Toward the Validation of Functional Neuroimaging as a Potential Biomarker for Alzheimer’s Disease: Implications for Drug Development

Despite investments carried out in the research since Alzheimers disease (AD) was firstly defined as an isolated clinical entity, there is still a lack of appropriate cure and effective therapies to halt or slow the disease progression. While fundamental research has provided a better characterization of AD, much remains to be done for the development of new biological treatment strategies. It is now being debated whether functional neuroimaging (FNI) could help improve diagnostic accuracy and become a possible biomarker of AD. The primary purpose of this review was to determine whether data already published in the literature meet formal technology assessment standards for using regional cerebral blood flow (rCBF) or glucose metabolism (rCMRGlu) as a biomarker for AD. The secondary purpose was to identify any remaining gaps that might need to be systematically addressed before drug developers and regulators accept FNI as a biomarker for AD. The present paper reviews the literature regarding metabolic positron emission tomography (PET) and perfusion single photon emission computed tomography (SPECT) studies in AD. There is evidence that treatment with acetylcholinesterase inhibitors (AChEI) leads to changes in brain physiology within the brain regions critical to AD pathology, i.e. the temporal, parietal and frontal association cortex. However, a thorough analysis combining functional and neuropsychological data has not yet been attempted, and much research is needed to validate the role of FNI as a surrogate endpoint for AD clinical trials.     

Brain perfusion assessed by 99mTc-ECD SPECT imaging in pediatric patients with neurally mediated reflex syncope

BACKGROUND: The involvement of cardiogenic and neurogenic mechanisms in neurally mediated reflex syncope is well documented. In our previous studies in patients with neurally mediated reflex syncope, we have found evidence for differential regulation of the noradrenergic receptors in tilt-positive and tilt-negative patients. The present work concentrates on the observations of differences in regional brain perfusion using brain SPECT via injecting the patient at the completion of the tilt test. METHODS AND RESULTS: The following study was designed to assess the reduction and regional differences in cerebral blood flow by means of SPECT using technetium-99m labeled V-oxo-1,2-N1ethylenedylbisl-cysteine diethylester (ECD) in patients with an injection during tilt testing. Twenty patients with NMS were included in the study with a mean age of 12.2 years (age range; 8-16 years). HUT was positive in 10 patients and negative in 10 patients. When tilt (+) and tilt (-) were evaluated together, regional cortical/cerebellum ratios were ranging from 0.85 to 1.25 in different cortical areas with highest variability of perfusion index in left frontoparietal cortex. The lowest perfusion index values were observed in the left anterior frontal region followed by the left prefrontal-frontoparietal-anterior, parietal-orbito frontal, and anterior temporal regions where perfusion is predominantly supplied via the anterior and middle cerebral arteries, while these differences did not reach statistical significance in a single dominant region compared to the other regions examined using ANOVA (P > 0.05) with this sample size. Decreases in [99mTc]ECD uptake were more widespread regionally on the left hemisphere than were decreases in right side of the brain. However when tilt- and tilt+ groups were compared, perfusion was significantly lower in the right periinsular posterior parietal and temporal regions (P < 0.05) in tilt + group. CONCLUSION: These tilt induced regional differences in brain perfusion suggest the distinct roles of middle cerebral artery dominant territory-related vasodepressor compensation mechanisms in neurally mediated reflex syncope phenomena where cerebral lateralization of cardiac control and insular ischemia may play an important role.     

Gated blood pool SPECT for measurement of left ventricular volumes and left ventricular ejection fraction: comparison of 8 and 16 frame gated blood pool SPECT

Gated blood pool SPECT (GBPS) is an alternative to planar radionuclide ventriculography (PRNV) and offers potential advantages. The aim of this study was to compare 8 and 16 frame GBPS for the determination of left ventricular ejection fraction(LVEF) and left ventricular volumes (LV) in subjects underwent two consecutive GBPS. Method: About 66 consecutive patients (30 men, 36 women; mean age 62.3 ± 10.4 years) referred for PRNV for evaluation of preoperative cardiac risk stratification (n=40), prechemotherapy cardiac function evaluation (n=18, breast cancer), and congestive heart failure patients (n=8). All patients underwent PRNV of 16 frame and GBPS with both of 8 and 16 frame. Results: The mean LVEF calculated with PRNV (58.3 ± 16.8), showed statistically lower than 8-GBPS (70.6 ± 17.7), and 16-GBPS (69.9 ± 16.8) (PRNV vs. 8-GBPS, p < 0.01; PRNV vs 16-GBPS, p < 0.01; 8-GBPS vs 16-GBPS, p > 0.05). The correlation of LVEFS between 8-GBPS and 16-GBPS showed a correlation coefficient of 0.9194 (p < 0.01, 95% CI=0.8712–0.9500). The mean left ventricular end-diastolic volumes (EDV) calculated with 8-GBPS (83.2 ± 33.5 ml), and 16-GBPS (88.4 ± 36.8 ml) showed no statistical differences (p > 0.05). The mean left ventricular end-systolic volumes (ESV) calculated with 8-GBPS (28.1 ± 31.4 ml), and 16-GBPS (30.5 ± 33 ml) showed also no statistical differences (p > 0.05). Comparison of EDV from 8 and 16-GBPS yielded a correlation coefficient of 0.7430 (p < 0.01, 95% CI=0.6108-0.8349). The correlation between ESV of 8-GBPS and 16-GBPS showed a correlation coefficient of 0.9522 (p < 0.01, 95% CI=0.9228–0.9705). Conclusion: This study demonstrated that the LVEFs of 8-GBPS correlated well with that of 16-GBPS. The LVEF of PRNV was significantly lower than those of 8 and 16-GBPS. Also, left ventricular EDV and ESV of 8-GBPS correlated well with those of 16-GBPS. Also, further studies, involving large lumber patients, should be performed to validate the usefulness of GBPS for the evaluation of left ventricular diastolic function.     

