Analysis of early phase [11C]BF-227 PET,and its application for anatomical standardization of late-phase images for 3D-SSP analysis

Purpose

To examine the usefulness of the early phase [¹¹C]BF-227 positron emission tomography (PET) for (1) conferring additional diagnostic value by providing perfusion-like information and (2) obtaining the appropriate anatomical standardization (AS) using three-dimensional stereotactic surface projection (3D-SSP) method.

Methods

This study included 20 mild cognitive impairment (MCI), 19 Alzheimer’s disease (AD), and 17 normal cognitive (NC) subjects. Early- and late-phase BF-227 PET images were obtained 0–10 and 40–60 min after the injection, respectively. AS for late-phase BF-227 images were performed by 2 methods: (1) method A, for AS of late-phase BF-227 images using ⁸F-fluorodeoxyglucose (FDG) images of the same subject and (2) method B, for AS of late-phase BF-227 images using early phase BF-227 images.

Results

Method B was successfully used for AS in all cases. The Z score maps of 3D-SSP analyses of FDG PET and early phase BF-227 PET for AD and MCI groups showed a typical AD-like pattern. Regional analyses revealed that the early phase BF-227 PET showed significant differences between AD and NC, and MCI and NC.

Conclusion

The early phase BF-227 PET images showed significant abnormal findings for the AD and MCI groups. AS of late-phase BF-227 images using early phase BF-227 images were successful, and enabled appropriate 3D-SSP analyses.     

Comparison of the binding characteristics of [18F]THK-523 and other amyloid imaging tracers to Alzheimer��s disease pathology

Purpose

Extensive deposition of senile plaques and neurofibrillary tangles in the brain is a pathological hallmark of Alzheimer??s disease (AD). Although several PET imaging agents have been developed for in vivo detection of senile plaques, no PET probe is currently available for selective detection of neurofibrillary tangles in the living human brain. Recently, [¹⁸F]THK-523 was developed as a potential in vivo imaging probe for tau pathology. The purpose of this study was to compare the binding properties of [¹⁸F]THK-523 and other amyloid imaging agents, including PiB, BF-227 and FDDNP, to synthetic protein fibrils and human brain tissue.

Methods

In vitro radioligand binding assays were conducted using synthetic amyloid ??₄₂ and K18??K280-tau fibrils. Nonspecific binding was determined by the addition of unlabelled compounds at a concentration of 2???M. To examine radioligand binding to neuropathological lesions, in vitro autoradiography was conducted using sections of AD brain.

Results

[¹⁸F]THK-523 showed higher affinity for tau fibrils than for A?? fibrils, whereas the other probes showed a higher affinity for A?? fibrils. The autoradiographic analysis indicated that [¹⁸F]THK-523 accumulated in the regions containing a high density of tau protein deposits. Conversely, PiB and BF-227 accumulated in the regions containing a high density of A?? plaques.

Conclusion

These findings suggest that the unique binding profile of [¹⁸F]THK-523 can be used to identify tau deposits in AD brain.     

2-(2-[2-Dimethylaminothiazol-5-yl]ethenyl)-6- (2-[fluoro]ethoxy)benzoxazole: a novel PET agent for in vivo detection of dense amyloid plaques in Alzheimer's disease patients.

Extensive deposition of dense amyloid fibrils is a characteristic neuropathologic hallmark in Alzheimer's disease (AD). Noninvasive detection of these molecules is potentially useful for early and precise detection of patients with AD. This study reports a novel compound, 2-(2-[2-dimethylaminothiazol-5-yl]ethenyl)-6-(2-[fluoro]ethoxy)benzoxazole (BF-227), for in vivo detection of dense amyloid deposits using PET. METHODS: The binding affinity of BF-227 to amyloid-beta (Abeta) fibrils was calculated. The binding property of BF-227 to amyloid plaques was evaluated by neuropathologic staining of AD brain sections. Brain uptake and in vivo binding of BF-227 to Abeta deposits were also evaluated using mice. For clinical evaluation of (11)C-BF-227 as a PET probe, 11 normal (healthy) subjects and 10 patients with AD participated in this study. Dynamic PET images were obtained for 60 min after administration of (11)C-BF-227. The regional standardized uptake value (SUV) and the ratio of regional to cerebellar SUV were calculated as an index of (11)C-BF-227 retention. The regional tracer distribution in AD patients was statistically compared with that of aged normal subjects on a voxel-by-voxel basis. RESULTS: BF-227 displayed high binding affinity to synthetic Abeta1-42 fibrils (K(i) [inhibition constant], 4.3 +/- 1.5 nM). Neuropathologic staining has demonstrated preferential binding of this agent to dense amyloid deposits in AD brain. Moreover, a biodistribution study of this agent revealed excellent brain uptake and specific labeling of amyloid deposits in transgenic mice. The present clinical PET study using (11)C-BF-227 demonstrated the retention of this tracer in cerebral cortices of AD patients but not in those of normal subjects. All AD patients were clearly distinguishable from normal individuals using the temporal SUV ratio. Voxel-by-voxel analysis of PET images revealed that cortical BF-227 retention in AD patients is distributed primarily to the posterior association area of the brain and corresponded well with the preferred site for neuritic plaque depositions containing dense Abeta fibrils. CONCLUSION: These findings suggest that BF-227 is a promising PET probe for in vivo detection of dense amyloid deposits in AD patients.     

