This report describes the first human study of a novel amyloid-imaging positron emission tomography (PET) tracer, termed Pittsburgh Compound-B (PIB), in 16 patients with diagnosed mild AD and 9 controls. Compared with controls, AD patients typically showed marked retention of PIB in areas of association cortex known to contain large amounts of amyloid deposits in AD. In the AD patient group, PIB retention was increased most prominently in frontal cortex (1.94-fold, p = 0.0001). Large increases also were observed in parietal (1.71-fold, p = 0.0002), temporal (1.52-fold, p = 0.002), and occipital (1.54-fold, p = 0.002) cortex and the striatum (1.76-fold, p = 0.0001). PIB retention was equivalent in AD patients and controls in areas known to be relatively unaffected by amyloid deposition (such as subcortical white matter, pons, and cerebellum). Studies in three young (21 years) and six older healthy controls (69.5 +/- 11 years) showed low PIB retention in cortical areas and no significant group differences between young and older controls. In cortical areas, PIB retention correlated inversely with cerebral glucose metabolism determined with 18F-fluorodeoxyglucose. This relationship was most robust in the parietal cortex (r = -0.72; p = 0.0001). The results suggest that PET imaging with the novel tracer, PIB, can provide quantitative information on amyloid deposits in living subjects.

Alzheimer's disease (AD) and antecedent factors associated with AD were explored using amyloid imaging and unbiased measures of longitudinal atrophy in combination with reanalysis of previous metabolic and functional studies. In total, data from 764 participants were compared across five in vivo imaging methods. Convergence of effects was seen in posterior cortical regions, including posterior cingulate, retrosplenial, and lateral parietal cortex. These regions were active in default states in young adults and also showed amyloid deposition in older adults with AD. At early stages of AD progression, prominent atrophy and metabolic abnormalities emerged in these posterior cortical regions; atrophy in medial temporal regions was also observed. Event-related functional magnetic resonance imaging studies further revealed that these cortical regions are active during successful memory retrieval in young adults. One possibility is that lifetime cerebral metabolism associated with regionally specific default activity predisposes cortical regions to AD-related changes, including amyloid deposition, metabolic disruption, and atrophy. These cortical regions may be part of a network with the medial temporal lobe whose disruption contributes to memory impairment.

OBJECTIVE

Amyloid-beta(42) (Abeta(42)) appears central to Alzheimer's disease (AD) pathogenesis and is a major component of amyloid plaques. Mean cerebrospinal fluid (CSF) Abeta(42) is decreased in dementia of the Alzheimer's type. This decrease may reflect plaques acting as an Abeta(42) "sink," hindering transport of soluble Abeta(42) between brain and CSF. We investigated this hypothesis.

METHODS

We compared the in vivo brain amyloid load (via positron emission tomography imaging of the amyloid-binding agent, Pittsburgh Compound-B [PIB]) with CSF Abeta(42) and other measures (via enzyme-linked immunosorbent assay) in clinically characterized research subjects.

RESULTS

Subjects fell into two nonoverlapping groups: those with positive PIB binding had the lowest CSF Abeta(42) level, and those with negative PIB binding had the highest CSF Abeta(42) level. No relation was observed between PIB binding and CSF Abeta(40), tau, phospho-tau(181), plasma Abeta(40), or plasma Abeta(42). Importantly, PIB binding and CSF Abeta(42) did not consistently correspond with clinical diagnosis; three cognitively normal subjects were PIB-positive with low CSF Abeta(42), suggesting the presence of amyloid in the absence of cognitive impairment (ie, preclinical AD).

CONCLUSIONS

These observations suggest that brain amyloid deposition results in low CSF Abeta(42), and that amyloid imaging and CSF Abeta(42) may potentially serve as antecedent biomarkers of (preclinical) AD.

OBJECTIVE

To characterize the prevalence of amyloid deposition in a clinically unimpaired elderly population, as assessed by Pittsburgh Compound B (PiB) positron emission tomography (PET) imaging, and its relationship to cognitive function, measured with a battery of neuropsychological tests.

METHODS

Subjects underwent cognitive testing and PiB PET imaging (15 mCi for 90 minutes with an ECAT HR+ scanner). Logan graphical analysis was applied to estimate regional PiB retention distribution volume, normalized to a cerebellar reference region volume, to yield distribution volume ratios (DVRs).

METHODS

University medical center.

METHODS

From a community-based sample of volunteers, 43 participants aged 65 to 88 years who did not meet diagnostic criteria for Alzheimer disease or mild cognitive impairment were included.

METHODS

Regional PiB retention and cognitive test performance.

RESULTS

Of 43 clinically unimpaired elderly persons imaged, 9 (21%) showed evidence of early amyloid deposition in at least 1 brain area using an objectively determined DVR cutoff. Demographic characteristics did not differ significantly between amyloid-positive and amyloid-negative participants, and neurocognitive performance was not significantly worse among amyloid-positive compared with amyloid-negative participants.