99Tcm-ECD SPECT非侵入性的定量测定平均CBFl和rCBF理论及其应用研究

目的定量评价大脑及局部的平均脑血流量,应用     

Interictal and Ictal Phase Study With Tc 99m HMPAO Brain SPECT in Juvenile Migraine With Aura

Single photon emission computed tomography (SPECT) was performed on 30 juvenile patients suffering from different types of migraine with aura. SPECT was carried out only during the pain-free interval in 11 patients. The other 19 patients underwent SPECT ictally and 9 of them also interictally. During the pain-free interval, the investigation was normal in 16 of 20 cases and revealed hypoperfused areas in 4 of 20 cases. Ictally, regional cerebral blood flow (rCBF) abnormalities were found in 14 of 19 cases: hypoperfusion in 11 patients and hyperperfusion in 3 patients. In most cases, rCBF abnormalities corresponded to the topography of neurologic symptoms. Our intericta period results do not agree with the previous studies in juvenile migraineurs, while during the ictal phase we demonstrated, for the first time, significant rCBF abnormalities in juvenile patients suffering from migraine with aura.     

Prognostic value of nitrate enhanced Tc99m MIBI SPECT study in detecting viable myocardium in patients with coronary artery disease

Background: Assessing the viability in akinetic myocardium is vital for predicting functional recovery after therapeutic management in patients with chronic coronary artery disease (CAD) and depressed left ventricular (LV) function. The present study aimed to evaluate the efficacy of Tc99m MIBI SPECT enhanced with nitroglycerine infusion in detecting myocardial viability, as well as to asses the relationship between the myocardial viability and the subsequent treatment and outcome of patients. Methods and results: Sixty-seven consecutive patients with CAD and LV dysfunction (LV ejection fraction 36.6 ± 8.4%) underwent Tc99m MIBI imaging – at rest and during intravenous nitroglycerine infusion – for viability assessment. Fourteen patients were treated pharmacologically (Group I), and fifty-three (Group II) were submitted to coronary revascularization (PTCR or CABG). Fifteen major cardiac events were observed during 25 months of the follow-up. A significantly worse event-free survival was registered in the subjects of Group I than in Group II subjects. The prognostic predictors of cardiac events were: (1) the number of viable, non-revascularized segments in perfusion imaging (p < 0.001), (2) the severity of the disease assessed by coronary angiography (p < 0.05). Conclusions: Viability detection in nitroglycerine infusion enhanced Tc99m MIBI imaging offers significant prognostic value in patients with CAD after myocardial infarction. Patients with preserved viability showed better prognosis after revascularization than those treated pharmacologically.     

Comparison of thallium-201 exercise SPECT and dobutamine stress echocardiography for diagnosis of coronary artery disease in patients with left bundle branch block

The present study assessed and compared the diagnostic accuracy of thallium-201 (Tl-201) exercise myocardial single photon emission computerised tomography (SPECT) and dobutamine stress echocardiography (DSE) for detection of coronary artery disease (CAD) in patients with left bundle branch block (LBBB). Study population consisted of 26 consecutive patients with permanent LBBB who were suffering from chest pain. Patients (8 women, 18 men mean age = 57 ± 8 years) were studied with DSE, Tl-201 SPECT and coronary angiography (CAG). Three different approaches for diagnosis of CAD were used to identify CAD in left arterial descending (LAD) coronary artery territories in scintigraphic studies: (1) Approach A (conventional approach): involvement of septal, and/or anterior, and/or apical wall. (2) Approach B: involvement of anterior and septal wall irrespective of apical wall. (3) Approach C: involvement of septum, anterior and apical wall. DSE gave a sensitivity of 91%, specificity of 92% and accuracy of 92% for diagnosis of CAD in the LAD coronary artery territory. Tl-201 SPECT (conventional approach) gave a sensitivity of 100%, specificity of 42% and diagnostic accuracy of 69% for diagnosis of CAD in the LAD coronary artery territory. Sensitivity, specificity and diagnostic accuracy of approach C were 33, 85 and 57% respectively. The specificity of Tl-201 SPECT significantly increased in approach C when compared with approach A and B (p < 0.02). However sensitivity of the Tl-201 SPECT with approach C showed significant decrease when compared with DSE and approach A and B (p < 0.005). Specificity of DSE for diagnosis of CAD in LAD were significantly higher than those of Tl-201 SPECT regarding the approach A and B (p < 0.01). In conclusion the use of DSE for diagnosis of CAD in patients with LBBB seems to be more suitable than Tl-201 SPECT.     

