The Spatial-Temporal Ordering of Amyloid Pathology and Opportunities for PET Imaging

Fantoni, E.; Collij, Lyduine E.; Alves, Isadora Lopes; Buckley, Christopher; Farrar, Gill

doi:10.2967/jnumed.119.235879

Cited by 46 publications

(60 citation statements)

References 52 publications

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“…including the most recent and extensive staging work to date. 6 21 22 This consistent discrepancy between neuropathology and PET-only studies has been described previously, 23 and is likely to be influenced by signal distortion present in PET imaging. Due to the proximity of medial regions to white matter and the additional grey matter signal spill-in from the contralateral hemisphere, medial regions such as those in stage 1 and 2 in this work are more frequently classified as abnormal in PET imaging compared to lateral counterparts, even when levels of pathology are comparable.. 24 While the discrepancy with pathological studies might be due to sample size, resolution limitations and differences in technique such as the intrinsic signal distortion of PET imaging, remaining differences across PET studies could also be explained by methodological choices including the use of partial volume correction (PVC).…”

Section: A C C E P T E Dsupporting

confidence: 65%

Multitracer model for staging cortical amyloid deposition using PET imaging

et al. 2020

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Objective:To develop and evaluate a model for staging cortical amyloid deposition using PET with high generalizability.Methods:3027 subjects (1763 Cognitively Unimpaired (CU), 658 Impaired, 467 Alzheimer’s disease (AD) dementia, 111 non-AD dementia, and 28 with missing diagnosis) from six cohorts (EMIF-AD, ALFA, ABIDE, ADC, OASIS-3, ADNI) who underwent amyloid PET were retrospectively included; 1049 subjects had follow-up scans. Applying dataset-specific cut-offs to global Standard Uptake Value ratio (SUVr) values from 27 regions, single-tracer and pooled multi-tracer regional rankings were constructed from the frequency of abnormality across 400 CU subjects (100 per tracer). The pooled multi-tracer ranking was used to create a staging model consisting of four clusters of regions as it displayed a high and consistent correlation with each single-tracer ranking. Relationships between amyloid stage, clinical variables and longitudinal cognitive decline were investigated.Results:SUVr abnormality was most frequently observed in cingulate, followed by orbitofrontal, precuneal, and insular cortices, then the associative, temporal and occipital regions. Abnormal amyloid levels based on binary global SUVr classification were observed in 1.0%, 5.5%, 17.9%, 90.0%, and 100.0% of stage 0-4 subjects, respectively. Baseline stage predicted decline in MMSE (ADNI: N=867, F=67.37, p<0.001; OASIS: (N=475, F=9.12, p<0.001) and faster progression towards an MMSE≤25 (ADNI: N=787, HRstage1=2.00, HRstage2=3.53, HRstage3=4.55, HRstage4=9.91, p<0.001; OASIS: N=469, HRstage4=4.80, p<0.001).Conclusion:The pooled multi-tracer staging model successfully classified the level of amyloid burden in >3000 subjects across cohorts and radiotracers, and detects pre-global amyloid burden and distinct risk profiles of cognitive decline within globally amyloid-positive subjects.

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Section: A C C E P T E Dsupporting

confidence: 65%

Multitracer model for staging cortical amyloid deposition using PET imaging

et al. 2020

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“…In addition, several studies have shown that measures of Aβ deposition below a threshold of established Aβ pathology carry critical information on initial pathological brain changes and may indicate appropriate time periods for interventions [19]. Moreover, the regional evolution of Aβ load may enable earlier identification of subjects in the AD pathologic continuum and may overcome dichotomous measures [20]. Regional information has shown to be relevant in staging Aβ pathology [21][22][23], tracking disease progression, and assessing the risk of cognitive decline [23][24][25].…”

