Serial Nigrostriatal Dopaminergic Imaging in Mild Cognitive Impairment With Lewy Bodies, Alzheimer Disease, and Age-Matched Controls.

BACKGROUND AND OBJECTIVES: Progressive nigrostriatal pathway degeneration occurs in individuals with dementia with Lewy bodies (LB). Our objective was to investigate whether repeat 123[I]-N-(3-fluoropropyl)-2ß-carboxymethoxy-3ß-(4-iodophenyl) nortropane (FP-CIT) single photon emission computed tomography (SPECT) can identify progressive dopaminergic loss in mild cognitive impairment (MCI) with Lewy bodies (MCI-LB). METHODS: Individuals with MCI-LB and MCI due to Alzheimer disease (MCI-AD) underwent comprehensive clinical assessment, 123[I]-FP-CIT SPECT at baseline and annual reviews, and baseline cardiac 123 iodine metaiodobenzylguanidine (I-MIBG). Mixed-effects models were used to investigate changes in 123[I]-FP-CIT specific binding ratio (SBR) in the striatum for each diagnostic group compared with controls. The time interval to the development of a quantitatively abnormal 123[I]-FP-CIT SPECT in the possible and probable MCI-LB groups was determined as the time it took for these groups to reach a striatal uptake 2 SDs below aged-matched controls. Test-retest variation was assessed using baseline and repeat scans in controls. RESULTS: We recruited 20 individuals with MCI-AD, 11 with possible MCI-LB, 25 with probable MCI-LB, and 29 age-matched controls. The mean time between baseline and the final image was 1.6 years (SD = 0.9, range 1.0-4.3). The annual estimated change in SBR was 0.23 for controls (95% CI -0.07 to 0.53), -0.09 (-0.55 to 0.36) for MCI-AD, -0.50 (-1.03 to 0.04) for possible MCI-LB, and -0.48 (-0.89 to -0.06) for probable MCI-LB. The median annual percentage change in SBR in MCI-LB was -5.6% (95% CI -8.2% to -2.9%) and 2.1% (-3.5% to 8.0%) for MCI-AD. The extrapolated time for a normal scan to become abnormal was 6 years. Controls and MCI-AD showed no significant change in dopaminergic binding over time. The mean test-retest variation in controls was 12% (SD 5.5%), which cautions against overinterpretation of small changes on repeat scanning. DISCUSSION: Progressive dopaminergic loss in the striatum is detectable using 123[I]-FP-CIT SPECT in MCI-LB at a group level. In clinical practice, individual change in striatal 123[I]-FP-CIT uptake seems to be of limited diagnostic value because of high test-retest variation. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that longitudinal declines in striatal uptake measured using 123[I]-FP-CIT SPECT are associated with MCI due to Lewy body disease but not MCI due to Alzheimer disease.

Spatial covariance analysis of FDG-PET and HMPAO-SPECT for the differential diagnosis of dementia with Lewy bodies and Alzheimer's disease.

We investigated diagnostic characteristics of spatial covariance analysis (SCA) of FDG-PET and HMPAO-SPECT scans in the differential diagnosis of dementia with Lewy bodies (DLB) and Alzheimer's disease (AD), in comparison with visual ratings and region of interest (ROI) analysis. Sixty-seven patients (DLB 29, AD 38) had both HMPAO-SPECT and FDG-PET scans. Spatial covariance patterns were used to separate AD and DLB in an initial derivation group (DLB n=15, AD n=19), before being forward applied to an independent group (DLB n=14, AD n=19). Visual ratings were by consensus, with ROI analysis utilising medial occipital/medial temporal uptake ratios. SCA of HMPAO-SPECT performed poorly (AUC 0.59±0.10), whilst SCA of FDG-PET (AUC 0.83±0.07) was significantly better. For FDG-PET, SCA showed similar diagnostic performance to ROI analysis (AUC 0.84±0.08) and visual rating (AUC 0.82±0.08). In contrast to ROI analysis, there was little concordance between SCA and visual ratings of FDG-PET scans. We conclude that SCA of FDG-PET outperforms that of HMPAO-SPECT. SCA of FDG-PET also performed similarly to the other analytical approaches, despite the limitations of a relatively small SCA derivation group. Compared to visual rating, SCA of FDG-PET relies on different sources of group variance to separate DLB from AD.

Uniformity of cardiac 123I-MIBG uptake on SPECT images in older adults with normal cognition and patients with dementia.