A modified method of 3D-SSP analysis for amyloid PET imaging using [11C]BF-227

Objective

Three-dimensional stereotactic surface projection (3D-SSP) analyses have been widely used in dementia imaging studies. However, 3D-SSP sometimes shows paradoxical results on amyloid positron emission tomography (PET) analyses. This is thought to be caused by errors in anatomical standardization (AS) based on an ¹⁸F-fluorodeoxyglucose (FDG) template. We developed a new method of 3D-SSP analysis for amyloid PET imaging, and used it to analyze ¹¹C-labeled 2-(2-[2-dimethylaminothiazol-5-yl]ethenyl)-6-(2-[fluoro]ethoxy)benzoxazole (BF-227) PET images of subjects with mild cognitive impairment (MCI) and Alzheimer’s disease (AD).

Methods

The subjects were 20 with MCI, 19 patients with AD, and 17 healthy controls. Twelve subjects with MCI were followed up for 3 years or more, and conversion to AD was seen in 6 cases. All subjects underwent PET with both FDG and BF-227. For AS and 3D-SSP analyses of PET data, Neurostat (University of Washington, WA, USA) was used. Method 1 involves AS for BF-227 images using an FDG template. In this study, we developed a new method (Method 2) for AS: First, an FDG image was subjected to AS using an FDG template. Then, the BF-227 image of the same patient was registered to the FDG image, and AS was performed using the transformation parameters calculated for AS of the corresponding FDG images. Regional values were normalized by the average value obtained at the cerebellum and values were calculated for the frontal, parietal, temporal, and occipital lobes. For statistical comparison of the 3 groups, we applied one-way analysis of variance followed by the Bonferroni post hoc test. For statistical comparison between converters and non-converters, the t test was applied. Statistical significance was defined as p < 0.05.

Results

Among the 56 cases we studied, Method 1 demonstrated slight distortions after AS of the image in 16 cases and heavy distortions in 4 cases in which the distortions were not observed with Method 2. Both methods demonstrated that the values in AD and MCI patients were significantly higher than those in the controls, in the parietal, temporal, and occipital lobes. However, only Method 2 showed significant differences in the frontal lobes. In addition, Method 2 could demonstrate a significantly higher value in MCI-to-AD converters in the parietal and frontal lobes.

Conclusions

Method 2 corrects AS errors that often occur when using Method 1, and has made appropriate 3D-SSP analysis of amyloid PET imaging possible. This new method of 3D-SSP analysis for BF-227 PET could prove useful for detecting differences between normal groups and AD and MCI groups, and between converters and non-converters.     

A European multicentre PET study of fibrillar amyloid in Alzheimer��s disease

Purpose

Amyloid PET tracers have been developed for in vivo detection of brain fibrillar amyloid deposition in Alzheimer??s disease (AD). To serve as an early biomarker in AD the amyloid PET tracers need to be analysed in multicentre clinical studies.

Methods

In this study 238 [¹¹C]Pittsburgh compound-B (PIB) datasets from five different European centres were pooled. Of these 238 datasets, 18 were excluded, leaving [¹¹C]PIB datasets from 97 patients with clinically diagnosed AD (mean age 69?±?8?years), 72 patients with mild cognitive impairment (MCI; mean age 67.5?±?8?years) and 51 healthy controls (mean age 67.4?±?6?years) available for analysis. Of the MCI patients, 64 were longitudinally followed for 28?±?15?months. Most participants (175 out of 220) were also tested for apolipoprotein E (ApoE) genotype.

Results

[¹¹C]PIB retention in the neocortical and subcortical brain regions was significantly higher in AD patients than in age-matched controls. Intermediate [¹¹C]PIB retention was observed in MCI patients, with a bimodal distribution (64?% MCI PIB-positive and 36?% MCI PIB-negative), which was significantly different the pattern in both the AD patients and controls. Higher [¹¹C]PIB retention was observed in MCI ApoE ??4 carriers compared to non-ApoE ??4 carriers (p?<?0.005). Of the MCI PIB-positive patients, 67?% had converted to AD at follow-up while none of the MCI PIB-negative patients converted.

Conclusion

This study demonstrated the robustness of [¹¹C]PIB PET as a marker of neocortical fibrillar amyloid deposition in brain when assessed in a multicentre setting. MCI PIB-positive patients showed more severe memory impairment than MCI PIB-negative patients and progressed to AD at an estimated rate of 25?% per year. None of the MCI PIB-negative patients converted to AD, and thus PIB negativity had a 100?% negative predictive value for progression to AD. This supports the notion that PIB-positive scans in MCI patients are an indicator of prodromal AD.     

