Related Articles

Amyloid imaging represents a major advance in neuroscience, enabling the detection and quantification of pathologic protein aggregations in the brain. In this review we survey current amyloid imaging techniques, focusing on positron emission tomography (PET) with 11carbon-labelled Pittsburgh Compound-B (11C-PIB), the most extensively studied and best validated tracer. PIB binds specifically to fibrillar beta-amyloid (Aβ) deposits, and is a sensitive marker for Aβ pathology in cognitively normal older individuals and patients with mild cognitive impairment (MCI) and Alzheimer's disease (AD). PIB-PET provides us with a powerful tool to examine in vivo the relationship between amyloid deposition, clinical symptoms, and structural and functional brain changes in the continuum between normal aging and AD. Amyloid imaging studies support a model in which amyloid deposition is an early event on the path to dementia, beginning insidiously in cognitively normal individuals, and accompanied by subtle cognitive decline and functional and structural brain changes suggestive of incipient AD. As patients progress to dementia, clinical decline and neurodegeneration accelerate and proceed independently of amyloid accumulation. In the future, amyloid imaging is likely to supplement clinical evaluation in selecting patients for anti-amyloid therapies, while MRI and FDG-PET may be more appropriate markers of clinical progression.

Background

A decreased concentration of beta amyloid (1–42) (Aβ42) has consistently been found in the cerebrospinal fluid (CSF) of patients with Alzheimer’s disease (AD) and is considered a diagnostic biomarker. However, it is not clear to which extent CSF Aβ42 levels are reflective of cerebral pathology in AD. The aim of the study was to determine the association between cerebral amyloid plaque load, as measured by means of the positron emission tomography (PET) tracer carbon-11-labeled Pittsburgh Compound B ([11C]PiB) and CSF Aβ42 in AD.

Methods

A group of 30 patients with probable AD, as defined by established clinical criteria and by an AD-typical pattern of tracer uptake in fluorine-18-labeled fluorodeoxyglucose ([18F]FDG) PET, were included. In all patients, [11C]PiB PET and CSF analysis were performed. The association between amyloid load and CSF Aβ42 levels was examined in three different ways: by linear regression analysis using an overall [11C]PiB value for the entire cerebrum, by correlation analyses using [11C]PiB measurements in anatomically defined regions of interest, and by voxel-based regression analyses.

Results

All patients showed a positive [11C]PiB scan demonstrating amyloid deposition. Linear regression analysis revealed a significant inverse correlation between the overall [11C]PiB uptake and CSF Aβ42 levels. Voxel-based regression and regional correlation analyses did not attain statistical significance after correction for multiple comparisons. Numerically, correlation coefficients were higher in brain regions adjacent to CSF spaces.

Conclusions

The study demonstrates a moderate linear negative association between cerebral amyloid plaque load and CSF Aβ42 levels in AD patients in vivo and suggests possible regional differences of the association.

Amyloid-β (Aβ) deposits are detectable in the brain in vivo using positron emission tomography (PET) and [C-11]-labeled Pittsburgh Compound B ([C-11]PiB); however, the sensitivity of this technique is not well understood. In this study, we examined Aβ pathology in an individual who had clinical diagnoses of probable dementia with Lewy bodies and possible Alzheimer’s disease (AD) but with no detectable [C-11]PiB PET retention ([C-11]PiB(−)) when imaged 17 months prior to death. Brain samples were processed in parallel with region-matched samples from an individual with a clinical diagnosis of probable AD and a positive [C-11]PiB PET scan ([C-11]PiB(+)) when imaged 10 months prior to death. In the [C-11]PiB(−) case, Aβ plaques were sparse, occupying less than 2% cortical area, and were weakly labeled with 6-CN-PiB, a highly fluorescent derivative of PiB. In contrast, Aβ plaques occupied up to 12% cortical area in the [C-11]PiB(+) case, and were intensely labeled with 6-CN-PIB. The [C-11]PiB(−) case had low levels of [H-3]PiB binding (<100 pmol/g) and Aβ1–42 (<500 pmol/g) concentration except in the frontal cortex where Aβ1–42 values (788 pmol/g) approached cortical values in the [C-11]PiB(+) case (800–1,700 pmol/g). In several cortical regions of the [C-11]PiB(−) case, Aβ1–40 levels were within the range of cortical Aβ1–40 values in the [C-11]PiB(+) case. Antemortem [C-11]PiB DVR values correlated well with region-matched postmortem measures of Aβ1–42 and Aβ1–40 in the [C-11]PiB(+), and with Aβ1–42 only in the [C-11]PiB(−) case. The low ratios of [H-3]PiB binding levels to Aβ concentrations and 6-CN-PiB to Aβ plaque loads in the [C-11]PiB(−) case indicate that Aβ pathology in the brain may be associated with low or undetectable levels of [C-11]PiB retention. Studies in greater numbers of [C-11]PiB PET autopsy cases are needed to define the Aβ concentration and [H-3]PiB binding levels required to produce a positive [C-11]PiB PET signal.