CONCLUSIONS

Amyloid deposition can be identified among cognitively normal elderly persons during life, and the prevalence of asymptomatic amyloid deposition may be similar to that of symptomatic amyloid deposition. In this group of participants without clinically significant impairment, amyloid deposition was not associated with worse cognitive function, suggesting that an elderly person with a significant amyloid burden can remain cognitively normal. However, this finding is based on relatively small numbers and needs to be replicated in larger cohorts. Longitudinal follow-up of these subjects will be required to support the potential of PiB imaging to identify preclinical Alzheimer disease, or, alternatively, to show that amyloid deposition is not sufficient to cause Alzheimer disease within some specified period.

To date, most diagnostic imaging comparisons between amyloid labelling ligands and other imaging modalities have been between the use of amyloid labelling ligand (11)C Pittsburgh Compound B (PiB) and FDG-PET. Our objectives were to compare cognitive performance and diagnostic group-wise discrimination between cognitively normal, amnestic mild cognitive impairment (MCI) and Alzheimer's disease subjects with MRI-based measures of hippocampal volume and PiB retention, and secondly to evaluate the topographic distribution of PiB retention and grey matter loss using 3D voxel-wise methods. Twenty cognitively normal, 17 amnestic MCI and 8 probable Alzheimer's disease subjects were imaged with both MRI and PiB. PiB retention was quantified as the ratio of uptake in cortical to cerebellar regions of interest (ROIs) 40-60 min post-injection. A global cortical PiB retention summary measure was derived from six cortical ROIs. Statistical parametric mapping (SPM) and voxel-based morphometry (VBM) were used to evaluate PiB retention and grey matter loss on a 3D voxel-wise basis. Alzheimer's disease subjects had high global cortical PiB retention and low hippocampal volume; most cognitively normal subjects had low PiB retention and high hippocampal volume; and on average amnestic MCI subjects were intermediate on both PiB and hippocampal volume. A target-to-cerebellar ratio of 1.5 was used to designate subjects with high or low PiB cortical retention. All Alzheimer's disease subjects fell above this ratio, as did 6 out of 20 cognitively normal subjects and 9 out of 17 MCI subjects, indicating bi-modal PiB retention in the latter two groups. Interestingly, we found no consistent differences in learning and memory performance between high versus low PiB cognitively normal or amnestic MCI subjects. The SPM/VBM voxel-wise comparisons of Alzheimer's disease versus cognitively normal subjects provided complementary information in that clear and meaningful similarities and differences in topographical distribution of amyloid deposition and grey matter loss were shown. The frontal lobes had high PiB retention with little grey matter loss, anteromedial temporal areas had low PiB retention with significant grey matter loss, whereas lateral temporoparietal association cortex displayed both significant PiB retention and grey matter loss. A voxel-wise SPM conjunction analysis revealed that subjects with high PiB retention shared a common PiB retention topographical pattern regardless of clinical category, and this matched that of amyloid plaque distribution from autopsy studies of Alzheimer's disease. Both global cortical PiB retention and hippocampal volumes demonstrated significant correlation in the expected direction with cognitive testing performance; however, correlations were stronger with MRI than PiB. Pair-wise inter-group diagnostic separation was significant for all group-wise pairs for both PiB and hippocampal volume with the exception of the comparison of cognitively normal versus amnestic MCI, which was not significant for PiB. PiB and MRI provided complementary information such that clinical diagnostic classification using both methods was superior to using either in isolation.

The positron emission tomography (PET) radiotracer Pittsburgh Compound-B (PiB) binds with high affinity to beta-pleated sheet aggregates of the amyloid-beta (Abeta) peptide in vitro. The in vivo retention of PiB in brains of people with Alzheimer's disease shows a regional distribution that is very similar to distribution of Abeta deposits observed post-mortem. However, the basis for regional variations in PiB binding in vivo, and the extent to which it binds to different types of Abeta-containing plaques and tau-containing neurofibrillary tangles (NFT), has not been thoroughly investigated. The present study examined 28 clinically diagnosed and autopsy-confirmed Alzheimer's disease subjects, including one Alzheimer's disease subject who had undergone PiB-PET imaging 10 months prior to death, to evaluate region- and substrate-specific binding of the highly fluorescent PiB derivative 6-CN-PiB. These data were then correlated with region-matched Abeta plaque load and peptide levels, [(3)H]PiB binding in vitro, and in vivo PET retention levels. We found that in Alzheimer's disease brain tissue sections, the preponderance of 6-CN-PiB binding is in plaques immunoreactive to either Abeta42 or Abeta40, and to vascular Abeta deposits. 6-CN-PiB labelling was most robust in compact/cored plaques in the prefrontal and temporal cortices. While diffuse plaques, including those in caudate nucleus and presubiculum, were less prominently labelled, amorphous Abeta plaques in the cerebellum were not detectable with 6-CN-PiB. Only a small subset of NFT were 6-CN-PiB positive; these resembled extracellular 'ghost' NFT. In Alzheimer's disease brain tissue homogenates, there was a direct correlation between [(3)H]PiB binding and insoluble Abeta peptide levels. In the Alzheimer's disease subject who underwent PiB-PET prior to death, in vivo PiB retention levels correlated directly with region-matched post-mortem measures of [(3)H]PiB binding, insoluble Abeta peptide levels, 6-CN-PiB- and Abeta plaque load, but not with measures of NFT. These results demonstrate, in a typical Alzheimer's disease brain, that PiB binding is highly selective for insoluble (fibrillar) Abeta deposits, and not for neurofibrillary pathology. The strong direct correlation of in vivo PiB retention with region-matched quantitative analyses of Abeta plaques in the same subject supports the validity of PiB-PET imaging as a method for in vivo evaluation of Abeta plaque burden.

