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.

Can early phase cardiac [123I]mIBG images be used to diagnose Lewy body disease?

PURPOSE: Some studies have suggested that cardiac [123I]metaiodobenzylguanidine images obtained 15-20 min after tracer administration are as accurate for dementia with Lewy bodies (DLB) diagnosis as standard images acquired after a delay of 3-4 h; some suggest delayed imaging is preferable. We compare early and delayed heart-to-mediastinum ratios (HMR) in a well-characterised research dataset and make recommendations for clinical practice. METHODS: Images were acquired using a Siemens gamma camera with medium energy collimators. Early images were obtained at 20 min and delayed at 4 h (± 30) min. In total 167 pairs of images were reviewed: 30 controls, 39 people with dementia and 98 with mild cognitive impairment. HMR normal cutoff values derived from control data were ≥2.10 for early imaging and ≥1.85 for delayed. RESULTS: HMR tended to drop between early and delayed for abnormal images, but increase for normal images. Histograms of early and delayed HMR showed a slightly better separation of results into two groups for delayed imaging. Accuracy results were slightly higher for delayed imaging than early imaging (73 vs. 77%), sensitivity 63 vs. 65% and specificity 82 vs. 88%. However, this was not statistically significant - in total only 8/167 (5%) of scans changed designation between early and delayed imaging. CONCLUSION: We suggest that a delayed image could be acquired only if the early result is borderline. This removes the need for delayed imaging in about 70% of patients. Adopting this protocol in clinical practice would reduce the time most patients have to wait and could free up scanner time.

Accuracy of Cardiac Innervation Scintigraphy for Mild Cognitive Impairment With Lewy Bodies.

OBJECTIVE: To provide evidence that cardiac I-123-metaiodobenzylguanidine sympathetic innervation imaging (MIBG) scintigraphy differentiates probable mild cognitive impairment with Lewy bodies (MCI-LB) from mild cognitive impairment due to Alzheimer disease (MCI-AD), we scanned patients with MCI and obtained consensus clinical diagnoses of their MCI subtype. We also performed baseline FP-CIT scans to compare the accuracy of MIBG and FP-CIT. METHODS: We conducted a prospective cohort study into the accuracy of cardiac MIBG scintigraphy in the diagnosis of MCI-LB. Follow-up clinical assessment was used to diagnose MCI-AD (no core features of MCI-LB and normal FP-CIT), probable MCI-LB (2 or more core features, or 1 core feature with abnormal FP-CIT), or possible MCI-LB (1 core feature or abnormal FP-CIT). For the comparison between MIBG and FP-CIT, only core clinical features were used for diagnosis. RESULTS: We recruited 95 people with mild cognitive impairment. Cardiac MIBG was abnormal in 22/37 probable and 2/15 possible MCI-LB cases and normal in 38/43 MCI-AD cases. The sensitivity in probable MCI-LB was 59% (95% confidence interval [CI], 42%-75%), specificity 88% (75%-96%), and accuracy 75% (64%-84%). The positive likelihood ratio was 5.1 and negative likelihood ratio 0.46. With symptom-only diagnoses, the accuracies were 79% for MIBG (95% CI, 68%-87%) and 76% for FP-CIT (95% CI, 65%-85%). CONCLUSIONS: Cardiac MIBG appears useful in early disease, with an abnormal scan highly suggestive of MCI-LB. Validation in a multicenter setting is justified. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that cardiac MIBG distinguishes MCI-LB from MCI-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.

123I-FP-CIT striatal binding ratios do not decrease significantly with age in older adults.

OBJECTIVE: I-123-2ß-Carbomethoxy-3ß-(4-iodophenyl)-N-(3-fluoropropyl)nortropane (FP-CIT) imaging is an established biomarker used in the diagnosis of Lewy body disease. Images are often reported with the aid of striatal binding ratios (SBRs), comparing uptake to a normal database via Z scores. It is well known that SBRs are age dependent. However, previous studies cover wide age ranges between 20 and 80 years, rather than focusing on older adults. Typically a linear relationship is reported, but some authors have suggested that SBRs do not decline as rapidly in old age. Commercial software packages usually adjust the SBR Z score to attempt to compensate for age-related decline, but the model used varies. Ensuring age correction is appropriate for older adults is important, given that the majority of patients referred for FP-CIT scans are aged over 60 years. We examined the relationship of SBR with age in older adults and the effect of age correction using research scans from 123 adults over 60 years of age. METHODS: Twenty-nine healthy older adults and twenty-three with MCI due to Alzheimer's disease were included as controls, i.e. individuals with no evidence of Lewy body disease. Their ages ranged from 60 to 92 years (mean 76; SD 7.9). SBRs and Z scores were calculated using BRASS (Hermes Medical) and DaTQUANT (GE Healthcare). SBRs were plotted against age and linear mixed effect models applied. We tested the effect of removing age correction in BRASS using an independent dataset of 71 older adults with dementia or mild cognitive impairment. RESULTS: The slopes of the linear fits between SBR and age per year were - 0.007 (p = 0.30) with BRASS and - 0.004 (p = 0.35) with DaTQUANT. The slopes are smaller than reported in the literature and show no statistically significant difference from zero. Switching age correction off in BRASS in the test subjects reduced Z scores by approximately 1 standard deviation at 80 years of age. CONCLUSION: We found no statistically significant age-related decline in SBR in adults over 60 years of age without Lewy body disease. Commercial software packages that apply a fixed rate of age correction may be overcorrecting for age in older adults, which could contribute to misdiagnosis.

