Three-dimensional stereotactic surface projection of brain perfusion SPECT improves diagnosis of Alzheimer’s disease

OBJECTIVES: Alzheimer's disease (AD) is diagnosed by either inspection of the brain perfusion SPECT, or three-dimensional stereotactic surface display (3D-SSP). The purpose was to compare diagnostic performances of these methods. METHODS: Sixteen nuclear medicine physicians independently interpreted 99mTc-ECD SPECT in one session and SPECT with 3D-SSP in another session without clinical information for 50 studies of AD patients and 40 studies of healthy volunteers. Probabilities of AD were reported according to a subjective scale from 0% (normal) to 100% (definite AD). Receiver operating characteristics curves were generated to calculate areas under the ROC curves (Az's) for the inspection as well as for an automated diagnosis based on a mean Z value in the bilateral posterior cingulate gyri in a 3D-SSP template. RESULTS: Mean Az for visual interpretation of SPECT alone (0.679 +/- 0.058) was significantly smaller than that for visual interpretation of both SPECT and 3D-SSP (0.778 +/- 0.060). Az for the automated diagnosis (0.883 +/- 0.037) was significantly greater than that for both modes of visual interpretation. CONCLUSIONS: 3D-SSP enhanced performance of the nuclear medicine physicians inspecting SPECT. Performance of the automated diagnosis exceeded that of the physicians inspecting SPECT with and without 3D-SSP.     

Distinct patterns of medial temporal impairment in degenerative dementia: a brain SPECT perfusion study in Alzheimer’s disease and frontotemporal dementia

Purpose

Medial temporal impairment can be detected clinically and by morphological imaging during Alzheimer’s disease (AD), but the existence of a functional impairment in this area seems to be less well established. Yet such functional impairment is classically found in other degenerative cortical dementias, such as the frontal variant of frontotemporal dementia (fv-FTD). The aim of this study was to characterize and compare brain SPECT perfusion of the medial temporal lobe in AD and fv-FTD.

Methods

Voxel-based comparisons were performed using SPM8 between cerebral SPECT images from 85 AD patients, 25 fv-FTD patients and 12 healthy controls at the whole-brain level and the medial temporal lobe level using a region of interest approach (p?<?0.001, corrected for the cluster).

Results

In the free and cued selective reminding test, used to evaluate medial temporal memory function, AD patients had significantly lower scores than the fv-FTD patients (p?<?0.005). AD and fv-FTD patients showed hypoperfused medial temporal structures in comparison to normal controls. However, fv-FTD patients had more pronounced hypoperfusion in this area, with a different topography, more anterior and more parahippocampal.

Conclusion

These results show that medial temporal hypoperfusion can be detected in degenerative dementias by SPECT. Paradoxically, the hypoperfusion is more severe in fv-FTD than in AD patients, even though the mnesic profile of AD is more altered, suggesting the existence of inefficient compensatory mechanisms.     

Diagnostic performance of Tc-99m HMPAO SPECT for early and late onset Alzheimer’s disease: a clinical evaluation of linearization correction

Objective  This study examined the influence of linearization correction (LC) on brain perfusion single-photon emission computed tomography (SPECT) for the diagnosis of Alzheimer’s disease (AD). Methods  The early onset group (<65 years old) consisted of 10 patients with AD, and the late onset group (≥65 years old) of 13 patients with AD. Age-matched controls included seven younger and seven older normal volunteers. Tc-99m hexamethyl propyleneamine oxine (HMPAO) SPECT images were reconstructed with or without LC [LC (+) or LC (−)] and a statistical analysis was performed using a three-dimensional stereotactic surface projection (3D-SSP). In addition, a fully automatic diagnostic system was developed, which calculated the proportion of the number of abnormal pixels in the superior and inferior parietal lobule, as well as in the precuneus and posterior cingulate gyrus. Results  The areas under the receiver-operating characteristic curve (AUCs) of the early onset group for conventional axial SPECT images, SPECT + 3D-SSP images and the fully automatic diagnostic system were 0.71, 0.88, and 0.92 in LC (−) and 0.67, 0.85, and 0.91 in LC (+), respectively. The AUCs of the late onset group were 0.50, 0.61, and 0.79 in LC (−) and 0.49, 0.67, and 0.85 in LC (+), respectively. Conclusion  LC on Tc-99m HMPAO SPECT did not significantly influence the diagnostic performance for differentiating between AD and normal controls in either early or late onset AD. Further examination with individuals suffering from very mild dementia is, therefore, expected to elucidate the effect of LC on minimally hypoperfused areas.     

