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1.  Association of plasma and cortical beta-amyloid is modulated by APOE ε4 status 
APOE ε4’s role as a modulator of the relationship between soluble plasma beta-amyloid (Aβ) and fibrillar brain Aβ measured by Pittsburgh Compound-B positron emission tomography ([11C]PiB PET) has not been assessed.
Ninety-six Alzheimer’s Disease Neuroimaging Initiative participants with [11C]PiB scans and plasma Aβ1-40 and Aβ1-42 measurements at time of scan were included. Regional and voxel-wise analyses of [11C]PiB data were used to determine the influence of APOE ε4 on association of plasma Aβ1-40, Aβ1-42, and Aβ1-40/Aβ1-42 with [11C]PiB uptake.
In APOE ε4− but not ε4+ participants, positive relationships between plasma Aβ1-40/Aβ1-42 and [11C]PiB uptake were observed. Modeling the interaction of APOE and plasma Aβ1-40/Aβ1-42 improved the explained variance in [11C]PiB binding compared to using APOE and plasma Aβ1-40/Aβ1-42 as separate terms.
The results suggest that plasma Aβ is a potential Alzheimer’s disease biomarker and highlight the importance of genetic variation in interpretation of plasma Aβ levels.
PMCID: PMC3750076  PMID: 23541187
Alzheimer’s disease (AD); mild cognitive impairment (MCI); Alzheimer’s Disease Neuroimaging Initiative (ADNI); beta-amyloid (Aβ); plasma beta-amyloid; positron emission tomography (PET); Pittsburgh Compound-B ([11C]PiB); Apolipoprotein E (APOE)
2.  Gene–Environment Interactions: Lifetime Cognitive Activity, APOE Genotype, and Beta-Amyloid Burden 
The Journal of Neuroscience  2014;34(25):8612-8617.
Carriers of the apolipoprotein E (APOE) ε4 allele, the major genetic risk for Alzheimer's disease (AD), harbor an increased load of β-amyloid (Aβ) plaque burden that is felt to be a major instigator of AD development. Data has suggested that lifestyle factors may reduce AD risk by directly mitigating Aβ pathology, which could be particularly beneficial in APOE ε4 carriers. We therefore examined the interaction between lifetime cognitive activity and the APOE ε4 allele in relation to brain Aβ burden. We obtained measures of lifetime cognitive activity in 118 cognitively normal human individuals (mean age: 76.13 ± 5.56 years, 70 women) using a validated questionnaire that included measures over early, middle, and current age epochs. Hierarchical regression models (adjusted for age, gender, and years of education) were conducted to examine effects of APOE ε4 carrier status, lifetime cognitive activity, and the interaction of the two factors with cortical Aβ deposition, quantified using [11C] Pittsburgh-compound-B (PIB)-PET. As expected, the ε4 carriers exhibited higher PIB retention compared with noncarriers. Lifetime cognitive activity moderated the APOE genotype effect such that cortical PIB retention was diminished in ε4 carriers that reported higher cognitive activity over the life course. The findings suggest that greater lifetime cognitive activity may forestall AD pathology, specifically in genetically susceptible individuals. The effect could imply that cognitive training promotes increased neural efficiency that might retard the lifelong neurally mediated deposition of Aβ.
PMCID: PMC4061397  PMID: 24948815
aging; Alzheimer's disease; APOE; β-amyloid; lifestyle activity; PIB-PET
3.  Comparing PET imaging and CSF measurements of Aβ 
Annals of neurology  2013;74(6):826-836.
We examined agreement and disagreement between two biomarkers of Aβ deposition (amyloid PET and CSF Aβ1-42) in normal aging and dementia in a large multicenter study.
Concurrently acquired florbetapir-PET and CSF Aβ were measured in cognitively normal, mild cognitive impairment (MCI), and Alzheimer’s disease (AD) participants (N=374) from the Alzheimer’s Disease Neuroimaging Initiative (ADNI). We also compared Aβ measurements in a separate group with serial CSF measurements over 3.1 +/− 0.8 yrs that preceded a single florbetapir session. Additional biomarker and cognitive data allowed us to further examine profiles of discordant cases.
Florbetapir and CSF Aβ were inversely correlated across all diagnostic groups, and dichotomous measurements were in agreement in 86% of subjects. Among subjects showing the most disagreement, the two discordant groups had different profiles: the florbetapir+/CSF Aβ− group was larger (N=13) and was made up of only normal and early MCI subjects; while the florbetapir−/CSF Aβ+ group was smaller (N=7), had poorer cognitive function and higher CSF tau, but no ApoE4 carriers. In the longitudinal sample, we observed both stable longitudinal CSF Aβ trajectories and those actively transitioning from normal to abnormal, but the final CSF Aβ measurements were in good agreement with florbetapir cortical retention.
CSF and amyloid-PET measurements of Aβ were consistent in the majority of subjects in the cross-sectional and longitudinal populations. Based on our analysis of discordant subjects, the available evidence did not show that CSF Aβ regularly becomes abnormal prior to fibrillar Aβ accumulation early in the course of disease.
PMCID: PMC3748164  PMID: 23536396
4.  The effect of amyloid β on cognitive decline is modulated by neural integrity in cognitively normal elderly 
Alzheimer’s disease (AD) pathology of amyloid β (Aβ) accumulation and neurodegeneration may be relevant to preclinical cognitive decline. The objective of this study was to relate AD-sensitive biomarkers of Aβ and neurodegeneration and their interaction to longitudinal cognitive change in cognitively normal elderly.
