[18F]Flutemetamol amyloid-beta PET imaging compared with [11C]PIB across the spectrum of Alzheimer’s disease

Purpose

The aim was to identify the amyloid beta (Aβ) deposition by positron emission tomography (PET) imaging with the ¹⁸F-labeled Pittsburgh compound B (PIB) derivative [¹⁸F]flutemetamol (FMM) across a spectrum of Alzheimer’s disease (AD) and to compare Aβ deposition between [¹⁸F]FMM and [¹¹C]PIB PET imaging.

Methods

The study included 36 patients with AD, 68 subjects with mild cognitive impairment (MCI), 41 older healthy controls (HC) (aged ≥56), 11 young HC (aged ≤45), and 10 transitional HC (aged 46–55). All 166 subjects underwent 30-min static [¹⁸F]FMM PET 85 min after injection, 60-min dynamic [¹¹C]PIB PET, and cognitive testing. [¹⁸F]FMM scans were assessed visually, and standardized uptake value ratios (SUVR) were defined quantitatively in regions of interest identified on coregistered MRI (cerebellar cortex as a reference region). The PIB distribution volume ratios (DVR) were determined in the same regions.

Results

Of 36 AD patients, 35 had positive scans, while 36 of 41 older HC subjects had negative scans. [¹⁸F]FMM scans had a sensitivity of 97.2 % and specificity of 85.3 % in distinguishing AD patients from older HC subjects, and a specificity of 100 % for young and transitional HC subjects. The [¹¹C]PIB scan had the same results. Interreader agreement was excellent (kappa score?=?0.81). The cortical FMM SUVR in AD patients was significantly greater than in older HC subjects (1.76?±?0.23 vs 1.30?±?0.26, p?<?0.01). Of the MCI patients, 68 had a bimodal distribution of SUVR, and 29 of them (42.6 %) had positive scans. Cortical FMM SUVR values were strongly correlated with PIB DVR (r?=?0.94, n?=?145, p?<?0.001).

Conclusion

[¹⁸F]FMM PET imaging detects Aβ deposition in patients along the continuum from normal cognitive status to dementia of AD and discriminates AD patients from HC subjects, similar to [¹¹C]PIB PET.     

Comparison of 11C-PiB and 18F-florbetaben for Aβ imaging in ageing and Alzheimer’s disease

Purpose

Amyloid imaging with ¹⁸F-labelled radiotracers will allow widespread use of this technique, facilitating research, diagnosis and therapeutic development for Alzheimer’s disease (AD). The purpose of this analysis was to compare data on cortical Aβ deposition in subjects who had undergone both ¹¹C-PiB (PiB) and ¹⁸F-florbetaben (FBB) PET imaging.

Methods

We identified ten healthy elderly controls (HC) and ten patients with AD who had undergone PET imaging after intravenous injection of 370?MBq of PiB and 300?MBq of FBB under separate research protocols. PiB and FBB images were coregistered so that placement of regions of interest was identical on both scans and standard uptake value ratios (SUVR) using the cerebellar cortex as reference region were calculated between 40 and 70?min and between 90 and 110?min after injection for PiB and FBB, respectively.

Results

Significantly higher SUVR values (p?r?=?0.97, p?d 3.3 for PiB and 3.0 for FBB).

Conclusion

FBB, while having a narrower dynamic range than PiB, clearly distinguished HC from AD patients, with a comparable effect size. FBB seems a suitable ¹⁸F radiotracer for imaging AD pathology in vivo.     

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.     

Comparison of dual-biomarker PIB-PET and dual-tracer PET in AD diagnosis

Objectives

To identify the optimal time window for capturing perfusion information from early ¹¹C-PIB imaging frames (perfusion PIB, ¹¹C-pPIB) and to compare the performance of ¹⁸F-FDG PET and "dual biomarker" ¹¹C-PIB PET [¹¹C-pPIB and amyloid PIB (¹¹C-aPIB)] for classification of AD, MCI and CN subjects.

