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.     

In vivo detection of prion amyloid plaques using [11C]BF-227 PET

Purpose

In vivo detection of pathological prion protein (PrP) in the brain is potentially useful for the diagnosis of transmissible spongiform encephalopathies (TSEs). However, there are no non-invasive ante-mortem means for detection of pathological PrP deposition in the brain. The purpose of this study is to evaluate the amyloid imaging tracer BF-227 with positron emission tomography (PET) for the non-invasive detection of PrP amyloid in the brain.

Methods

The binding ability of BF-227 to PrP amyloid was investigated using autoradiography and fluorescence microscopy. Five patients with TSEs, including three patients with Gerstmann-Sträussler-Scheinker disease (GSS) and two patients with sporadic Creutzfeldt-Jakob disease (CJD), underwent [¹¹C]BF-227 PET scans. Results were compared with data from 10 normal controls and 17 patients with Alzheimer’s disease (AD). The regional to pons standardized uptake value ratio was calculated as an index of BF-227 retention.

Results

Binding of BF-227 to PrP plaques was confirmed using brain samples from autopsy-confirmed GSS cases. In clinical PET study, significantly higher retention of BF-227 was detected in the cerebellum, thalamus and lateral temporal cortex of GSS patients compared to that in the corresponding tissues of normal controls. GSS patients also showed higher retention of BF-227 in the cerebellum, thalamus and medial temporal cortex compared to AD patients. In contrast, the two CJD patients showed no obvious retention of BF-227 in the brain.

Conclusion

Although [¹¹C]BF-227 is a non-specific imaging marker of cerebral amyloidosis, it is useful for in vivo detection of PrP plaques in the human brain in GSS, based on the regional distribution of the tracer. PET amyloid imaging might provide a means for both early diagnosis and non-invasive disease monitoring of certain forms of TSEs.     

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.     

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.     

[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.     

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.     

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.     

Early [<Superscript>18</Superscript>F]florbetaben and [<Superscript>11</Superscript>C]PiB PET images are a surrogate biomarker of neuronal injury in Alzheimer’s disease

Purpose

[¹⁸F]FDG is a commonly used neuronal injury biomarker for early and differential diagnosis of dementia. Typically, the blood supply to the brain is closely coupled to glucose consumption. Early uptake of the Aβ tracer [¹¹C]PiB on PET images is mainly determined by cerebral blood flow and shows a high correlation with [¹⁸F]FDG uptake. Uptake data for ¹⁸F-labelled Aβ PET tracers are, however, scarce. We investigated the value of early PET images using the novel Aβ tracer [¹⁸F]FBB in the diagnosis of Alzhimers disease (AD).

Methods

This retrospective analysis included 22 patients with MCI or dementia who underwent dual time-point PET imaging with either [¹¹C]PiB (11 patients) or [¹⁸F]FBB (11 patients) in routine clinical practice. Images were acquired 1 – 9 min after administration of both tracers and 40 – 70 min and 90 – 110 min after administration of [¹¹C]PiB and [¹⁸F]FBB, respectively. The patients also underwent [¹⁸F]FDG brain PET imaging. PET data were analysed visually and semiquantitatively. Associations between early Aβ tracer uptake and dementia as well as brain atrophy were investigated.

Results

Regional visual scores of early Aβ tracer and [¹⁸F]FDG PET images were significantly correlated (Spearman’s ρ?=?0.780, P?<?0.001). Global brain visual analysis revealed identical results between early Aβ tracer and [¹⁸F]FDG PET images. In a VOI-based analysis, the early Aβ tracer data correlated significantly with the [¹⁸F]FDG data (r?=?0.779, P?<?0.001), but there were no differences between [¹⁸F]FBB and [¹¹C]PiB. Cortical SUVRs in regions typically affected in AD on early Aβ tracer and [¹⁸F]FDG PET images were correlated with MMSE scores (ρ?=?0.458, P?=?0.032, and ρ?=?0.456, P?=?0.033, respectively). A voxel-wise group-based search for areas with relatively higher tracer uptake on early Aβ tracer PET images compared with [¹⁸F]FDG PET images revealed a small cluster in the midbrain/pons; no significant clusters were found for the opposite comparison.

Conclusion

Early [¹⁸F]FBB and [¹¹C]PiB PET brain images are similar to [¹⁸F]FDG PET images in AD patients, and these tracers could potentially be used as biomarkers in place of [¹⁸F]FDG. Thus, Aβ tracer PET imaging has the potential to provide biomarker information on AD pathology and neuronal injury. The potential of this approach for supporting the diagnosis of AD needs to be confirmed in prospective studies in larger cohorts.

     

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.     

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.

     

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.     

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.     