Thirty-eight older people completed at least three consecutive neuropsychological examinations. Using positron emission tomography (PET), Aβ plaque burden was measured with [11C] Pittsburgh compound B (PiB). PiB retention was dichotomized into a positive (n = 13) and negative (n = 25) PiB status. Neurodegenerative biomarkers were extracted within AD-vulnerable regions of interest (ROIs)—namely, the hippocampus and temporoparietal cortical areas. Within each ROI, metabolism was quantified with [18F] fluorodeoxyglucose (FDG) PET, and the gray matter structure was evaluated using volume (hippocampus) or thickness (cortical regions). ROI-specific functional and structural biomarkers were combined further into cross-modality neurodegenerative composite measures. Using hierarchical regression models, PiB and the neurodegenerative biomarkers were related to cognitive trajectories.
PiB positivity was associated with memory and nonmemory worsening. The neurodegenerative biomarkers modified these relationships. Longitudinal cognitive decline was accelerated in those individuals who exhibited both PiB positivity and lower neurodegenerative biomarker scores, although the two measures appeared to be independent. PiB retention interacted predominantly with the cortical neurodegenerative composite for nonmemory change. Memory decline was best explained by the interaction between PiB and the hippocampal neurodegenerative composite, suggesting regional specificity of the neurodegenerative modulations.
Our findings indicate that cognitive trajectories deteriorate at a faster rate in cognitively normal individuals expressing Aβ burden and neurodegeneration within specific AD-sensitive regions.
PMCID: PMC3823816  PMID: 23474040
Alzheimer’s disease; Cognitive aging; Memory; Preclinical decline; Amyloid; PiB; Glucose metabolism; FDG; Gray matter structure
5.  Genetic effects on behavior are mediated by neurotransmitters and large-scale neural networks 
NeuroImage  2012;0:203-214.
Claims of gene-behavior associations are complex and sometimes difficult to replicate because these relationships involve many downstream endogenous and environmental processes that mediate genetic effects. Knowing these mediating processes is critical to understanding the links between genes and behavior and how these factors differ between people. We identified and characterized the effects of a gene on neurochemistry and neural networks to elucidate the mechanism, at the systems level, whereby genes influence cognition. Catechol-O-methyltransferase (COMT) degrades dopamine in the prefrontal cortex (PFC) and is polymorphic with alleles differing in enzymatic activity. We found that COMT genotype determined dopamine synthesis, such that individuals with greater COMT activity synthesized more dopamine. Dopamine synthesis in the midbrain and ventral striatum affected functional connectivity in the default mode network, likely through the mesocorticolimbic pathway, in an inverted-U pattern with greater functional connectivity in medial PFC associated with intermediate levels of COMT activity and dopamine. Greater functional connectivity correlated with greater deactivation during performance of a set-shifting task that engaged the PFC. Greater deactivation was in turn associated with better performance. The integration of these results yields a model whereby COMT affects prefrontal function by a mechanism involving dopaminergic modulation of the default mode network. The model features the well-known inverted-U function between dopamine and performance and supports the hypothesis that dopamine and the default mode network shift attentional resources to influence prefrontal cognition.
PMCID: PMC3587048  PMID: 23142068
COMT; dopamine; prefrontal cortex; default mode network; set shifting
6.  Effect of Cognitive Reserve Markers on Alzheimer Pathological Progression 
Alzheimer disease and associated disorders  2013;27(4):10.1097/WAD.0b013e3182900b2b.
Education, occupation, premorbid intelligence and brain size are surrogate markers for cognitive reserve. Whether these markers have biological influence on Alzheimer disease (AD) pathology is not known. We thus aimed to investigate the effect of cognitive reserve proxies on longitudinal change of AD biomarkers. A total of 819 participants with normal cognition (NC), mild cognitive impairment (MCI) and mild AD were enrolled in the Alzheimer’s Disease Neuroimaging Initiative and followed up with repeated measures of CSF, PET and MRI biomarkers. Generalized estimating equations were employed to assess whether biomarker rates of change were modified by reserve proxies. CSF Aβ42 decline was slower in NC participants with higher cognitive reserve indexed by education, occupation and American National Adult Reading Test (ANART). The decline of [18F] fluorodeoxyglucose PET uptake was slower in AD participants with better performance on the ANART. Education, occupation and ANART did not modify the rates of MRI hippocampal atrophy in any group. These findings remained unchanged after accounting for APOE 4, longitudinal missing data and baseline cognitive performance. Higher levels of reserve markers may slow the rate of amyloid deposition before cognitive impairment and preserve glucose metabolism at the dementia stage over the course of AD pathological progression.
PMCID: PMC3745532  PMID: 23552443
cognitive reserve; Alzheimer disease; aging; biomarker; longitudinal study
7.  Focal Hemosiderin Deposits and β-Amyloid Load in the ADNI Cohort 
Prevalence and risk factors for focal hemosiderin deposits are important considerations when planning amyloid–modifying trials for treatment and prevention of Alzheimer’s disease (AD).
Subjects were cognitively normal (n=171), early-mild cognitive impairment (MCI) (n=240), late-MCI (n=111) and AD (n=40) from the Alzheimer’s Disease Neuroimaging Initiative (ADNI). Microhemorrhages and superficial siderosis were assessed at baseline and on all available MRIs at 3, 6 and 12 months. β-amyloid load was assessed with 18F-florbetapir PET.
Prevalence of superficial siderosis was 1% and prevalence of microhemorrhages was 25% increasing with age (p<0.001) and β-amyloid load (p<0.001). Topographic densities of microhemorrhages were highest in the occipital lobes and lowest in the deep/infratentorial regions. A greater number of microhemorrhages at baseline was associated with a greater annualized rate of additional microhemorrhages by last follow-up (rank correlation=0.49;P<0.001).
Focal hemosiderin deposits are relatively common in the ADNI cohort and are associated with β-amyloid load.