Background

Cerebral amyloid angiopathy (CAA) is characterized by deposition of fibrillar amyloid β (Aβ) within cerebral vessels. It is commonly seen in the elderly and almost universally present in patients with Alzheimer's Disease (AD). In both patient populations, CAA is an independent risk factor for lobar hemorrhage, ischemic stroke, and dementia. To date, definitive diagnosis of CAA requires obtaining pathological tissues via brain biopsy (which is rarely clinically indicated) or at autopsy. Though amyloid tracers labeled with positron-emitting radioligands such as [11C]PIB have shown promise for non-invasive amyloid imaging in AD patients, to date they have been unable to clarify whether the observed amyloid load represents neuritic plaques versus CAA due in large part to the low resolution of PET imaging and the almost equal affinity of these tracers for both vascular and parenchymal amyloid. Therefore, the development of a precise and specific non-invasive technique for diagnosing CAA in live patients is desired.

Results

We found that the phenoxazine derivative resorufin preferentially bound cerebrovascular amyloid deposits over neuritic plaques in the aged Tg2576 transgenic mouse model of AD/CAA, whereas the congophilic amyloid dye methoxy-X34 bound both cerebrovascular amyloid deposits and neuritic plaques. Similarly, resorufin-positive staining was predominantly noted in fibrillar Aβ-laden vessels in postmortem AD brain tissues. Fluorescent labeling and multi-photon microscopy further revealed that both resorufin- and methoxy-X34-positive staining is colocalized to the vascular smooth muscle (VSMC) layer of vessel segments that have severe disruption of VSMC arrangement, a characteristic feature of CAA. Resorufin also selectively visualized vascular amyloid deposits in live Tg2576 mice when administered topically, though not systemically. Resorufin derivatives with chemical modification at the 7-OH position of resorufin also displayed a marked preferential binding affinity for CAA, but with enhanced lipid solubility that indicates their use as a non-invasive imaging tracer for CAA is feasible.

Conclusions

To our knowledge, resorufin analogs are the fist class of amyloid dye that can discriminate between cerebrovascular and neuritic forms of amyloid. This unique binding selectivity suggests that this class of dye has great potential as a CAA-specific amyloid tracer that will permit non-invasive detection and quantification of CAA in live patients.

The secretase BACE1 is fundamentally involved in the development of cerebral amyloid pathology in Alzheimer's disease (AD). It has not been studied so far to what extent BACE1 activity in cerebrospinal fluid (CSF) mirrors in vivo amyloid load in AD. We explored associations between CSF BACE1 activity and fibrillar amyloid pathology as measured by carbon-11-labelled Pittsburgh Compound B positron emission tomography ([11C]PIB PET). [11C]PIB and CSF studies were performed in 31 patients with AD. Voxel-based linear regression analysis revealed significant associations between CSF BACE1 activity and [11C]PIB tracer uptake in the bilateral parahippocampal region, the thalamus, and the pons. Our study provides evidence for a brain region-specific correlation between CSF BACE1 activity and in-vivo fibrillar amyloid pathology in AD. Associations were found in areas close to the brain ventricles, which may have important implications for the use of BACE1 in CSF as a marker for AD pathology and for antiamyloid treatment monitoring.

Although β-amyloid (Aβ) plaques are a primary diagnostic criterion for Alzheimer's disease, this pathology is commonly observed in the brains of non-demented older individuals. To explore the importance of this pathology in the absence of dementia, we compared levels of amyloid deposition (via ‘Pittsburgh Compound-B’ (PIB) positron emission tomography (PET) imaging) to hippocampus volume (HV) and episodic memory (EM) in three groups: (i) normal controls (NC) from the Berkeley Aging Cohort (BAC NC, n = 20); (ii) normal controls (NC) from the Alzheimer's disease neuroimaging initiative (ADNI NC, n = 17); and (iii) PIB+ mild cognitive impairment subjects from the ADNI (ADNI PIB+ MCI, n = 39). Age, gender and education were controlled for in each statistical model, and HV was adjusted for intracranial volume (aHV). In BAC NC, elevated PIB uptake was significantly associated with smaller aHV (P = 0.0016) and worse EM (P = 0.0086). Within ADNI NC, elevated PIB uptake was significantly associated with smaller aHV (P = 0.047) but not EM (P = 0.60); within ADNI PIB+ MCI, elevated PIB uptake was significantly associated with both smaller aHV (P = 0.00070) and worse EM (P = 0.046). To further understand these relationships, a recursive regression procedure was conducted within all ADNI NC and PIB+ MCI subjects (n = 56) to test the hypothesis that HV mediates the relationship between Aβ and EM. Significant correlations were found between PIB index and EM (P = 0.0044), PIB index and aHV (P < 0.0001), as well as between aHV and EM (P < 0.0001). When both aHV and PIB were included in the same model to predict EM, aHV remained significant (P = 0.0015) whereas PIB index was no longer significantly associated with EM (P = 0.50). These results are consistent with a model in which Aβ deposition, hippocampal atrophy, and EM occur sequentially in elderly subjects, with Aβ deposition as the primary event in this cascade. This pattern suggests that declining EM in older individuals may be caused by Aβ-induced hippocampus atrophy.