Effects of partial volume correction on discrimination between very early Alzheimer’s dementia and controls using brain perfusion SPECT

We assessed the accuracy of brain perfusion single-photon emission computed tomography (SPECT) in discriminating between patients with probable Alzheimers disease (AD) at the very early stage and age-matched controls before and after partial volume correction (PVC). Three-dimensional MRI was used for PVC. We randomly divided the subjects into two groups. The first group, comprising 30 patients and 30 healthy volunteers, was used to identify the brain area with the most significant decrease in regional cerebral blood flow (rCBF) in patients compared with normal controls based on the voxel-based analysis of a group comparison. The second group, comprising 31 patients and 31 healthy volunteers, was used to study the improvement in diagnostic accuracy provided by PVC. A Z score map for a SPECT image of a subject was obtained by comparison with mean and standard deviation SPECT images of the healthy volunteers for each voxel after anatomical standardization and voxel normalization to global mean or cerebellar values using the following equation: Z score = ([control mean]–[individual value] )/(control SD). Analysis of receiver operating characteristics curves for a Z score discriminating AD and controls in the posterior cingulate gyrus, where a significant decrease in rCBF was identified in the first group, showed that the PVC significantly enhanced the accuracy of the SPECT diagnosis of very early AD from 73.9% to 83.7% with global mean normalization. The PVC mildly enhanced the accuracy from 73.1% to 76.3% with cerebellar normalization. This result suggests that early diagnosis of AD requires PVC in a SPECT study.     

Brain perfusion SPECT correlates with CSF biomarkers in Alzheimer’s disease

Purpose  

Our aim was to study the correlations between cerebrospinal fluid (CSF) biomarker levels such as β-amyloid 42 (Aβ₄₂), total and phosphorylated tau protein (T-tau and P-tau) and brain perfusion SPECT in Alzheimer’s disease (AD) using a voxel-based methodology.     

The effect of education on rCBF changes in Alzheimer’s disease: a longitudinal SPECT study

Purpose  To determine the relationship of differing levels of education on regional cerebral blood flow (rCBF) in patients with Alzheimer’s disease (AD). Methods  Fifty-three patients with AD followed-up for an average of 36 months were divided into the high-educated group (HE, ≥12 years of schooling) and low-educated group (LE, <12 years of schooling). The cognitive and functional impairment was assessed using the Mini-Mental State Examination (MMSE) and the Functional Assessment Staging (FAST), respectively. Initial and follow-up rCBF were assessed using SPECT with N-isopropyl-p-[¹²³I]-iodoamphetamine and the SPECT data were analyzed by 3D-stereotactic surface projections. Results  At initial evaluation, the HE group had greater rCBF deficits in the parietotemporal regions than did the LE group, even though both groups had comparable MMSE and FAST scores. When compared with initial SPECT, follow-up SPECT showed a significant rCBF reduction in widespread regions, including the frontal, parietal, temporal, and limbic lobes of the HE group, while it a significant rCBF reduction in scattered and small regions of the parietotemporal, cingulate, and occipital areas of the LE group, as the HE group had faster cognitive and functional decline than the LE group. Conclusion  The HE group showed lower rCBF at initial SPECT than the LE group, suggesting more advanced AD pathology. As a result, the HE group demonstrated a more extensive and severe reduction of rCBF on follow-up SPECT in association with faster cognitive and functional decline than the LE group. Our SPECT study provides stronger support for the cognitive reserve effects of education in AD.     

Diagnosis of Alzheimer’s disease using brain perfusion SPECT and MR imaging: which modality achieves better diagnostic accuracy?

Purpose The purpose of this study was to compare the accuracy of MR imaging and brain perfusion single-photon emission tomography (SPECT) in diagnosing Alzheimers disease (AD).Methods The transaxial section display of brain perfusion SPECT, three-dimensional stereotactic surface projection (3D-SSP) SPECT image sets, thin-section MR imaging of the hippocampus and perfusion MR imaging were evaluated in 66 subjects comprising 35 AD patients and 31 subjects without AD. SPECT and MR imaging were visually interpreted by two experts and two novices, and the diagnostic ability of each modality was evaluated by receiver operating characteristic (ROC) analysis.Results In the experts interpretations, there was no significant difference in the area under the ROC curve ( A_z) between 3D-SSP and thin-section MR imaging, whereas the A_z of transaxial SPECT display was significantly lower than that of 3D-SSP (3D-SSP: 0.97, thin-section MR imaging: 0.96, transaxial SPECT: 0.91), and the A_z of perfusion MR imaging was lowest (0.63). The sensitivity and specificity of each modality were, respectively, 80.0% and 96.8% for 3D-SSP, 77.1% and 96.8% for thin-section MR imaging, 60.0% and 93.5% for transaxial SPECT display and 34.3% and 100% for perfusion MR imaging. In the novices interpretations, the A_z, sensitivity and specificity of 3D-SSP were superior to those of thin-section MR imaging.Conclusion Thin-section hippocampal MR imaging and 3D-SSP image sets had potentially equivalent value for the diagnosis of AD, and they were superior to transaxial SPECT display and perfusion MR imaging. For avoidance of the effect of interpreters experience on image evaluation, 3D-SSP appears to be optimal.     