PMCID: PMC3770782  PMID: 23375568
ADNI; microhemorrhage; superficial siderosis; MRI; Amyloid; PET; Florbetapir; Alzheimer’s disease; mild cognitive impairment; early mild cognitive impairment
8.  APOE and BCHE as modulators of cerebral amyloid deposition: a florbetapir PET genome-wide association study 
Molecular psychiatry  2013;19(3):351-357.
Deposition of amyloid-β (Aβ) in the cerebral cortex is thought to be a pivotal event in Alzheimer’s disease (AD) pathogenesis with a significant genetic contribution. Molecular imaging can provide an early noninvasive phenotype but small samples have prohibited genome-wide association studies (GWAS) of cortical Aβ load until now. We employed florbetapir (18F) positron emission tomography (PET) imaging to assess brain Aβ levels in vivo for 555 participants from the Alzheimer’s Disease Neuroimaging Initiative (ADNI). More than six million common genetic variants were tested for association to quantitative global cortical Aβ load controlling for age, gender, and diagnosis. Independent genome-wide significant associations were identified on chromosome 19 within APOE (rs429358, p = 5.5 × 10−14) and on chromosome 3 upstream of BCHE (rs509208, p = 2.7 × 10−8) in a region previously associated with serum butyrylcholinesterase activity. Together, these loci explained 15% of the variance in cortical Aβ levels in this sample (APOE 10.7%, BCHE 4.3%). Suggestive associations were identified within ITGA6, near EFNA5, EDIL3, ITGA1, PIK3R1, NFIB, and ARID1B, and between NUAK1 and C12orf75. These results confirm the association of APOE with Aβ deposition and represent the largest known effect of BCHE on an AD-related phenotype. Butyrylcholinesterase has been found in senile plaques and this new association of genetic variation at the BCHE locus with Aβ burden in humans may have implications for potential disease-modifying effects of butyrylcholinesterase-modulating agents in the AD spectrum.
PMCID: PMC3661739  PMID: 23419831
Alzheimer’s disease (AD); amyloid; apolipoprotein E (APOE); butyrylcholinesterase (BCHE); florbetapir (AV-45); genome-wide association study (GWAS)
9.  Dissociable Effects of Alzheimer Disease and White Matter Hyperintensities on Brain Metabolism 
JAMA neurology  2013;70(8):1039-1045.
Cerebrovascular disease and Alzheimer disease (AD) frequently co-occur and seem to act through different pathways in producing dementia.
To examine cerebrovascular disease and AD markers in relation to brain glucose metabolism in patients with mild cognitive impairment.
Design and Setting
Cohort study among the Alzheimer Disease Neuroimaging Initiative clinical sites in the United States and Canada.
Two hundred three patients having amnestic mild cognitive impairment (74 of whom converted to AD) with serial imaging during a 3-year follow-up period.
Main Outcomes and Measures
Quantified white matter hyperintensities (WMHs) represented cerebrovascular disease, and cerebrospinal fluid β-amyloid represented AD pathology. Brain glucose metabolism in temporoparietal and frontal brain regions was measured using positron emission tomography with fluorodeoxyglucose F18.
In converters, greater WMHs were associated with decreased frontal metabolism (−0.048; 95% CI, −0.067 to −0.029) but not temporoparietal metabolism (0.010; 95% CI, −0.010 to 0.030). Greater cerebrospinal fluid β-amyloid (per 10-pg/mL increase) was associated with increased temporoparietal metabolism (0.005; 95% CI, 0.000–0.010) but not frontal metabolism (0.002; 95% CI, −0.004 to 0.007) in the same patients. In nonconverters, similar relationships were observed except for a positive association of greater WMHs with increased temporoparietal metabolism (0.051; 95% CI, 0.027–0.076).
Conclusions and Relevance
The dissociation of WMHs and cerebrospinal fluid β-amyloid in relation to regional glucose metabolism suggests that these pathologic conditions operate through different and independent pathways in AD that reflect dysfunction in different brain systems. The positive association of greater WMHs with temporoparietal metabolism suggests that these pathologic processes do not co-occur in nonconverters.
PMCID: PMC3779687  PMID: 23779022
10.  Frontotemporal Network Connectivity during Memory Encoding Is Increased with Aging and Disrupted by Beta-Amyloid 
The Journal of Neuroscience  2013;33(47):18425-18437.
Approximately 30% of cognitively normal older adults harbor brain β-amyloid (Aβ), a prominent feature of Alzheimer's disease associated with neural alterations and episodic memory decline. We examined how aging and Aβ deposition affect neural function during memory encoding of visual scenes using functional magnetic resonance imaging (fMRI) in humans. Thirty-six cognitively normal older people underwent fMRI scanning, and positron emission tomography with [11C] Pittsburgh compound B to measure fibrillar brain Aβ; 15 young subjects were studied with fMRI. Older adults without Aβ deposition showed reduced regional brain activation (compared with young subjects) with decreased task-independent functional connectivity between parahippocampal gyrus and prefrontal cortex. In this network, task-related connectivity was increased compared with young subjects, and the degree of connectivity was related to memory performance. In contrast, older individuals with Aβ deposition showed no such increased task-related network connectivity, but did display increased regional activity unassociated with performance. These findings suggest that network connectivity plays a significant role in compensating for reduced regional activity during successful memory encoding in aging without Aβ deposition, while in those with Aβ this network compensation fails and is accompanied by inefficient regional hyperactivation.
PMCID: PMC3834050  PMID: 24259567
11.  Dorsal Striatal Dopamine, Food Preference and Health Perception in Humans 
PLoS ONE  2014;9(5):e96319.