Fibrillar amyloid-beta (Abeta) is found in the brains of many cognitively normal older people. Whether or not this reflects a predisposition to Alzheimer's disease (AD) is unknown. We used Pittsburgh Compound B (PiB) PET to characterize the relationship between fibrillar Abeta burden and this predisposition in cognitively normal older people at 3 mean levels of genetic risk for AD. Dynamic PiB PET scans, the Logan method, statistical parametric mapping, and automatically labeled regions of interest (ROIs) were used to characterize and compare cerebral-to-cerebellar PIB distribution volume ratios, reflecting fibrillar Abeta burden, in 28 cognitively normal persons (mean age, 64 years) with a reported family history of AD and 2 copies, 1 copy, and no copies of the apolipoprotein E (APOE) epsilon4 allele. The 8 epsilon4 homozygotes, 8 heterozygotes, and 12 noncarriers did not differ significantly in terms of age, sex, or cognitive scores. Fibrillar Abeta was significantly associated with APOE epsilon4 carrier status and epsilon4 gene dose in AD-affected mean cortical, frontal, temporal, posterior cingulate-precuneus, parietal, and basal ganglia ROIs, and was highest in an additional homozygote who had recently developed mild cognitive impairment. These findings suggest that fibrillar Abeta burden in cognitively normal older people is associated with APOE epsilon4 gene dose, the major genetic risk factor for AD. Additional studies are needed to track fibrillar Abeta accumulation in persons with different kinds and levels of AD risk; to determine the extent to which fibrillar Abeta, alone or in combination with other biomarkers and risk factors, predicts rates of cognitive decline and conversion to clinical AD; and to establish the role of fibrillar Abeta imaging in primary prevention trials.

Beta-amyloid (Abeta) deposition is pathognomic for Alzheimer's disease (AD), but may occur in normal elderly people without apparent cognitive effect. Episodic memory impairment is an early and prominent sign of AD, but its relationship with Abeta burden in non-demented persons and in AD patients is unclear. We examined this relationship using 11C-PIB-PET as a quantitative marker of Abeta burden in vivo in healthy ageing (HA), mild cognitive impairment (MCI) and AD. Thirty-one AD, 33 MCI and 32 HA participants completed neuropsychological assessment and a 11C-PIB-PET brain scan. Multiple linear regression analyses were conducted relating episodic memory performance and other cognitive functions to Abeta burden. Ninety-seven percent of AD, 61% of MCI and 22% of HA cases had increased cortical PIB binding, indicating the presence of Abeta plaques. There was a strong relationship between impaired episodic memory performance and PIB binding, both in MCI and HA. This relationship was weaker in AD and less robust for non-memory cognitive domains. Abeta deposition in the asymptomatic elderly is associated with episodic memory impairment. This finding, together with the strong relationship between PIB binding and the severity of memory impairment in MCI, suggests that individuals with increased cortical PIB binding are on the path to Alzheimer's disease. The data also suggests that early intervention trials for AD targeted to non-demented individuals with cerebral Abeta deposition are warranted.

A valid quantitative imaging method for the measurement of amyloid deposition in humans could improve Alzheimer's disease (AD) diagnosis and antiamyloid therapy assessment. Our group developed Pittsburgh Compound-B (PIB), an amyloid-binding radiotracer, for positron emission tomography (PET). The current study was aimed to further validate PIB PET through quantitative imaging (arterial input) and inclusion of subjects with mild cognitive impairment (MCI). Pittsburgh Compound-B studies were performed in five AD, five MCI, and five control subjects and five subjects were retested within 20 days. Magnetic resonance images were acquired for partial volume correction and region-of-interest definition (e.g., posterior cingulate: PCG; cerebellum: CER). Data were analyzed using compartmental and graphical approaches. Regional distribution volume (DV) values were normalized to the reference region (CER) to yield DV ratios (DVRs). Good agreement was observed between compartmental and Logan DVR values (e.g., PCG: r=0.89, slope=0.91); the Logan results were less variable. Nonspecific PIB retention was similar across subjects (n=15, Logan CER DV: 3.63+/-0.48). Greater retention was observed in AD cortical areas, relative to controls (P<0.05). The PIB retention in MCI subjects appeared either 'AD-like' or 'control-like'. The mean test/retest variation was approximately 6% in primary areas-of-interest. The Logan analysis was the method-of-choice for the PIB PET data as it proved stable, valid, and promising for future larger studies and voxel-based statistical analyses. This study also showed that it is feasible to perform quantitative PIB PET imaging studies that are needed to validate simpler methods for routine use across the AD disease spectrum.