Amyloid PET imaging in Alzheimer’s disease: a comparison of three radiotracers

Purpose

The increasing use of amyloid PET in Alzheimer’s disease research and clinical trials has motivated efforts to standardize methodology. We compared retention of the ¹¹C radiotracer Pittsburgh Compound B (PiB) and that of two ¹⁸F amyloid radiotracers (florbetapir and flutemetamol) using two study populations. We also examined the feasibility of converting between tracer-specific measures, using PiB as the common link between the two ¹⁸F tracers.

Methods

One group of 40 subjects underwent PiB and flutemetamol imaging sessions and a separate group of 32 subjects underwent PiB and florbetapir imaging sessions. We compared cortical and white matter retention for each ¹⁸F tracer relative to that of PiB, as well as retention in several reference regions and image analysis methods. Correlations between tracer pairs were used to convert tracer-specific threshold values for amyloid positivity between tracers.

Results

Cortical retention for each pair of tracers was strongly correlated regardless of reference region (PiB–flutemetamol, ρ?=?0.84–0.99; PiB–florbetapir, ρ?=?0.83–0.97) and analysis method (ρ?=?0.90–0.99). Compared to PiB, flutemetamol had higher white matter retention, while florbetapir had lower cortical retention. Two previously established independent thresholds for amyloid positivity were highly consistent when values were converted between tracer pairs.

Conclusion

Despite differing white and grey matter retention characteristics, cortical retention for each ¹⁸F tracer was highly correlated with that of PiB, enabling conversion of thresholds across tracer measurement scales with a high level of internal consistency. Standardization of analysis methods and measurement scales may facilitate the comparison of amyloid PET data obtained using different tracers.     

How few cancer cells can be detected by positron emission tomography? A frequent question addressed by an in vitro study

Purpose

Positron emission tomography (PET) has gained widespread use in cancer diagnosis and treatment, but how many malignant cells are required for a tumour to be detected by PET?

Methods

Three human cancer cell lines [glioblastoma and two subtypes of small cell lung cancer (SCLC)] in concentrations from 10⁴ to 10⁷ were seeded on six-well plates or plastic tubes and treated with [¹⁸F]fluorodeoxy-glucose (FDG) in vitro. FDG retention was measured in a PET/CT scanner and in a calibrated well counter. The clinical situation was simulated using a cylinder phantom with a background concentration of FDG.

Results

The theoretical detection limit was found to be around 10⁵ malignant cells. In a cylinder phantom the detection limit was increased by a factor of 10. The FDG retention by the glioblastoma cell line was significantly higher than the activity of the SCLC cell line. FDG retention measured by PET and a gamma counter was closely correlated to the number of cells and a linear relationship was found.

Discussion

The detection limit of PET is in the magnitude of 10⁵ to 10⁶ malignant cells. The experimental set-up was robust and well suited as a platform for further investigations of factors influencing the detection limit of PET.     

Diagnostic accuracy of 18F-FDG PET/CT for detection of suspected recurrence in patients with oesophageal carcinoma

Purpose

To evaluate the role of ¹⁸F-FDG PET/CT in the detection of recurrence in patients with oesophageal carcinoma, suspected clinically or following conventional investigations.

Methods

This was a retrospective study. Data from 180 patients (age 56.3?±?10.4 years; 126 men, 54 women) with histopathologically proven oesophageal carcinoma (squamous cell 115, adenocarcinoma 59, neuroendocrine carcinoma 4, small cell 1, poorly differentiated 1) who had undergone 227 ¹⁸F-FDG PET/CT studies for suspected recurrence were analysed. Recurrence was suspected clinically or following conventional investigations. PET/CT images were revaluated by two nuclear medicine physicians in consensus. Findings were grouped into local, nodal and distant recurrence. Results were compared to those from contrast-enhanced (CE) CT when available (109 patients). Clinical/imaging follow-up (minimum 6 months) with histopathology (when available) was taken as the reference standard.

Results

Of the 227 ¹⁸F-FDG PET/CT studies,166 were positive and 61 were negative for recurrent disease. PET/CT showed local recurrence in 134, nodal recurrence in 115 and distant recurrence in 47, with more than one site of recurrence in 34. The PET/CT findings were true-positive in 153 studies, true-negative in 54, false-positive in 13 and false-negative in 7. The sensitivity of ¹⁸F-FDG PET/CT was 96 %, the specificity was 81 %, the positive and negative predictive values were 92 % and 89 %, respectively, and the accuracy was 91 %. PET/CT showed similar accuracy in patients with squamous cell carcinoma and in those with adenocarcinoma (P?=?0.181).¹⁸F-FDG PET/CT was more specific than CECT (67 % vs. 21 %; P?<?0.0001). PET/CT was superior to CECT for the detection of nodal recurrence (P?<?0.0001), but not local recurrence (P?=?0.093) or distant metastases (P?=?0.441).

