11C-Pittsburgh Compound Research Articles

Distinct binding of amyloid imaging ligands to unique amyloid-β deposited in the presubiculum of Alzheimer's disease.

Non-invasive determination of amyloid-β peptide (Aβ) deposition with radioligands serves for the early diagnosis and clarification of pathogenetic mechanisms of Alzheimer's disease (AD). The polymorphic binding site on multimeric Aβ for current radioligands, however, is little understood. In this study, we investigated the binding of several radioligands including (11)C-Pittsburgh Compound B ((11)C-PiB), (3)H-AZD2184, and two recently developed compounds, (125)I-DRM106 and (125)I-DRK092, with unique presubicular Aβ deposits lacking interaction with the commonly used amyloid dyes FSB. (11)C-PiB, (3)H-AZD2184, and (125)I-DRK092 showed overt binding to presubicular Aβ deposits, while (125)I-DRM106 barely bound to these aggregates despite its strong binding in the hippocampal CA1 sector. Unlike neuritic plaques in the CA1, Aβ lesions in the presubiculum were not accompanied by inflammatory gliosis enriched with 18-kDa translocator protein (TSPO). Thus, there are at least two different components in Aβ aggregates providing distinct binding sites for the current amyloid radioligands, and one of these binding components is distinctly present in the presubicular Aβ deposits. Amyloid radioligands lacking affinity for this component, such as (125)I-DRM106, may selectively capture Aβ deposits tightly associated with TSPO neuroinflammation and neurodegeneration as exemplified by CA1 neuritic plaques. Hence, comparative autoradiographic assessments of radioligand binding in CA1 and presubiculum could serve for the development of an amyloid PET imaging agent visualizing neurotoxicity-related Aβ pathologies. Non-invasive determination of amyloid-β peptide (Aβ) serves for the early diagnosis and clarification of pathogenetic mechanisms of Alzheimer's disease (AD). We found that there are at least two different amyloid components in hippocampal CA1 and presubiculum providing distinct binding sites for the current amyloid radioligands. Comparative analysis for radioligand binding in these two regions could serve for developing novel imaging agents selectively visualizing neurotoxicity-related Aβ pathologies.

Performance of 11C-Pittsburgh Compound B PET Binding Potential Images in the Detection of Amyloid Deposits on Equivocal Static Images.

The goal of this study was to clarify whether binding potential (BP) images using (11)C-Pittsburgh compound B ((11)C-PiB) and dynamic PET can reliably detect cortical amyloid deposits for patients whose (11)C-PiB PET static images are ambiguous and whether visual ratings are affected by white matter retention. Static and BP images were constructed for 85 consecutive patients with cognitive impairment after (11)C-PiB dynamic PET. Cortical uptake was visually assessed as positive, negative, or equivocal for both types of images. Quantitatively, the standardized uptake value ratio (SUVR) from the static image, the nondisplaceable BP from the dynamic image for mean gray matter uptake, and the ratio of gray matter uptake to white matter retention were compared among (11)C-PiB-positive, (11)C-PiB-equivocal, and (11)C-PiB-negative groups. Forty-three scans were visually assessed as (11)C-PiB-positive in both the static and the BP images. Ten scans were (11)C-PiB-equivocal in the static images. In 8 of them, the BP images were (11)C-PiB-positive, whereas the other 2 were (11)C-PiB-equivocal. Thirty-two scans were assessed as (11)C-PiB-negative in the static images. In the BP images, 4 were (11)C-PiB-positive and 2 were (11)C-PiB-equivocal. The mean gray matter uptake of (11)C-PiB in SUVR and nondisplaceable BP, respectively, showed statistically significant differences among the (11)C-PiB-positive, (11)C-PiB-equivocal, and (11)C-PiB-negative groups. The ratio of gray matter uptake to white matter retention was lower in the BP images than static images from the (11)C-PiB-negative and (11)C-PiB-equivocal groups, whereas it was higher in the (11)C-PiB-positive group. (11)C-PiB PET BP images can clarify visual interpretation of clinical static (11)C-PiB-equivocal images by reducing the interference of nonspecific white matter retention. We conclude that (11)C-PiB-equivocal PET findings on static images reflect cortical amyloid deposits, which can be verified using BP images. Furthermore, quantitative assessments, such as SUVR and nondisplaceable BP, are of no use for correctly rating equivocal visual findings.