Amyloid containing deposits are a defining neuropathological feature of a wide range of dementias and movement disorders. The positron emission tomography tracer PIB (Pittsburgh Compound-B, 2-[4′-(methylamino)phenyl]-6-hydroxybenzothiazole) was developed to target senile plaques, an amyloid containing pathological hallmark of Alzheimer's disease, formed from the amyloid-β peptide. Despite the fact that PIB was developed from the pan-amyloid staining dye thioflavin T, no detailed characterisation of its interaction with other amyloid structures has been reported. In this study, we demonstrate the presence of a high affinity binding site (Kd∼4 nM) for benzothiazole derivatives, including [3H]-PIB, on α-synuclein (AS) filaments generated in vitro, and further characterise this binding site through the use of radioligand displacement assays employing 4-N-methylamino-4′-hydroxystilbene (SB13) (Ki = 87 nM) and 2-(1-{6-[(2-fluoroethyl(methyl)amino]-2-naphthyl}ethylidene)malononitrile (FDDNP) (Ki = 210 nM). Despite the presence of a high-affinity binding site on AS filaments, no discernible interaction of [3H]-PIB was detected with amygdala sections from Parkinson's disease cases containing frequent AS-immunoreactive Lewy bodies and related neurities. These findings suggest that the density and/or accessibility of AS binding sites in vivo are significantly less than those associated with amyloid-β peptide lesions. Lewy bodies pathology is therefore unlikely to contribute significantly to the retention of PIB in positron emission tomography imaging studies.

J. Neurochem. (2008) 105, 1428–1437.

Objective:

To investigate the specificity of in vivo amyloid imaging with [11C]–Pittsburgh Compound B (PIB) in Parkinson disease dementia (PDD).

Methods:

We performed detailed neuropathologic examination for 3 individuals with PDD who had PIB PET imaging within 15 months of death.

Results:

We observed elevated cortical uptake of [11C]-PIB on in vivo PET imaging in 2 of the 3 cases. At autopsy, all 3 individuals had abundant cortical Lewy bodies (Braak PD stage 6), and were classified as low-probability Alzheimer disease (AD) based on NIA-Reagan criteria. The 2 PIB-positive individuals had abundant diffuse Aβ plaques but only sparse neuritic plaques and intermediate neurofibrillary tangle pathology. The PIB-negative individual had rare diffuse plaques, no neuritic plaques, and low neurofibrillary tangle burden.

Conclusions:

[11C]–Pittsburgh Compound B (PIB) PET is specific for fibrillar Aβ molecular pathology but not for pathologic diagnosis of comorbid Alzheimer disease in individuals with Parkinson disease dementia. The ability to specifically identify fibrillar Aβ amyloid in the setting of α-synucleinopathy makes [11C]-PIB PET a valuable tool for prospectively evaluating how the presence of Aβ amyloid influences the clinical course of dementia in patients with Lewy body disorders.

GLOSSARY

= Alzheimer disease;

= binding potentials;

= Clinical Dementia Rating;

= dementia of the Alzheimer type;

= dementia with Lewy bodies;

= distribution volume;

= Mental State Examination;

= Neuropsychiatric Inventory Questionnaire;

= Parkinson disease dementia;

= Pittsburgh Compound B;

= Unified Parkinson's Disease Rating Scale.

Although dementia is a clinical diagnosis, neuroimaging often is crucial for proper assessment. Magnetic resonance imaging (MRI) and computed tomography (CT) may identify nondegenerative and potentially treatable causes of dementia. Recent neuroimaging advances, such as the Pittsburgh Compound-B (PIB) ligand for positron emission tomography imaging in Alzheimer’s disease, will improve our ability to differentiate among the neurodegenerative dementias. High-resolution volumetric MRI has increased the capacity to identify the various forms of the frontotemporal lobar degeneration spectrum and some forms of parkinsonism or cerebellar neurodegenerative disorders, such as corticobasal degeneration, progressive supranuclear palsy, multiple system atrophy, and spinocerebellar ataxias. In many cases, the specific pattern of cortical and subcortical abnormalities on MRI has diagnostic utility. Finally, among the new MRI methods, diffusion-weighted MRI can help in the early diagnosis of Creutzfeldt-Jakob disease. Although only clinical assessment can lead to a diagnosis of dementia, neuroimaging is clearly an invaluable tool for the clinician in the differential diagnosis.

Objective:

Several factors may influence the relationship between Alzheimer disease (AD) lesions and the expression of dementia, including those related to brain and cognitive reserve. Other factors may confound the association between AD pathology and dementia. We tested whether factors thought to influence the association of AD pathology and dementia help to accurately identify dementia of the Alzheimer type (DAT) when considered together with amyloid imaging.