Conclusion

¹⁸F-FDG PET/CT shows high accuracy in the detection of suspected recurrence in patients with oesophageal carcinoma. It is more specific than and is superior to CECT in the detection of nodal recurrence.     

Detection of amyloid in Alzheimer’s disease with positron emission tomography using [11C]AZD2184

Purpose

Current positron emission tomography (PET) radioligands for detection of Aβ amyloid in Alzheimer’s disease (AD) are not ideal for quantification. To improve the signal to noise ratio we have developed the radioligand [¹¹C]AZD2184 and report here the first clinical evaluation.

Methods

Eight AD patients and four younger control subjects underwent 93-min PET measurements with [¹¹C]AZD2184. A ratio approach using the cerebellum as reference region was applied to determine binding parameters.

Results

Brain uptake of [¹¹C]AZD2184 peaked within 1 min at 3–4% of injected radioactivity. AD patients had high radioactivity in cortical regions while controls had uniformly low radioactivity uptake. Specific binding peaked within 30 min at which time standardized uptake value ratios (SUVR) ranged between 1.19 and 2.57.

Conclusion

[¹¹C]AZD2184 is a promising radioligand for detailed mapping of Aβ amyloid depositions in Alzheimer’s disease, due to low non-specific binding, high signal to background ratio and reversible binding as evident from early peak equilibrium.     

In vivo evaluation of a novel tau imaging tracer for Alzheimer’s disease

Purpose

Diagnosis of tauopathies such as Alzheimer’s disease (AD) still relies on post-mortem examination of the human brain. A non-invasive method of determining brain tau burden in vivo would allow a better understanding of the pathophysiology of tauopathies. The purpose of the study was to evaluate ¹⁸F-THK523 as a potential tau imaging tracer.

Methods

Ten healthy elderly controls, three semantic dementia (SD) and ten AD patients underwent neuropsychological examination, MRI as well as ¹⁸F-THK523 and ¹¹C-Pittsburgh compound B (PIB) positron emission tomography (PET) scans. Composite memory and non-memory scores, global and hippocampal brain volume, and partial volume-corrected tissue ratios for ¹⁸F-THK523 and ¹¹C-PIB were estimated for all participants. Correlational analyses were performed between global and regional ¹⁸F-THK523, ¹¹C-PIB, cognition and brain volumetrics.

Results

¹⁸F-THK523 presented with fast reversible kinetics. Significantly higher ¹⁸F-THK523 retention was observed in the temporal, parietal, orbitofrontal and hippocampi of AD patients when compared to healthy controls and SD patients. White matter retention was significantly higher than grey matter retention in all participants. The pattern of cortical ¹⁸F-THK523 retention did not correlate with Aβ distribution as assessed by ¹¹C-PIB and followed the known distribution of tau in the AD brain, being higher in temporal and parietal areas than in the frontal region. Unlike ¹¹C-PIB, hippocampal ¹⁸F-THK523 retention was correlated with several cognitive parameters and with hippocampal atrophy.

Conclusion

¹⁸F-THK523 does not bind to Aβ in vivo, while following the known distribution of paired helical filaments (PHF)-tau in the brain. Significantly higher cortical ¹⁸F-THK523 retention in AD patients as well as the association of hippocampal ¹⁸F-THK523 retention with cognitive parameters and hippocampal volume suggests ¹⁸F-THK523 selectively binds to tau in AD patients. Unfortunately, the very high ¹⁸F-THK523 retention in white matter precludes simple visual inspection of the images, preventing its use in research or clinical settings.     

Perfusion-like template and standardized normalization-based brain image analysis using 18F-florbetapir (AV-45/Amyvid) PET

Purpose

Amyloid positron emission tomography (PET) is an important noninvasive method for detecting amyloid burden in Alzheimer’s disease (AD) patients. As amyloid PET images have limited anatomical information, magnetic resonance (MR) imaging is usually acquired to perform reliable spatial normalization needed for large-scale analysis. This work proposed and evaluated the performance of new MR-free spatial normalization methods using a perfusion-like template for amyloid PET imaging.

Methods

Amyloid PET and MR images were collected in 35 subjects (cohort 1: 8 AD patients and 6 controls; cohort 2: 15 AD patients and 6 controls). Three ligand-related templates (AD, control, mixed group) and a perfusion-like template (pAV-45) from early time frames of amyloid PET images were constructed from cohort 1. The variations of ¹⁸F-AV-45 standardized uptake value ratios (SUVRs) among AD patients, controls, and all subjects were tested with repeated two-way (template × brain region) analysis of variance (ANOVA) in cohort 2. ¹⁸F-AV-45 SUVRs by region of interest analysis and voxelwise analysis between MR-based and MR-free approaches were compared and correlated to clinical and image parameters. Effect size (group mean SUVR difference between AD and control/standard deviation) was also evaluated for each template method.