INTRODUCTION: Some studies report that assessing regional 123I-cardiac MIBG uptake can aid in the diagnosis of Lewy body disease, but others report heterogeneity in healthy controls. We aimed to evaluate regional cardiac MIBG uptake patterns in healthy older adults and patients with dementia. METHODS: 31 older adults with normal cognition, 15 Alzheimer's disease (AD), and 17 Dementia with Lewy bodies (DLB) patients were recruited. 5 individuals had previous myocardial infarction. Participants with sufficient cardiac uptake for regional SPECT analysis (29/31 controls, 15/15 AD, 5/17 DLB) had relative uptake pattern recorded. Controls were assessed for risk of future cardiovascular events using QRISK2, a validated online tool. RESULTS: In controls uptake was reduced in the inferior wall (85%), apex (23%), septum (15%), and lateral wall (8%). AD and DLB showed similar patterns to controls. Lung or liver interference was present in 61% of cases. Myocardial infarction cases showed regional reductions in uptake, but normal/borderline planar uptake. In controls, there was no relationship between cardiovascular risk score and uptake pattern. CONCLUSIONS: Significant variability of regional cardiac 123I-MIBG uptake is common in cases with normal planar cardiac uptake. Heterogeneity of regional uptake appears non-specific and unlikely to aid in the diagnosis of Lewy body disease.

A comparison of visual and semiquantitative analysis methods for planar cardiac 123I-MIBG scintigraphy in dementia with Lewy bodies.

OBJECTIVES: Cardiac I-MIBG imaging is an established technique for the diagnosis of dementia with Lewy bodies but various analysis methods are reported in the literature. We assessed different methods in the same cohort of patients to inform best practice. PATIENTS AND METHODS: Seventeen patients with dementia with Lewy bodies, 15 with Alzheimer's disease and 16 controls were included. Planar images were acquired 20 min and 4 h after injection. Nine operators produced heart-to-mediastinum ratios (HMRs) using freehand and 6, 7 and 8 cm diameter circular cardiac regions. Interoperator variation was measured using the coefficient of variation. HMR differences between methods were assessed using analysis of variance. Seven raters assessed the images visually. Accuracy was compared using receiver operating characteristic analysis. RESULTS: There were significant differences in HMR between region methods (P=0.006). However, with optimised cut-offs there was no significant difference in accuracy (P=0.2-1.0). The sensitivity was 65-71% and specificity 100% for all HMR methods. Variation was lower with fixed regions than freehand (P<0.001). Visual rating sensitivity and specificity were 65 and 77% on early images and 76 and 71% on delayed images. There was no significant difference in HMR between early and delayed images (P=0.4-0.7) although a greater separation between means was seen on delayed images (0.73 vs. 0.95). CONCLUSION: HMR analysis using a suitable cut-off is more accurate than visual rating. Accuracy is similar for all methods, but freehand regions are more variable and 6 cm circles easiest to place. We recommend calculating HMR using a 6 cm circular cardiac region of interest on delayed images.

Cardiac 123I-MIBG planar heart to mediastinum ratios depend on patient size; phantom studies suggest SPECT-CT could improve quantification.

INTRODUCTION: Planar 123I-MIBG (meta-iodobenzylguanidine) cardiac imaging is listed as an indicative biomarker in the 2017 international consensus criteria for the diagnosis of dementia with Lewy bodies. There has been very little research into the relationship between apparent cardiac uptake and patient size, or in the possible advantage of attenuation and scatter corrected SPECT-CT compared to planar imaging. We aimed to evaluate this in both a chest phantom and in older adults with normal cognition. MATERIALS AND METHODS: An anthropomorphic chest phantom was filled with 123I solution using activities typical of healthy subjects. The phantom was scanned on a Siemens Intevo gamma camera with MELP collimators using both planar and SPECT-CT techniques. Further scans were acquired with a PMMA chest plate added, then water filled plastic breasts. The SPECT-CT images were reconstructed using a resolution recovery OSEM method with and without attenuation and scatter correction (ACSC) applied. Twenty-nine adults over 60 years of age (mean 75.2 ± 8.3 years) underwent planar cardiac MIBG imaging, followed by SPECT-CT. SPECT images were reconstructed as above. Heart-to-mediastinum ratios (HMRs) were calculated for planar and SPECT images. RESULTS: Phantom planar HMR decreased by 20% with the PMMA chest plate added; 39% with plate and breasts. ACSC SPECT cardiac counts showed less dependence on phantom size than SPECT without ACSC (3% versus 37%). The body mass indices (BMI) of the older adults ranged from 22 to 38. There was a significant linear relationship between planar HMR and BMI (R2 = 0.44, p<0.01), but not for ACSC SPECT. However, there was no significant difference between the slopes for planar and ACSC SPECT (p = 0.11). CONCLUSION: Planar cardiac 123I-MIBG HMR results are correlated with BMI. Phantom results suggest that ACSC SPECT can correct for patient size. A large patient population or clinical database would be required to demonstrate a clinical effect.

A new visual rating scale for Ioflupane imaging in Lewy body disease.