SPECT imaging of GABAA/benzodiazepine receptors and cerebral perfusion in mild cognitive impairment

Purpose

The involvement of neocortical and limbic GABA_A/benzodiazepine (BZD) receptors in Alzheimer’s disease (AD) is controversial and mainly reported in advanced stages. The status of these receptors in the very early stages of AD is unclear and has not been explored in vivo. Our aims were to investigate in vivo the integrity of cerebral cortical GABA_A/BZD receptors in subjects with amnestic mild cognitive impairment (MCI) and to compare possible receptor changes to those in cerebral perfusion.

Methods

[¹²³I]Iomazenil and [^99mTc]HMPAO SPECT images were acquired in 16 patients with amnestic MCI and in 14 normal elderly control subjects (only [¹²³I]iomazenil imaging in 5, only [^99mTc]HMPAO imaging in 4, and both [¹²³I]iomazenil and [^99mTc]HMPAO imaging in 5). Region of interest (ROI) analysis and voxel-based analysis were performed with cerebellar normalization.

Results

Neither ROI analysis nor voxel-based analysis showed significant [¹²³I]iomazenil binding changes in MCI patients compared to control subjects, either as a whole group or when considering only those patients with MCI that converted to AD within 2 years of clinical follow-up. In contrast, the ROI analysis revealed significant hypoperfusion of the precuneus and posterior cingulate cortex in the whole group of MCI patients and in MCI converters as compared to control subjects. Voxel-based analysis showed similar results.

Conclusion

These results indicate that in the very early stages of AD, neocortical and limbic neurons/synapses expressing GABA_A/BZD receptors are essentially preserved. They suggest that in MCI patients functional changes precede neuronal/synaptic loss in neocortical posterior regions and that [^99mTc]HMPAO rCBF imaging is more sensitive than [¹²³I]iomazenil GABA_A/BZD receptor imaging in detecting prodromal AD.     

Contrast between hypervascularized liver lesions and hepatic parenchyma: early dynamic PET versus contrast-enhanced CT

Objectives

To detect hypervascularized liver lesions, early dynamic (ED) ¹⁸F-FDG PET may be an alternative when contrast-enhanced (CE) imaging is infeasible. This retrospective pilot analysis compared contrast between such lesions and liver parenchyma, an important objective image quality variable, in ED PET versus CE CT.

Materials and methods

Twenty-eight hypervascularized liver lesions detected by CE CT [21 (75 %) hepatocellular carcinomas; mean (range) diameter 4.9 ± 3.5 (1–14) cm] in 20 patients were scanned with ED PET. Using regions of interest, maximum and mean lesional and parenchymal signals at baseline, arterial and venous phases were calculated for ED PET and CE CT.

Results

Lesional/parenchymal signal ratio was significantly higher (P < 0.005) with ED PET versus CE CT at the arterial phase and similar between the methods at the venous phase.

Conclusion

In liver imaging, ED PET generates greater lesional–parenchymal contrast during the arterial phase than does CE CT; these observations should be formally, prospectively evaluated.     

Normal variants of bowel FDG uptake in dual-time-point PET/CT imaging

Objective

To evaluate the normal variants of the physiological bowel 2-deoxy-2-[¹⁸F]fluoro-d-glucose (FDG) uptake in dual-time-point positron emission tomography/computed tomography (PET/CT).

Methods

We performed a retrospective review of 206 consecutive asymptomatic subjects who underwent whole-body FDG PET/CT for medical checkup in our institution. The criteria for exclusion of the subjects from this study were as follows: history of abdominal surgeries or endoscopic mucosal resection, history of any malignant tumors, symptoms of diarrhea or constipation, a positive fecal occult blood test, elevated serum carcinoembryonic antigen (CEA) level, and hyperglycemia (more than 110 mg/dl). A total of 39 subjects (32 males, 7 females, mean age 58.1 years old) were enrolled in this retrospective study. Two radiologists evaluated the dual-time-point FDG PET/CT images of these 39 subjects, retrospectively. FDG uptakes in 5 areas (small bowel (SB), cecum and ascending colon (AC), transverse colon (TC), descending colon (DC), and rectosigmoid colon (RS)) were scored visually in comparison with the activity in the liver (0 = no uptake, 1 = activity less than that in the liver, and 2 = activity equal to or greater than that in the liver) in the early and delayed image. The scores decided by two radiologists were averaged and this average score was defined as the bowel uptake score (BUS). For 34 areas with the BUS of 2 in either the early or delayed images, the maximum standardized uptake values (SUV_max) were measured for semiquantitative analysis. Wilcoxon’s signed rank test and paired t test were adopted for the statistical analyses.

Results

The average BUS in the early/delayed images was 1.19/1.17 (SB), 0.81/1.23 (AC), 0.10/0.35 (TC), 0.35/0.59 (DC), and 1.17/1.54 (RS), respectively. The average SUV_max of the 34 areas with a score of 2 was 3.11 in the early images and 3.76 in the delayed images. The scores in the AC, TC, DC and RS, and the SUV_max were significantly higher in the delayed images (p < 0.05).

