽

2021 ◽

pp. 0271678X2098150

Author(s):

June van Aalst ◽

Jenny Ceccarini ◽

Stefan Sunaert ◽

Patrick Dupont ◽

Michel Koole ◽

...

Keyword(s):

Glucose Metabolism ◽

Medial Temporal Lobe ◽

Regional Differences ◽

Specific Binding ◽

Aerobic Glycolysis ◽

Glucose Consumption ◽

Brain Regions ◽

Synaptic Density ◽

Energy Demands

Preclinical and postmortem studies have suggested that regional synaptic density and glucose consumption (CMRGlc) are strongly related. However, the relation between synaptic density and cerebral glucose metabolism in the human brain has not directly been assessed in vivo. Using [11C]UCB-J binding to synaptic vesicle glycoprotein 2 A (SV2A) as indicator for synaptic density and [18F]FDG for measuring cerebral glucose consumption, we studied twenty healthy female subjects (age 29.6 ± 9.9 yrs) who underwent a single-day dual-tracer protocol (GE Signa PET-MR). Global measures of absolute and relative CMRGlc and specific binding of [11C]UCB-J were indeed highly significantly correlated ( r > 0.47, p < 0.001). However, regional differences in relative [18F]FDG and [11C]UCB-J uptake were observed, with up to 19% higher [11C]UCB-J uptake in the medial temporal lobe (MTL) and up to 17% higher glucose metabolism in frontal and motor-related areas and thalamus. This pattern has a considerable overlap with the brain regions showing different levels of aerobic glycolysis. Regionally varying energy demands of inhibitory and excitatory synapses at rest may also contribute to this difference. Being unaffected by astroglial and/or microglial energy demands, changes in synaptic density in the MTL may therefore be more sensitive to early detection of pathological conditions compared to changes in glucose metabolism.

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Spatial inhibition of return is impaired in mild cognitive impairment and mild Alzheimer’s disease

10.1101/2020.05.11.089383 ◽

2020 ◽

Author(s):

Xiong Jiang ◽

James H. Howard ◽

G. Wiliam Rebeck ◽

R. Scott Turner

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cognitive Impairment ◽

Mild Cognitive Impairment ◽

Medial Temporal Lobe ◽

Inhibition Of Return ◽

Memory Performance ◽

Brain Regions ◽

List Type ◽

Older Individuals

ABSTRACTSpatial inhibition of return (IOR) refers to the phenomenon by which individuals are slower to respond to stimuli appearing at a previously cued location compared to un-cued locations. Here we provide evidence supporting that spatial IOR is mildly impaired in individuals with mild cognitive impairment (MCI) or mild Alzheimer’s disease (AD), and the impairment is readily detectable using a novel double cue paradigm. Furthermore, reduced spatial IOR in high-risk healthy older individuals is associated with reduced memory and other neurocognitive task performance, suggesting that the novel double cue spatial IOR paradigm may be useful in detecting MCI and early AD.SIGNIFICANCE STATEMENTNovel double cue spatial inhibition of return (IOR) paradigm revealed a robust effect IOR deficits in individuals with mild cognitive impairment (MCI) or mild Alzheimer’s disease (AD)Spatial IOR effect correlates with memory performance in healthy older adults at a elevated risk of Alzheimer’s disease (with a family history or APOE e4 allele)The data suggests that double cue spatial IOR may be sensitive to detect early AD pathological changes, which may be linked to disease progress at the posterior brain regions (rather than the medial temporal lobe)

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Automated segmentation of medial temporal lobe subregions on in vivo T1-weighted MRI in early stages of Alzheimer's disease

Human Brain Mapping ◽

10.1002/hbm.24607 ◽

2019 ◽

Vol 40 (12) ◽

pp. 3431-3451 ◽

Cited By ~ 13

Author(s):

Long Xie ◽

Laura E. M. Wisse ◽

John Pluta ◽

Robin de Flores ◽

Virgine Piskin ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Temporal Lobe ◽

Medial Temporal Lobe ◽

Automated Segmentation ◽

Early Stages

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Computerized Cognitive Tests Are Associated with Biomarkers of Alzheimer’s Disease in Cognitively Normal Individuals 10 Years Prior

Journal of the International Neuropsychological Society ◽

10.1017/s1355617716000722 ◽

2016 ◽

Vol 22 (10) ◽

pp. 968-977 ◽

Cited By ~ 6

Author(s):