Methods

Forty subjects (14 CN, 12 MCI and 14 AD patients) underwent ¹⁸F-FDG and ¹¹C-PIB PET studies. Pearson correlation between the ¹⁸F-FDG image and sum of early ¹¹C-PIB frames was maximised to identify the optimal time window for ¹¹C-pPIB. The classification power of imaging parameters was evaluated with a leave-one-out validation.

Results

A 7-min time window yielded the highest correlation between ¹⁸F-FDG and ¹¹C-pPIB. ¹¹C-pPIB and ¹⁸F-FDG images shared a similar radioactive distribution pattern. ¹⁸F-FDG performed better than ¹¹C-pPIB for the classification of both AD vs. CN and MCI vs. CN. ¹¹C-pPIB?+?¹¹C-aPIB and ¹⁸F-FDG?+?¹¹C-aPIB yielded the highest classification accuracy for the classification of AD vs. CN, and ¹⁸F-FDG?+?¹¹C-aPIB had the best classification performance for the classification of MCI vs. CN.

Conclusion

C-pPIB could serve as a useful biomarker of rCBF for measuring neural activity and improve the diagnostic power of PET for AD in conjunction with ¹¹C-aPIB. ¹⁸F-FDG and ¹¹C-PIB dual-tracer PET examination could better detect MCI.

Key Points

? Dual-tracer PET examination provides neurofunctional and neuropathological information for AD diagnosis. ? The identified optimal 11C-pPIB time frames had highest correlation with 18F-FDG. ? 11C-pPIB images shared a similar radioactive distribution pattern with 18F-FDG images. ? 11C-pPIB can provide neurofunctional information. ? Dual-tracer PET examination could better detect MCI.     

Insight on AV-45 binding in white and grey matter from histogram analysis: a study on early Alzheimer’s disease patients and healthy subjects

Purpose

AV-45 amyloid biomarker is known to show uptake in white matter in patients with Alzheimer’s disease (AD), but also in the healthy population. This binding, thought to be of a non-specific lipophilic nature, has not yet been investigated. The aim of this study was to determine the differential pattern of AV-45 binding in white matter in healthy and pathological populations.

Methods

We recruited 24 patients presenting with AD at an early stage and 17 matched, healthy subjects. We used an optimized positron emission tomography-magnetic resonance imaging (PET-MRI) registration method and an approach based on an intensity histogram using several indices. We compared the results of the intensity histogram analyses with a more canonical approach based on target-to-cerebellum Standard Uptake Value (SUVr) in white and grey matter using MANOVA and discriminant analyses. A cluster analysis on white and grey matter histograms was also performed.

Results

White matter histogram analysis revealed significant differences between AD and healthy subjects, which were not revealed by SUVr analysis. However, white matter histograms were not decisive to discriminate groups, and indices based on grey matter only showed better discriminative power than SUVr. The cluster analysis divided our sample into two clusters, showing different uptakes in grey, but also in white matter.

Conclusion

These results demonstrate that AV-45 binding in white matter conveys subtle information not detectable using the SUVr approach. Although it is not more efficient than standard SUVr in discriminating AD patients from healthy subjects, this information could reveal white matter modifications.     

[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.     

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.     

Education increases reserve against Alzheimer’s disease—evidence from structural MRI analysis

Introduction

The aim of this study was to determine whether years of schooling influences regional cortical thicknesses and volumes in Alzheimer’s disease (AD), mild cognitive impairment (MCI), and healthy age-matched controls.

Methods

Using an automated image analysis pipeline, 33 regional cortical thickness and 15 regional volumes measures from MRI images were determined in 121 subjects with MCI, 121 patients with AD, and 113 controls from AddNeuroMed study. Correlations with years of schooling were determined and more highly and less highly educated subjects compared, controlling for intracranial volume, age, gender, country of origin, cognitive status, and multiple testing.