Type 2 diabetes mellitus and biomarkers of neurodegeneration

Our objective was to investigate whether type 2 diabetes mellitus (T2DM) influences neurodegeneration in a manner similar to Alzheimer disease (AD), by promoting brain β-amyloid (Aβ) or tau. We studied the cross-sectional associations of T2DM with cortical thickness, brain Aβ load, and CSF levels of Aβ and tau in a sample of people from the Alzheimer's Disease Neuroimaging Initiative with diagnoses of AD dementia, mild cognitive impairment, and normal cognition. All (n=816) received MRI, and a subsample underwent brain amyloid imaging (n=102) and CSF Aβ and tau measurements (n=415). Analyses were performed across and within cognitive diagnostic strata. There were 124 people with T2DM (mean age 75.5 years) and 692 without T2DM (mean age 74.1 years). After adjusting for age, sex, total intracranial volume, APO ε4 status, and cognitive diagnosis, T2DM was associated with lower bilateral frontal and parietal cortical thickness (mL) (β=-0.03, p=0.01). T2DM was not associated with 11C Pittsburgh compound B standardized uptake value ratio (AU) in any brain region or with CSF Aβ42 levels (pg/mL). T2DM was associated with greater CSF total tau (pg/mL) (β=16.06, p=0.04) and phosphorylated tau (β=5.84, p=0.02). The association between T2DM and cortical thickness was attenuated by 15% by the inclusion of phosphorylated tau. T2DM may promote neurodegeneration independent of AD dementia diagnosis, and its effect may be driven by tau phosphorylation. The mechanisms through which T2DM may promote tau phosphorylation deserve further study.

Alzheimer's Disease Normative Cerebrospinal Fluid Biomarkers Validated in PET Amyloid-β Characterized Subjects from the Australian Imaging, Biomarkers and Lifestyle (AIBL) study.

The cerebrospinal fluid (CSF) amyloid-β (Aβ)(1-42), total-tau (T-tau), and phosphorylated-tau (P-tau181P) profile has been established as a valuable biomarker for Alzheimer's disease (AD). The current study aimed to determine CSF biomarker cut-points using positron emission tomography (PET) Aβ imaging screened subjects from the Australian Imaging, Biomarkers and Lifestyle (AIBL) study of aging, as well as correlate CSF analyte cut-points across a range of PET Aβ amyloid ligands. Aβ pathology was determined by PET imaging, utilizing ¹¹C-Pittsburgh Compound B, ¹⁸F-flutemetamol, or ¹⁸F-florbetapir, in 157 AIBL participants who also underwent CSF collection. Using an INNOTEST assay, cut-points were established (Aβ(1-42) >544 ng/L, T-tau <407 ng/L, and P-tau181P <78 ng/L) employing a rank based method to define a "positive" CSF in the sub-cohort of amyloid-PET negative healthy participants (n = 97), and compared with the presence of PET demonstrated AD pathology. CSF Aβ(1-42) was the strongest individual biomarker, detecting cognitively impaired PET positive mild cognitive impairment (MCI)/AD with 85% sensitivity and 91% specificity. The ratio of P-tau181P or T-tau to Aβ(1-42) provided greater accuracy, predicting MCI/AD with Aβ pathology with ≥92% sensitivity and specificity. Cross-validated accuracy, using all three biomarkers or the ratio of P-tau or T-tau to Aβ(1-42) to predict MCI/AD, reached ≥92% sensitivity and specificity. CSF Aβ(1-42) levels and analyte combination ratios demonstrated very high correlation with PET Aβ imaging. Our study offers additional support for CSF biomarkers in the early and accurate detection of AD pathology, including enrichment of patient cohorts for treatment trials even at the pre-symptomatic stage.

Diagnostic value of 18F-FDG PET and 11C-PIB PET on early stage posterior cortical atrophy