BACKGROUND

Carbon-11-labelled Pittsburgh compound B ((11)C-PiB) PET is a marker of cortical fibrillar amyloid-beta load in vivo. We used (11)C-PiB PET to investigate whether bapineuzumab, a humanised anti-amyloid-beta monoclonal antibody, would reduce cortical fibrillar amyloid-beta load in patients with Alzheimer's disease.

METHODS

Patients with mild-to-moderate Alzheimer's disease were randomly assigned to receive intravenous bapineuzumab or placebo in a ratio of seven to three in three ascending dose groups (0.5, 1.0, or 2.0 mg/kg). Each dose group was enrolled after safety review of the previous group. Randomisation was by interactive voice response system; masking was achieved with numbered kit allocation. Patients, investigators, study site personnel, sponsor staff, and carers were masked to treatment. Patients received up to six infusions, 13 weeks apart, and had (11)C-PiB PET scans at baseline and at weeks 20, 45, and 78. The primary outcome was the difference between the pooled bapineuzumab group and the pooled placebo group in mean change from screening to week 78 in (11)C-PiB cortical to cerebellar retention ratio averaged across six cortical regions of interest. Analysis was by modified intention to treat. This study is registered with EudraCT, number 2004-004120-12; ISRCTN17517446.

RESULTS

28 patients were assigned to bapineuzumab (n=20) or placebo (n=8). 19 patients in the bapineuzumab group and seven in the placebo group were included in the modified intention-to-treat analysis. Estimated mean (11)C-PiB retention ratio change from baseline to week 78 was -0.09 (95% CI -0.16 to -0.02; p=0.014) in the bapineuzumab group and 0.15 (95% CI 0.02 to 0.28; p=0.022) in the placebo group. Estimated mean difference in (11)C-PiB retention ratio change from baseline to week 78 between the bapineuzumab group and the placebo group was -0.24 (95% CI -0.39 to -0.09; p=0.003). Differences between the bapineuzumab group and the placebo group in the individual regions of interest were similar to the overall mean difference. Adverse events were typically mild to moderate in severity and transient. Two patients in the 2.0 mg/kg bapineuzumab group had transient cerebral vasogenic oedema.

CONCLUSIONS

Treatment with bapineuzumab for 78 weeks reduced cortical (11)C-PiB retention compared with both baseline and placebo. (11)C-PiB PET seems to be useful in assessing the effects of potential Alzheimer's disease treatments on cortical fibrillar amyloid-beta load in vivo.

BACKGROUND

Elan Pharmaceuticals and Wyeth Research.

OBJECTIVE

Assess Aβ deposition longitudinally and explore its relationship with cognition and disease progression.

METHODS

Clinical follow-up was obtained 20 ± 3 months after [¹¹C]Pittsburgh compound B (PiB)-positron emission tomography in 206 subjects: 35 with dementia of the Alzheimer type (DAT), 65 with mild cognitive impairment (MCI), and 106 age-matched healthy controls (HCs). A second PiB scan was obtained at follow-up in 185 subjects and a third scan after 3 years in 57.

RESULTS

At baseline, 97% of DAT, 69% of MCI, and 31% of HC subjects showed high PiB retention. At 20-month follow-up, small but significant increases in PiB standardized uptake value ratios were observed in the DAT and MCI groups, and in HCs with high PiB retention at baseline (5.7%, 2.1%, and 1.5%, respectively). Increases were associated with the number of apolipoprotein E ε4 alleles. There was a weak correlation between PiB increases and decline in cognition when all groups were combined. Progression to DAT occurred in 67% of MCI with high PiB versus 5% of those with low PiB, but 20% of the low PiB MCI subjects progressed to other dementias. Of the high PiB HCs, 16% developed MCI or DAT by 20 months and 25% by 3 years. One low PiB HC developed MCI.

CONCLUSIONS

Aβ deposition increases slowly from cognitive normality to moderate severity DAT. Extensive Aβ deposition precedes cognitive impairment, and is associated with ApoE genotype and a higher risk of cognitive decline in HCs and progression from MCI to DAT over 1 to 2 years. However, cognitive decline is only weakly related to change in Aβ burden, suggesting that downstream factors have a more direct effect on symptom progression.