Results

After controlling for confounding factors and multiple testing, in the control group, subjects with more education had larger regional cortical thickness in transverse temporal cortex, insula, and isthmus of cingulate cortex than subjects with less education. However, in the AD group, the subjects with more education had smaller regional cortical thickness in temporal gyrus, inferior and superior parietal gyri, and lateral occipital cortex than the subjects with less education. No significant difference was found in the MCI group.

Conclusion

Education may increase regional cortical thickness in healthy controls, leading to increased brain reserve, as well as helping AD patients to cope better with the effects of brain atrophy by increasing cognitive reserve.     

Comparison of different methods of spatial normalization of FDG-PET brain images in the voxel-wise analysis of MCI patients and controls

Objective

One of the most interesting clinical applications of 18F-FDG PET imaging in neurodegenerative pathologies is that of establishing the prognosis of patients with mild cognitive impairment (MCI), some of whom have a high risk of progressing to Alzheimer’s disease (AD). One method of analyzing these images is to perform statistical parametric mapping (SPM) analysis. Spatial normalization is a critical step in such an analysis. The purpose of this study was to assess the effect of using different methods of spatial normalization on the results of SPM analysis of 18F-FDG PET images by comparing patients with MCI and controls.

Methods

We evaluated the results of three spatial normalization methods in an SPM analysis by comparing patients diagnosed with MCI with a group of control subjects. We tested three methods of spatial normalization: MRI-DARTEL and MRI-SPM8, which combine structural and functional images, and FDG-SPM8, which is based on the functional images only.

Results

The results obtained with the three methods were consistent in terms of the main pattern of functional alterations detected; namely, a bilateral reduction in glucose metabolism in the frontal and parietal cortices in the patient group. However, MRI-SPM8 also revealed differences in the left temporal cortex, and MRI-DARTEL revealed further differences in the left temporal cortex, precuneus, and left posterior cingulate.

Conclusions

The results obtained with MRI-DARTEL were the most consistent with the pattern of changes in AD. When we compared our observations with those of previous reports, MRI-SPM8 and FDG-SPM8 seemed to show an incomplete pattern. Our results suggest that basing the spatial normalization method on functional images only can considerably impair the results of SPM analysis of 18F-FDG PET studies.     

Performance characteristics of amyloid PET with florbetapir F 18 in patients with alzheimer's disease and cognitively normal subjects

The objectives of this study were to examine the effective dose range and the test-retest reliability of florbetapir F 18 using, first, visual assessment by independent raters masked to clinical information and, second, semiautomated quantitative measures of cortical target area to cerebellum standardized uptake value ratios (SUVr) as primary outcome measures. Visual ratings of PET image quality and tracer retention or β-amyloid (Aβ) binding expressed as SUVrs were compared after intravenous administration of either 111 MBq (3 mCi) or 370 MBq (10 mCi) of florbetapir F 18 in patients with Alzheimer's disease (AD) (n = 9) and younger healthy controls (YHCs) (n = 11). In a separate set of subjects (AD, n = 10; YHCs, n = 10), test-retest reliability was evaluated by comparing intrasubject visual read ratings and SUVrs for 2 PET images acquired within 4 wk of each other. RESULTS: There were no meaningful differences between the 111-MBq (3-mCi) and 370-MBq (10-mCi) dose in the visual rating or SUVr. The difference in the visual quality across 111 and 370 MBq showed a trend toward lower image quality, but no statistical significance was achieved (t test; t(1) = -1.617, P = 0.12) in this relatively small sample of subjects. At both dose levels, visual ratings of amyloid burden identified 100% of AD subjects as Aβ-positive and 100% of YHCs as Aβ-negative. Mean intrasubject test-retest variability for cortical average SUVrs with the cerebellum as a reference over the 50- to 70-min period was 2.4% ± 1.41% for AD subjects and 1.5% ± 0.84% for controls. The overall SUVr test-retest correlation coefficient was 0.99. The overall κ-statistic for test-retest agreement for Aβ classification of the masked reads was 0.89 (95% confidence interval, 0.69-1.0). CONCLUSION: Florbetapir F 18 appears to have a wide effective dose range and a high test-retest reliability for both quantitative (SUVr) values and visual assessment of the ligand. These imaging performance properties provide important technical information on the use of florbetapir F 18 and PET to detect cerebral amyloid aggregates.     

