Spatial pattern of beta-amyloid accumulation in Alzheimer’s disease as measured with positron emission tomography
Year: 2018
Type: dissertation
Abstract: Knowledge about spatial and temporal patterns of beta-amyloid (Aβ) accumulation is essential for understanding Alzheimer's disease (AD) and design of anti-amyloid drug trials.In this thesis, I studied the spatial pattern of Aβ accumulation in subjects with preclinical and manifest sporadic AD (sAD) and autosomal dominant AD (ADAD), as measured with positron emission tomography (PET).Analyzed were baseline and two years' follow-up PET and magnetic resonance imaging data from the Alzheimer's disease Neuroimaging Initiative and Dominantly Inherited Alzheimer Network databases.After pre-processing and partial volume correction of PET images, regional standard uptake values (SUV) were extracted using a probabilistic brain atlas.In the first project, the regional pattern of annual accumulation rate (AAR) of 18 F-florbteapir was investigated in 58 Aβ-positive patients with incipient and manifest dementia due to sAD.A pseudo-temporal accumulation rate was estimated from baseline PET only by determining how fast regional SUVR changes relative to the whole gray matter SUVR.The so-called pseudo-temporal measurements explained 87% (p<0.001) of the variance in longitudinal AARs across 62 regions.Thus, this method allows identification of brain regions with a high accumulation rate of Aβ, which are of particular interest for antiamyloid clinical trials.In the second project, I examined a longitudinal trajectory of AAR in the pre-dementia stage of sAD, using 18 F-florbteapir PET data of 246 Aβpositive cognitively normal subjects and patients with mild cognitive impairment.Subjects with baseline SUVR in whole gray matter (SUVRGM) of 0.56 to 0.92 (n=134) appeared to accumulate Aβ approximately 1.5 times faster than remaining subjects.In subjects with SUVRGM above 0.95, most active Aβ accumulating regions were outside the established set of AD-typical regions.When these patterns are taken into account, the sample size in anti-amyloid trials can be substantially reduced.Finally, our data strongly suggested that treated and placebo groups should be matched for baseline SUVRGM.Otherwise, a treatment effect can be significantly over-or underestimated.In the third project, I studied the spatial and temporal pattern of Aβ accumulation in ADAD.Analyzed were Pittsburg compound B PET data of 97 mutation carriers (MC) (APP=19, PSEN1=72, PSEN2=6) and 50 Aβ-negative asymptomatic non-mutation carriers (NC).I found that overall the spatial and temporal pattern of Aβ accumulation in MC was very similar to that of sAD except for subcortical nuclei.As compared to sAD, these nuclei appeared to be fast Aβ accumulating regions.However, due to their relatively small size, these regions did not significantly contribute to the set of AD-typical regions.Thus, the established set of AD-typical regions can be used as target region to detect longitudinal SUVR changes in Aβ-positive MC, too.In summary, the findings of this thesis provide meaningful references for planning and analyses of anti-amyloid clinical trials with PET as biomarker.
Author: Tengfei Guo
Language: English
Subfield: Psychiatry and Mental health
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W2948133997