The synthesis and evaluation of a series of neutral analogues of thioflavin-T (termed BTA's) with high affinities for aggregated amyloid and a wide range of lipophilicities are reported. Radiolabeling with high specific activity [(11)C]methyl iodide provided derivatives for in vivo evaluation. Brain entry in control mice and baboons was high for nearly all of the analogues at early times after injection, but the clearance rate of radioactivity from brain tissue varied by more than 1 order of magnitude. Upon the basis of its rapid clearance from normal mouse and baboon brain tissues, [N-methyl-(11)C]2-(4'-methylaminophenyl)-6-hydroxybenzothiazole (or [(11)C]6-OH-BTA-1) was selected as the lead compound for further evaluation. The radiolabeled metabolites of [(11)C]6-OH-BTA-1 were polar and did not enter brain. The binding affinities of [N-methyl-(3)H]6-OH-BTA-1 for homogenates of postmortem AD frontal cortex and synthetic Abeta(1-40) fibrils were similar (K(d) = 1.4 nM and 4.7 nM, respectively), but the ligand-to-Abeta peptide binding stoichiometry was approximately 400-fold higher for AD brain than Abeta(1-40) fibrils. Staining of AD frontal cortex tissue sections with 6-OH-BTA-1 indicated the selective binding of the compound to amyloid plaques and cerebrovascular amyloid. The encouraging in vitro and in vivo properties of [(11)C]6-OH-BTA-1 support the choice of this derivative for further evaluation in human subject studies of brain Abeta deposition.

BACKGROUND

This is a progress report of the Alzheimer's Disease Neuroimaging Initiative (ADNI) positron emission tomography (PET) Core.

METHODS

The Core has supervised the acquisition, quality control, and analysis of longitudinal [(18)F]fluorodeoxyglucose PET (FDG-PET) data in approximately half of the ADNI cohort. In an "add on" study, approximately 100 subjects also underwent scanning with [(11)C] Pittsburgh compound B PET for amyloid imaging. The Core developed quality control procedures and standardized image acquisition by developing an imaging protocol that has been widely adopted in academic and pharmaceutical industry studies. Data processing provides users with scans that have identical orientation and resolution characteristics despite acquisition on multiple scanner models. The Core labs have used many different approaches to characterize differences between subject groups (Alzheimer's disease, mild cognitive impairment, controls), to examine longitudinal change over time in glucose metabolism and amyloid deposition, and to assess the use of FDG-PET as a potential outcome measure in clinical trials.

RESULTS

ADNI data indicate that FDG-PET increases statistical power over traditional cognitive measures, might aid subject selection, and could substantially reduce the sample size in a clinical trial. Pittsburgh compound B PET data showed expected group differences, and identified subjects with significant annual increases in amyloid load across the subject groups. The next activities of the PET core in ADNI will entail developing standardized protocols for amyloid imaging using the [(18)F]-labeled amyloid imaging agent AV45, which can be delivered to virtually all ADNI sites.

CONCLUSIONS

ADNI has demonstrated the feasibility and utility of multicenter PET studies and is helping to clarify the role of biomarkers in the study of aging and dementia.

OBJECTIVE

Cerebrovascular deposition of beta-amyloid (cerebral amyloid angiopathy [CAA]) is a major cause of hemorrhagic stroke and a likely contributor to vascular cognitive impairment. We evaluated positron emission tomographic imaging with the beta-amyloid-binding compound Pittsburgh Compound B (PiB) as a potential noninvasive method for detection of CAA. We hypothesized that amyloid deposition would be observed with PiB in CAA, and based on the occipital predilection of CAA pathology and associated hemorrhages, that specific PiB retention would be disproportionately greater in occipital lobes.

METHODS

We compared specific cortical PiB retention in 6 nondemented subjects diagnosed with probable CAA with 15 healthy control subjects and 9 patients with probable Alzheimer's disease (AD).

RESULTS

All CAA and AD subjects were PiB-positive, both by distribution volume ratio measurements and by visual inspection of positron emission tomographic images. Global cortical PiB retention was significantly increased in CAA (distribution volume ratio 1.18 +/- 0.06) relative to healthy control subjects (1.04 +/- 0.10; p = 0.0009), but was lower in CAA than in AD subjects (1.41 +/- 0.17; p = 0.002). The occipital-to-global PiB ratio, however, was significantly greater in CAA than in AD subjects (0.99 +/- 0.07 vs 0.86 +/- 0.05; p = 0.003).

CONCLUSIONS

We conclude that PiB-positron emission tomography can detect cerebrovascular beta-amyloid and may serve as a method for identifying the extent of CAA in living subjects.

PET studies have been performed using the amyloid binding radiotracer Pittsburgh Compound B (PIB). Previous quantitative analyses using arterial blood showed that the Logan graphical analysis using 90 min of emission data (ART90) provided a reliable measure of PIB retention. This work reports on simplified methods of analysis for human PIB imaging.

