Development of a new PET biomarker for synaptic function (original) (raw)
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Neurochem Int, 2010
Earlier post-mortem histological and autoradiographic studies have indicated a reduction of cell numbers in the locus coeruleus (LC) and a corresponding decrease in norepinephrine transporter (NET) in brains obtained from Alzheimer's disease (AD) patients as compared to age-matched healthy controls. In order to test the hypothesis that the regional decrease of NET is a disease specific biomarker in AD and as such, it can be used in PET imaging studies for diagnostic considerations, regional differences in the density of NET in various anatomical structures were measured in whole hemisphere human brain slices obtained from AD patients and age-matched control subjects in a series of autoradiographic experiments using the novel selective PET radioligand for NET (S,S)-[18F]FMeNER-D2. (S,S)-[18F]FMeNER-D2 appears to be a useful imaging biomarker for quantifying the density of NET in various brain structures, including the LC and the thalamus wherein the highest densities are found in physiological conditions. In AD significant decreases of NET densities can be demonstrated with the radioligand in both structures as compared to age-matched controls. The decreases in AD correlate with the progress of the disease as indicated by Braak grades. As the size of the LC is below the spatial resolution of the PET scanners, but the size of the thalamus can be detected with appropriate spatial accuracy in advanced scanners, the present findings confirm our earlier observations with PET that the in vivo imaging of NET with (S,S)-[18F]FMeNER-D2 in the thalamus is viable. Nevertheless, further studies are warranted to assess the usefulness of such an imaging approach for the early detection of changes in thalamic NET densities as a disease-specific biomarker and the possible use of (S,S)-[18F]FMeNER-D2 as a molecular imaging biomarker in AD.
In vivo measurement of widespread synaptic loss in Alzheimer's disease with SV2A PET
Alzheimer's & Dementia, 2020
IntroductionSynaptic loss is a robust and consistent pathology in Alzheimer's disease (AD) and the major structural correlate of cognitive impairment. Positron emission tomography (PET) imaging of synaptic vesicle glycoprotein 2A (SV2A) has emerged as a promising biomarker of synaptic density.MethodsWe measured SV2A binding in 34 participants with early AD and 19 cognitively normal (CN) participants using [11C]UCB‐J PET and a cerebellar reference region for calculation of the distribution volume ratio.ResultsWe observed widespread reductions of SV2A binding in medial temporal and neocortical brain regions in early AD compared to CN participants. These reductions were largely maintained after correction for volume loss and were more extensive than decreases in gray matter volume.ConclusionWe were able to measure widespread synaptic loss due to AD using [11C]UCB‐J PET. Future studies will continue to evaluate the utility of SV2A PET for tracking AD progression and for monitoring p...
American Journal of Neuroradiology, 2010
BACKGROUND AND PURPOSE: Different biomarkers for AD may potentially be complementary in diagnosis and prognosis of AD. Our aim was to combine MR imaging, FDG-PET, and CSF biomarkers in the diagnostic classification and 2-year prognosis of MCI and AD, by examining the following: 1) which measures are most sensitive to diagnostic status, 2) to what extent the methods provide unique information in diagnostic classification, and 3) which measures are most predictive of clinical decline. MATERIALS AND METHODS: ADNI baseline MR imaging, FDG-PET, and CSF data from 42 controls, 73 patients with MCI, and 38 patients with AD; and 2-year clinical follow-up data for 36 controls, 51 patients with MCI, and 25 patients with AD were analyzed. The hippocampus and entorhinal, parahippocampal, retrosplenial, precuneus, inferior parietal, supramarginal, middle temporal, lateral, and medial orbitofrontal cortices were used as regions of interest. CSF variables included A42, t-tau, p-tau, and ratios of t-tau/A42 and p-tau/A42. Regression analyses were performed to determine the sensitivity of measures to diagnostic status as well as 2-year change in CDR-SB, MMSE, and delayed logical memory in MCI. RESULTS: Hippocampal volume, retrosplenial thickness, and t-tau/A42 uniquely predicted diagnostic group. Change in CDR-SB was best predicted by retrosplenial thickness; MMSE, by retrosplenial metabolism and thickness; and