Methods:

Participants with normal cognition (n = 180) and with DAT (n = 25), aged 50 years or older, took part in clinical, neurologic, and psychometric assessments. PET with the Pittsburgh compound B (PiB) tracer was used to measure brain amyloid, yielding a mean cortical binding potential (MCBP) reflecting PiB uptake. Logistic regression was used to generate receiver operating characteristic curves, and the areas under those curves (AUC), to compare the predictive accuracy of using MCBP alone vs MCBP together with other variables selected using a stepwise selection procedure to identify participants with DAT vs normal cognition.

Results:

The AUC resulting from MCBP alone was 0.84 (95% confidence interval [CI] = 0.73–0.94; cross-validated AUC = 0.80, 95% CI = 0.68–0.92). The AUC for the predictive equation generated by a stepwise model including education, normalized whole brain volume, physical health rating, gender, and use of medications that may interfere with cognition was 0.94 (95% CI = 0.90–0.98; cross-validated AUC = 0.91, 95% CI = 0.85–0.96), an improvement (p = 0.025) over that yielded using MCBP alone.

Conclusion:

Results suggest that factors reported to influence associations between AD pathology and dementia can improve the predictive accuracy of amyloid imaging for the identification of symptomatic AD.

GLOSSARY

β = amyloid-β;

= Alzheimer disease;

= area under receiver operating characteristic curve;

= binding potential;

= Clinical Dementia Rating;

= confidence interval;

= dementia of the Alzheimer type;

= distribution volume;

= mean cortical binding potential;

= normalized whole brain volume;

= odds ratio;

= Pittsburgh compound B;

= receiver operating characteristic curve;

= region of interest.

The availability of new PET ligands offers the potential to measure fibrillar β-amyloid in the brain. Nevertheless, physiological information in the form of perfusion or metabolism may still be useful in differentiating causes of dementia during life. In this study we investigated whether early 11C-PIB PET frames (perfusion, pPIB) can provide information equivalent to blood flow and metabolism by assessing the similarity of pPIB and 18F-FDG PET images first in a test cohort with various clinical diagnoses (N=10) and then validating the results on a cohort of Alzheimer’s disease (AD, N=42, age 66.6±10.6, MMSE 22.2±6.0) and frontotemporal lobar degeneration (FTLD, N=31, age 63.9±7.1, MMSE 23.8±6.7) patients.

METHODS

To identify the 11C-PIB frames best representing perfusion, an iterative algorithm was run on the test cohort. This included: (1) generating normalized (cerebellar reference) perfusion pPIB images across variable frame ranges, and (2) calculating Pearson’s R values of the sum of these pPIB frames with the sum of all 18F-FDG frames (cerebellar normalized) for all brain tissue voxels. Once this perfusion frame range was determined on the test cohort, it was then validated on an extended cohort and the power of pPIB in differential diagnosis was compared to 18F-FDG by performing a logistic regression of ROI tracer measure (pPIB or 18F-FDG) versus diagnosis.

RESULTS

A seven-minute window, corresponding to minutes 1–8 (frame 5–15) produced the highest voxel-wise correlation between 18F-FDG and pPIB (R=0.78±0.05). This pPIB frame range was further validated on the extended AD and FTLD cohort across 12 ROIs (R=0.91±0.09). A logistic model using pPIB was able to classify 90.5% of the AD and 83.9% of the FTLD patients correctly. Using 18F-FDG, 88.1% of AD and 83.9% of FTLD patients were classified correctly. The temporal pole and the temporal neocortex were significant discriminators (p<0.05) in both models, whereas in the model with pPIB the frontal region was also significant.

CONCLUSIONS

The high correlation between pPIB and 18F-FDG measures and their comparable performance in differential diagnosis is promising in providing functional information using 11C-PIB PET data. This could be a useful approach, obviating the need for 18F-FDG scans when longer-lived amyloid imaging agents become available

Imaging agents capable of assessing amyloid-beta (Aβ) content in vivo in the brains of Alzheimer’s disease (AD) subjects likely will be important as diagnostic agents to detect Aβ plaques in the brain, to help test the amyloid cascade hypothesis of AD, and as an aid to assess the efficacy of anti-amyloid therapeutics currently under development and in clinical trials. Positron emission tomography (PET) imaging studies of amyloid deposition in human subjects with several Aβ imaging agents are currently underway. We reported the first PET studies of the carbon-11-labeled thioflavin-T derivative Pittsburgh Compound B ([11C]PiB) in 2004, and this work has subsequently been extended to include a variety of subject groups including AD, mild cognitive impairment (MCI), and healthy controls. The ability to quantify regional Aβ plaque load in the brains of living human subjects has provided a means to begin to apply this technology as a diagnostic agent to detect regional concentrations of Aβ plaques and as a surrogate marker of therapeutic efficacy in anti-amyloid drug trials.

Objective

To determine whether preclinical Alzheimer’s disease (AD), as detected by the amyloid imaging agent Pittsburgh Compound B (PIB) in cognitively normal older adults, is associated with risk of symptomatic AD.

Design

A longitudinal cohort study of cognitively normal older adults assessed with positron emission tomography (PET) to determine the mean cortical binding potential for PIB and followed with annual clinical and cognitive assessments for progression to very mild dementia of the Alzheimer type (DAT).