Background Posterior cortical atrophy (PCA) is a kind of progressive neurodegenerative disease with cortical visual impairment as the first symptom. Because of rare clinical incidence, early onset age, special clinical symptoms and unobvious MRI abnormality, the definitive diagnosis of PCA is difficult. This study used 18 F-fluoro-2-deoxy-D-glucose ( 18 F-FDG) PET and 11 C-Pittsburgh compound B ( 11 C-PIB) PET for PCA patients with unobvious MRI abnormality, so as to discuss the value of PET in the early diagnosis of PCA. Methods Five patients diagnosed as PCA in our hospital between April 2012 and March 2015 were enrolled in this study. Cognitive function was measured by Mini-Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA), Activities of Daily Living (ADL) and Clock Drawing Test (CDT). Brain MRI, 18 F-FDG PET and 11 C-PIB PET were performed to analyze glucose metabolism and perfusion of posterior cortex. Results Neuropsychological tests revealed that the ability of writing, calculating, visuospatial and executive function of all these patients were impaired. Color vision tests showed abnormal results. MRI showed that the posterior atrophy (PA) scores were 0-2 (average 1) on the left side and 0-1 (average 0.80) on the right side. The medial temporal atrophy (MTA) scores were 1-3 (average 1.80) on the left side and 1-4 (average 2) on the right side. The ventricular enlargement (VE) scores were 1-2 (average 1.80) on the left side and 1-2 (average 1.60) on the right side. 18 F-FDG PET showed glucose metabolism decreased obviously on bilateral temporo-parieto-occipital cortex, precuneus and cingulate gyrus, and slightly on frontal lobes and subcortical structure. 11 C-PIB PET showed radioactive 11 C-PIB deposition on bilateral frontal, temporal, parietal and occipital cortex, and the outline of cerebellar cortex was clear. Conclusions For PCA patients whose parietal and occipital cortical atrophy is not obvious on MRI, 18 F-FDG PET combined with 11 C-PIB PET plays an important role in early diagnosis. DOI: 10.3969/j.issn.1672-6731.2015.08.005

Spotlight on the August 25 Issue

#### Notable in Neurology This issue features an article investigating the SQSTM1 splice site mutation in distal myopathy with rimmed vacuoles and another on PET imaging results of amyloid-β 11C-Pittsburgh compound B from 2 randomized bapineuzumab phase 3 Alzheimer disease trials. Another featured article focuses on migraine and the risk of stroke in older adults. ### Rapid progression of familial amyloidotic polyneuropathy: A multinational natural history study This study offers a worldwide perspective on familial amyloidotic polyneuropathy—its natural history, severity, and progression. In a population of 283 patients, …

Asymmetries of amyloid-β burden and neuronal dysfunction are positively correlated in Alzheimer's disease.

Clinical Alzheimer's disease affects both cerebral hemispheres to a similar degree in clinically typical cases. However, in atypical variants like logopenic progressive aphasia, neurodegeneration often presents asymmetrically. Yet, no in vivo imaging study has investigated whether lateralized neurodegeneration corresponds to lateralized amyloid-β burden. Therefore, using combined (11)C-Pittsburgh compound B and (18)F-fluorodeoxyglucose positron emission tomography, we explored whether asymmetric amyloid-β deposition in Alzheimer's disease is associated with asymmetric hypometabolism and clinical symptoms. From our database of patients who underwent positron emission tomography with both (11)C-Pittsburgh compound B and (18)F-fluorodeoxyglucose (n = 132), we included all amyloid-positive patients with prodromal or mild-to-moderate Alzheimer's disease (n = 69). The relationship between (11)C-Pittsburgh compound B binding potential and (18)F-fluorodeoxyglucose uptake was assessed in atlas-based regions of interest covering the entire cerebral cortex. Lateralizations of amyloid-β and hypometabolism were tested for associations with each other and with type and severity of cognitive symptoms. Positive correlations between asymmetries of Pittsburgh compound B binding potential and hypometabolism were detected in 6 of 25 regions (angular gyrus, middle frontal gyrus, middle occipital gyrus, superior parietal gyrus, inferior and middle temporal gyrus), i.e. hypometabolism was more pronounced on the side of greater amyloid-β deposition (range: r = 0.41 to 0.53, all P < 0.001). Stronger leftward asymmetry of amyloid-β deposition was associated with more severe language impairment (P < 0.05), and stronger rightward asymmetry with more severe visuospatial impairment (at trend level, P = 0.073). Similarly, patients with predominance of language deficits showed more left-lateralized amyloid-β burden and hypometabolism than patients with predominant visuospatial impairment and vice versa in several cortical regions. Associations between amyloid-β deposition and hypometabolism or cognitive impairment were predominantly observed in brain regions with high amyloid-β load. The relationship between asymmetries of amyloid-β deposition and hypometabolism in cortical regions with high amyloid-β load is in line with the detrimental effect of amyloid-β burden on neuronal function. Asymmetries were also concordant with lateralized cognitive symptoms, indicating their clinical relevance.

Quantification of β-Amyloidosis and rCBF with Dedicated PET, 7 T MR Imaging, and High-Resolution Microscopic MR Imaging at 16.4 T in APP23 Mice.