Effect of subthalamic nucleus deep brain stimulation on balance in Parkinson’s disease: A static posturographic analysis

BackgroundThe effect of subthalamic deep brain stimulation on balance in Parkinson’s disease remains unclear.ObjectiveTo evaluate the effect of subthalamic nucleus stimulation on balance in Parkinson’s disease using posturography.Methods16 patients (9 women) who underwent subthalamic deep brain stimulation [mean age 59.6 years (46–70); mean disease duration 15.6 years (7–25); mean duration of subthalamic stimulation 32.1 months (3.0–69.6)] and 13 healthy age-matched controls were evaluated using a static posturography analysis. Patients were assessed under four conditions: 1) off medication/off stimulation; 2) off medication/on stimulation; 3) on medication/off stimulation and 4) on medication/on stimulation in ten experimental paradigms, some reproducing common situations of daily living. The displacement of the centre of pressure was analyzed using 14 posturographic parameters. The Mann-Whitney test was used to compare patients with controls. The Wilcoxon signed rank test was used to compare patients under different clinical conditions.ResultsPatients off medication/off stimulation showed larger and more rapid displacements of the centre of pressure than controls in most paradigms (p < 0.05), particularly when performing a dual task. Subthalamic stimulation alone reduced the lateral excursion and anterior-posterior velocity of the centre of pressure in quite stance paradigms (p < 0.05). Subthalamic stimulation combined with antiparkinsonian medication did not induce statistically significant changes in posturagraphic measures in any experimental paradigm.ConclusionsAlthough subthalamic stimulation alone may induce some positive effect on balance, subthalamic stimulation in addition to antiparkinsonian medication, which is the usual treatment in clinical practice, did not modify balance as assessed by static posturography in patients with Parkinson’s disease.     

Regional cerebral perfusion in patients with Alzheimer’s disease and mild cognitive impairment: effect of APOE Epsilon4 allele

Introduction

The objective of this study was to evaluate the effect of apolipoprotein E (APOE) epsilon 4 allele on regional cerebral perfusion (rCBF) changes using arterial spin labeling (ASL) magnetic resonance imaging (MRI) in subjects who are carriers or noncarriers of this risk factor for Alzheimer disease (AD).

Methods

Twenty-five subjects with AD, 25 with amnestic mild cognitive impairment (MCI) and 25 cognitively normal (CN) subjects underwent isotropic volumetric T1-weighted imaging and pulsed ASL MRI. All subjects were divided into carrier or noncarriers of the epsilon4 allele. Voxel-based statistical analyses were performed among groups on rCBF by ANOVA tests. In each subject group, we also evaluated the rCBF change between carrier and noncarrier groups.

Results

rCBF was significantly reduced in AD subjects compared to other subjects. In CN and AD subjects, rCBF in the carrier group was significantly reduced in several areas of the brain compared with that of the noncarrier group. In the carrier group, rCBF was significantly increased in the right parahippocampal gyrus, the bilateral cingulate gyri and the right posterior cingulate on the MCI group in addition to the right superior frontal gyrus in the AD group.

Conclusion

rCBF in the CN and AD groups were significantly reduced in the subjects with the carriers of the epsilon4 allele, which is a risk factor for Alzheimer’s disease. In addition, rCBF in the MCI group was significantly increased in subjects who were carriers. Therefore, rCBF can be used as a biomarker to show disease progression in areas of the brain of MCI subjects.     