Setting

Alzheimer’s Disease Research Center

Participants

One hundred and fifty-nine participants with mean age of 71.5 y in a longitudinal study of memory and aging had a PET PIB scan when cognitively normal with Clinical Dementia Rating (CDR) of 0.

Outcome Measure

Progression from CDR 0 status to CDR 0.5 (very mild dementia).

Results

Twenty-three participants progressed to CDR 0.5 at follow-up assessment (range: 1–5 assessments after PET PIB). Of these, 9 also were diagnosed with DAT. Higher MCBP values for PIB (hazard ratio 4.85, 95% CI, 1.22–19.01, p = .02) and age (hazard ratio 1.14, 95% CI 1.02–1.28, p = .03) predicted progression to CDR 0.5 DAT. The CDR 0.5 DAT group showed decline in three cognitive domains (episodic memory, semantic memory, and visuospatial performance) and had volume loss in the parahippocampal gyrus (includes entorhinal cortex) compared with individuals who remained CDR 0.

Conclusions

Preclinical AD, as detected by PET PIB, is not benign as it is associated with progression to symptomatic AD.

For 100 years, β-amyloid (Aβ) plaques and neurofibrillary tangles (NFTs) have been recognized as the neuropathological hallmarks of Alzheimer’s disease (AD), and their presence or absence could only be assessed postmortem using stains and dyes that identified these microscopic structures. Approximately 10 years ago, the first successful Aβ plaque–specific positron emission tomography (PET) imaging study was conducted in a living human subject clinically diagnosed with probable AD using the 11C-labeled radiopharmaceutical Pittsburgh Compound B (PiB). Laboratory studies and preclinical evaluations to design PiB began a decade earlier than the first human PiB PET study and involved chemical modifications of different well-known dyes that bound specifically to the extended β-pleated sheets that comprise the fibrils of amyloid proteins such as Aβ plaques, NFTs, β-synuclein deposits, and prions. These preclinical studies were conducted in our laboratories at the University of Pittsburgh, starting with Congo red derivatives, followed by Chrysamine G derivatives, followed by X-series compounds, and finally with neutral derivatives of thioflavin-T. The in vitro and in vivo evaluations of the different derivatives as candidate PET radioligands for imaging Aβ plaques and neurofibrillary tangles in human brain are described in this review, along with the specific evaluation criteria by which the candidate radioligands were judged. Out of these studies came PiB, a PET radioligand that binds selectively and with high affinity to only fibrillar forms of Aβ. PiB has been used in many different human research protocols throughout the world and has demonstrated the usefulness of assessing the Aβ plaque status of subjects many years before the clinical diagnosis of probable AD. Recently, longer-lived 18F-radiolabeled Aβ-selective radiopharmaceuticals have been developed. It is likely that the full clinical impact of these imaging agents will be realized by identifying presymptomatic subjects who would benefit from early drug treatments with future disease-modifying AD therapeutics.

Objective:

To compare the diagnostic performance of PET with the amyloid ligand Pittsburgh compound B (PiB-PET) to fluorodeoxyglucose (FDG-PET) in discriminating between Alzheimer disease (AD) and frontotemporal lobar degeneration (FTLD).

Methods:

Patients meeting clinical criteria for AD (n = 62) and FTLD (n = 45) underwent PiB and FDG-PET. PiB scans were classified as positive or negative by 2 visual raters blinded to clinical diagnosis, and using a quantitative threshold derived from controls (n = 25). FDG scans were visually rated as consistent with AD or FTLD, and quantitatively classified based on the region of lowest metabolism relative to controls.

Results:

PiB visual reads had a higher sensitivity for AD (89.5% average between raters) than FDG visual reads (77.5%) with similar specificity (PiB 83%, FDG 84%). When scans were classified quantitatively, PiB had higher sensitivity (89% vs 73%) while FDG had higher specificity (83% vs 98%). On receiver operating characteristic analysis, areas under the curve for PiB (0.888) and FDG (0.910) were similar. Interrater agreement was higher for PiB (κ = 0.96) than FDG (κ = 0.72), as was agreement between visual and quantitative classification (PiB κ = 0.88–0.92; FDG κ = 0.64–0.68). In patients with known histopathology, overall classification accuracy (2 visual and 1 quantitative classification per patient) was 97% for PiB (n = 12 patients) and 87% for FDG (n = 10).

Conclusions:

PiB and FDG showed similar accuracy in discriminating AD and FTLD. PiB was more sensitive when interpreted qualitatively or quantitatively. FDG was more specific, but only when scans were classified quantitatively. PiB slightly outperformed FDG in patients with known histopathology.

Background

High levels of amyloid-β (Aβ) characterize Alzheimer’s disease.

Objective

To investigate whether longitudinal changes in Aβ deposition can be detected in vivo in older adults without dementia (hereafter referred to as nondemented).

Design

Prospective study.

Setting

Community-dwelling older adults.

