- Email: [email protected]
ADORA2A POLYMORPHISM IS ASSOCIATED WITH CEREBRAL BLOOD FLOW IN MILD COGNITIVE IMPAIRMENT (MCI) AND ALZHEIMER'S DISEASE
P46
Poster Presentations: Saturday, July 15, 2017
Table 1 Demographic and clinical characteristics Groups
N Prodromal AD/ AD dementia Sex (%male) Age (mean6SD) Education (median, range) MMSE (mean6SD)
ε2
ε3/ ε3
ε3/ε4
ε4/ε4
NC
Difference
38 6/32
40 12/28
37 8/29
40 10/30
45 -
n.s. n.s.
48 68.868.5 5 (1-7) 22.964.7
58 68.766.9 5 (3-7) 23.664.2
48 68.766.8 5 (2-7) 24.064.0
57 69.266.6 5 (3-7) 23.264.1
53 67.368.0 6 (2-7) 28.062.1
n.s. n.s. n.s. n.s *
NC – amyloid-negative ε3/ε3 normal controls. AD – Alzheimer’s disease. MMSE – mini mental state examination. * No difference between AD groups, all AD groups differed significantly from normal controls.
and distribution of gray matter atrophy of ε2 carriers with MCI or dementia -due-to-AD. Methods: 38 ε2 carriers (all ε2/ε3) with a clinical diagnosis of MCI or dementia -due-to-AD based on positive amyloid PET and/or CSF amyloid-beta1-42 were included. This group was matched for age, sex and education with an amyloid-negative cognitively normal ε3/ε3 (NC) group, and groups of amyloid-positive ε3/ε3, ε3/ε4, and ε4/ε4 AD patients (Table 1). Neuropsychological test scores were converted into Z-scores using the mean and standard deviation of the NC group and then categorized into 4 cognitive domains (i.e. memory, attention, executive functioning and language). ANCOVA analyses adjusted for age, sex, education and disease-stage (MCI/ dementia) were used to compare cognition between AD groups. Voxel-based morphometry was conducted in statistical parametric mapping 12 to assess voxelwise differences in gray matter atrophy between AD groups and controls. The models included age, sex, scanner-type and total intracranial volume as covariates. Results: ε2 carriers had more impaired language function compared to all other AD groups (F(3)¼6.29, p<.01; Figure 1), while memory was relatively preserved in ε2 carriers compared to ε4/ε4 carriers (F(3)¼2.67, p¼.05). Voxelwise contrasts against controls revealed relative sparing of the medial temporal lobe in ε2 compared to ε4 carriers (p<.05, family-wise error corrected; Figure 2). Similar analyses using a less stringent threshold (p<.001, uncorrected; Figure 3) revealed that ε2 carriers displayed i) an atrophy pattern that was mostly restricted to temporoparietal regions compared to wider neocortical involvement in other groups, and ii) left>right asymmetry. Conclusions: The observed atrophy pattern in ε2 carriers (i.e. left>right asymmetry and relatively spared medial temporal lobes) matches their neuropsychological profile with prominent language deficits and relatively preserved memory performance. These results help to elucidate differences in regional vulnerability across APOE genotypes and better understand clinical heterogeneity in AD.
IC-P-056
endogenous production and the widening of blood vessels. Adenosine Receptor Subtype A2a (ADORA2A) is a G-protein-coupled adenosine receptor that is involved in controlling synaptic plasticity in glutamatergic synapses. Previously, we identified the minor allele of rs9608282 in ADORA2A associated with larger hippocampal volumes, especially for participants with increased amyloid-b burden as measured by [18F]Florbetapir PET. Since selective blockade of the adenosine A2A receptor reduced the pial vasodilation in certain situations, we tested the hypothesis that rs9608282 in ADORA2A is significantly associated with cerebral blood flow (CBF). Methods: Non-Hispanic Caucasian participants from the Alzheimer’s Disease Neuroimaging Initiative GO/2 (ADNIGO/2) cohort with arterial spin labeling (ASL) perfusion imaging (N¼220) and genotype data were used. Statistical Parametric Mapping 8 (Wellcome Trust Centre for Neuroimaging) with a cluster threshold of 25 voxels was used to perform voxelwise analysis of the effect of rs9608282-T variant in the ADORA2A gene on CBF. Age, sex and diagnosis were used as covariates. Results: Voxel-wise analysis of ASL perfusion demonstrated significantly decreased regional CBF especially in the left cerebrum, temporal lobe, and superior temporal gyrus in individuals with at least one minor alleles (T) of rs9608282 compared to those with no minor allele (Figure 1). Conclusions: Hippocampal volume typically decreases as AD progresses. However, cerebral blood flow can increase or decrease in the brain, a phenomenon that might relate to compensatory mechanisms during early stages of disease. However, individuals who carry the minor allele of rs9608282 appear to show differential responsiveness to adenosine binding to Adenosine Receptor Subtype A2a.
ADORA2A POLYMORPHISM IS ASSOCIATED WITH CEREBRAL BLOOD FLOW IN MILD COGNITIVE IMPAIRMENT (MCI) AND ALZHEIMER’S DISEASE
Emrin Horgusluoglu1,2, Shannon L. Risacher1,2, Andrew J. Saykin1,2,3, Kwangsik Nho1,2, 1Indiana University School of Medicine, Indianapolis, IN, USA; 2Indiana Alzheimer Disease Center, Indianapolis, IN, USA; 3 Indiana University Network Science Institute, Bloomington, IN, USA. Contact e-mail: [email protected] Background: Adenosine controls the pial vasodilation in the cerebral vasculature through binding of A2A receptors secondary to
Figure 1. Individuals with at least one minor alleles (T) of rs9608282 associated with perfusion decrease.