We present a combined PET/7 T MR imaging and 16.4 T microscopic MR imaging dual-modality imaging approach enabling quantification of the amyloid load at high sensitivity and high resolution, and of regional cerebral blood flow (rCBF) in the brain of transgenic APP23 mice. Moreover, we demonstrate a novel, voxel-based correlative data analysis method for in-depth evaluation of amyloid PET and rCBF data. We injected 11C-Pittsburgh compound B (PIB) intravenously in transgenic and control APP23 mice and performed dynamic PET measurements. rCBF data were recorded with a flow-sensitive alternating inversion recovery approach at 7 T. Subsequently, the animals were sacrificed and their brains harvested for ex vivo microscopic MR imaging at 16.4 T with a T2*-weighted gradient-echo sequence at 30-μm spatial resolution. Additionally, correlative amyloid histology was performed. The 11C-PIB PET data were quantified to nondisplaceable binding potentials (BPND) using the Logan graphical analysis; flow-sensitive alternating inversion recovery data were quantified with a simplified version of the Bloch equation. Amyloid load assessed by both 11C-PIB PET and amyloid histology was highest in the frontal cortex of transgenic mice (11C-PIB BPND: 0.93±0.08; amyloid histology: 15.1%±1.5%), followed by the temporoparietal cortex (11C-PIB BPND: 0.75±0.08; amyloid histology: 13.9%±0.7%) and the hippocampus (11C-PIB BPND: 0.71±0.09; amyloid histology: 9.2%±0.9%), and was lowest in the thalamus (11C-PIB BPND: 0.40±0.07; amyloid histology: 6.6%±0.6%). However, 11C-PIB BPND and amyloid histology linearly correlated (R2=0.82, P<0.05) and were significantly higher in transgenic animals (P<0.01). Similarly, microscopic MR imaging allowed quantifying the amyloid load, in addition to the detection of substructures within single amyloid plaques correlating with amyloid deposition density and the measurement of hippocampal atrophy. Finally, we found an inverse relationship between 11C-PIB BPND and rCBF MR imaging in the voxel-based analysis that was absent in control mice (slopetg: -0.11±0.03; slopeco: 0.004±0.005; P=0.014). Our dual-modality imaging approach using 11C-PIB PET/7 T MR imaging and 16.4 T microscopic MR imaging allowed amyloid-load quantification with high sensitivity and high resolution, the identification of substructures within single amyloid plaques, and the quantification of rCBF.

Comment: Yet another "disconnect" between amyloid and Alzheimer disease?

Amyloid plaque pathology is a defining characteristic of Alzheimer disease (AD), and the amyloid cascade hypothesis remains a central focus of AD research. Yet at least a dozen treatment trials have achieved target engagement by reducing fibrillar amyloid or its production, but have shown no clinical benefit. The article by Liu et al.1 shows that the monoclonal anti‐Aβ antibody bapineuzumab diminished binding of 11C–Pittsburgh compound B (PiB) in mild to moderate AD dementia, most notably in persons with APOE e4.

Recurrence of Cerebral Amyloid Angiopathy-Related Inflammation: A Report of Two Cases from the iCAβ International Network

Cerebral amyloid angiopathy-related inflammation (CAA-ri) represents the most readily responsive form of CAA, if diagnosed and treated early. Although CAA-ri typically presents with a monophasic pattern, recurrences have been occasionally reported. To describe the evolution of the clinical and neuroradiological features of CAA-ri recurrence. From the 60 CAA-ri cases recruited through the iCAβ International Network, we identified those patients who experienced a CAA-ri recurrence at more than 12 months after the first inflammatory event. Neuroradiological evidence of cerebral inflammation (vasogenic edema) and sulcal superficial siderosis or multiple areas of cortical/subcortical microhemorrhages (MHs) were evaluated based upon fluid-attenuated inversion recovery and T2*-weighted gradient echo or susceptibility weighted imaging, respectively. In one patient, the deposition of amyloid-β was evaluated using 11C-Pittsburgh Compound B-positron emission tomography (PiB-PET). Of the 60 cases, two were identified as having experienced a late CAA-ri recurrence, at two and seven years after the first presentation, respectively. At recurrence, the inflammatory lesions colocalized with the appearance of new MHs and were observed in brain areas different from those where the first onset occurred. PiB-PET four months after remission showed particularly low amyloid-β deposition in the left frontal lobe, while no change was observed in the area of the inflammatory relapse. Our observations highlight the importance of not underestimating any new neurological symptoms in patients who have already experienced an episode of CAA-ri. Although the frequency of CAA-ri recurrences is rare, in cases of suspected relapse, a prompt clinical and radiological follow-up should be considered in order to obtain a timely diagnosis and treatment, having a potential strong impact on patients' clinical outcome.