Participants

Twenty-four nondemented participants (4 with a baseline Clinical Dementia Rating Scale score of 0.5; mean [SD] age 79.2 [8.1] years) in the Baltimore Longitudinal Study of Aging underwent serial carbon 11-labeled Pittsburgh Compound B- positron emission tomography ([11C]PiB-PET) (follow-up at a mean [SD] of 1.5 [0.5] years), with 5 participants undergoing a third [11C]PiB-PET examination.

Main Outcome Measures

Annual changes in distribution volume ratio (DVR) were evaluated using a global index of cortical DVR (cDVR) and region-of-interest analyses. Given the variability of cDVR at initial PiB-PET, annual changes in cDVR in those with minimal vs those with elevated initial cDVR were compared.

Results

In nondemented older adults, annual increase in [11C]PiB retention is 0.011 DVR per year (0.9%; P=0.01) which localizes to prefrontal, parietal, lateral temporal, and occipital cortices as well as anterior and posterior cingulate cortices. Annual change in cDVR is greater in older adults with elevated cDVR than in those with minimal initial cDVR (p=0.006).

Conclusions

Fibrillar Aβ detected by [11C]PiB-PET increases over time even in nondemented older adults. Individuals with higher initial [11C]PiB retention have greater rates of Aβ deposition, providing evidence for differential rates of Aβ deposition. Moreover, regional vulnerabilities to Aβ deposition allow for more targeted investigation of early Aβ changes.

There is increasing evidence for an empiric link between late-life depression and Alzheimer disease (AD). The neuropathology of AD, previously only confirmed at autopsy, may now be detectable in vivo using selective imaging ligands for β-amyloid. Positron emission tomography (PET) with [11C] 6-OH-BTA-1 [Pittsburgh Compound-B (PiB)] has shown high tracer retention in cortical areas in patients with clinical diagnoses of probable AD and low retention in age-matched controls. We also previously reported variable PiB retention in patients with mild cognitive impairment (MCI). In this study, we used PiB-PET to evaluate whether amyloid is present in elders with treated major depression, many of whom have persistent cognitive impairment. We evaluated 9 subjects with remitted major depression [3M: 6F, mean (SD) age=71.8(5.7) y]. Seven of the 9 depressed subjects also met criteria for the diagnosis of MCI. PiB-PET data from healthy elders [n=8; mean (SD) age=71.5(3.0) y] were used for comparison. PET was acquired with arterial sampling and PiB retention was quantified using magnetic resonance imaging-guided cortical regions and graphical analysis of time-activity data; arterial line failure led to exclusion of 1 depressed subject. The data demonstrated variably elevated PiB retention. PiB retention in the 2 depressed subjects with normal cognitive ability was in the range of nondepressed cognitively normal subjects. PiB retention in 3 of the 6 depressed subjects with MCI fell in the range of subjects with AD. PiB retention in the remaining 3 depressed subjects with cooccurring MCI was variable and generally was intermediate to the other subjects. Our findings are consistent with and supportive of the hypothesis that depression may herald the development of AD in some individuals.

The positron emission tomography (PET) radiotracer Pittsburgh Compound-B (PiB) binds with high affinity to β-pleated sheet aggregates of the amyloid-β (Aβ) 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 Aβ 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 Aβ-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 Aβ plaque load and peptide levels, [3H]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 Aβ42 or Aβ40, and to vascular Aβ 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 Aβ 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 [3H]PiB binding and insoluble Aβ 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 [3H]PiB binding, insoluble Aβ peptide levels, 6-CN-PiB- and Aβ 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) Aβ deposits, and not for neurofibrillary pathology. The strong direct correlation of in vivo PiB retention with region-matched quantitative analyses of Aβ plaques in the same subject supports the validity of PiB-PET imaging as a method for in vivo evaluation of Aβ plaque burden.

Pittsburgh compound-B (PiB), an amyloid-binding positron emission tomography (PET) tracer, is widely used for imaging amyloid-β in those with and at risk for Alzheimer disease. Here, we report on an otherwise normal 68-year-old female with abnormally high and very focal PiB retention. Coregistered T1-weighted magnetic resonance imaging and dynamic 2-fluoro-2-deoxy-D-glucose (FDG) images confirmed that the focal PiB enhancement was in the superior sagittal and transverse sinuses, outside of the adjacent cortex. Flow through the venous vasculature was normal as assessed by dynamic FDG PET imaging. These features supported the conclusion that PiB retention was not simply due to a hemodynamic abnormality, but may have represented PiB binding to fibrillar deposits of a β-sheet protein (ie, amyloid), whose nature is currently unclear.

Background

Clinicopathologic studies of Parkinson disease dementia (PDD) and dementia with Lewy bodies (DLB) commonly reveal abnormal β-amyloid deposition in addition to diffuse Lewy bodies (α-synuclein aggregates), but the relationship among these neuropathologic features and the development of dementia in these disorders remains uncertain.

Objective

To determine whether amyloid-βdeposition detected by PET imaging with Pittsburgh Compound B (PIB) distinguishes clinical subtypes of Lewy body-associated disorders.