Section: Introductionmentioning

confidence: 99%

Early detection of amyloid load using 18F-florbetaben PET

Bullich¹,

Roé-Vellvé²,

Marquié

et al. 2021

Alz Res Therapy

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Background A low amount and extent of Aβ deposition at early stages of Alzheimer’s disease (AD) may limit the use of previously developed pathology-proven composite SUVR cutoffs. This study aims to characterize the population with earliest abnormal Aβ accumulation using 18F-florbetaben PET. Quantitative thresholds for the early (SUVRearly) and established (SUVRestab) Aβ deposition were developed, and the topography of early Aβ deposition was assessed. Subsequently, Aβ accumulation over time, progression from mild cognitive impairment (MCI) to AD dementia, and tau deposition were assessed in subjects with early and established Aβ deposition. Methods The study population consisted of 686 subjects (n = 287 (cognitively normal healthy controls), n = 166 (subjects with subjective cognitive decline (SCD)), n = 129 (subjects with MCI), and n = 101 (subjects with AD dementia)). Three categories in the Aβ-deposition continuum were defined based on the developed SUVR cutoffs: Aβ-negative subjects, subjects with early Aβ deposition (“gray zone”), and subjects with established Aβ pathology. Results SUVR using the whole cerebellum as the reference region and centiloid (CL) cutoffs for early and established amyloid pathology were 1.10 (13.5 CL) and 1.24 (35.7 CL), respectively. Cingulate cortices and precuneus, frontal, and inferior lateral temporal cortices were the regions showing the initial pathological tracer retention. Subjects in the “gray zone” or with established Aβ pathology accumulated more amyloid over time than Aβ-negative subjects. After a 4-year clinical follow-up, none of the Aβ-negative or the gray zone subjects progressed to AD dementia while 91% of the MCI subjects with established Aβ pathology progressed. Tau deposition was infrequent in those subjects without established Aβ pathology. Conclusions This study supports the utility of using two cutoffs for amyloid PET abnormality defining a “gray zone”: a lower cutoff of 13.5 CL indicating emerging Aβ pathology and a higher cutoff of 35.7 CL where amyloid burden levels correspond to established neuropathology findings. These cutoffs define a subset of subjects characterized by pre-AD dementia levels of amyloid burden that precede other biomarkers such as tau deposition or clinical symptoms and accelerated amyloid accumulation. The determination of different amyloid loads, particularly low amyloid levels, is useful in determining who will eventually progress to dementia. Quantitation of amyloid provides a sensitive measure in these low-load cases and may help to identify a group of subjects most likely to benefit from intervention. Trial registration Data used in this manuscript belong to clinical trials registered in ClinicalTrials.gov (NCT00928304, NCT00750282, NCT01138111, NCT02854033) and EudraCT (2014-000798-38).

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“…Our results support this hypothesis especially when the amyloid deposition is plentiful, as in our study, and higher than 2 times amount in age-matched older persons, it should not be considered as the "normal" effect of aging. Conversely, the presence of high amyloid burden with global diffusion in the cerebral cortex is associated with an increased risk of developing AD over time [45,46].…”

Section: Discussionmentioning

confidence: 99%

Relationship between comprehensive geriatric assessment and amyloid PET in older persons with MCI

et al. 2020

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Background The association between amyloid deposition and cognitive, behavioral and physical performance in mild cognitive impairment (MCI) due to Alzheimer’s disease (AD) has been poorly investigated, especially in older persons. Methods We studied the in vivo correlation between the amyloid deposition at Positron Emission Tomography (amyloid-PET) and the presence of memory loss, reduced executive function, neuropsychiatric symptoms and physical performance in older persons with MCI. Amyloid-PET was performed with 18F-flutemetamol and quantitatively analyzed. Results We evaluated 48 subjects, 21 men and 27 women. We performed in each patient a comprehensive geriatric assessment (CGA) including Mini Mental State Examination (MMSE), Clock Drawing Test (CDT), Activity Daily Living (ADL), Instrumental Activity of Daily Living (IADL), Neuropsychiatric inventory (NPI) questionnaire, 15 Geriatric Depression Scale (GDS), Short Physical Performance Battery (SPPB) and Hand Grip strength. Then, each patient underwent amyloid-PET. Mean age of the enrolled subjects was 74.6 ± 7.8 years. All of these subjects showed preserved cognitive function at MMSE > 24, while 29 of 48 subjects (61.0%) had altered CDT. Mean NPI score was 6.9 ± 5.9. The mean value of SPPB score was 9.0 ± 2.6, while the average muscle strength of the upper extremities measured by hand grip was 25.6 ± 7.7 Kg. CT/MRI images showed cortical atrophic changes in 26 of the 48 examined subjects (54.0%), while cerebrovascular modifications were present in 31 subjects (64.5%). Pathological burden of amyloid deposits was detected in 25 of 48 (52.0%) patients with a mean value of global z-score of 2.8 (subjects defined as MCI due to AD). After stratifying subjects in subclasses of clinical alterations, more probability of pathological amyloid deposition was found in subjects with impaired CDT and higher NPI score (O.R. = 3.45 [1.01–11.2], p = 0.04), with both impaired CDT and low physical performance (O.R. = 5.80 [1.04–32.2], p = 0.04), with altered CDT and high NPI score (O.R. = 7.98 [1.38–46.0], p = 0.02), and finally in those subjects with altered CDT, high NPI and low physical performance (O.R. = 5.80 [1.05–32.2], p = 0.04). Conclusion Our findings support the recent hypothesis that amyloid deposition could be associated with multiple cerebral dysfunction, mainly affecting executive, behavioral and motor abilities.

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The Spatial-Temporal Ordering of Amyloid Pathology and Opportunities for PET Imaging

Cited by 46 publications

References 52 publications

Multitracer model for staging cortical amyloid deposition using PET imaging

Multitracer model for staging cortical amyloid deposition using PET imaging

Early detection of amyloid load using 18F-florbetaben PET

Relationship between comprehensive geriatric assessment and amyloid PET in older persons with MCI

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