To date, few studies have explored the neurochemical mechanisms supporting individual differences in food preference in humans. Here we investigate how dorsal striatal dopamine, as measured by the positron emission tomography (PET) tracer [18F]fluorometatyrosine (FMT), correlates with food-related decision-making, as well as body mass index (BMI) in 16 healthy-weight to moderately obese individuals. We find that lower PET FMT dopamine synthesis binding potential correlates with higher BMI, greater preference for perceived “healthy” foods, but also greater healthiness ratings for food items. These findings further substantiate the role of dorsal striatal dopamine in food-related behaviors and shed light on the complexity of individual differences in food preference.
PMCID: PMC4012945  PMID: 24806534
12.  Subjective cognition and amyloid deposition imaging: a Pittsburgh Compound B positron emission tomography study in normal elderly individuals 
Archives of Neurology  2012;69(2):223-229.
Subjective cognitive impairment (SCI) as an early clinical manifestation in Alzheimer disease (AD) is a central and highly debated question.
To study the relationship between subjective cognition and the neuropathological hallmark of AD, amyloid-beta (Aβ) deposition, imaged with [11C]-Pittsburg compound B (PiB) - positron emission tomography (PET), in normal elderly individuals.
Cross-sectional analysis.
Forty-eight cognitively normal elderly subjects (11 with high PiB uptake and 28 with low PiB uptake) were included. All underwent clinical and neuropsychological evaluations and MRI and PET scanning.
High PiB subjects showed significantly lower performance than low PiB subjects on an episodic memory measure, and were less confident about their general memory abilities when required to evaluate themselves relative to other people of the same age. High and low PiB groups did not differ on the accuracy of their cognitive self-reports compare to objective cognitive performance. General memory self-reports from the whole group were significantly correlated to regional PiB uptake in the right medial prefrontal cortex (PFC)/anterior cingulate cortex (ACC) and in the right precuneus/posterior cingulate cortex (PCC). Reduced confidence about memory abilities was associated with greater PiB in these brain regions. All results are independent of demographic variables and depressive affects.
Our findings suggest that a decrease of self-confidence about memory abilities in cognitively normal elderly subjects is related to the neuropathological hallmark of AD measured with PiB-PET imaging. The relevance of SCI in the early stages of the AD pathological process is addressed.
PMCID: PMC4004919  PMID: 22332189
Aged; Aged, 80 and over; Aging; physiology; Amyloid beta-Peptides; metabolism; Aniline Compounds; Biological Markers; Cerebral Cortex; radionuclide imaging; Cognition; physiology; Cognition Disorders; metabolism; psychology; radionuclide imaging; Cohort Studies; Female; Humans; Image Processing, Computer-Assisted; Magnetic Resonance Imaging; Male; Memory; physiology; Middle Aged; Neuropsychological Tests; Positron-Emission Tomography; Prefrontal Cortex; radionuclide imaging; Radiopharmaceuticals; Reference Values; Thiazoles; subjective cognition; normal aging; Alzheimer's disease (AD); amyloid-beta (Aβ); [11C]-Pittsburgh compound B (PiB) - positron emission tomography (PET)
13.  The Aging Brain and Cognition 
JAMA neurology  2013;70(4):488-495.
β-Amyloid (Aβ) deposition and vascular brain injury (VBI) frequently co-occur and are both associated with cognitive decline in aging. Determining whether a direct relationship exists between them has been challenging. We sought to understand VBI’s influence on cognition and clinical impairment, separate from and in conjunction with pathologic changes associated with Alzheimer disease (AD).
To examine the relationship between neuroimaging measures of VBI and brain Aβ deposition and their associations with cognition.
Design and Setting
A cross-sectional study in a community- and clinic-based sample recruited for elevated vascular disease risk factors.
Clinically normal (mean age, 77.1 years [N=30]), cognitively impaired (mean age, 78.0 years [N=24]), and mildly demented (mean age, 79.8 years [N=7]) participants.
Magnetic resonance imaging, Aβ (Pitts-burgh Compound B–positron emission tomographic [PiB-PET]) imaging, and cognitive testing.
Main Outcome Measures
Magnetic resonance images were rated for the presence and location of infarct (34 infarct-positive participants, 27 infarct-negative participants) and were used to quantify white matter lesion volume. The PiB-PET uptake ratios were used to create a PiB index by averaging uptake across regions vulnerable to early Aβ deposition; PiB positivity (29 PiB-positive participants, 32 PiB-negative participants) was determined from a data-derived threshold. Standardized composite cognitive measures included executive function and verbal and nonverbal memory.
Vascular brain injury and Aβ were independent in both cognitively normal and impaired participants. Infarction, particularly in cortical and subcortical gray matter, was associated with lower cognitive performance in all domains (P<.05 for all comparisons). Pittsburgh Compound B positivity was neither a significant predictor of cognition nor interacted with VBI.
Conclusions and Relevance
In this elderly sample with normal cognition to mild dementia, enriched for vascular disease, VBI was more influential than Aβ in contemporaneous cognitive function and remained predictive after including the possible influence of Aβ. There was no evidence that VBI increases the likelihood of Aβ deposition. This finding highlights the importance of VBI in mild cognitive impairment and suggests that the impact of cerebrovascular disease should be considered with respect to defining the etiology of mild cognitive impairment.
PMCID: PMC3771392  PMID: 23400560
14.  Parallel ICA of FDG-PET and PiB-PET in three conditions with underlying Alzheimer's pathology 
NeuroImage : Clinical  2014;4:508-516.