Equal sensitivity of early and late scans after injection of FDG for the detection of Alzheimer pattern: an analysis of 3D PET data from J-ADNI, a multi-center study

Objective

To determine the optimal accumulation time for three-dimensional positron emission tomography (3D-PET) with ¹⁸F-2-fluoro-2-deoxy-d-glucose (¹⁸F-FDG) to detect the brain uptake pattern typical of Alzheimer’s disease (AD).

Methods

Patients with mild AD or amnestic mild cognitive impairment (MCI) and normal control subjects were recruited in the Japanese Alzheimer’s disease neuroimaging initiative and examined with a PET scan during the 30–60 min after FDG injection. Three independent blinded experts interpreted the 30- to 60-min sum images, and images of patients with AD and MCI presenting AD patterns and normal subjects presenting normal patterns were used in the analysis. Early-scan (ES) and late-scan (LS) images were obtained from the data acquired at 30–35 min and 55–60 min after the injection, respectively. Separate target regions of interest (ROI) for ES and LS were defined as areas of significant reductions in the posterior cingulate and parietotemporal lobe in both hemispheres from the results of an initial cohort with 21 patients (AD 16, MCI 5) and 19 controls. A subsequent sample of 36 (AD 9, MCI 27) patients and 38 controls were used to compare the diagnostic capability of ES and LS using Z scores within the target ROI in individual statistical parametric mapping analysis.

Results

Compared to LS, ES showed lower activity in the frontal lobes and higher activity in the venous sinus than LS; however, the diagnostic capability of ES and LS did not significantly differ (sensitivity 0.97 and 0.97, specificity 0.82 and 0.84, area under the receiver-operating characteristic curve 0.96 and 0.97, respectively).

Conclusions

For a qualitative diagnosis of the AD pattern in 3D FDG-PET, results of ES were equivalent to those of LS. ES may be an option to shorten the entire PET procedure time, particularly in diagnosing early stages of AD.     

Volume changes in Alzheimer’s disease and mild cognitive impairment: cognitive associations

Objective

To assess the relationship between MRI-derived changes in whole-brain and ventricular volume with change in cognitive scores in Alzheimer’s disease (AD), mild cognitive impairment (MCI) and control subjects.

Material and methods

In total 131 control, 231 MCI and 99 AD subjects from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) cohort with T1-weighted volumetric MRIs from baseline and 12-month follow-up were used to derive volume changes. Mini mental state examination (MMSE), Alzheimer’s disease assessment scale (ADAS)-cog and trails test changes were calculated over the same period.

Results

Brain atrophy rates and ventricular enlargement differed between subject groups (p?<?0.0005) and in MCI and AD were associated with MMSE changes. Both measures were additionally associated with ADAS-cog and trails-B in MCI patients, and ventricular expansion was associated with ADAS-cog in AD patients. Brain atrophy (p?<?0.0005) and ventricular expansion rates (p?=?0.001) were higher in MCI subjects who progressed to AD within 12 months of follow-up compared with MCI subjects who remained stable. MCI subjects who progressed to AD within 12 months had similar atrophy rates to AD subjects.

Conclusion

Whole-brain atrophy rates and ventricular enlargement differed between patient groups and healthy controls, and tracked disease progression and psychological decline, demonstrating their relevance as biomarkers.     