Results

Significantly different ¹⁸F-AV-45 SUVRs between MR-free spatial normalization and MR-based reference images were found among AD patients, controls, and all subjects by the effect of template and brain regions. The highest correlation (r=0.991) of ¹⁸F-AV-45 SUVR to MR-based reference was found in the pAV-45 group. The SUVR percentage difference to MR-based reference showed the least variation and bias (control: ?1.31±3.47 %; AD: ?0.36±2.50 %) in the pAV-45 group as well. The voxelwise analysis showed the smallest t statistic value in pAV-45 followed by mixed, control, and AD groups when compared to MR-based reference images. Moreover, an overall larger effect size but compatible to that of MR-based reference result was observed in the pAV-45 group as compared to those of the other MR-free template.

Conclusion

The novel MR-free template based on the early-phase perfusion images pAV-45 approach for amyloid imaging showed significantly better performance in quantitation accuracy, effect size, and stability when compared with other MR-free PET templates and thus has potential for large-scale clinical applications.     

Utility of 18F-FDG PET(/CT) in patients with systemic and localized amyloidosis

Purpose

Amyloidosis is a group of diseases characterized by deposition of fibrils and this deposition may be localized or systemic. The presence of giant cells is typical of localized AL amyloidosis in contrast to systemic amyloidosis. Because of this presence of giant cells we hypothesize that ¹⁸F-fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) may show uptake in localized amyloidosis but not in systemic amyloidosis. The aim of the study was to evaluate the utility of ¹⁸F-FDG PET/CT in distinguishing systemic amyloidosis from localized amyloidosis.

Methods

A retrospective search in the hospital computer system showed 21 patients with histologically proven systemic or localized amyloidosis who recently had undergone ¹⁸F-FDG PET/CT. Twenty patients also had undergone ¹²³I-serum amyloid P component (SAP) scintigraphy.

Results

Of 11 patients with localized amyloidosis, 10 showed markedly increased FDG uptake at the amyloid site, whereas one showed slightly increased FDG uptake. ¹²³I-SAP scintigraphy (in ten patients) was positive in three patients at the amyloid site and negative for any other specific organ involvement in nine patients, with a weakly positive spleen in one other patient. In ten patients with systemic amyloidosis, increased FDG uptake was not found in any affected organ containing amyloid, whereas ¹²³I-SAP scintigraphy was positive for specific organ involvement in nine patients.

Conclusion

¹⁸F-FDG PET/CT may be supportive of the usual diagnostic tests in differentiating between systemic amyloidosis (no increased FDG uptake at the amyloid site) and localized amyloidosis (increased FDG uptake at the amyloid site). Apart from diagnosis, this finding has potential clinical application in therapy evaluation and follow-up.     

[11C]PIB, [18F]FDG and MR imaging in patients with mild cognitive impairment

Purpose

Cortical glucose metabolism, brain amyloid β accumulation and hippocampal atrophy imaging have all been suggested as potential biomarkers in predicting which patients with mild cognitive impairment (MCI) will convert to Alzheimer’s disease (AD). The aim of this study was to compare the prognostic ability of [¹¹C]PIB PET, [¹⁸F]FDG PET and quantitative hippocampal volumes measured with MR imaging in predicting conversion to AD in patients with MCI.

Methods

The study group comprised 29 patients with MCI who underwent [¹¹C]PIB PET and MR imaging. Of these, 22 also underwent [¹⁸F]FDG PET. All subjects were invited back for clinical evaluation after 2 years.

Results

During the follow-up time 17 patients had converted to AD while 12 continued to meet the criteria for MCI. The two groups did not differ in age, gender or education level, but the converter group tended to have lower MMSE and Word List learning than the nonconverter group. High [¹¹C]PIB retention in the frontotemporal regions and anterior and posterior cingulate (p?<?0.05) predicted conversion to AD. Also reduced [¹⁸F]FDG uptake in the left lateral temporal cortex (LTC) predicted conversion (p?<?0.05), but quantitative hippocampal volumes did not (p?>?0.1). In receiver operating characteristic (ROC) analysis the measurements that best predicted the conversion were [¹¹C]PIB retention in the lateral frontal cortex and [¹⁸F]FDG uptake in the left LTC. Both PET methods resulted in good sensitivity and specificity and neither was significantly superior to the other.

Conclusion

The findings indicate that [¹¹C]PIB and [¹⁸F]FDG are superior to hippocampal volumes in predicting conversion to AD in patients with MCI.     