Quantitation,regional vulnerability,and kinetic modeling of brain glucose metabolism in mild Alzheimer’s disease

Purpose To examine CMRglc measures and corresponding glucose transport (K ₁ and k ₂) and phosphorylation (k ₃) rates in the medial temporal lobe (MTL, comprising the hippocampus and amygdala) and posterior cingulate cortex (PCC) in mild Alzheimer’s disease (AD). Methods Dynamic FDG PET with arterial blood sampling was performed in seven mild AD patients (age 68 ± 8 years, four females, median MMSE 23) and six normal (NL) elderly (age 69 ± 9 years, three females, median MMSE 30). Absolute CMRglc (μmol/100 g/min) was calculated from MRI-defined regions of interest using multiparametric analysis with individually fitted kinetic rate constants, Gjedde-Patlak plot, and Sokoloff’s autoradiographic method with population-based rate constants. Relative ROI/pons CMRglc (unitless) was also examined. Results With all methods, AD patients showed significant CMRglc reductions in the hippocampus and PCC, and a trend towards reduced parietotemporal CMRglc, as compared with NL. Significant k ₃ reductions were found in the hippocampus, PCC and amygdala. K ₁ reductions were restricted to the hippocampus. Relative CMRglc had the largest effect sizes in separating AD from NL. However, the magnitude of CMRglc reductions was 1.2- to 1.9-fold greater with absolute than with relative measures. Conclusion CMRglc reductions are most prominent in the MTL and PCC in mild AD, as detected with both absolute and relative CMRglc measures. Results are discussed in terms of clinical and pharmaceutical applicability.     

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.     

The importance of appropriate partial volume correction for PET quantification in Alzheimer’s disease

Purpose  

Alzheimer’s disease (AD) is the most common form of dementia. Clinically, it is characterized by progressive cognitive and functional impairment with structural hallmarks of cortical atrophy and ventricular expansion. Amyloid plaque aggregation is also known to occur in AD subjects. In-vivo imaging of amyloid plaques is now possible with positron emission tomography (PET) radioligands. PET imaging suffers from a degrading phenomenon known as the partial volume effect (PVE). The quantitative accuracy of PET images is reduced by PVEs primarily due to the limited spatial resolution of the scanner. The degree of PVE is influenced by structure size, with smaller structures tending to suffer from more severe PVEs such as atrophied grey matter regions. The aims of this paper were to investigate the effect of partial volume correction (PVC) on the quantification of amyloid PET and to highlight the importance of selecting an appropriate PVC technique.     

Comparison of the diagnostic performance of FDG-PET and VBM-MRI in very mild Alzheimer’s disease

Purpose The aim of this study was to compare the diagnostic performance of ¹⁸F-fluorodeoxyglucose (FDG) positron emission tomography (PET) and voxel-based morphometry (VBM) on magnetic resonance imaging (MRI) in the same group of patients with very mild Alzheimer’s disease (AD). Methods Thirty patients with very mild AD (age 67.0±5.8 years; MMSE score 25.5±1.2, range 24–28), 32 patients with mild AD (age 67.0±4.5 years, MMSE score 22.1±0.8, range 21–23) and 60 age- and sex-matched normal volunteers underwent both FDG-PET and three-dimensional spoiled gradient echo MRI. Statistical parametric mapping was used to conduct voxel by voxel analysis and Z score mapping. First, the region of interest (ROI) maps of significant reductions in glucose metabolism and grey matter density in the mild AD patients were defined. Secondly, analysis of receiver operating characteristic (ROC) curves for Z scores in the ROI maps discriminating very mild AD patients and normal controls was performed. Results In mild AD patients, FDG-PET indicated significant reductions in glucose metabolism in the bilateral posterior cingulate gyri and the right parietotemporal area, while VBM analysis showed a significant decrease in grey matter volume density in the bilateral amygdala/hippocampus complex, compared with the normal control group. ROC analysis showed that in very mild AD patients the accuracy of FDG-PET diagnosis was 89% and that of VBM-MRI diagnosis was 83%. The accuracy of the combination of FDG-PET and VBM-MRI diagnosis was 94%. Conclusion In very mild AD, both FDG-PET and VBM-MRI had high accuracy for diagnosis, but FDG-PET showed slightly higher accuracy than VBM-MRI. Combination of the two techniques will yield a higher diagnostic accuracy in very mild AD by making full use of functional and morphological images.     

Amyloid and tau signatures of brain metabolic decline in preclinical Alzheimer’s disease

Purpose

We aimed to determine the amyloid (Aβ) and tau biomarker levels associated with imminent Alzheimer’s disease (AD) - related metabolic decline in cognitively normal individuals.