Relative 11C-PiB Delivery as a Proxy of Relative CBF: Quantitative Evaluation Using Single-Session 15O-Water and 11C-PiB PET.

The primary goal of this study was to assess the suitability of (11)C-Pittsburgh compound B ((11)C-PiB) blood-brain barrier delivery (K1) and relative delivery (R1) parameters as surrogate indices of cerebral blood flow (CBF), with a secondary goal of directly examining the extent to which simplified uptake measures of (11)C-PiB retention (amyloid-β load) may be influenced by CBF, in a cohort of controls and patients with mild cognitive impairment (MCI) and Alzheimer disease (AD). Nineteen participants (6 controls, 5 AD, 8 MCI) underwent MR imaging, (15)O-water PET, and (11)C-PiB PET in a single session. Fourteen regions of interest (including cerebellar reference region) were defined on MR imaging and applied to dynamic coregistered PET to generate time-activity curves. Multiple analysis approaches provided regional (15)O-water and (11)C-PiB measures of delivery and (11)C-PiB retention that included compartmental modeling distribution volume ratio (DVR), arterial- and reference-based Logan DVR, simplified reference tissue modeling 2 (SRTM2) DVR, and standardized uptake value ratios. Spearman correlation was performed among delivery measures (i.e., (15)O-water K1 and (11)C-PiB K1, relative K1 normalized to cerebellum [Rel-K1-Water and Rel-K1-PiB], and (11)C-PiB SRTM2-R1) and between delivery measures and (11)C-PiB retention, using the Bonferroni method for multiple-comparison correction. Primary analysis showed positive correlations (ρ ≈0.2-0.5) between (15)O-water K1 and (11)C-PiB K1 that did not survive Bonferroni adjustment. Significant positive correlations were found between Rel-K1-Water and Rel-K1-PiB and between Rel-K1-Water and (11)C-PiB SRTM2-R1 (ρ ≈0.5-0.8, P < 0.0036) across primary cortical regions. Secondary analysis showed few significant correlations between (11)C-PiB retention and relative (11)C-PiB delivery measures (but not (15)O-water delivery measures) in primary cortical areas that arose only after accounting for cerebrospinal fluid dilution. (11)C-PiB SRTM2-R1 is highly correlated with regional relative CBF, as measured by (15)O-water K1 normalized to cerebellum, and cross-sectional (11)C-PiB retention did not strongly depend on CBF across primary cortical regions. These results provide further support for potential dual-imaging assessments of regional brain status (i.e., amyloid-β load and relative CBF) through dynamic (11)C-PiB imaging.

Combination of dynamic 11C-PIB PET and structural MRI improves diagnosis of Alzheimer’s disease

Structural magnetic resonance imaging (sMRI) is an established technique for measuring brain atrophy, and dynamic positron emission tomography with 11C-Pittsburgh compound B (11C-PIB PET) has the potential to provide both perfusion and amyloid deposition information. It remains unclear, however, how to better combine perfusion, amyloid deposition and morphological information extracted from dynamic 11C-PIB PET and sMRI with the goal of improving the diagnosis of Alzheimer’s disease (AD) and mild cognitive impairment (MCI). We adopted a linear sparse support vector machine to build classifiers for distinguishing AD and MCI subjects from cognitively normal (CN) subjects based on different combinations of regional measures extracted from imaging data, including perfusion and amyloid deposition information extracted from early and late frames of 11C-PIB separately, and gray matter volumetric information extracted from sMRI data. The experimental results demonstrated that the classifier built upon the combination of imaging measures extracted from early and late frames of 11C-PIB as well as sMRI achieved the highest classification accuracy in both classification studies of AD (100%) and MCI (85%), indicating that multimodality information could aid in the diagnosis of AD and MCI.

Clustering-initiated factor analysis application for tissue classification in dynamic brain positron emission tomography.