Quantitative longitudinal interrelationships between brain metabolism and amyloid deposition during a 2-year follow-up in patients with early Alzheimer’s disease

Purpose

Similar regional anatomical distributions were reported for fibrillary amyloid deposition [measured by ¹¹C-Pittsburgh compound B (PIB) positron emission tomography (PET)] and brain hypometabolism [measured by ¹⁸F-fluorodeoxyglucose (FDG) PET] in numerous Alzheimer’s disease (AD) studies. However, there is a lack of longitudinal studies evaluating the interrelationships of these two different pathological markers in the same AD population. Our most recent AD study suggested that the longitudinal pattern of hypometabolism anatomically follows the pattern of amyloid deposition with temporal delay, which indicates that neuronal dysfunction may spread within the anatomical pattern of amyloid pathology. Based on this finding we now hypothesize that in early AD patients quantitative longitudinal decline in hypometabolism may be related to the amount of baseline amyloid deposition during a follow-up period of 2?years.

Methods

Fifteen patients with mild probable AD underwent baseline (T1) and follow-up (T2) examination after 24?±?2.1?months with [¹⁸F]FDG PET, [¹¹C]PIB PET, structural T1-weighted MRI and neuropsychological testing [Consortium to Establish a Registry for Alzheimer's Disease (CERAD) neuropsychological battery]. Longitudinal cognitive measures and quantitative PET measures of amyloid deposition and metabolism [standardized uptake value ratios (SUVRs)] were obtained using volume of interest (VOI)-based approaches in the frontal-lateral-retrosplenial (FLR) network and in predefined bihemispheric brain regions after partial volume effect (PVE) correction of PET data. Statistical group comparisons (SUVRs and cognitive measures) between patients and 15 well-matched elderly controls who had undergone identical imaging procedures once as well as Pearson’s correlation analyses within patients were performed.

Results

Group comparison revealed significant cognitive decline and increased mean PIB/decreased FDG SUVRs in the FLR network as well as in several AD-typical regions in patients relative to controls. Concurrent with cognitive decline patients showed longitudinal increase in mean PIB/decrease in mean FDG SUVRs over time in the FLR network and in several AD-typical brain regions. Correlation analyses of FLR network SUVRs in patients revealed significant positive correlations between PIB T1 and delta FDG (FDG T1-T2) SUVRs, between PIB T1 and PIB T2 SUVRs, between FDG T1 and PIB T2 SUVRs as well as between FDG T1 and FDG T2 SUVRs, while significant negative correlations were found between FDG T1 and delta PIB (PIB T1-T2) SUVRs as well as between FDG T2 and delta FDG (FDG T1-T2) SUVRs. These findings were confirmed in locoregional correlation analyses, revealing significant associations in the same directions for two left hemispheric regions and nine right hemispheric regions, showing the strongest association for bilateral precuneus.

Conclusion

Baseline amyloid deposition in patients with mild probable AD was associated with longitudinal metabolic decline. Additionally, mildly decreased/relatively preserved baseline metabolism was associated with a longitudinal increase in amyloid deposition. The latter bidirectional associations were present in the whole AD-typical FLR network and in several highly interconnected hub regions (i.e. in the precuneus). Our longitudinal findings point to a bidirectional quantitative interrelationship of the two investigated AD pathologies, comprising an initial relative maintenance of neuronal activity in already amyloid-positive hub regions (neuronal compensation), followed by accelerated amyloid deposition, accompanied by functional neuronal decline (neuronal breakdown) along with cognitive decline.     

Assessment of response of brain metastases to radiotherapy by PET imaging of apoptosis with 18F-ML-10

Purpose

Early assessment of tumor response to therapy is vital for treatment optimization for the individual cancer patient. Induction of apoptosis is an early and nearly universal effect of anticancer therapies. The purpose of this study was to assess the performance of ¹⁸F-ML-10, a novel PET radiotracer for apoptosis, as a tool for the early detection of response of brain metastases to whole-brain radiation therapy (WBRT).

Materials and methods

Ten patients with brain metastases treated with WBRT at 30?Gy in ten daily fractions were enrolled in this trial. Each patient underwent two ¹⁸F-ML-10 PET scans, one prior to the radiation therapy (baseline scan), and the second after nine or ten fractions of radiotherapy (follow-up scan). MRI was performed at 6–8?weeks following completion of the radiation therapy. Early treatment-induced changes in tumor ¹⁸F-ML-10 uptake on the PET scan were measured by voxel-based analysis, and were then evaluated by correlation analysis as predictors of the extent of later changes in tumor anatomical dimensions as seen on MRI scans 6–8?weeks after completion of therapy.

Results

In all ten patients, all brain lesions were detected by both MRI and the ¹⁸F-ML-10 PET scan. A highly significant correlation was found between early changes on the ¹⁸F-ML-10 scan and later changes in tumor anatomical dimensions (r?=?0.9).

Conclusion

These results support the potential of ¹⁸F-ML-10 PET as a novel tool for the early detection of response of brain metastases to WBRT.     