BACKGROUND: Dopaminergic loss on 123I-Ioflupane brain imaging is a recognised biomarker for dementia with Lewy bodies. It is usually assessed using a visual rating scale developed for Parkinson's disease, which may not be optimal for dementia with Lewy bodies, as patterns of dopaminergic loss can be different. OBJECTIVES: We aimed to develop a new visual rating scale for 123I-Ioflupane brain images in Lewy body disease that encompasses appearances seen in dementia with Lewy bodies, and validate this against autopsy diagnosis. METHODS: Four experienced observers developed and tested a new scale consisting of two metrics, reflecting overall loss and heterogeneity of loss. 66 subjects were used during development including clinical diagnoses of Alzheimer's disease (n = 14), Parkinson's disease (n = 9), Parkinson's disease dementia (n = 9), dementia with Lewy bodies (n = 15) and normal controls (n = 19). The scale was then tested on an independent group of 46 subjects with autopsy confirmed diagnosis: Alzheimer's disease (n = 11), Parkinson's disease (n = 3), Parkinson's disease dementia (n = 15), dementia with Lewy bodies (n = 12), normal controls (n = 4) and Frontotemporal dementia (n = 1). RESULTS: In the autopsy validation the sensitivity and specificity of the new scale for Lewy body disease was 97% and 100% respectively, compared with the standard scale which had the same sensitivity (97%), but lower specificity (80%). The new scale had excellent inter rater reliability (intra-class correlation coefficient 0.93). CONCLUSION: A new robust and reliable rating scale is described that straightforwardly captures the visual appearance of 123I-Ioflupane brain images. It demonstrated high accuracy in autopsy confirmed cases and offers advantages over the existing visual rating scale.

Multivariate spatial covariance analysis of 99mTc-exametazime SPECT images in dementia with Lewy bodies and Alzheimer's disease: utility in differential diagnosis.

We examined (99m)Tc-exametazime brain blood flow single-photon emission computed tomography (SPECT) images using a spatial covariance analysis (SCA) approach to assess its diagnostic value in distinguishing dementia with Lewy bodies (DLB) from Alzheimer's disease (AD). Voxel SCA was simultaneously applied to a set of preprocessed images (AD, n=40; DLB, n=26), generating a series of eigenimages representing common intercorrelated voxels in AD and DLB. Linear regression derived a spatial covariance pattern (SCP) that discriminated DLB from AD. To investigate the diagnostic value of the model SCP, the SCP was validated by applying it to a second, independent, AD and DLB cohort (AD, n=34; DLB, n=29). Mean SCP expressions differed between AD and DLB (F(1,64)=36.2, P<0.001) with good diagnostic accuracy (receiver operating characteristic (ROC) curve area 0.87, sensitivity 81%, specificity 88%). Forward application of the model SCP to the independent cohort revealed similar differences between groups (F(1,61)=38.4, P<0.001), also with good diagnostic accuracy (ROC 0.86, sensitivity 80%, specificity 80%). Multivariate analysis of blood flow SPECT data appears to be robust and shows good diagnostic accuracy in two independent cohorts for distinguishing DLB from AD.

A comparison of 99mTc-exametazime and 123I-FP-CIT SPECT imaging in the differential diagnosis of Alzheimer's disease and dementia with Lewy bodies.

BACKGROUND: The aim of this study is to investigate the diagnostic value of perfusion 99mTc-exametazime single photon emission computed tomography (SPECT) in the diagnosis of dementia with Lewy bodies (DLB) and Alzheimer's disease (AD) in comparison with dopaminergic 123I-2beta-carbomethoxy-3beta-(4-iodophenyl)-n-(3-fluoropropyl) nortropane (FP-CIT) SPECT imaging. METHODS: Subjects underwent 99mTc-exametazime scanning (39 controls, 36 AD, 30 DLB) and 123I-FP-CIT scanning (33 controls, 33 AD, 28 DLB). For each scan, five raters performed visual assessments blind to clinical diagnosis on selected transverse 99mTc-exametazime images in standard stereotactic space. Diagnostic accuracy of 99mTc-exametazime was compared to 123I-FP-CIT results for the clinically relevant subgroups AD and DLB using receiver operating characteristic (ROC) curve analysis. RESULTS: Inter-rater agreement for categorizing uptake was "moderate" (mean kappa = 0.53) for 99mTc-exametazime and "excellent" (mean kappa = 0.88) for 123I-FP-CIT. For AD and DLB, consensus rating matched clinical diagnosis in 56% of cases using 99mTc-exametazime and 84% using 123I-FP-CIT. In distinguishing AD from DLB, ROC analysis revealed superior diagnostic accuracy with 123I-FP-CIT (ROC curve area 0.83, sensitivity 78.6%, specificity 87.9%) compared to occipital 99mTc-exametazime (ROC curve area 0.64, sensitivity 64.3%, specificity 63.6%) p = 0.03. CONCLUSION: Diagnostic accuracy was superior with 123I-FP-CIT compared to 99mTc-exametazime in the differentiation of DLB from AD.