Poster Presentations: Saturday, July 15, 2017
Table 1 Demographic and clinical characteristics Groups
N Prodromal AD/ AD dementia Sex (%male) Age (mean6SD) Education (median, range) MMSE (mean6SD)
ε2
ε3/ ε3
ε3/ε4
ε4/ε4
NC
Difference
38 6/32
40 12/28
37 8/29
40 10/30
45 -
n.s. n.s.
48 68.868.5 5 (1-7) 22.964.7
58 68.766.9 5 (3-7) 23.664.2
48 68.766.8 5 (2-7) 24.064.0
57 69.266.6 5 (3-7) 23.264.1
53 67.368.0 6 (2-7) 28.062.1
n.s. n.s. n.s. n.s *
NC – amyloid-negative ε3/ε3 normal controls. AD – Alzheimer’s disease. MMSE – mini mental state examination. * No difference between AD groups, all AD groups differed significantly from normal controls.
and distribution of gray matter atrophy of ε2 carriers with MCI or dementia -due-to-AD. Methods: 38 ε2 carriers (all ε2/ε3) with a clinical diagnosis of MCI or dementia -due-to-AD based on positive amyloid PET and/or CSF amyloid-beta1-42 were included. This group was matched for age, sex and education with an amyloid-negative cognitively normal ε3/ε3 (NC) group, and groups of amyloid-positive ε3/ε3, ε3/ε4, and ε4/ε4 AD patients (Table 1). Neuropsychological test scores were converted into Z-scores using the mean and standard deviation of the NC group and then categorized into 4 cognitive domains (i.e. memory, attention, executive functioning and language). ANCOVA analyses adjusted for age, sex, education and disease-stage (MCI/ dementia) were used to compare cognition between AD groups. Voxel-based morphometry was conducted in statistical parametric mapping 12 to assess voxelwise differences in gray matter atrophy between AD groups and controls. The models included age, sex, scanner-type and total intracranial volume as covariates. Results: ε2 carriers had more impaired language function compared to all other AD groups (F(3)¼6.29, p<.01; Figure 1), while memory was relatively preserved in ε2 carriers compared to ε4/ε4 carriers (F(3)¼2.67, p¼.05). Voxelwise contrasts against controls revealed relative sparing of the medial temporal lobe in ε2 compared to ε4 carriers (p<.05, family-wise error corrected; Figure 2). Similar analyses using a less stringent threshold (p<.001, uncorrected; Figure 3) revealed that ε2 carriers displayed i) an atrophy pattern that was mostly restricted to temporoparietal regions compared to wider neocortical involvement in other groups, and ii) left>right asymmetry. Conclusions: The observed atrophy pattern in ε2 carriers (i.e. left>right asymmetry and relatively spared medial temporal lobes) matches their neuropsychological profile with prominent language deficits and relatively preserved memory performance. These results help to elucidate differences in regional vulnerability across APOE genotypes and better understand clinical heterogeneity in AD.
IC-P-056
endogenous production and the widening of blood vessels. Adenosine Receptor Subtype A2a (ADORA2A) is a G-protein-coupled adenosine receptor that is involved in controlling synaptic plasticity in glutamatergic synapses. Previously, we identified the minor allele of rs9608282 in ADORA2A associated with larger hippocampal volumes, especially for participants with increased amyloid-b burden as measured by [18F]Florbetapir PET. Since selective blockade of the adenosine A2A receptor reduced the pial vasodilation in certain situations, we tested the hypothesis that rs9608282 in ADORA2A is significantly associated with cerebral blood flow (CBF). Methods: Non-Hispanic Caucasian participants from the Alzheimer’s Disease Neuroimaging Initiative GO/2 (ADNIGO/2) cohort with arterial spin labeling (ASL) perfusion imaging (N¼220) and genotype data were used. Statistical Parametric Mapping 8 (Wellcome Trust Centre for Neuroimaging) with a cluster threshold of 25 voxels was used to perform voxelwise analysis of the effect of rs9608282-T variant in the ADORA2A gene on CBF. Age, sex and diagnosis were used as covariates. Results: Voxel-wise analysis of ASL perfusion demonstrated significantly decreased regional CBF especially in the left cerebrum, temporal lobe, and superior temporal gyrus in individuals with at least one minor alleles (T) of rs9608282 compared to those with no minor allele (Figure 1). Conclusions: Hippocampal volume typically decreases as AD progresses. However, cerebral blood flow can increase or decrease in the brain, a phenomenon that might relate to compensatory mechanisms during early stages of disease. However, individuals who carry the minor allele of rs9608282 appear to show differential responsiveness to adenosine binding to Adenosine Receptor Subtype A2a.
ADORA2A POLYMORPHISM IS ASSOCIATED WITH CEREBRAL BLOOD FLOW IN MILD COGNITIVE IMPAIRMENT (MCI) AND ALZHEIMER’S DISEASE
Emrin Horgusluoglu1,2, Shannon L. Risacher1,2, Andrew J. Saykin1,2,3, Kwangsik Nho1,2, 1Indiana University School of Medicine, Indianapolis, IN, USA; 2Indiana Alzheimer Disease Center, Indianapolis, IN, USA; 3 Indiana University Network Science Institute, Bloomington, IN, USA. Contact e-mail: [email protected] Background: Adenosine controls the pial vasodilation in the cerebral vasculature through binding of A2A receptors secondary to
Figure 1. Individuals with at least one minor alleles (T) of rs9608282 associated with perfusion decrease.