The goal is to quantify the fraction of tissues that exhibit specific tracer binding in dynamic brain positron emission tomography (PET). It is achieved using a new method of dynamic image processing: clustering-initiated factor analysis (CIFA). Standard processing of such data relies on region of interest analysis and approximate models of the tracer kinetics and of tissue properties, which can degrade accuracy and reproducibility of the analysis. Clustering-initiated factor analysis allows accurate determination of the time-activity curves and spatial distributions for tissues that exhibit significant radiotracer concentration at any stage of the emission scan, including the arterial input function. We used this approach in the analysis of PET images obtained using (11)C-Pittsburgh Compound B in which specific binding reflects the presence of β-amyloid. The fraction of the specific binding tissues determined using our approach correlated with that computed using the Logan graphical analysis. We believe that CIFA can be an accurate and convenient tool for measuring specific binding tissue concentration and for analyzing tracer kinetics from dynamic images for a variety of PET tracers. As an illustration, we show that four-factor CIFA allows extraction of two blood curves and the corresponding distributions of arterial and venous blood from PET images even with a coarse temporal resolution.

Can Studies of Neuroinflammation in a TSPO Genetic Subgroup (HAB or MAB) Be Applied to the Entire AD Cohort?

Neuroinflammation plays a significant role in Alzheimer disease (AD), and translocator protein (TSPO) PET imaging allows us to quantify this process. However, the binding of second-generation TSPO tracers depends on the TSPO genotype coded by the rs6971 single-nucleotide polymorphism, with a 40%-50% increase in BP in high-affinity binders (HABs) compared with mixed-affinity binders (MABs), whereas low-affinity binders (LABs) are unsuitable for evaluation. Hence, several studies are using either HAB alone or HAB and MAB subjects. To translate the findings of neuroinflammation studies to the entire population, it is crucial to establish the influence of TSPO genotypes on AD. Here, we investigated whether different TSPO genotypes influence cognitive function, amyloid load, and disease progression over time. We evaluated 798 subjects (225 control, 388 with mild cognitive impairment [MCI], and 185 with AD) from the Alzheimer's Disease Neuroimaging Initiative database at baseline and during follow-up. All subjects were screened for TSPO genotype and underwent detailed clinical and neuropsychologic assessments yearly for 4 y. Of the 798 subjects, 255 also had T1- and T2-weighted MR imaging and amyloid PET with (11)C-Pittsburgh compound B or (18)F-florbetapir. We demonstrated that all TSPO binding groups (HAB, MAB, and LAB) have same level of amyloid load in AD and MCI subjects. We also demonstrated that the prevalence is 50.3% for HAB, 41.2% for MAB, and 8.5% for LAB, without a statistical difference among the AD, MCI, and control groups. During longitudinal follow-up, the mean change in neuropsychometric test scores on the Mini-Mental State Examination, the cognitive and modified Alzheimer Disease Assessment Scales (ADASs), and the Geriatric Depression Scale over time were similar in AD and MCI subjects among the 3 TSPO binding groups. Analysis of the covariates showed that diagnostic group (control, MCI, AD), apolipoprotein E4 status, and sex had a significant effect on decline on the modified Alzheimer Disease Assessment Scale (>3 points of the scale), but age and TSPO genotype did not. This study suggests that information obtained from evaluating a subgroup of AD or MCI subject using second-generation TSPO tracers can be translated to the entire AD and MCI population. Thus, we can study fewer AD subjects in evaluating new antineuroinflammatory and antimicroglial agents in intervention studies and in observational studies evaluating the role of neuroinflammation.

Modeling clustered activity increase in amyloid-beta positron emission tomographic images with statistical descriptors.

BackgroundAmyloid-beta (Aβ) imaging with positron emission tomography (PET) holds promise for detecting the presence of Aβ plaques in the cortical gray matter. Many image analyses focus on regional average measurements of tracer activity distribution; however, considerable additional information is available in the images. Metrics that describe the statistical properties of images, such as the two-point correlation function (S2), have found wide applications in astronomy and materials science. S2 provides a detailed characterization of spatial patterns in images typically referred to as clustering or flocculence. The objective of this study was to translate the two-point correlation method into Aβ-PET of the human brain using 11C-Pittsburgh compound B (11C-PiB) to characterize longitudinal changes in the tracer distribution that may reflect changes in Aβ plaque accumulation.MethodsWe modified the conventional S2 metric, which is primarily used for binary images and formulated a weighted two-point correlation function (wS2) to describe nonbinary, real-valued PET images with a single statistical function. Using serial 11C-PiB scans, we calculated wS2 functions from two-dimensional PET images of different cortical regions as well as three-dimensional data from the whole brain. The area under the wS2 functions was calculated and compared with the mean/median of the standardized uptake value ratio (SUVR). For three-dimensional data, we compared the area under the wS2 curves with the subjects’ cerebrospinal fluid measures.ResultsOverall, the longitudinal changes in wS2 correlated with the increase in mean SUVR but showed lower variance. The whole brain results showed a higher inverse correlation between the cerebrospinal Aβ and wS2 than between the cerebrospinal Aβ and SUVR mean/median. We did not observe any confounding of wS2 by region size or injected dose.ConclusionThe wS2 detects subtle changes and provides additional information about the binding characteristics of radiotracers and Aβ accumulation that are difficult to verify with mean SUVR alone.