Methods

A threshold analysis was performed in 120 cognitively normal elderly individuals by modelling 2-year declines in brain glucose metabolism measured with [¹⁸F]fluorodeoxyglucose ([¹⁸F]FDG) as a function of [¹⁸F]florbetapir Aβ positron emission tomography (PET) and cerebrospinal fluid phosphorylated tau biomarker thresholds. Additionally, using a novel voxel-wise analytical framework, we determined the sample sizes needed to test an estimated 25% drugeffect with 80% of power on changes in FDG uptake over 2 years at every brain voxel.

Results

The combination of [¹⁸F]florbetapir standardized uptake value ratios and phosphorylated-tau levels more than one standard deviation higher than their respective thresholds for biomarker abnormality was the best predictor of metabolic decline in individuals with preclinical AD. We also found that a clinical trial using these thresholds would require as few as 100 individuals to test a 25% drug effect on AD-related metabolic decline over 2 years.

Conclusions

These results highlight the new concept that combined Aβ and tau thresholds can predict imminent neurodegeneration as an alternative framework with a high statistical power for testing the effect of disease-modifying therapies on [¹⁸F]FDG uptake decline over a typical 2-year clinical trial period in individuals with preclinical AD.

     

Comparative value of brain perfusion SPECT and [123I]MIBG myocardial scintigraphy in distinguishing between dementia with Lewy bodies and Alzheimer’s disease

Purpose Both decreased occipital perfusion on brain single-photon emission computed tomography (SPECT) and reduction in cardiac ¹²³I-metaiodobenzylguanidine (MIBG) uptake are characteristic features of dementia with Lewy bodies (DLB), and potentially support the clinical diagnosis of DLB. The aim of this study was to compare the diagnostic value of these two methods for differentiation of DLB from Alzheimers disease (AD).Methods The study population comprised 19 patients with probable DLB and 39 patients with probable AD who underwent both SPECT with N-isopropyl-p-[¹²³I]iodoamphetamine and MIBG myocardial scintigraphy. Objective and quantitative measurement of perfusion in the medial occipital lobe, including the cuneus and lingual gyrus, was performed by the use of three-dimensional stereotactic surface projections.Results Medial occipital perfusion was significantly decreased in the DLB group compared with the AD group. The mean heart/mediastinum ratios of MIBG uptake were significantly lower in the DLB group than in the AD group. Although SPECT failed to demonstrate significant hypoperfusion in the medial occipital lobe in five patients with DLB, marked reduction of MIBG uptake was found in all patients with DLB. Receiver operating characteristic analysis revealed that MIBG myocardial scintigraphy enabled more accurate discrimination between DLB and AD than was possible with perfusion SPECT.Conclusion MIBG myocardial scintigraphy may improve the sensitivity in the detection of DLB. In particular, this method may provide a powerful differential diagnostic tool when it is difficult to distinguish cases of DLB from AD using brain perfusion SPECT.An editorial commentary on this paper is available at     

Individual cerebral metabolic deficits in Alzheimer’s disease and amnestic mild cognitive impairment: an FDG PET study

PURPOSE: The purpose of the study was the identification of group and individual subject patterns of cerebral glucose metabolism (CMRGlu) in patients with Alzheimer's disease (AD) and with amnestic mild cognitive impairment (aMCI). METHODS: [(18)F]fluorodeoxyglucose positron emission tomography (PET) studies and neuropsychological tests were performed in 16 aMCI patients (ten women, age 75 +/- 8 years) and in 14 AD patients (ten women, age 75 +/- 9 years). Comparisons between patient subgroups and with a control population were performed using Statistical Parametric Mapping. RESULTS: Clusters of low CMRGlu were observed bilaterally in the posterior cingulate cortex (PCC), in the precuneus, in the inferior parietal lobule and middle temporal gyrus of AD patients. In aMCI patients, reduced CMRGlu was found only in PCC. Areas of low CMRGlu in PCC were wider in AD compared to aMCI and extended to the precuneus, while low CMRGlu was found in the lateral parietal cortex in AD but not in aMCI patients. Individual subject pattern analysis revealed that 86% of AD patients had low CMRGlu in the PCC (including the precuneus in 71%), 71% in the temporal cortex, 64% in the parietal cortex and 35% in the frontal cortex. Among the aMCI patients, 56% had low CMRGlu in the PCC, 44% in the temporal cortex, 18% in the frontal cortex and none in the parietal cortex. CONCLUSION: This study demonstrates that both AD and aMCI patients have highly heterogeneous metabolic impairment. This potential of individual metabolic PET imaging in patients with AD and aMCI may allow timely identification of brain damage on individual basis and possibly help planning tailored early interventions.     

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.