METHODS

PIB PET scans were conducted in 24 subjects (6 Alzheimer's disease [AD], 10 mild cognitive impairment [MCI], 8 controls) with arterial blood sampling. Retest scans were performed on 8 subjects (3 AD, 1 MCI, 4 controls) within 28 d. Data were analyzed over 60 and 90 min using the Logan analysis and (a) metabolite-corrected input functions based on arterial plasma (ART60, ART90), (b) carotid artery time-activity data with a population average metabolite correction (CAR60, CAR90); and (c) cerebellar reference tissue (CER60, CER90). Data also were analyzed using the simplified reference tissue method (SRTM60, SRTM90) and a single-scan method based on late-scan ratios of standardized uptake values (SUVR60, SUVR90).

RESULTS

All methods of analysis examined effectively discerned regional differences between AD and control subjects in amyloid-laden cortical regions, although the performance of the simplified methods varied in terms of bias, test-retest variability, intersubject variability, and effect size. CAR90 best agreed with ART90 distribution volume ratio (DVR) measures across brain regions and subject groups and demonstrated satisfactory test-retest variability (+/-7.1% across regions). CER90 and CER60 showed negative biases relative to ART90 in high-DVR subjects but had the lowest test-retest variability. The single-scan SUV-based methods showed the largest effect sizes for AD and control group differences and performed well in terms of intersubject and test-retest variability.

CONCLUSIONS

Of the simplified methods for PIB analysis examined, CAR90 provided DVR measures that were most comparable to ART90; CER90 was the most reproducible and SUVR90 produced the largest effect size. All simplified methods were effective at distinguishing AD and control differences and may be effectively used in the analysis of PIB. SUVR60 data can be obtained with as little as 20 min of PET emission data collection. The relative strengths and limitations of each method must be considered for each experimental design.

Microglial cells aggregate around amyloid plaques in Alzheimer's disease, but, despite their therapeutic potential, various aspects of their reactive kinetics and role in plaque pathogenesis remain hypothetical. Through use of in vivo imaging and quantitative morphological measures in transgenic mice, we demonstrate that local resident microglia rapidly react to plaque formation by extending processes and subsequently migrating toward plaques, in which individual transformed microglia somata remain spatially stable for weeks. The number of plaque-associated microglia increased at a rate of almost three per plaque per month, independent of plaque volume. Larger plaques were surrounded by larger microglia, and a subset of plaques changed in size over time, with an increase or decrease related to the volume of associated microglia. Far from adopting a more static role, plaque-associated microglia retained rapid process and membrane movement at the plaque/glia interface. Microglia internalized systemically injected amyloid-binding dye at a much higher rate in the vicinity of plaques. These results indicate a role for microglia in plaque maintenance and provide a model with multiple targets for therapeutic intervention.

The amyloid cascade hypothesis suggests that the aggregation and deposition of amyloid-beta protein is an initiating event in Alzheimer's disease (AD). Using amyloid imaging technology, such as the positron emission tomography (PET) agent Pittsburgh compound-B (PiB), it is possible to explore the natural history of preclinical amyloid deposition in people at high risk for AD. With this goal in mind, asymptomatic (n = 5) and symptomatic (n = 5) carriers of presenilin-1 (PS1) mutations (C410Y or A426P) that lead to early-onset AD and noncarrier controls from both kindreds (n = 2) were studied with PiB-PET imaging and compared with sporadic AD subjects (n = 12) and controls from the general population (n = 18). We found intense and focal PiB retention in the striatum of all 10 PS1 mutation carriers studied (ages 35-49 years). In most PS1 mutation carriers, there also were increases in PiB retention compared with controls in cortical brain areas, but these increases were not as great as those observed in sporadic AD subjects. The two PS1 mutation carriers with a clinical diagnosis of early-onset AD did not show the typical regional pattern of PiB retention observed in sporadic AD. Postmortem evaluation of tissue from two parents of PS1C410Y subjects in this study confirmed extensive striatal amyloid deposition, along with typical cortical deposition. The early, focal striatal amyloid deposition observed in these PS1 mutation carriers is often is not associated with clinical symptoms.

BACKGROUND

Pathology reports have shown that cholinergic forebrain neuronal losses in parkinsonian dementia (PDem) are equal to or greater than those in Alzheimer disease (AD). We hypothesized that patients with PDem would have cholinergic deficits that were similar to or greater than those of patients with AD.

OBJECTIVE

To determine in vivo cortical acetylcholinesterase (AChE) activity in healthy control subjects and in patients with mild AD, PDem, and Parkinson disease without dementia using AChE positron emission tomography.

METHODS

University and Veterans' Administration medical center. Design and Patients Group comparison design of patients with AD (n = 12), PDem (n = 14), and Parkinson disease without dementia (n = 11), and controls (n = 10) who underwent AChE imaging between July 1, 2000, and January 31, 2003. Patients with AD and PDem had approximately equal dementia severity.

METHODS

Cerebral AChE activity.