Clinicopathologic and 11C-Pittsburgh compound B implications of Thal amyloid phase across the Alzheimer's disease spectrum.

Thal amyloid phase, which describes the pattern of progressive amyloid-β plaque deposition in Alzheimer's disease, was incorporated into the latest National Institute of Ageing - Alzheimer's Association neuropathologic assessment guidelines. Amyloid biomarkers (positron emission tomography and cerebrospinal fluid) were included in clinical diagnostic guidelines for Alzheimer's disease dementia published by the National Institute of Ageing - Alzheimer's Association and the International Work group. Our first goal was to evaluate the correspondence of Thal amyloid phase to Braak tangle stage and ante-mortem clinical characteristics in a large autopsy cohort. Second, we examined the relevance of Thal amyloid phase in a prospectively-followed autopsied cohort who underwent ante-mortem (11)C-Pittsburgh compound B imaging; using the large autopsy cohort to broaden our perspective of (11)C-Pittsburgh compound B results. The Mayo Clinic Jacksonville Brain Bank case series (n = 3618) was selected regardless of ante-mortem clinical diagnosis and neuropathologic co-morbidities, and all assigned Thal amyloid phase and Braak tangle stage using thioflavin-S fluorescent microscopy. (11)C-Pittsburgh compound B studies from Mayo Clinic Rochester were available for 35 participants scanned within 2 years of death. Cortical (11)C-Pittsburgh compound B values were calculated as a standard uptake value ratio normalized to cerebellum grey/white matter. In the high likelihood Alzheimer's disease brain bank cohort (n = 1375), cases with lower Thal amyloid phases were older at death, had a lower Braak tangle stage, and were less frequently APOE-ε4 positive. Regression modelling in these Alzheimer's disease cases, showed that Braak tangle stage, but not Thal amyloid phase predicted age at onset, disease duration, and final Mini-Mental State Examination score. In contrast, Thal amyloid phase, but not Braak tangle stage or cerebral amyloid angiopathy predicted (11)C-Pittsburgh compound B standard uptake value ratio. In the 35 cases with ante-mortem amyloid imaging, a transition between Thal amyloid phases 1 to 2 seemed to correspond to (11)C-Pittsburgh compound B standard uptake value ratio of 1.4, which when using our pipeline is the cut-off point for detection of clear amyloid-positivity regardless of clinical diagnosis. Alzheimer's disease cases who were older and were APOE-ε4 negative tended to have lower amyloid phases. Although Thal amyloid phase predicted clinical characteristics of Alzheimer's disease patients, the pre-mortem clinical status was driven by Braak tangle stage. Thal amyloid phase correlated best with (11)C-Pittsburgh compound B values, but not Braak tangle stage or cerebral amyloid angiopathy. The (11)C-Pittsburgh compound B cut-off point value of 1.4 was approximately equivalent to a Thal amyloid phase of 1-2.

Amyloid β accumulation assessed with ¹¹C-Pittsburgh compound B PET and postmortem neuropathology.

¹¹C-Pittsburgh compound B (PiB) uptake in PET images is frequently used to analyze β amyloid (Aβ) deposition in living individuals, but its correlation with histologically determined Aβ has not been examined. Six individuals with dementia underwent PiB-PET imaging, and their brains were analyzed neuropathologically (mean interval between imaging and death: 816 days; PiB positive:negative, 3:3; male:female, 3:3; mean age: 84.0 years). PiB uptake (reported as standardized uptake value ratio [SUVR]) was analyzed in 11 cortical regions and 10 subcortical grey matter areas and compared with the Aβ load (% area [the percentage of total area positive for Aβ] and number of neuritic plaques) seen with immunohistochemical staining with an anti-Aβ 11-28 antibody. Two PiB-positive subjects had abundant neuritic plaques and were diagnosed with Alzheimer’s disease (AD). SUVR and % area were strongly correlated in the cortical regions of these subjects (subject 1: r = 0.65, p = 0.03; subject 2: r = 0.80, p = 0.003). The other PiBpositive subject (subject 3) showed focal PiB uptake. In subject 3 and the 3 PiB-negative subjects (subjects 4-6), there was no correlation between regional SUVR and % area or neuritic plaques. PiB uptake was not correlated with Aβ deposition in subcortical regions. High PiB positivity in the cerebral cortex suggests the presence of substantial Aβ deposition and neuritic plaques associated with the pathologic changes of AD. Our results suggest that high cortical SUVR is a reliable marker of AD. Subcortical PiB positivity must be interpreted more carefully.