Conclusions

Physiological FDG uptake in the colon increases significantly from the early to the delayed phase in dual-time-point PET/CT imaging, which should be carefully taken into consideration in the diagnosis of bowel diseases.     

Using PET with 18F-AV-45 (florbetapir) to quantify brain amyloid load in a clinical environment

Purpose

Positron emission tomography (PET) imaging of brain amyloid load has been suggested as a core biomarker for Alzheimer’s disease (AD). The aim of this study was to test the feasibility of using PET imaging with ¹⁸F-AV-45 (florbetapir) in a routine clinical environment to differentiate between patients with mild to moderate AD and mild cognitive impairment (MCI) from normal healthy controls (HC).

Methods

In this study, 46 subjects (20 men and 26 women, mean age of 69.0?±?7.6?years), including 13?with AD, 12 with MCI and 21 HC subjects, were enrolled from three academic memory clinics. PET images were acquired over a 10-min period 50?min after injection of florbetapir (mean ± SD of radioactivity injected, 259?±?57?MBq). PET images were assessed visually by two individuals blinded to any clinical information and quantitatively via the standard uptake value ratio (SUVr) in the specific regions of interest, which were defined in relation to the cerebellum as the reference region.

Results

The mean values of SUVr were higher in AD patients (median 1.20, Q1-Q3 1.16-1.30) than in HC subjects (median 1.05, Q1-Q3 1.04-1.08; p?=?0.0001) in the overall cortex and all cortical regions (precuneus, anterior and posterior cingulate, and frontal median, temporal, parietal and occipital cortex). The MCI subjects also showed a higher uptake of florbetapir in the posterior cingulate cortex (median 1.06, Q1-Q3 0.97-1.28) compared with HC subjects (median 0.95, Q1-Q3 0.82-1.02; p?=?0.03). Qualitative visual assessment of the PET scans showed a sensitivity of 84.6% (95% CI 0.55–0.98) and a specificity of 38.1% (95% CI 0.18–0.62) for discriminating AD patients from HC subjects; however, the quantitative assessment of the global cortex SUVr showed a sensitivity of 92.3% and specificity of 90.5% with a cut-off value of 1.122 (area under the curve 0.894).

Conclusion

These preliminary results suggest that PET with florbetapir is a safe and suitable biomarker for AD that can be used routinely in a clinical environment. However, the low specificity of the visual PET scan assessment could be improved by the use of specific training and automatic or semiautomatic quantification tools.     

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.     

Prediction of outcomes in MCI with 123I-IMP-CBF SPECT: a multicenter prospective cohort study

Objective

The multicenter prospective cohort study (Japan Cooperative SPECT Study on Assessment of Mild Impairment of Cognitive Function: J-COSMIC) aimed to examine the value of ¹²³I-N-isopropyl-4-iodoamphetamine cerebral blood flow (IMP-CBF) SPECT in regards to early diagnosis of Alzheimer’s disease (AD) in patients with mild cognitive impairment (MCI).

Methods

Three hundred and nineteen patients with amnestic MCI at 41 participating institutions each underwent clinical and neuropsychological examinations and ¹²³I-IMP-CBF SPECT at baseline. Subjects were followed up periodically for 3 years, and progression to dementia was evaluated. SPECT images were classified as AD/DLB (dementia with Lewy bodies) pattern and non-AD/DLB pattern by central image interpretation and automated region of interest (ROI) analysis, respectively. Logistic regression analyses were used to assess whether baseline ¹²³I-IMP-CBF SPECT was predictive of longitudinal clinical outcome.

Results

Ninety-nine of 216 amnestic MCI patients (excluding 3 cases with epilepsy (n = 2) or hydrocephalus (n = 1) and 100 cases with incomplete follow-up) converted to AD within the observation period. Central image interpretation and automated ROI analysis predicted conversion to AD with 56 and 58 % overall diagnostic accuracy (sensitivity, 76 and 81 %; specificity, 39 and 37 %), respectively. Multivariate logistic regression analysis identified SPECT as a predictor, which distinguished AD converters from non-converters. The odds ratio for a positive SPECT to predict conversion to AD with automated ROI analysis was 2.5 and combining SPECT data with gender and mini-mental state examination (MMSE) further improved classification (joint odds ratio 20.08).

Conclusions

¹²³I-IMP-CBF SPECT with both automated ROI analysis and central image interpretation was sensitive but relatively nonspecific for prediction of clinical outcome during the 3-year follow-up in individual amnestic MCI patients. A combination of statistically significant predictors, both SPECT with automated ROI analysis and neuropsychological evaluation, may increase predictive utility.     

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.

     

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.