Astrocytosis measured by 11C-deprenyl PET correlates with decrease in gray matter density in the parahippocampus of prodromal Alzheimer’s patients

Purpose

The Alzheimer’s disease (AD) pathology is characterized by fibrillar amyloid deposits and neurofibrillary tangles, as well as the activation of astrocytosis, microglia activation, atrophy, dysfunctional synapse, and cognitive impairments. The aim of this study was to test the hypothesis that astrocytosis is correlated with reduced gray matter density in prodromal AD.

Methods

Twenty patients with AD or mild cognitive impairment (MCI) underwent multi-tracer positron emission tomography (PET) studies with ¹¹C-Pittsburgh compound B (¹¹C-PIB), ¹⁸?F-Fluorodeoxyglucose (¹⁸?F-FDG), and ¹¹C-deuterium-L-deprenyl (¹¹C-DED) PET imaging, as well as magnetic resonance imaging (MRI) scanning, cerebrospinal fluid (CSF) biomarker analysis, and neuropsychological assessments. The parahippocampus was selected as a region of interest, and each value was calculated for four different imaging modalities. Correlation analysis was applied between DED slope values and gray matter (GM) densities by MRI. To further explore possible relationships, correlation analyses were performed between the different variables, including the CSF biomarker.

Results

A significant negative correlation was obtained between DED slope values and GM density in the parahippocampus in PIB-positive (PIB?+?ve) MCI patients (p?=?0.025) (prodromal AD). Furthermore, in exploratory analyses, a positive correlation was observed between PIB-PET retention and DED binding in AD patients (p?=?0.014), and a negative correlation was observed between PIB retention and CSF Aβ42 levels in MCI patients (p?=?0.021), while the GM density and CSF total tau levels were negatively correlated in both PIB?+?ve MCI (p?=?0.002) and MCI patients (p?=?0.001). No significant correlation was observed with FDG-PET and with any of the other PET, MRI, or CSF biomarkers.

Conclusions

High astrocytosis levels in the parahippocampus of PIB?+?ve MCI (prodromal AD) patients suggest an early preclinical influence on cellular tissue loss. The lack of correlation between astrocytosis and CSF tau levels, and a positive correlation between astrocytosis and fibrillar amyloid deposition in clinical demented AD together indicate that parahippocampal astrocytosis might have some causality within the amyloid pathology.     

Visualization of multiple organ amyloid involvement in systemic amyloidosis using <Superscript>11</Superscript>C-PiB PET imaging

Purpose

To investigate the utility of Pittsburgh compound B (PiB) positron emission tomography (PET) imaging for evaluating whole-body amyloid involvement in patients with systemic amyloidosis.

Methods

Whole-body ¹¹C-PiB PET was performed in seven patients with systemic immunoglobulin light-chain (AL) amyloidosis, seven patients with hereditary transthyretin (ATTRm) amyloidosis, one asymptomatic TTR mutation carrier and three healthy controls. The correlations between clinical organ involvement, radiological ¹¹C-PiB uptake and histopathological findings were analysed for each organ.

Results

Organ involvement on ¹¹C-PiB PET imaging showed good correlations with the clinical findings for the heart and stomach. Abnormal tracer uptake was also observed in the spleen, lachrymal gland, submandibular gland, sublingual gland, lymph node, brain, scalp, extraocular muscles, nasal mucosa, pharynx, tongue and nuchal muscles, most of which were asymptomatic. Physiological tracer uptake was universally observed in the urinary tract (kidney, renal pelvis, ureter and bladder) and enterohepatic circulatory system (liver, gallbladder, bile duct and small intestine) in all participants. Most of the patients and one healthy control subject showed asymptomatic tracer uptake in the lung and parotid gland. The peripheral nervous system did not show any tracer uptake even in patients with apparent peripheral neuropathy. Histological amyloid deposition was confirmed in biopsied myocardium and gastric mucosa where abnormal ¹¹C-PiB retention was observed.

Conclusions

¹¹C-PiB PET imaging can be used clinically in the systemic evaluation of amyloid distribution in patients with AL and ATTRm amyloidosis. Quantitative analysis of ¹¹C-PiB PET images may be useful in therapy evaluation and will reveal whether amyloid clearance is correlated with clinical response.

     

Imaging of amyloid deposition in human brain using positron emission tomography and [18F]FACT: comparison with [11C]PIB

Purpose

The characteristic neuropathological changes in Alzheimer’s disease (AD) are deposition of amyloid senile plaques and neurofibrillary tangles. The ¹⁸F-labeled amyloid tracer, [¹⁸F]2-[(2-{(E)-2-[2-(dimethylamino)-1,3-thiazol-5-yl]vinyl}-1,3-benzoxazol-6-yl)oxy]-3-fluoropropan-1-ol (FACT), one of the benzoxazole derivatives, was recently developed. In the present study, deposition of amyloid senile plaques was measured by positron emission tomography (PET) with both [¹¹C]Pittsburgh compound B (PIB) and [¹⁸F]FACT in the same subjects, and the regional uptakes of both radiotracers were directly compared.