Imaging characteristic of dual-phase <Superscript>18</Superscript>F-florbetapir (AV-45/Amyvid) PET for the concomitant detection of perfusion deficits and beta-amyloid deposition in Alzheimer’s disease and mild cognitive impairment

Purpose

We investigated dual-phase ¹⁸F-florbetapir (AV-45/Amyvid) PET imaging for the concomitant detection of brain perfusion deficits and beta-amyloid deposition in patients with Alzheimer’s disease (AD) and amnestic mild cognitive impairment (MCI), and in cognitively healthy controls (HCs).

Methods

A total of 82 subjects (24 AD patients, 44 MCI patients and 14 HCs) underwent both dual-phase ¹⁸F-AV-45 PET and MRI imaging. Dual-phase dynamic PET imaging consisted of (1) five 1-min scans obtained 1?–?6 min after tracer injection (perfusion ¹⁸F-AV-45 imaging, pAV-45), and (2) ten 1-min scans obtained 50?–?60 min after tracer injection (amyloid ¹⁸F-AV-45 imaging). Amyloid-negative MCI/AD patients were excluded. Volume of interest analysis and statistical parametric mapping of pAV-45 and ¹⁸F-AV-45 images were performed to investigate the perfusion deficits and the beta-amyloid burden in the three study groups. The associations between Mini-Mental State Examination (MMSE) scores and global perfusion deficits and amyloid deposition were investigated with linear and segmental linear correlation analyses.

Results

HCs generally had normal pAV-45 findings, whereas perfusion deficits were evident in the hippocampus, and temporal, parietal and middle frontal cortices in both MCI and AD patients. The motor-sensory cortex was relatively preserved. MMSE scores in the entire study cohort were significantly associated with the degree of perfusion impairment as assessed by pAV-45 imaging (r?=?0.5156, P?<?0.0001). ¹⁸F-AV-45 uptake was significantly higher in AD patients than in the two other study groups. However, the correlation between MMSE scores and ¹⁸F-AV-45 uptake in MCI patients was more of a binary phenomenon and began in MCI patients with MMSE score 23.14 when ¹⁸F-AV-45 uptake was higher and MMSE score lower than in patients with early MCI. Amyloid deposition started in the precuneus and the frontal and temporal regions in early MCI, ultimately reaching the maximum burden in advanced MCI.

Conclusion

Our results indicate that brain perfusion deficits and beta-amyloid deposition in AD follow different trajectories that can be successfully traced using dual-phase ¹⁸F-AV-45 PET imaging.

     

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 comparison of CT- and MR-based attenuation correction in neurological PET

Purpose

To assess the quantitative accuracy of current MR attenuation correction (AC) methods in neurological PET, in comparison to data derived using CT AC.

Methods

This retrospective study included 25 patients who were referred for a neurological FDG PET examination and were imaged sequentially by PET/CT and simultaneous PET/MR. Differences between activity concentrations derived using Dixon and ultrashort echo time (UTE) MR-based AC and those derived from CT AC were compared using volume of interest and voxel-based approaches. The same comparisons were also made using PET data represented as SUV ratios (SUVr) using grey matter cerebellum as the reference region.

Results

Extensive and statistically significant regional underestimations of activity concentrations were found with both Dixon AC (P?<?0.001) and UTE AC (P?<?0.001) in all brain regions when compared to CT AC. The greatest differences were found in the cortical grey matter (Dixon AC 21.3 %, UTE AC 15.7 %) and cerebellum (Dixon AC 19.8 %, UTE AC 17.3 %). The underestimation using UTE AC was significantly less than with Dixon AC (P?<?0.001) in most regions. Voxel-based comparisons showed that all cortical grey matter and cerebellum uptake was underestimated with Dixon AC compared to CT AC. Using UTE AC the extent and significance of these differences were reduced. Inaccuracies in cerebellar activity concentrations led to a mixture of predominantly cortical underestimation and subcortical overestimation in SUVr PET data for both MR AC methodologies.

Conclusion

MR-based AC results in significant underestimation of activity concentrations throughout the brain, which makes the use of SUVr data difficult. These effects limit the quantitative accuracy of neurological PET/MR.     