Anja Soldan ◽

Corinne Pettigrew ◽

Abhay Moghekar ◽

Marilyn Albert ◽

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Visual Search ◽

Medial Temporal Lobe ◽

Search Task ◽

Visual Search Task ◽

Csf Biomarkers ◽

Cognitive Tests ◽

Cognitively Normal ◽

Normal Individuals

AbstractObjectives: Evidence suggests that Alzheimer’s disease (AD) biomarkers become abnormal many years before the emergence of clinical symptoms of AD, raising the possibility that biomarker levels measured in cognitively normal individuals would be associated with cognitive performance many years later. This study examined whether performance on computerized cognitive tests is associated with levels of cerebrospinal fluid (CSF) biomarkers of amyloid, tau, and phosphorylated tau (p-tau) obtained approximately 10 years earlier, when individuals were cognitively normal and primarily middle-aged. Methods: Individuals from the BIOCARD cohort (mean age at testing=69 years) were tested on two computerized tasks hypothesized to rely on brain regions affected by the early accumulation of AD pathology: (1) a Paired Associates Learning (PAL) task (n=67) and (2) a visual search task (n=86). Results: In regression analyses, poorer performance on the PAL task was associated with higher levels of CSF p-tau obtained years earlier, whereas worse performance in the visual search task was associated with lower levels of CSF Aβ1-42. Conclusions: These findings suggest that AD biomarker levels may be differentially predictive of specific cognitive functions many years later. In line with the pattern of early accumulation of AD pathology, the PAL task, hypothesized to rely on medial temporal lobe function, was associated with CSF p-tau, whereas the visual search task, hypothesized to rely on frontoparietal function, was associated with CSF amyloid. Studies using amyloid and tau PET imaging will be useful in examining these hypothesized relationships further. (JINS, 2016, 22, 968–977)

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In vivo changes in microglial activation and amyloid deposits in brain regions with hypometabolism in Alzheimer’s disease

European Journal of Nuclear Medicine and Molecular Imaging ◽

10.1007/s00259-010-1612-0 ◽

2010 ◽

Vol 38 (2) ◽

pp. 343-351 ◽

Cited By ~ 97

Author(s):

Masamichi Yokokura ◽

Norio Mori ◽

Shunsuke Yagi ◽

Etsuji Yoshikawa ◽

Mitsuru Kikuchi ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Microglial Activation ◽

Brain Regions ◽

Amyloid Deposits

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Association between GAB2 haplotype and higher glucose metabolism in Alzheimer's disease-affected brain regions in cognitively normal APOEε4 carriers

NeuroImage ◽

10.1016/j.neuroimage.2010.09.066 ◽

2011 ◽

Vol 54 (3) ◽

pp. 1896-1902 ◽

Cited By ~ 14

Author(s):

Winnie S. Liang ◽

Kewei Chen ◽

Wendy Lee ◽

Kunal Sidhar ◽

Jason J. Corneveaux ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Glucose Metabolism ◽

Brain Regions ◽

Cognitively Normal

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Dementia is strongly associated with medial temporal atrophy even after accounting for neuropathologies

10.1101/2021.06.06.21258383 ◽

2021 ◽

Author(s):

Davis Christopher Woodworth ◽

Nasim Sheikh-Bahaei ◽

Kiana A Scambray ◽

Michael J Phelan ◽

Mari Perez-Rosendahl ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Temporal Lobe ◽

Medial Temporal Lobe ◽

Hippocampal Sclerosis ◽

Clinical Status ◽

Amyloid Angiopathy ◽

Linear Regression Models ◽

Partial Correlations

Objective: Brain atrophy is associated with degenerative neuropathologies as well as clinical status of dementia. Whether dementia influences atrophy independent of neuropathologies is not known. In this study, we examined the pattern of atrophy associated with dementia while accounting for the most common dementia-related neuropathologies. Methods: We used data from National Alzheimer's Coordinating Center (NACC, N=129) and Alzheimer's Disease Neuroimaging Initiative (ADNI, N=47) participants with suitable in-vivo 3D-T1w MRI and autopsy data. We determined dementia status at visit closest to MRI. We examined the following dichotomized neuropathological variables: Alzheimer's disease neuropathology, hippocampal sclerosis, Lewy Bodies, cerebral amyloid angiopathy, atherosclerosis. Voxel-based morphometry (VBM) identified areas associated with dementia after accounting for neuropathologies. Identified regions of interest were further analyzed. We used multiple linear regression models adjusted for neuropathologies and demographic variables. Results: We found strong associations for dementia with volumes of the hippocampus, amygdala, and parahippocampus (semi-partial correlations≥0.28, P<0.0001 for all regions in NACC; semi-partial correlations≥0.35, P≤0.01 for hippocampus and parahippocampus in ADNI). Dementia status accounted for more unique variance in atrophy in these structures (~8%) compared with neuropathological variables; the only exception was hippocampal sclerosis which accounted for more variance in hippocampal atrophy (10%). Conclusion: Even after accounting for the most common neuropathologies, dementia still had among the strongest correlations with atrophy of medial temporal lobe structures. This suggests that atrophy of the medial temporal lobe is most related to clinical status of dementia as opposed to Alzheimer's or other neuropathologies.