The relationships between clinical phenotype, β-amyloid (Aβ) deposition and neurodegeneration in Alzheimer's disease (AD) are incompletely understood yet have important ramifications for future therapy. The goal of this study was to utilize multimodality positron emission tomography (PET) data from a clinically heterogeneous population of patients with probable AD in order to: (1) identify spatial patterns of Aβ deposition measured by (11C)-labeled Pittsburgh Compound B (PiB-PET) and glucose metabolism measured by FDG-PET that correlate with specific clinical presentation and (2) explore associations between spatial patterns of Aβ deposition and glucose metabolism across the AD population. We included all patients meeting the criteria for probable AD (NIA–AA) who had undergone MRI, PiB and FDG-PET at our center (N = 46, mean age 63.0 ± 7.7, Mini-Mental State Examination 22.0 ± 4.8). Patients were subclassified based on their cognitive profiles into an amnestic/dysexecutive group (AD-memory; n = 27), a language-predominant group (AD-language; n = 10) and a visuospatial-predominant group (AD-visuospatial; n = 9). All patients were required to have evidence of amyloid deposition on PiB-PET. To capture the spatial distribution of Aβ deposition and glucose metabolism, we employed parallel independent component analysis (pICA), a method that enables joint analyses of multimodal imaging data. The relationships between PET components and clinical group were examined using a Receiver Operator Characteristic approach, including age, gender, education and apolipoprotein E ε4 allele carrier status as covariates. Results of the first set of analyses independently examining the relationship between components from each modality and clinical group showed three significant components for FDG: a left inferior frontal and temporoparietal component associated with AD-language (area under the curve [AUC] 0.82, p = 0.011), and two components associated with AD-visuospatial (bilateral occipito-parieto-temporal [AUC 0.85, p = 0.009] and right posterior cingulate cortex [PCC]/precuneus and right lateral parietal [AUC 0.69, p = 0.045]). The AD-memory associated component included predominantly bilateral inferior frontal, cuneus and inferior temporal, and right inferior parietal hypometabolism but did not reach significance (AUC 0.65, p = 0.062). None of the PiB components correlated with clinical group. Joint analysis of PiB and FDG with pICA revealed a correlated component pair, in which increased frontal and decreased PCC/precuneus PiB correlated with decreased FDG in the frontal, occipital and temporal regions (partial r = 0.75, p < 0.0001). Using multivariate data analysis, this study reinforced the notion that clinical phenotype in AD is tightly linked to patterns of glucose hypometabolism but not amyloid deposition. These findings are strikingly similar to those of univariate paradigms and provide additional support in favor of specific involvement of the language network, higher-order visual network, and default mode network in clinical variants of AD. The inverse relationship between Aβ deposition and glucose metabolism in partially overlapping brain regions suggests that Aβ may exert both local and remote effects on brain metabolism. Applying multivariate approaches such as pICA to multimodal imaging data is a promising approach for unraveling the complex relationships between different elements of AD pathophysiology.
•Multivariate approaches may be best suited to study links between biomarkers.•This is the first effort to apply pICA to FDG and PiB data in three groups with AD.•Hypometabolism was focal but amyloid binding was similar across conditions.•Results provide support for involvement of functional networks in variants of AD.•Aβ may exert both local and remote effects on brain metabolism.
PMCID: PMC3984448  PMID: 24818077
Multivariate data analysis; Parallel ICA; Alzheimer's disease; Amyloid imaging; PiB-PET; FDG-PET; Functional connectivity; Networks; AD or AD-memory, Alzheimer's disease; AUC, area under the curve; AD-language or LPA, logopenic variant primary progressive aphasia; PCA or AD-visuospatial, posterior cortical atrophy; PCC, posterior cingulate cortex; PPC, posterior parietal cortex
15.  Greater medial temporal hypometabolism and lower cortical amyloid burden in ApoE4-positive AD patients 
ApoE4 has been associated with an increased risk of Alzheimer’s disease (AD), amyloid deposition and hypometabolism. ApoE4 is less prevalent in non-amnestic AD variants suggesting a direct effect on the clinical phenotype. However, the impact of ApoE4 on amyloid burden and glucose metabolism across different clinical AD syndromes is not well understood. We aimed to assess the relationship between amyloid deposition, glucose metabolism and ApoE4 genotype in a clinically heterogeneous population of AD patients.
Fifty-two patients with probable AD (NIA-AA) underwent [11C]Pittsburgh compound B (PIB) and [18F]fluorodeoxyglucose (FDG) PET scans. All patients had positive PIB-PET scans. 23 were ApoE4+ (14 heterozygous, 9 homozygous) and 29 were ApoE4−. Groups consisted of language-variant AD, visual-variant AD, and AD patients with amnestic and dysexecutive deficits. 52 healthy controls were included for comparison. FDG and PIB uptake was compared between groups on a voxel-wise basis and in regions-of-interest.
Whilst PIB patterns were diffuse in both patient groups, ApoE4− patients showed higher PIB uptake than ApoE4+ patients across the cortex. Higher PIB uptake in ApoE4− patients was particularly significant in right lateral frontotemporal regions. In contrast, similar patterns of hypometabolism relative to controls were found in both patient groups, mainly involving lateral temporoparietal cortex, precuneus, posterior cingulate cortex, and middle frontal gyrus. Comparing patient groups, ApoE4+ subjects showed greater hypometabolism in bilateral medial temporal and right lateral temporal regions, and ApoE4− patients showed greater hypometabolism in cortical areas including supplementary motor cortex and superior frontal gyrus.
ApoE4+ AD patients showed lower global amyloid burden and greater medial temporal hypometabolism compared to matched ApoE4− patients. These findings suggest that ApoE4 may increase susceptibility to molecular pathology and modulate the anatomic pattern of neurodegeneration in AD.