Methods

Nine healthy controls (HC), eight PD with no cognitive impairment (PD-noCI), nine PD with mild cognitive impairment (PD-MCI), six dementia with Lewy bodies (DLB) and fifteen PD with dementia (PDD) patients underwent [11C]-PIB PET imaging, clinical examination, and cognitive testing. The binding potential (BP) of PIB for predefined regions and the mean cortical BP (MCBP) were calculated for each participant. Annual longitudinal follow-up and postmortem examinations were performed on a subset of participants.

Results

Regional PIB BPs and the proportion of individuals with abnormally elevated MCBP were not significantly different across participant groups. Elevated PIB binding was associated with worse global cognitive impairment in participants with Lewy body disorders but was not associated with any other clinical or neuropsychological features, including earlier onset or faster rate of progression of cognitive impairment.

Conclusions

These results suggest that the presence of fibrillar amyloid-βdoes not distinguish between clinical subtypes of Lewy body-associated disorders, although larger numbers are needed to more definitively rule out this association. Amyloid-βmay modify the severity of global cognitive impairment in individuals with Lewy body-associated dementia.

Objective

The objective of the study is to compare the diagnostic value of regional sampling of the cerebral metabolic rate of glucose metabolism (MRglc) using [18F]-fluoro-2-deoxyglucose ([18F]FDG)-positron emission tomography (PET) and amyloid-beta pathology using Pittsburgh Compound-B ([11C]PIB)-PET in the evaluation of patients with Alzheimer’s disease (AD) and mild cognitive impairment (MCI) compared to normal elderly (NL).

Materials and methods

AD patients, 7 NL, 13 MCI, and 17, received clinical, neuropsychological, magnetic resonance imaging (MRI), FDG, and PIB-PET exams. Parametric images of PIB uptake and MRglc were sampled using automated regions-of-interest (ROI).

Results

AD showed global MRglc reductions, and MCI showed reduced hippocampus (HIP) and inferior parietal lobe (IP) MRglc compared to NL. On PIB, AD patients showed significantly increased uptake in the middle frontal gyrus (MFG), posterior cingulate cortex (PCC), and IP (ps < 0.05). PIB uptake in MCI subjects was either AD or NL-like. HIP MRglc and MFG PIB uptake were the best discriminators of NL from MCI and NL from AD. These two best measures showed high diagnostic agreement for AD (94%) and poor agreement for MCI (54%). For the NL vs. MCI discrimination, combining the two best measures increased the accuracy for PIB (75%) and for FDG (85%) to 90%.

Conclusion

For AD, the pattern of regional involvement for FDG and PIB differ, but both techniques show high diagnostic accuracy and 94% case by case agreement. In the classification of NL and MCI, FDG is superior to PIB, but there is only 54% agreement at a case level. Combining the two modalities improves the diagnostic accuracy for MCI.

Objective

The objective of the study is to compare the diagnostic value of regional sampling of the cerebral metabolic rate of glucose metabolism (MRglc) using [18F]-fluoro-2-deoxyglucose ([18F]FDG)-positron emission tomography (PET) and amyloid-beta pathology using Pittsburgh Compound-B ([11C]PIB)-PET in the evaluation of patients with Alzheimer's disease (AD) and mild cognitive impairment (MCI) compared to normal elderly (NL).

Materials and methods

AD patients, 7 NL, 13 MCI, and 17, received clinical, neuropsychological, magnetic resonance imaging (MRI), FDG, and PIB-PET exams. Parametric images of PIB uptake and MRglc were sampled using automated regions-of-interest (ROI).

Results

AD showed global MRglc reductions, and MCI showed reduced hippocampus (HIP) and inferior parietal lobe (IP) MRglc compared to NL. On PIB, AD patients showed significantly increased uptake in the middle frontal gyrus (MFG), posterior cingulate cortex (PCC), and IP (ps< 0.05). PIB uptake in MCI subjects was either AD or NL-like. HIP MRglc and MFG PIB uptake were the best discriminators of NL from MCI and NL from AD. These two best measures showed high diagnostic agreement for AD (94%) and poor agreement for MCI (54%). For the NL vs. MCI discrimination, combining the two best measures increased the accuracy for PIB (75%) and for FDG (85%) to 90%.

Conclusion

For AD, the pattern of regional involvement for FDG and PIB differ, but both techniques show high diagnostic accuracy and 94% case by case agreement. In the classification of NL and MCI, FDG is superior to PIB, but there is only 54% agreement at a case level. Combining the two modalities improves the diagnostic accuracy for MCI.

Background:

Extrapyramidal motor symptoms precede dementia in Parkinson disease (PDD) by many years, whereas dementia occurs early in dementia with Lewy bodies (DLB). Despite this clinical distinction, the neuropsychological and neuropathologic features of these conditions overlap. In addition to widespread distribution of Lewy bodies, both diseases have variable burdens of neuritic plaques and neurofibrillary tangles characteristic of Alzheimer disease (AD).