delayed logical memory, by hippocampal volume. CONCLUSIONS: All biomarkers were sensitive to the diagnostic group. Combining MR imaging morphometry and CSF biomarkers improved diagnostic classification (controls versus AD). MR imaging morphometry and PET were largely overlapping in value for discrimination. Baseline MR imaging and PET measures were more predictive of clinical change in MCI than were CSF measures. ABBREVIATIONS: A42 ϭ  amyloid 1-42; AD ϭ Alzheimer disease; ADNI ϭ Alzheimer's Disease Neuroimaging Initiative; AUC ϭ area under the curve; B ϭ B coefficient for each predictor in the regression equation; CDR-SB ϭ Clinical Dementia Rating sum of boxes; Corr. Class.ϭ correlation classification; CSHC ϭ Center for the Study of Human Cognition; FDA ϭ US Food and Drug Administration; 18F-FDG ϭ [ 18 F] fluorodeoxyglucose; FDG-PET ϭ fluorodeoxyglucose-positronemission tomography; inf. ϭ inferior; lat. ϭ lateral; LM-del ϭ delayed Logical Memory from the Wechsler Memory Scale Logical Memory II; M ϭ mean; MCI ϭ mild cognitive impairment; med. orb. front. ϭ medial orbital frontal; mid ϭ middle; MMSE ϭ Mini-Mental State Examination; MRI ϭ MR imaging; NIH ϭ National Institutes of Health; NC ϭ healthy control; orb. front. ϭ orbital frontal; p-tau ϭ phosphorylated tau protein 181; parahippoc. ϭ parahippocampus; PET ϭ positron-emission tomography; t-tau ϭ tau protein; ROC ϭ receiver operating characteristics
2017
Background: Evidence suggests that the concordance between amyloid-PET and cerebrospinal fluid (CSF) amyloid- (A) increases when the CSF A 1-42 /A 1-40 ratio is used as compared to CSF A 1-42 levels alone. Objective: In order to test this hypothesis, we set up a prospective longitudinal study comparing the concordance between different amyloid biomarkers for Alzheimer's disease (AD) in a clinical setting. Methods: Seventy-eight subjects (AD dementia (n = 17), mild cognitive impairment (MCI, n = 48), and cognitively healthy controls (n = 13)) underwent a [ 18 F]Florbetapir ([ 18 F]AV45) PET scan, [ 18 F]FDG PET scan, MRI scan, and an extensive neuropsychological examination. In a large subset (n = 67), a lumbar puncture was performed and AD biomarkers were analyzed (A 1-42 , A 1-40 , T-tau, P-tau 181). Results: We detected an increased concordance in the visual and quantitative (standardized uptake value ratio (SUVR) and total volume of distribution (V T)) [ 18 F]AV45 PET measures when the CSF A 1-42 /A 1-40 was applied compared to A 1-42 alone. CSF biomarkers were stronger associated to [ 18 F]AV45 PET for SUVR values when considering the total brain white matter as reference region instead of cerebellar grey matter .
[18F]FDG-PET as a Biomarker for Early Alzheimer`s Disease~!2009-10-01~!2010-01-07~!2010-05-06~!
The Open Nuclear Medicine Journal, 2010
18 Fluorine]fluorodeoxiglucose-Positron Emission Tomgraphy ( 18 F FDG-PET) has gained a leading role in the diagnostic assessment of patients with cognitive complaints, notably Mild Cognitive Impairment (MCI) and Alzheimer's Disease (AD). Together with morphological Magnetic Resonance Imaging (MRI) and cerebrospinal fluid biomarker assays it allows early identification of subjects with neurodegeneration of the AD-type, which is crucial in view of effective disease-modifying drugs.
Journal of Alzheimer's Disease
Background: Evidence suggests that the concordance between amyloid-PET and cerebrospinal fluid (CSF) amyloid- (A) increases when the CSF A 1-42 /A 1-40 ratio is used as compared to CSF A 1-42 levels alone. Objective: In order to test this hypothesis, we set up a prospective longitudinal study comparing the concordance between different amyloid biomarkers for Alzheimer's disease (AD) in a clinical setting. Methods: Seventy-eight subjects (AD dementia (n = 17), mild cognitive impairment (MCI, n = 48), and cognitively healthy controls (n = 13)) underwent a [ 18 F]Florbetapir ([ 18 F]AV45) PET scan, [ 18 F]FDG PET scan, MRI scan, and an extensive neuropsychological examination. In a large subset (n = 67), a lumbar puncture was performed and AD biomarkers were analyzed (A 1-42 , A 1-40 , T-tau, P-tau 181). Results: We detected an increased concordance in the visual and quantitative (standardized uptake value ratio (SUVR) and total volume of distribution (V T)) [ 18 F]AV45 PET measures when the CSF A 1-42 /A 1-40 was applied compared to A 1-42 alone. CSF biomarkers were stronger associated to [ 18 F]AV45 PET for SUVR values when considering the total brain white matter as reference region instead of cerebellar grey matter .