PMCID: PMC3946299  PMID: 23965289
Alzheimer’s disease; PET; amyloid; glucose metabolism; apolipoprotein E
16.  Diverging patterns of amyloid deposition and hypometabolism in clinical variants of probable Alzheimer’s disease 
Brain  2013;136(3):844-858.
The factors driving clinical heterogeneity in Alzheimer’s disease are not well understood. This study assessed the relationship between amyloid deposition, glucose metabolism and clinical phenotype in Alzheimer’s disease, and investigated how these relate to the involvement of functional networks. The study included 17 patients with early-onset Alzheimer’s disease (age at onset <65 years), 12 patients with logopenic variant primary progressive aphasia and 13 patients with posterior cortical atrophy [whole Alzheimer’s disease group: age = 61.5 years (standard deviation 6.5 years), 55% male]. Thirty healthy control subjects [age = 70.8 (3.3) years, 47% male] were also included. Subjects underwent positron emission tomography with 11C-labelled Pittsburgh compound B and 18F-labelled fluorodeoxyglucose. All patients met National Institute on Ageing–Alzheimer’s Association criteria for probable Alzheimer’s disease and showed evidence of amyloid deposition on 11C-labelled Pittsburgh compound B positron emission tomography. We hypothesized that hypometabolism patterns would differ across variants, reflecting involvement of specific functional networks, whereas amyloid patterns would be diffuse and similar across variants. We tested these hypotheses using three complimentary approaches: (i) mass-univariate voxel-wise group comparison of 18F-labelled fluorodeoxyglucose and 11C-labelled Pittsburgh compound B; (ii) generation of covariance maps across all subjects with Alzheimer’s disease from seed regions of interest specifically atrophied in each variant, and comparison of these maps to functional network templates; and (iii) extraction of 11C-labelled Pittsburgh compound B and 18F-labelled fluorodeoxyglucose values from functional network templates. Alzheimer’s disease clinical groups showed syndrome-specific 18F-labelled fluorodeoxyglucose patterns, with greater parieto-occipital involvement in posterior cortical atrophy, and asymmetric involvement of left temporoparietal regions in logopenic variant primary progressive aphasia. In contrast, all Alzheimer’s disease variants showed diffuse patterns of 11C-labelled Pittsburgh compound B binding, with posterior cortical atrophy additionally showing elevated uptake in occipital cortex compared with early-onset Alzheimer’s disease. The seed region of interest covariance analysis revealed distinct 18F-labelled fluorodeoxyglucose correlation patterns that greatly overlapped with the right executive-control network for the early-onset Alzheimer’s disease region of interest, the left language network for the logopenic variant primary progressive aphasia region of interest, and the higher visual network for the posterior cortical atrophy region of interest. In contrast, 11C-labelled Pittsburgh compound B covariance maps for each region of interest were diffuse. Finally, 18F-labelled fluorodeoxyglucose was similarly reduced in all Alzheimer’s disease variants in the dorsal and left ventral default mode network, whereas significant differences were found in the right ventral default mode, right executive-control (both lower in early-onset Alzheimer’s disease and posterior cortical atrophy than logopenic variant primary progressive aphasia) and higher-order visual network (lower in posterior cortical atrophy than in early-onset Alzheimer’s disease and logopenic variant primary progressive aphasia), with a trend towards lower 18F-labelled fluorodeoxyglucose also found in the left language network in logopenic variant primary progressive aphasia. There were no differences in 11C-labelled Pittsburgh compound B binding between syndromes in any of the networks. Our data suggest that Alzheimer’s disease syndromes are associated with degeneration of specific functional networks, and that fibrillar amyloid-β deposition explains at most a small amount of the clinico-anatomic heterogeneity in Alzheimer’s disease.
PMCID: PMC3580269  PMID: 23358601
Alzheimer’s disease; posterior cortical atrophy; logopenic variant of PPA; positron emission tomography (PET); functional networks
17.  Update on hypothetical model of Alzheimer’s disease biomarkers 
Lancet neurology  2013;12(2):207-216.
In 2010, the authors published a hypothetical model of the major biomarkers of Alzheimer’s disease (AD). The model was received with interest because we described the temporal evolution of AD biomarkers in relation to each other and to the onset and progression of clinical symptoms. In the interim, evidence has accumulated that supports the major assumptions of this model. Evidence has also appeared that challenges some of the assumptions underlying our original model. Recent evidence has allowed us to modify our original model. Refinements include indexing subjects by time rather than clinical symptom severity; incorporating inter-subject variability in cognitive response to the progression of AD pathophysiology; modifications of the specific temporal ordering of some biomarkers; and, recognition that the two major proteinopathies underlying AD biomarker changes, Aβ and tau, may be initiated independently in late onset AD where we hypothesize that an incident Aβopathy can accelerate an antecedent tauopathy.
PMCID: PMC3622225  PMID: 23332364
18.  Dopamine supports coupling of attention-related networks 
Attentional processing has been associated with the dorsal attention, default mode, and fronto-parietal control networks. The dorsal attention network is involved in externally focused attention whereas the default mode network is involved in internally directed attention. The fronto-parietal control network has been proposed to mediate the transition between external and internal attention by coupling its activity to either the dorsal attention network or the default mode network depending on the attentional demand. Dopamine is hypothesized to modulate attention and has been linked to the integrity of these three attention-related networks. We used positron emission tomography (PET) with 6-[18F]fluoro-L-m-tyrosine to quantify dopamine synthesis capacity in vivo and functional magnetic resonance imaging (fMRI) to acquire stimulus-independent brain activity in cognitively healthy human subjects. We found that in the resting state where internal cognition dominates, dopamine enhances the coupling between the fronto-parietal control network and the default mode network while reducing the coupling between the fronto-parietal control network and the dorsal attention network. These results add a neurochemical perspective to the role of network interaction in modulating attention.