RESULTS

Compared with controls, mean cortical AChE activity was lowest in patients with PDem (-20.0%), followed by patients with Parkinson disease without dementia (-12.9%; P<.001). Mean cortical AChE activity was relatively preserved in patients with AD (-9.1%), except for regionally selective involvement of the lateral temporal cortex (-15%; P<.001).

CONCLUSIONS

Reduced cortical AChE activity is more characteristic of patients with PDem than of patients with mild AD.

OBJECTIVE

To examine region- and substrate-specific autoradiographic and in vitro binding patterns of positron emission tomography tracer [F-18]-AV-1451 (previously known as T807), tailored to allow in vivo detection of paired helical filament-tau-containing lesions, and to determine whether there is off-target binding to other amyloid/non-amyloid proteins.

METHODS

We applied [F-18]-AV-1451 phosphor screen autoradiography, [F-18]-AV-1451 nuclear emulsion autoradiography, and [H-3]-AV-1451 in vitro binding assays to the study of postmortem samples from patients with a definite pathological diagnosis of Alzheimer disease, frontotemporal lobar degeneration-tau, frontotemporal lobar degeneration-transactive response DNA binding protein 43 (TDP-43), progressive supranuclear palsy, corticobasal degeneration, dementia with Lewy bodies, multiple system atrophy, cerebral amyloid angiopathy and elderly controls free of pathology.

RESULTS

Our data suggest that [F-18]-AV-1451 strongly binds to tau lesions primarily made of paired helical filaments in Alzheimer brains (eg, intraneuronal and extraneuronal tangles and dystrophic neurites), but does not seem to bind to a significant extent to neuronal and glial inclusions mainly composed of straight tau filaments in non-Alzheimer tauopathy brains or to lesions containing β-amyloid, α-synuclein, or TDP-43. [F-18]-AV-1451 off-target binding to neuromelanin- and melanin-containing cells and, to a lesser extent, to brain hemorrhagic lesions was identified.

CONCLUSIONS

Our data suggest that [F-18]-AV-1451 holds promise as a surrogate marker for the detection of brain tau pathology in the form of tangles and paired helical filament-tau-containing neurites in Alzheimer brains but also point to its relatively lower affinity for lesions primarily made of straight tau filaments in non-Alzheimer tauopathy cases and to the existence of some [F-18]-AV-1451 off-target binding. These findings provide important insights for interpreting in vivo patterns of [F-18]-AV-1451 retention.

OBJECTIVE

We utilized the amyloid imaging ligand Pittsburgh Compound B (PiB) to determine the presence of Alzheimer's disease (AD) pathology in different mild cognitive impairment (MCI) subtypes and to relate increased PiB binding to other markers of early AD and longitudinal outcome.

METHODS

Twenty-six patients with MCI (13 single-domain amnestic-MCI [a-MCI], 6 multidomain a-MCI, and 7 nonamnestic MCI) underwent PiB imaging. Twenty-three had clinical follow-up (21.2 +/- 16.0 [standard deviation] months) subsequent to their PiB scan.

RESULTS

Using cutoffs established from a control cohort, we found that 14 (54%) patients had increased levels of PiB retention and were considered "amyloid-positive." All subtypes were associated with a significant proportion of amyloid-positive patients (6/13 single-domain a-MCI, 5/6 multidomain a-MCI, 3/7 nonamnestic MCI). There were no obvious differences in the distribution of PiB retention in the nonamnestic MCI group. Predictors of conversion to clinical AD in a-MCI, including poorer episodic memory, and medial temporal atrophy, were found in the amyloid-positive relative to amyloid-negative a-MCI patients. Longitudinal follow-up demonstrated 5 of 13 amyloid-positive patients, but 0 of 10 amyloid-negative patients, converted to clinical AD. Further, 3 of 10 amyloid-negative patients "reverted to normal."

CONCLUSIONS

These data support the notion that amyloid-positive patients are likely to have early AD, and that the use of amyloid imaging may have an important role in determining which patients are likely to benefit from disease-specific therapies. In addition, our data are consistent with longitudinal studies that suggest a significant percentage of all MCI subtypes will develop AD.

OBJECTIVE

To determine the correspondence between uptake of Pittsburgh Compound B (PiB) in life and measures of beta-amyloid (Abeta) in postmortem tissue analysis. Patient A 76-year-old man with a clinical diagnosis of dementia with Lewy bodies underwent fluorodeoxyglucose (18)F and PiB positron emission tomographic brain scans. Imaging revealed marked region specific binding of PiB and abnormal fluorodeoxyglucose uptake. Intervention Autopsy was performed 3 months after the PiB scan.

RESULTS

Autopsy confirmed the clinical diagnosis; in addition, there was severe cerebral amyloid angiopathy and only moderate numbers of parenchymal Abeta plaques. Biochemical measures revealed a positive correlation between Abeta levels and regional PiB binding.