White matter integrity in dementia with Lewy bodies: a voxel-based analysis of diffusion tensor imaging

Many patients with dementia with Lewy bodies (DLB) have overlapping Alzheimer's disease (AD)–related pathology, which may contribute to white matter (WM) diffusivity alterations on diffusion tensor imaging (DTI). Consecutive patients with DLB (n = 30), age- and sex-matched AD patients (n = 30), and cognitively normal controls (n = 60) were recruited. All subjects underwent DTI, 18F 2-fluoro-deoxy-d-glucose, and 11C Pittsburgh compound B positron emission tomography scans. DLB patients had reduced fractional anisotropy (FA) in the parietooccipital WM but not elsewhere compared with cognitively normal controls, and elevated FA in parahippocampal WM compared with AD patients, which persisted after controlling for β-amyloid load in DLB. The pattern of WM FA alterations on DTI was consistent with the more diffuse posterior parietal and occipital glucose hypometabolism of 2-fluoro-deoxy-d-glucose positron emission tomography in the cortex. DLB is characterized by a loss of parietooccipital WM integrity, independent of concomitant AD-related β-amyloid load. Cortical glucose hypometabolism accompanies WM FA alterations with a concordant pattern of gray and WM involvement in the parietooccipital lobes in DLB.

Challenges in Production of Alzheimer’s Tracer C-11 PiB

Beta-amyloid plaques and neurofibrillary tangles have been known as the neuro- pathological hallmarks of Alzheimer’s disease. 11C Pittsburgh Compound B (PiB) ([C-11]PiB) is the first successful and well-studied radiopharmaceutical for Positron Emission Tomography (PET) imaging of beta-amyloid deposition in the brain. Although [C-11]PiB has been used in western countries since 2002, Wattanosoth Hospital was the only center with the capacity to produce [C-11]PiB in South-East Asia in 2012. This article describes briefly the challenges the PET radiopharmaceutical team at Wattanosoth Hospital have been facing in the production of [C-11]PiB. It also provides a brief protocol used here for production of [C-11]PiB.

Prefrontal hypometabolism in Alzheimer disease is related to longitudinal amyloid accumulation in remote brain regions.

In PET studies of patients with Alzheimer disease (AD), prominent hypometabolism can occur in brain regions without major amyloid load. These hypometabolism-only (HO) areas may not be explained easily as a consequence of local amyloid toxicity. The aim of this longitudinal multimodal imaging study was the investigation of locoregional and remote relationships between metabolism in HO areas and longitudinal amyloid increase in functionally connected brain areas, with a particular focus on intrinsic functional connectivity as a relevant linking mechanism between pathology and dysfunction. Fifteen AD patients underwent longitudinal examinations with (11)C-Pittsburgh compound B ((11)C-PiB) and (18)F-FDG PET (mean follow-up period, 2 y). The peak HO region was identified by the subtraction of equally thresholded statistical T maps (hypometabolism minus amyloid burden), resulting from voxel-based statistical parametric mapping group comparisons between the AD patients and 15 healthy controls. Then functionally connected and nonconnected brain networks were identified by means of seed-based intrinsic functional connectivity analysis of the resting-state functional MRI data of healthy controls. Finally, network-based, region-of-interest-based, and voxel-based correlations were calculated between longitudinal changes of normalized (11)C-PiB binding and (18)F-FDG metabolism. Positive voxel-based and region-of-interest-based correlations were demonstrated between longitudinal (11)C-PiB increases in the HO-connected network, encompassing bilateral temporoparietal and frontal brain regions, and metabolic changes in the peak HO region as well as locoregionally within several AD-typical brain regions. Our results indicate that in AD amyloid accumulation in remote but functionally connected brain regions may significantly contribute to longitudinally evolving hypometabolism in brain regions not strongly affected by local amyloid pathology, supporting the amyloid- and network-degeneration hypothesis.