君复康对海洛因成瘾者稽延性戒断症状作用靶点的研究

目的探讨君复康治疗海洛因成瘾者稽延性戒断症状的作用靶点。方法将海洛因稽延性戒断综合症患者60例随机分组成君复康组50例和纳曲酮组10例,分别服用君复康或纳曲酮治疗6个月。另取18例正常志愿者作为对照组。3组皆行99mTc-2-β[N,N-双(2-巯乙基)乙撑二胺基]甲基,3-β(4-氯苯基)托烷(TRODAT-1)多巴胺转运体(DAT)单光子发射计算机断层(SPECT)显像,2组患者治疗后再次显像。采用定性分析和定量分析。结果定性分析显示,18例正常志愿者双侧纹状体基本等大,DAT分布均匀、对称。海洛因稽延性戒断综合症患者治疗前双侧纹状体明显变小,DAT分布减少;君复康治疗6个月后,双侧纹状体皆不同程度恢复,接近正常志愿者;但纳曲酮治疗后变化不大。定量分析示,与对照组相比,海洛因稽延性戒断综合症患者的体积(V,cm3)、质量(m,g)、纹状体与全脑放射性百分比值(Ra,%)差异非常显著(t>3.13,P<0.01-0.05)。君复康治疗前后相比,体积(V,cm3)、质量(m,g)、纹状体与全脑放射性百分比值(Ra,%)分别为29.17±3.39,30.45±3.54,6.43±0.13,差异非常显著(P<0.01)。而纳曲酮治疗前后相比,体积(V,cm3)、质量(m,g)、纹状体与全脑放射性百分比值(Ra,%)分别为22.33±4.97,23.10±4.01,6.11±2.05,无显著差异(P>0.05)。结论君复康治疗海洛因成瘾者稽延性戒断症状有效,其作用靶点是多巴胺(DA)能神经元突触前膜的DAT。     

单椎体转移瘤的CT、MRI、SPECT/CT骨显像诊断

目的:评价CT、MRI、SPECT/CT骨显像在单椎体转移瘤中的诊断价值。方法:本组单椎体转移瘤66例,所有病例均行CT、MRI、SPECT/CT骨显像检查,并经手术及病理证实。结果:CT阳性率75.76%,MRI阳性率90.90%,SPECT/CT骨显像阳性率100%。CT符合率69.69%,MRI符合率89.39%,SPECT/CT骨显像符合率90.90%。结论:SPECT/CT骨显像可作为筛选临床疑诊椎体转移瘤的首选检查,MRI、CT是其必要的补充手段。     

Single-photon emission computed tomography perfusion imaging in the differential diagnosis of dementia: a retrospective regional audit

A retrospective audit of (99m)Tc-HMPAO SPECT scans was undertaken to assess the utility of brain perfusion imaging in a cohort of young cognitively impaired patients in whom diagnostic uncertainty remained after standard clinical and neuropsychological assessment and structural brain imaging. SPECT scans were assessed by five raters (two neurologists and three nuclear medicine specialists) on two occasions 6 months apart, first without any clinical data and second with brief pertinent clinical information. SPECT diagnoses were compared with criterion diagnoses subsequently established by the two neurologists with access to all clinical, neuropsychological and neuroimaging data. Despite reasonable intra- and interrater reliability, diagnostic accuracy ranged from 32 to 58%. SPECT scan normality or abnormality in blind and informed viewings gave respective sensitivities of 77 and 71%, specificities of 44 and 38%, positive predictive values of 88 and 87% and negative predictive values of 27 and 18%. Calculating pairwise disease group comparisons, likelihood ratios suggested some diagnostic gain in differentiating AD from 'not AD' and from FTD/focal syndromes. SPECT scanning was of little help in establishing diagnoses in this cohort of patients, a finding which supports the conclusion of the American Academy of Neurology evidence-based review that SPECT imaging cannot be recommended for either the initial or the differential diagnosis of suspected dementia because it has not demonstrated superiority to clinical criteria.