Effect of sex, age, and weight on ejection fraction and end-systolic volume reference limits in gated myocardial perfusion SPECT.

BACKGROUND: The left-ventricular ejection fraction (EF) and end-systolic volume (ESV) are strong predictors of prognosis for cardiac death. Gated myocardial perfusion single-photon emission computed tomography (gSPECT) may be used to measure ESV and EF. However, systematic differences may exist between referred populations. Our aim was to derive male and female reference limits for left-ventricular functional parameters, and determine the effect of age, weight, and body surface area (BSA). METHODS AND RESULTS: The ejection fraction and ESV were derived using QGS software for 127 patients with normal gSPECT studies. The lower reference limits of EF were 46.2% and 55.6% for men and women, respectively. The upper reference limits of ESV were 30.4 mL and 21.4 mL, and 15.7 mL/m(2) and 11.1 mL/m(2), when indexed to BSA for men and women, respectively. There was no correlation between EF and age, weight, or BSA (P > .05). There was a small decrease in ESV with age, and an increase with weight and BSA (P < .05). The sex-specific differences remained after adjusting for confounding variables. CONCLUSIONS: We demonstrated a significant sex difference for all functional parameters measured, and we established the influence of patient age and weight. Local reference limits for ESV and EF have been established, and the latter are transferable to other departments operating similar protocols.

Progression of dopaminergic degeneration in dementia with Lewy bodies and Parkinson's disease with and without dementia assessed using 123I-FP-CIT SPECT.

PURPOSE: The objective of this study was to investigate the rate of progression of nigrostriatal dopaminergic loss in subjects with dementia with Lewy bodies (DLB), Parkinson's disease (PD) and PD with dementia (PDD) using serial 123I-FP-CIT SPECT imaging. We hypothesised that striatal rates of decline in patients would be greater than in controls, and that DLB and PDD would show similar rates, reflecting the similarity in neurobiological mechanisms of dopaminergic loss between the two disorders. METHODS: We studied 20 patients with DLB, 20 with PD, 15 with PDD and 22 healthy age-matched controls. Semi-automated region of interest (ROI) analysis was performed on both baseline and repeat scans for each subject and mean striatal uptake ratios (caudate, anterior and posterior putamen) were calculated. RESULTS: Rates of decline in striatal binding between groups were assessed using ANCOVA. Significant differences between patients and controls were observed in caudate (DLB, PD, PDD, p< or =0.01), anterior putamen (DLB, PDD, p< or =0.05; PD, p=0.07) and posterior putamen (DLB, PD, PDD, p<0.006). Rates of decline were similar between DLB, PD and PDD. CONCLUSION: In conclusion, this is the first study to show that significant progressive dopaminergic loss occurs in DLB and PDD using serial 123I-FP-CIT SPECT. Dementia severity and motor impairment were correlated with decline, suggesting that dopaminergic loss may play an important role in cognitive as well as motor features.

The effect of imaging time, radiopharmaceutical, full fat milk and water on interfering extra-cardiac activity in myocardial perfusion single photon emission computed tomography.

BACKGROUND AND AIM: Extra-cardiac activity can interfere with observer interpretation of myocardial perfusion single photon emission computed tomography (SPECT) images. Fatty meals and drinks to reduce interference have been tested; however, a simple study of delayed imaging with (99m)Tc-tetrofosmin and (99m)Tc-sestamibi has not been specifically addressed. The aim was to quantify the effects of imaging time, radiopharmaceutical and oral administration of full fat milk and water on interfering activity. METHODS: Myocardial perfusion SPECT images were acquired using either tetrofosmin or sestamibi. Patients were imaged at 0.5, 1 or 2 h post-injection (tetrofosmin, 59; sestamibi, 72). Additional groups of patients were imaged either with or without milk (tetrofosmin, 54; sestamibi, 45) and with milk and water (sestamibi, 30). A myocardial region was drawn on the anterior projection and a thin adjacent extra-cardiac region was generated automatically. The count density ratio was calculated and validated with a trial of five observers. A decreasing ratio correlated significantly with observer rank of increasing interference with SPECT image interpretation (r=0.95, P=0.001). RESULTS: The ratio improved significantly as the imaging time increased for both tetrofosmin and sestamibi groups (P<0.05). The groups given milk or milk plus water showed no significant improvement against control groups (P > or = 0.2). There was no significant difference between tetrofosmin and sestamibi at any time point (P > or = 0.4). CONCLUSIONS: Image interpretation may be improved by delayed imaging for tetrofosmin and sestamibi. However, in contrast with common practice, the administration of milk or water appears to be of no clinical value compared with delayed imaging, and there is no significant difference between interfering activity from tetrofosmin and sestamibi.