PMCID: PMC3410707  PMID: 22787044
19.  Before it is too late: professional responsibilities in late-onset Alzheimer’s research and pre-symptomatic prediction 
The development of a wide array of molecular and neuroscientific biomarkers can provide the possibility to visualize the course of Alzheimer’s disease (AD) at early stages. Many of these biomarkers are aimed at detecting not only a preclinical, but also a pre-symptomatic state. They are supposed to facilitate clinical trials aiming at treatments that attack the disease at its earliest stage or even prevent it. The increasing number of such biomarkers currently tested and now partly proposed for clinical implementation calls for critical reflection on their aims, social benefits, and risks. This position paper summarizes major challenges and responsibilities. Its focus is on the ethical and social problems involved in the organization and application of dementia research, as well as in healthcare provision from a cross-national point of view. The paper is based on a discussion of leading dementia experts from neuroscience, neurology, social sciences, and bioethics in the United States and Europe. It thus reflects a notable consensus across various disciplines and national backgrounds. We intend to initiate a debate on the need for actions within the researchers’ national and international communities.
PMCID: PMC4238325  PMID: 25477802
late-onset Alzheimer’s dementia; medical ethics; recommendations; biomarker; public health policy; research participation; cultural diversity; public engagement
20.  Striatal dopamine influences the default mode network to affect shifting between object features 
Journal of cognitive neuroscience  2012;24(9):1960-1970.
Cognitive flexibility, or the ability to change behavior in response to external cues, is conceptualized as two processes: one for shifting between perceptual features of objects and another for shifting between the abstract rules governing the selection of these objects. Object and rule shifts are believed to engage distinct anatomical structures and functional processes. Dopamine activity has been associated with cognitive flexibility, but patients with dopaminergic deficits are not impaired on all tasks assessing cognitive flexibility, suggesting that dopamine may have different roles in the shifting of objects and rules. The goals of this study were to identify brain regions supporting object and rule shifts and to examine the role of dopamine in modulating these two forms of cognitive flexibility. Sixteen young, healthy subjects underwent functional magnetic resonance imaging while performing a setshift task designed to differentiate shifting between object features from shifting between abstract task rules. Subjects also underwent positron emission tomography with 6-[18F]-fluoro-L-m-tyrosine (FMT), a radiotracer measuring dopamine synthesis capacity. Shifts of abstract rules were not associated with activation in any brain region, and FMT uptake did not correlate with rule shift performance. Shifting between object features deactivated the medial prefrontal cortex and the posterior cingulate and activated the lateral prefrontal cortex, posterior parietal areas, and the striatum. FMT signal in the striatum correlated negatively with object shift performance and deactivation in the medial prefrontal cortex, a component of the default mode network, suggesting that dopamine influences object shifts via modulation of activity in the default mode network.
PMCID: PMC3510672  PMID: 22640392
21.  Practical utility of amyloid and FDG-PET in an academic dementia center 
Neurology  2014;82(3):230-238.
To evaluate the effect of amyloid imaging on clinical decision making.
We conducted a retrospective analysis of 140 cognitively impaired patients (mean age 65.0 years, 46% primary β-amyloid (Aβ) diagnosis, mean Mini-Mental State Examination 22.3) who underwent amyloid (Pittsburgh compound B [PiB]) PET as part of observational research studies and were evaluated clinically before and after the scan. One hundred thirty-four concurrently underwent fluorodeoxyglucose (FDG)-PET. We assessed for changes between the pre- and post-PET clinical diagnosis (from Aβ to non-Aβ diagnosis or vice versa) and Alzheimer disease treatment plan. The association between PiB/FDG results and changes in management was evaluated using χ2 and multivariate logistic regression. Postmortem diagnosis was available for 24 patients (17%).
Concordance between scan results and baseline diagnosis was high (PiB 84%, FDG 82%). The primary diagnosis changed after PET in 13/140 patients (9%) overall but in 5/13 (38%) patients considered pre-PET diagnostic dilemmas. When examined independently, discordant PiB and discordant FDG were both associated with diagnostic change (unadjusted p < 0.0001). However, when examined together in a multivariate logistic regression, only discordant PiB remained significant (adjusted p = 0.00013). Changes in treatment were associated with discordant PiB in patients with non-Aβ diagnoses (adjusted p = 0.028), while FDG had no effect on therapy. Both PiB (96%) and FDG (91%) showed high agreement with autopsy diagnosis.
PET had a moderate effect on clinical outcomes. Discordant PiB had a greater effect than discordant FDG, and influence on diagnosis was greater than on treatment. Prospective studies are needed to better characterize the clinical role of amyloid PET.
PMCID: PMC3902757  PMID: 24353340
22.  Effects of age and beta-amyloid on cognitive changes in normal elderly people 
Neurobiology of aging  2012;33(12):2746-2755.
Age-related decline is common in multiple cognitive domains. β-amyloid (Aβ) deposition, a pathological hallmark of Alzheimer’s disease, is also associated with cognitive changes in many older people. In this study, we examined a wide range of cognitive function in order to differentiate the effect of age and Aβ on cognition during aging. Using PET imaging with the radiotracer Pittsburgh compound B (PIB), we classified normal older subjects as High PIB-Old and Low PIB-Old and applied sequential multivariate analyses (i.e., principal components analysis [PCA] and discriminant analysis) to obtain summary measures of cognitive tests encompassing multiple cognitive domains. Among 5 cognitive components, a significant age effect was observed in component scores of visual memory and executive functions, regardless of the level of Aβ. Discriminant scores (weighted scores of the 5 cognitive components) revealed a significant effect of both age and Aβ and were further associated with quantitative PIB counts. The results of the current study highlight both effects of age and Aβ on cognitive changes in normal elderly.