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.

Beta amyloid deposition maps onto hippocampal and subiculum atrophy in dementia with Lewy bodies.

Although dementia with Lewy bodies (DLB) is a synucleinopathy, it is frequently accompanied by beta amyloid (Aß) accumulation. Elucidating the relationships of Aß with gray matter atrophy in DLB may yield insights regarding the contributions of comorbid Alzheimer's disease to its disease progression. Twenty healthy controls and 25 DLB subjects underwent clinical assessment, [18F]-Florbetapir, and 3T magnetic resonance imaging. FreeSurfer was used to estimate cortical thickness and subcortical volumes, and PetSurfer was used to quantify [18F]-Florbetapir standardized uptake value ratio. Principal component analysis was used to identify the dominant Aß component for correlations with regional cortical thickness, hippocampal subfields, and subcortical structures. Relative to healthy controls, the DLB group demonstrated increased Aß in widespread regions encompassing the frontal and temporoparietal cortices, whereas cortical thinning was restricted to the temporal lobe. Among DLB subjects, the Aß component was significantly associated with more severe hippocampal and subiculum atrophy. These findings may reflect an early process of superimposed AD-like atrophy in DLB, thereby conferring support for the therapeutic potential of anti-Aß interventions in people with DLB.

Assessment of normal reference values for thyroid uptake of technetium-99m pertechnetate in a single centre UK population.

OBJECTIVE: This study aims to explore the normal reference values for thyroid uptake of technetium-99m (Tc) pertechnetate in a UK population. PATIENTS AND METHODS: A retrospective review of 60 euthyroid patients who underwent thyroid imaging with Tc pertechnetate between January 2012 to April 2014 as part of dual-tracer subtraction parathyroid scintigraphy. Tc pertechnetate thyroid uptake values were determined for each patient. Medical records and biochemical thyroid function tests were reviewed to ensure that all patients were not on medication that could affect thyroid function and they were both clinically and biochemically euthyroid 6 months before and following the scan. RESULTS: Median and interquartile uptake range of Tc pertechnetate in euthyroid patients were 0.9 and 0.5-1.4%, respectively. The normal reference range in the study population was 0.2-2.0%. Thyroid uptake inversely correlated with age in females (r=-0.40, P=0.04), males (r=-0.50, P=0.04), and whole group (r=-0.40, P=0.002). CONCLUSION: The calculated normal reference range in this study was found to be less than that used in our own and many other UK institutions. The results demonstrate the importance of periodic evaluation of normal uptake values and provide support for prospective studies defining the normal reference range to be performed.

Associations between COPD related manifestations: a cross-sectional study.

BACKGROUND: Cardiovascular disease, osteoporosis and emphysema are associated with COPD. Associations between these factors and whether they predict all-cause mortality in COPD patients are not well understood. Therefore, we examined associations between markers of cardiovascular disease (coronary artery calcification [CAC], thoracic aortic calcification [TAC] and arterial stiffness), bone density (bone attenuation of the thoracic vertebrae), emphysema (PI-950 and 15th percentile) and all-cause mortality in a COPD cohort. METHODS: We assessed CAC, TAC, bone attenuation of the thoracic vertebrae, PI-950 and 15th percentile on low-dose chest computed tomography in COPD subjects. We measured arterial stiffness as carotid-radial pulse wave velocity (PWV), and identified deaths from the national register. RESULTS: We studied 119 COPD subjects; aged 67.8 ±7.3, 66% were males and mean FEV1% predicted was 46.0 ±17.5. Subjects were classified into three pre-specificed groups: CAC = 0 (n = 14), 0 < CAC ≤ 400 (n = 41) and CAC > 400 (n = 64). Subjects with higher CAC were more likely to be older (p < 0.001) and male (p = 0.03), and more likely to have higher systolic blood pressure (p = 0.001) and a history of hypertension (p = 0.002) or ischemic heart disease (p = 0.003). Higher CAC was associated with higher PWV (OR 1.62, p = 0.04) and lower bone attenuation (OR 0.32, p = 0.02), but not with 15th percentile, after adjustment for age, sex and pack-years of smoking. In a Cox proportional hazards model, CAC, TAC and 15th percentile predicted all-cause mortality (HR 2.01, 2.09 and 0.66, respectively). CONCLUSIONS: Increased CAC was associated with increased arterial stiffness and lower bone density in a COPD cohort. In addition, CAC, TAC and extent of emphysema predicted all-cause mortality. TRIAL REGISTRATION: Lothian NHS Board, Lothian Research Ethics Committee, LREC/2003/8/28.