Objectives:

To determine whether amyloid deposition, as assessed by PET imaging with the β-amyloid–binding compound Pittsburgh Compound B (PiB), can distinguish DLB from PDD, and to assess whether regional patterns of amyloid deposition correlate with specific motor or cognitive features.

Methods:

Eight DLB, 7 PDD, 11 Parkinson disease (PD), 15 AD, and 37 normal control (NC) subjects underwent PiB-PET imaging and neuropsychological assessment. Amyloid burden was quantified using the PiB distribution volume ratio.

Results:

Cortical amyloid burden was higher in the DLB group than in the PDD group, comparable to the AD group. Amyloid deposition in the PDD group was low, comparable to the PD and NC groups. Relative to global cortical retention, occipital PiB retention was lower in the AD group than in the other groups. For the DLB, PDD, and PD groups, amyloid deposition in the parietal (lateral and precuneus)/posterior cingulate region was related to visuospatial impairment. Striatal PiB retention in the DLB and PDD groups was associated with less impaired motor function.

Conclusions:

Global cortical amyloid burden is high in dementia with Lewy bodies (DLB) but low in Parkinson disease dementia. These data suggest that β-amyloid may contribute selectively to the cognitive impairment of DLB and may contribute to the timing of dementia relative to the motor signs of parkinsonism.

GLOSSARY

= Automated Anatomic Labeling;

= Alzheimer disease;

= Alzheimer’s Disease Research Center;

= American version of the National Adult Reading Test;

= analysis of covariance;

= Blessed Dementia Scale;

= cerebral amyloid angiopathy;

= Clinical Dementia Rating;

= Clinical Dementia Rating Sum of Boxes;

= dementia with Lewy bodies;

= distribution volume ratio;

= Cued Selective Reminding Test;

= Free Selective Reminding Test;

= Hoehn and Yahr;

= Massachusetts General Hospital;

= Mini-Mental State Examination;

= normal control;

= neurofibrillary tangle;

= Neuropsychiatric Inventory Questionnaire;

= not significant;

= Parkinson disease;

= Parkinson disease dementia;

= Pittsburgh Compound B;

= region of interest;

= Statistical Parametric Mapping;

= UK Parkinson’s Disease Society Brain Bank Research Center;

= United Parkinson’s Disease Rating Scale;

= Wechsler Adult Intelligence Scale–Revised.

It has been suggested that glucose metabolism within the brain's default network is directly associated with—and may even cause—the amyloid pathology of Alzheimer's disease (AD). Here we performed 2-[18F]fluoro-2-deoxy-D-glucose (FDG) and [11C]-labeled Pittsburgh Compound B (PIB) positron emission tomography (PET) on cognitively normal elderly subjects and on AD patients and conducted quantitative regional analysis of FDG- and PIB-PET images using an automated region of interest technique. We confirmed that resting glucose metabolism within the posterior components of the brain's default network is high in normal elderly subjects and low in AD patients, which is partially in agreement with the regional pattern of PIB uptake within the default network of AD patients. However, in several regions outside the default network, glucose metabolism was high in normal elderly subjects but was not depressed in AD patients, who exhibited significantly increased PIB uptakes in these regions. In contrast, the level of resting glucose metabolism in the default network and in regions outside the default network in normal elderly subjects was significantly correlated with the level of regional PIB uptake in AD patients. These results are discussed with experimental evidence suggesting that beta amyloid production and amyloid precursor protein regulation are dependent on neuronal activity.

Background

Alzheimer disease (AD) is defined neuropathologically by the presence of neurofibrillary tangles and plaques associated with tau and β-amyloid protein deposition. The colocalization of microglia and β-amyloid plaques has been widely reported in pathological examination of AD and suggests that neuroinflammation may play a role in pathogenesis and/or progression. Because postmortem histopathological analyses are limited to single end-stage assessment, the time course and nature of this relationship are not well understood.

Objective

To image microglial activation and β-amyloid deposition in the brains of subjects with and without AD.

Design, Setting, and Participants

Using two carbon 11 ([11C])–labeled positron emission tomographic imaging agents, Pittsburgh Compound B (PiB) and (R)-PK11195, we examined the relationship between amyloid deposition and microglial activation in different stages of AD using 5 control subjects, 6 subjects diagnosed with mild cognitive impairment, and 6 patients with mild to moderate AD.

Results

Consistent with prior reports, subjects with a clinical diagnosis of probable AD showed significantly greater levels of [11C]PiB retention than control subjects, whereas patients with mild cognitive impairment spanned a range from control-like to AD-like levels of [11C]PiB retention. Additionally, 2 asymptomatic control subjects also exhibited evidence of elevated PiB retention in regions associated with the early emergence of plaques in AD and may represent prodromal cases of AD. We observed no differences in brain [11C](R)-PK11195 retention when subjects were grouped by clinical diagnosis or the presence or absence of β-amyloid pathological findings as indicated by analyses of [11C]PiB retention.

Conclusions

These findings suggest that either microglial activation is limited to later stages of severe AD or [11C](R)-PK11195 is too insensitive to detect the level of microglial activation associated with mild to moderate AD.