PMCID: PMC3381075  PMID: 22429886
Age; beta-amyloid; PIB-PET; cognition; principal component analysis; discriminant analysis
23.  CSF biomarker associations with change in hippocampal volume and precuneus thickness: implications for the Alzheimer’s pathological cascade 
Brain imaging and behavior  2012;6(4):599-609.
Neurofibrillary tangles (NFT) and amyloid plaques are hallmark neuropathological features of Alzheimer’s disease (AD). There is some debate as to which neuropathological feature comes first in the disease process, with early autopsy studies suggesting that NFT develop first, and more recent neuroimaging studies supporting the early role of amyloid beta (Aβ) deposition. Cerebrospinal fluid (CSF) biomarkers of Aβ42 and hyperphosphorylated tau (p-tau) have been shown to serve as in vivo proxy measures of amyloid plaques and NFT, respectively. The aim of this study was to examine the association between CSF biomarkers and rate of atrophy in the precuneus and hippocampus. These regions were selected because the precuneus appears to be affected early and severely by Aβ deposition, and the hippocampus similarly by NFT pathology. We predicted (1) baseline Aβ42 would be related to accelerated rate of cortical thinning in the precuneus and volume loss in the hippocampus, with the latter relationship expected to be weaker, (2) baseline p-tau181p would be related to accelerated rate of hippocampal atrophy and cortical thinning in the precuneus, with the latter relationship expected to be weaker. Using all ADNI cohorts, we fitted separate linear mixed-effects models for changes in hippocampus and precuneus longitudinal outcome measures with baseline CSF biomarkers modeled as predictors. Results partially supported our hypotheses: Both baseline p-tau181p and Aβ42 were associated with hippocampal atrophy over time. Neither p-tau181p nor Aβ42 were significantly related to cortical thinning in the precuneus over time. However, follow-up analyses demonstrated that having abnormal levels of both Aβ42 and p-tau181p was associated with an accelerated rate of atrophy in both the hippocampus and precuneus. Results support early effects of Aβ in the Alzheimer’s disease process, which are less apparent than and perhaps dependent on p-tau effects as the disease progresses. However, amyloid deposition alone may be insufficient for emergence of significant morphometric changes and clinical symptoms.
PMCID: PMC3656503  PMID: 22614327
Biomarkers; Beta Amyloid; Phosphorylated Tau; MRI; Alzheimer’s Disease; Hippocampus; Precuneus
24.  Relative Contributions of Biomarkers in Alzheimer’s Disease 
Annals of epidemiology  2012;22(12):868-875.
To assess relationships between biomarkers for Alzheimer’s Disease (AD) and their potential contributions to AD.
Biomarkers and cognitive evaluations were assessed longitudinally for 179 patients with mild cognitive impairment (MCI), from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) from 2003–2006, and were used to examine, at any given time, the joint contributions of hippocampal volume, whole brain volume, and brain glucose metabolism on clinical AD progression, using the Alzheimer’s Disease Assessment Scale-Cognitive subscale (ADAS-Cog). Marginal structural models (MSMs) were applied, and inverse-probability of treatment weight (IPTW) estimation was utilized to account for time-dependent confounding between study variables.
At any given time, population-level differences (e.g. 1-standard deviation (SD) increase) in brain glucose metabolism (−1.036 95% CI: −1.608, −0.464) and hippocampal volume (−1.537 95% CI: −2.399, −0.674) independently reduced mean ADAS-Cog, whereas a 1-SD increase in whole brain volume did not (0.372 95% CI: −0.283, 1.027). Effects of brain glucose metabolism differed in subgroups defined by baseline covariates (e.g., age), but no subgroup effects were observed for hippocampal volume and brain volume.
Brain glucose metabolism and hippocampal volume represent relevant biological markers in subjects at risk for AD.
PMCID: PMC3510749  PMID: 23102709
biological markers; causality; dementia; longitudinal studies
25.  Anatomical Mapping of White Matter Hyperintensities (WMH) 
Stroke; a journal of cerebral circulation  2004;36(1):10.1161/01.STR.0000150668.58689.f2.
Background and Purpose
MRI segmentation and mapping techniques were used to assess evidence in support of categorical distinctions between periventricular white matter hyperintensities (PVWMH) and deep WMH (DWMH). Qualitative MRI studies generally identify 2 categories of WMH on the basis of anatomical localization. Separate pathophysiologies and behavioral consequences are often attributed to these 2 classes of WMH. However, evidence to support these empirical distinctions has not been rigorously sought.
MRI analysis of 55 subjects included quantification of WMH volume, mapping onto a common anatomical image, and spatial localization of each WMH voxel. WMH locations were then divided into PVWMH and DWMH on the basis of distance from the lateral ventricles and correlations, with total WMH volume determined. Periventricular distance histograms of WMH voxels were also calculated.
PVWMH and DWMH were highly correlated with total WMH (R2>0.95) and with each other (R2>0.87). Mapping of all WMH revealed smooth expansion from around central cerebrospinal fluid spaces into more distal cerebral white matter with increasing WMH volume.
PVWMH, DWMH, and total WMH are highly correlated with each other. Moreover, spatial analysis failed to identify distinct subpopulations for PVWMH and DWMH. These results suggest that categorical distinctions between PVWMH and DWMH may be arbitrary, and conclusions regarding individual relationships between causal factors or behavior for PVWMH and DWMH may more accurately reflect total WMH volume relationships.
PMCID: PMC3816357  PMID: 15576652
cerebrovascular disorders; magnetic resonanace imaging; white matter

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