Decreased cerebral ��4��2* nicotinic acetylcholine receptor availability in patients with mild cognitive impairment and Alzheimer��s disease assessed with positron emission tomography

Purpose

Postmortem studies indicate a loss of nicotinic acetylcholine receptor (nAChRs) in Alzheimer??s disease (AD). In order to establish whether these changes in the cholinergic system occur at an early stage of AD, we carried out positron emission tomography (PET) with a specific radioligand for the ??4??2* nicotinic acetylcholine receptor (??4??2* nAChR) in patients with mild to moderate AD and in patients with amnestic mild cognitive impairment (MCI), who have a high risk to progress to AD.

Methods

Nine patients with moderate AD, eight patients with MCI and seven age-matched healthy controls underwent 2-[¹⁸F]fluoro-3-(2(S)-azetidinylmethoxy)pyridine (2-[¹⁸F]FA-85380) PET. After coregistration with individual magnetic resonance imaging the binding potential (BP_ND) of 2-[¹⁸F]FA-85380 was calculated using either the corpus callosum or the cerebellum as reference regions. PET data were analysed by region of interest analysis and by voxel-based analysis.

Results

Both patients with AD and MCI showed a significant reduction in 2-[¹⁸F]FA-85380 BP_ND in typical AD-affected brain regions. Thereby, the corpus callosum was identified as the most suitable reference region. The 2-[¹⁸F]FA-85380 BP_ND correlated with the severity of cognitive impairment. Only MCI patients that converted to AD in the later course (n?=?5) had a reduction in 2-[¹⁸F]FA-85380 BP_ND.

Conclusion

2-[¹⁸F]FA-85380 PET appears to be a sensitive and feasible tool for the detection of a reduction in ??4??2* nAChRs which seems to be an early event in AD. In addition, 2-[¹⁸F]FA-85380 PET might give prognostic information about a conversion from MCI to AD.     

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.     

Early identification of MCI converting to AD: a FDG PET study

Purpose

Mild cognitive impairment (MCI) is a transitional pathological stage between normal ageing (NA) and Alzheimer’s disease (AD). Although subjects with MCI show a decline at different rates, some individuals remain stable or even show an improvement in their cognitive level after some years. We assessed the accuracy of FDG PET in discriminating MCI patients who converted to AD from those who did not.

Methods

FDG PET was performed in 42 NA subjects, 27 MCI patients who had not converted to AD at 5 years (nc-MCI; mean follow-up time 7.5 ± 1.5 years), and 95 MCI patients who converted to AD within 5 years (MCI-AD; mean conversion time 1.8 ± 1.1 years). Relative FDG uptake values in 26 meta-volumes of interest were submitted to ANCOVA and support vector machine analyses to evaluate regional differences and discrimination accuracy.

Results

The MCI-AD group showed significantly lower FDG uptake values in the temporoparietal cortex than the other two groups. FDG uptake values in the nc-MCI group were similar to those in the NA group. Support vector machine analysis discriminated nc-MCI from MCI-AD patients with an accuracy of 89% (AUC 0.91), correctly detecting 93% of the nc-MCI patients.

Conclusion

In MCI patients not converting to AD within a minimum follow-up time of 5 years and MCI patients converting within 5 years, baseline FDG PET and volume-based analysis identified those who converted with an accuracy of 89%. However, further analysis is needed in patients with amnestic MCI who convert to a dementia other than AD.

     

Does posterior cingulate hypometabolism result from disconnection or local pathology across preclinical and clinical stages of Alzheimer’s disease?

Purpose

Posterior cingulate cortex (PCC) hypometabolism as measured by FDG PET is an indicator of Alzheimer’s disease (AD) in prodromal stages, such as in mild cognitive impairment (MCI), and has been found to be closely associated with hippocampus atrophy in AD dementia. We studied the effects of local and remote atrophy and of local amyloid load on the PCC metabolic signal in patients with different preclinical and clinical stages of AD.