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Progressive Memory Circuit Impairments along with Alzheimer’s Disease Neuropathology Spread: Evidence from in vivo Neuroimaging

Cerebral Cortex ◽

10.1093/cercor/bhaa162 ◽

2020 ◽

Vol 30 (11) ◽

pp. 5863-5873

Author(s):

Kaicheng Li ◽

Shuyue Wang ◽

Xiao Luo ◽

Qingze Zeng ◽

Yerfan Jiaerken ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Memory Performance ◽

Cognitively Normal ◽

Memory Circuit ◽

Group 4 ◽

Group 3 ◽

Group 2 ◽

Disease Stages

Abstract During the progression of Alzheimer’s disease (AD), neuropathology may propagate transneuronally, cause disruption in memory circuit, and lead to memory impairment. However, there is a lack of in vivo evidence regarding this process. Thus, we aim to simulate and observe the progression of neuropathology in AD continuum. We included cognitively normal (CN), mild cognitive impairments (MCI), and AD subjects, and further classified them using the A/T/N scheme (Group 0: CN, A − T−; Group 1: CN, A + T−; Group 2: CN, A + T+; Group 3: MCI, A + T+; Group 4: AD, A + T+). We investigated alterations of three core memory circuit structures: hippocampus (HP) subfields volume, cingulum-angular bundles (CAB) fiber integrity, and precuneus cortex volume. HP subfields volume showed the trend of initially increased and then decreased (starting from Group 2), while precuneus volume decreased in Groups 3 and 4. The CAB integrity degenerated in Groups 3 and 4 and aggravated with higher disease stages. Further, memory circuit impairments were correlated with neuropathology biomarkers and memory performance. Conclusively, our results demonstrated a pattern of memory circuit impairments along with AD progression: starting from the HP, then propagating to the downstream projection fiber tract and cortex. These findings support the tau propagation theory to some extent.

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Evaluation of Imaging Windows for Tau PET Imaging Using 18F-PI2620 in Cognitively Normal Individuals, Mild Cognitive Impairment, and Alzheimer’s Disease Patients

Molecular Imaging ◽

10.1177/1536012120947582 ◽

2020 ◽

Vol 19 ◽

pp. 153601212094758 ◽

Cited By ~ 1

Author(s):

Chanisa Chotipanich ◽

Monchaya Nivorn ◽

Anchisa Kunawudhi ◽

Chetsadaporn Promteangtrong ◽

Natphimol Boonkawin ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cognitive Impairment ◽

Mild Cognitive Impairment ◽

Standardized Uptake Value ◽

Brain Regions ◽

Post Injection ◽

Cognitively Normal ◽

Scanning Time ◽

Normal Individuals

Background: The study aimed to evaluate the appropriate uptake-timing in cognitively normal individuals, mild cognitive impairment (MCI), and Alzheimer’s disease (AD) patients, using 18F-PI 2620 dynamic PET acquisition. Methods: Thirty-four MCI patients, 6 AD patients, and 24 cognitively normal individuals were enrolled in this study. A dynamic 18F-PI 2620 PET study was conducted at 30-75 minutes post-injection in these groups. Co-registration was applied between the dynamic acquisition PET and T1-weighted MRI to delineate various cortical regions. The standardized uptake value ratio (SUVR) was used for quantitative analysis. P-mod software with the Automated Anatomical Labeling (AAL)-merged atlas was employed to generate automatic volumes of interest for 11 brain regions. Results: The curves in most brain regions presented an average SUVR stability at 30-40 minutes post-injection in each group. The appropriate uptake-timing interval of 18F-PI 2620 was 30-75 minutes post injection for AD group and 30-40 minutes post injection for both cognitively normal individuals and MCI groups. Conclusion: Short uptake time around 30-40 minutes post-injection would be more comfortable and convenient for all patients, especially in those with dementia who were unable to stay motionless for long periods of scanning time in the scanner.

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