CONCLUSIONS

This report confirms that PiB detects Abeta in the living patient and demonstrates that amyloid deposited as cerebral amyloid angiopathy can be the dominant source of signal.

During the development of in vivo amyloid imaging agents, an effort was made to use micro-positron emission tomography (PET) imaging in the presenilin-1 (PS1)/amyloid precursor protein (APP) transgenic mouse model of CNS amyloid deposition to screen new compounds and further study Pittsburgh Compound-B (PIB), a PET tracer that has been shown to be retained well in amyloid-containing areas of Alzheimer's disease (AD) brain. Unexpectedly, we saw no significant retention of PIB in this model even at 12 months of age when amyloid deposition in the PS1/APP mouse typically exceeds that seen in AD. This study describes a series of ex vivo and postmortem in vitro studies designed to explain this low retention. Ex vivo brain pharmacokinetic studies confirmed the low in vivo PIB retention observed in micro-PET experiments. In vitro binding studies showed that PS1/APP brain tissue contained less than one high-affinity (K(d) = 1-2 nm) PIB binding site per 1000 molecules of amyloid-beta (Abeta), whereas AD brain contained >500 PIB binding sites per 1000 molecules of Abeta. Synthetic Abeta closely resembled PS1/APP brain in having less than one high-affinity PIB binding site per 1000 molecules of Abeta, although the characteristics of the few high-affinity PIB binding sites found on synthetic Abeta were very similar to those found in AD brain. We hypothesize that differences in the time course of deposition or tissue factors present during deposition lead to differences in secondary structure between Abeta deposited in AD brain and either synthetic Abeta or Abeta deposited in PS1/APP brain.

The identification of amyloid deposits in living Alzheimer disease (AD) patients is important for both early diagnosis and for monitoring the efficacy of newly developed anti-amyloid therapies. Methoxy-X04 is a derivative of Congo red and Chrysamine-G that contains no acid groups and is therefore smaller and much more lipophilic than Congo red or Chrysamine-G. Methoxy-X04 retains in vitro binding affinity for amyloid beta (Abeta) fibrils (Ki = 26.8 nM) very similar to that of Chrysamine-G (Ki = 25.3 nM). Methoxy-X04 is fluorescent and stains plaques, tangles, and cerebrovascular amyloid in postmortem sections of AD brain with good specificity. Using multiphoton microscopy to obtain high-resolution (1 microm) fluorescent images from the brains of living PSI/APP mice, individual plaques could be distinguished within 30 to 60 min after a single i.v. injection of 5 to 10 mg/kg methoxy-X04. A single i.p. injection of 10 mg/kg methoxy-X04 also produced high contrast images of plaques and cerebrovascular amyloid in PSI/APP mouse brain. Complementary quantitative studies using tracer doses of carbon- 11-labeled methoxy-X04 show that it enters rat brain in amounts that suggest it is a viable candidate as a positron emission tomography (PET) amyloid-imaging agent for in vivo human studies.

(11)C-Pittsburgh compound B ((11)C-PiB) and (18)F-florbetapir amyloid-β (Aβ) PET radioligands have had a substantial impact on Alzheimer disease research. Although there is evidence that both radioligands bind to fibrillar Aβ in the brain, direct comparisons in the same individuals have not been reported. Here, we evaluated PiB and florbetapir in a retrospective convenience sample of cognitively normal older controls, patients with mild cognitive impairment, and patients with Alzheimer disease from the Alzheimer's Disease Neuroimaging Initiative (ADNI).

METHODS

From the ADNI database, 32 participants were identified who had undergone at least 1 PiB study and subsequently underwent a florbetapir study approximately 1.5 y after the last PiB study. Cortical PiB and florbetapir retention was quantified using several different methods to determine the effect of preprocessing factors (such as smoothing and reference region selection) and image processing pipelines.

RESULTS

There was a strong association between PiB and florbetapir cortical retention ratios (Spearman ρ = 0.86-0.95), and these were slightly lower than cortical retention ratios for consecutive PiB scans (Spearman ρ = 0.96-0.98) made approximately 1.1 y apart. Cortical retention ratios for Aβ-positive subjects tended to be higher for PiB than for florbetapir images, yielding slopes for linear regression of florbetapir against PiB of 0.59-0.64. Associations between consecutive PiB scans and between PiB and florbetapir scans remained strong, regardless of processing methods such as smoothing, spatial normalization to a PET template, and use of reference regions. The PiB-florbetapir association was used to interconvert cutoffs for Aβ positivity and negativity between the 2 radioligands, and these cutoffs were highly consistent in their assignment of Aβ status.

CONCLUSIONS

PiB and florbetapir retention ratios were strongly associated in the same individuals, and this relationship was consistent across several data analysis methods, despite scan-rescan intervals of more than a year. Cutoff thresholds for determining positive or negative Aβ status can be reliably transformed from PiB to florbetapir units or vice versa using a population scanned with both radioligands.