Methods

We determined the volume of the hippocampus and PCC grey matter based on volumetric MRI scans, PCC amyloid load based on AV45 PET, and PCC metabolism based on FDG PET in 667 subjects participating in the Alzheimer’s Disease Neuroimaging Initiative spanning the range from cognitively normal ageing through prodromal AD to AD dementia.

Results

In cognitively normal individuals and those with early MCI, PCC hypometabolism was exclusively associated with hippocampus atrophy, whereas in subjects with late MCI it was associated with both local and remote effects of atrophy as well as local amyloid load. In subjects with AD dementia, PCC hypometabolism was exclusively related to local atrophy.

Conclusion

Our findings suggest that the effects of remote pathology on PCC hypometabolism decrease and the effects of local pathology increase from preclinical to clinical stages of AD, consistent with a progressive disconnection of the PCC from downstream cortical and subcortical brain regions.

     

Automated analysis of FDG PET as a tool for single-subject probabilistic prediction and detection of Alzheimer’s disease dementia

Purpose

To introduce, evaluate and validate a voxel-based analysis method of ¹⁸F-FDG PET imaging for determining the probability of Alzheimer’s disease (AD) in a particular individual.

Methods

The subject groups for model derivation comprised 80 healthy subjects (HS), 36 patients with mild cognitive impairment (MCI) who converted to AD dementia within 18 months, 85 non-converter MCI patients who did not convert within 24 months, and 67 AD dementia patients with baseline FDG PET scan were recruited from the AD Neuroimaging Initiative (ADNI) database. Additionally, baseline FDG PET scans from 20 HS, 27 MCI and 21 AD dementia patients from our institutional cohort were included for model validation. The analysis technique was designed on the basis of the AD-related hypometabolic convergence index adapted for our laboratory-specific context (AD-PET index), and combined in a multivariable model with age and gender for AD dementia detection (AD score). A logistic regression analysis of different cortical PET indexes and clinical variables was applied to search for relevant predictive factors to include in the multivariable model for the prediction of MCI conversion to AD dementia (AD-Conv score). The resultant scores were stratified into sixtiles for probabilistic diagnosis.

Results

The area under the receiver operating characteristic curve (AUC) for the AD score detecting AD dementia in the ADNI database was 0.879, and the observed probability of AD dementia in the six defined groups ranged from 8 % to 100 % in a monotonic trend. For predicting MCI conversion to AD dementia, only the posterior cingulate index, Mini-Mental State Examination (MMSE) score and apolipoprotein E4 genotype (ApoE4) exhibited significant independent effects in the univariable and multivariable models. When only the latter two clinical variables were included in the model, the AUC was 0.742 (95 % CI 0.646 – 0.838), but this increased to 0.804 (95 % CI 0.714 – 0.894, bootstrap p?=?0.027) with the addition of the posterior cingulate index (AD-Conv score). Baseline clinical diagnosis of MCI showed 29.7 % of converters after 18 months. The observed probability of conversion in relation to baseline AD-Conv score was 75 % in the high probability group (sixtile 6), 34 % in the medium probability group (merged sixtiles 4 and 5), 20 % in the low probability group (sixtile 3) and 7.5 % in the very low probability group (merged sixtiles 1 and 2). In the validation population, the AD score reached an AUC of 0.948 (95 % CI 0.625 – 0.969) and the AD-Conv score reached 0.968 (95 % CI 0.908 – 1.000), with AD patients and MCI converters included in the highest probability categories.

Conclusion

Posterior cingulate hypometabolism, when combined in a multivariable model with age and gender as well as MMSE score and ApoE4 data, improved the determination of the likelihood of patients with MCI converting to AD dementia compared with clinical variables alone. The probabilistic model described here provides a new tool that may aid in the clinical diagnosis of AD and MCI conversion.