Methods

Two PET scans, one of each with [¹¹C]PIB and [¹⁸F]FACT, were performed sequentially on six normal control subjects, two mild cognitive impairment (MCI) patients, and six AD patients. The standardized uptake value ratio of brain regions to the cerebellum was calculated with partial volume correction using magnetic resonance (MR) images to remove the effects of white matter accumulation.

Results

No significant differences in the cerebral cortical uptake were observed between normal control subjects and AD patients in [¹⁸F]FACT studies without partial volume correction, while significant differences were observed in [¹¹C]PIB. After partial volume correction, the cerebral cortical uptake was significantly larger in AD patients than in normal control subjects for [¹⁸F]FACT studies as well as [¹¹C]PIB. Relatively lower uptakes of [¹¹C]PIB in distribution were observed in the medial side of the temporal cortex and in the occipital cortex as compared with [¹⁸F]FACT. Relatively higher uptake of [¹¹C]PIB in distribution was observed in the frontal and parietal cortices.

Conclusion

Since [¹⁸F]FACT might bind more preferentially to dense-cored amyloid deposition, regional differences in cerebral cortical uptake between [¹¹C]PIB and [¹⁸F]FACT might be due to differences in regional distribution between diffuse and dense-cored amyloid plaque shown in the autoradiographic and histochemical assays of postmortem AD brain sections.     

The effect of amyloid pathology and glucose metabolism on cortical volume loss over time in Alzheimer’s disease

Purpose

The present multimodal neuroimaging study examined whether amyloid pathology and glucose metabolism are related to cortical volume loss over time in Alzheimer’s disease (AD) patients and healthy elderly controls.

Methods

Structural MRI scans of eleven AD patients and ten controls were available at baseline and follow-up (mean interval 2.5 years). Change in brain structure over time was defined as percent change of cortical volume within seven a-priori defined regions that typically show the strongest structural loss in AD. In addition, two PET scans were performed at baseline: [¹¹C]PIB to assess amyloid-β plaque load and [¹⁸F]FDG to assess glucose metabolism. [¹¹C]PIB binding and [¹⁸F]FDG uptake were measured in the precuneus, a region in which both amyloid deposition and glucose hypometabolism occur early in the course of AD.

Results

While amyloid-β plaque load at baseline was not related to cortical volume loss over time in either group, glucose metabolism within the group of AD patients was significantly related to volume loss over time (rho?=?0.56, p?<?0.05).

Conclusion

The present study shows that in a group of AD patients amyloid-β plaque load as measured by [¹¹C]PIB behaves as a trait marker (i.e., all AD patients showed elevated levels of amyloid, not related to subsequent disease course), whilst hypometabolism as measured by [¹⁸F]FDG changed over time indicating that it could serve as a state marker that is predictive of neurodegeneration.     

18F-FDG PET/CT in HIV-related central nervous system pathology

Purpose

To evaluate the utility of ¹⁸F-FDG PET/CT in suspected cerebral pathology in HIV-infected individuals.

Methods

¹⁸F-FDG PET/CT scans from 29 HIV-infected individuals (29 brain scans, 22 whole-body scans) who presented with neurological symptoms and signs were retrospectively reviewed and compared with subsequent clinical investigations.

Results

The majority of patients (n?=?25) were referred to differentiate infection from malignant causes of cerebral pathology. Ten of the 11 patients with an eventual diagnosis of toxoplasmosis infection were correctly diagnosed by ¹⁸F-FDG PET/CT showing lesional uptake less than that of normal brain cortex (mean SUVmax 3.5, range 1.9 – 5.8). All five patients with a final diagnosis of primary central nervous system lymphoma (PCNSL) were correctly diagnosed by ¹⁸F-FDG PET/CT showing lesional uptake greater than that of normal brain cortex (mean SUVmax 18.8, range 12.4 – 29.9). Four of the five patients with ¹⁸F-FDG PET/CT features suggesting a vasculitic process had vasculitis confirmed as the final diagnosis. Three patients showed variable uptake in multiple cerebral lesions (including final diagnoses of tuberculosis and metastases from lung cancer in two patients) and there were four other miscellaneous diagnoses. In 12 patients biopsies were performed at sites guided by PET abnormality (7 brain, 5 lymph nodes) confirming or excluding significant disease in 11.

Conclusion

¹⁸F-FDG PET/CT is particularly useful for differentiating between infection and PCNSL in HIV-infected patients with a cerebral lesion on MRI or CT. ¹⁸F-FDG PET/CT was also a helpful tool in the diagnostic work-up of patients with other HIV-related cerebral pathology. Additional advantages of ¹⁸F-FDG PET/CT are the abilities to assess abnormally increased glucose metabolism in the body and to identify potential sites for biopsy.