Biomarker response to high-specific-activity I-131 meta-iodobenzylguanidine in pheochromocytoma/paraganglioma.

The objective of this study is to present the complete biomarker response dataset from a pivotal trial evaluating the efficacy and safety of high-specific-activity I-131 meta-iodobenzylguanidine in patients with advanced pheochromocytoma or paraganglioma. Biomarker status was assessed and post-treatment responses were analyzed for catecholamines, metanephrines, and serum chromogranin A. Complete biomarker response (normalization) or partial response, defined as at least 50% reduction from baseline if above the normal range, was evaluated at specified time points over a 12-month period. These results were correlated with two other study objectives: blood pressure control and objective tumor response as per RECIST 1.0. In this open-label, single-arm study, 68 patients received at least one therapeutic dose (~18.5 GBq (~500 mCi)) of high-specific-activity I-131 meta-iodobenzylguanidine. Of the patients, 79% and 72% had tumors associated with elevated total plasma free metanephrines and serum chromogranin A levels, respectively. Best overall biomarker responses (complete or partial response) for total plasma free metanephrines and chromogranin A were observed in 69% (37/54) and 80% (39/49) of patients, respectively. The best response for individual biomarkers was observed 6-12 months following the first administration of high-specific-activity I-131 meta-iodobenzylguanidine. Biochemical tumor marker response was significantly associated with both reduction in antihypertensive medication use (correlation coefficient 0.35; P = 0.006) as well as objective tumor response (correlation coefficient 0.36; P = 0.007). Treatment with high-specific-activity I-131 meta-iodobenzylguanidine resulted in long-lasting biomarker responses in patients with advanced pheochromocytoma or paraganglioma that correlated with blood pressure control and objective response rate. ClinicalTrials.gov number: NCT00874614.

Disruption of cholinergic neurotransmission, within a cognitive challenge paradigm, is indicative of Aß-related cognitive impairment in preclinical Alzheimer's disease after a 27-month delay interval.

BACKGROUND: Abnormal beta-amyloid (Aß) is associated with deleterious changes in central cholinergic tone in the very early stages of Alzheimer's disease (AD), which may be unmasked by a cholinergic antagonist (J Prev Alzheimers Dis 1:1-4, 2017). Previously, we established the scopolamine challenge test (SCT) as a "cognitive stress test" screening measure to identify individuals at risk for AD (Alzheimer's & Dementia 10(2):262-7, 2014) (Neurobiol. Aging 36(10):2709-15, 2015). Here we aim to demonstrate the potential of the SCT as an indicator of cognitive change and neocortical amyloid aggregation after a 27-month follow-up interval. METHODS: Older adults (N = 63, aged 55-75 years) with self-reported memory difficulties and first-degree family history of AD completed the SCT and PET amyloid imaging at baseline and were then seen for cognitive testing at 9, 18, and 27 months post-baseline. Repeat PET amyloid imaging was completed at the time of the 27-month exam. RESULTS: Significant differences in both cognitive performance and in Aß neocortical burden were observed between participants who either failed vs. passed the SCT at baseline, after a 27-month follow-up period. CONCLUSIONS: Cognitive response to the SCT (Alzheimer's & Dementia 10(2):262-7, 2014) at baseline is related to cognitive change and PET amyloid imaging results, over the course of 27 months, in preclinical AD. The SCT may be a clinically useful screening tool to identify individuals who are more likely to both have positive evidence of amyloidosis on PET imaging and to show measurable cognitive decline over several years.

FDG PET/CT of Infection: Should It Replace Labeled Leukocyte Scintigraphy of Inpatients?

OBJECTIVE. The purpose of this study was to compare the sensitivity, specificity, and helpfulness to referring clinicians of labeled leukocyte scintigraphy versus FDG PET/CT in inpatients with suspected infection. MATERIALS AND METHODS. In this retrospective study, labeled leukocyte scintigraphy and FDG PET/CT examinations performed from 2009 to 2017 for suspected infection in inpatients were identified. Sensitivity, specificity, and helpfulness of PET/CT versus labeled leukocyte scintigraphy were calculated by means of a mixed generalized linear model. Number of yearly tests and radiopharmaceutical costs were also assessed. RESULTS. Fifty-seven patients (30 men, 27 women; median age, 65 years; range, 21-91 years) underwent whole-body labeled leukocyte scintigraphy. Forty-two patients (30 male patients, 12 female patients; median age, 62.5 years; range, 12-91 years) underwent PET/CT for suspected infection. Labeled leukocyte scintigraphy was 66.7% sensitive, whereas the sensitivity of PET/CT was 89.7% (p = 0.0485). The higher sensitivity of PET/CT did not come at a cost to specificity, which was 73.3% as opposed to 76.9% for labeled leukocyte scintigraphy (p = 0.8050). The odds of a positive study being helpful increased 4.6-fold for PET/CT versus labeled leukocyte scintigraphy (p = 0.0412). From 2009 to 2011, 33 labeled leukocyte scintigraphic examinations were performed versus two PET/CT examinations; and from 2012 to 2014, 16 labeled leukocyte scintigraphic versus 22 PET/CT examinations; from 2015 to 2017, eight labeled leukocyte scintigraphic versus 18 PET/CT examinations. The cost of labeled leukocytes increased between 2009 and 2017, but that of FDG decreased. By 2017, a labeled leukocyte radiopharmaceutical dose was approximately 10 times the cost of an FDG dose. CONCLUSION. PET/CT was more sensitive than and as specific as labeled leukocyte scintigraphy for identifying a source of infection in inpatients, and it was more helpful to referring clinicians. Use of PET/CT increased over time and was associated with substantial savings in radiopharmaceutical cost.

ACR Appropriateness Criteria® Right Upper Quadrant Pain.

Although right upper quadrant pain is a very common clinical presentation, it can be nonspecific. However, acute cholecystitis is very often the diagnosis of exclusion. This review focuses on the recommended imaging evaluation in the most commonly encountered clinical scenarios presenting with right upper quadrant abdominal pain, including suspected biliary disease, suspected acute cholecystitis, and suspected acalculous cholecystitis. This document hopes to clarify the appropriate utilization of the many imaging procedures that are available and commonly employed in these clinical settings. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision include an extensive analysis of current medical literature from peer reviewed journals and the application of well-established methodologies (RAND/UCLA Appropriateness Method and Grading of Recommendations Assessment, Development, and Evaluation or GRADE) to rate the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances where evidence is lacking or equivocal, expert opinion may supplement the available evidence to recommend imaging or treatment.

Efficacy and Safety of High-Specific-Activity 131I-MIBG Therapy in Patients with Advanced Pheochromocytoma or Paraganglioma.

Patients with metastatic or unresectable (advanced) pheochromocytoma and paraganglioma (PPGL) have poor prognoses and few treatment options. This multicenter, phase 2 trial evaluated the efficacy and safety of high-specific-activity 131I-meta-iodobenzylguanidine (HSA 131I-MIBG) in patients with advanced PPGL. Methods: In this open-label, single-arm study, 81 PPGL patients were screened for enrollment, and 74 received a treatment-planning dose of HSA 131I-MIBG. Of these patients, 68 received at least 1 therapeutic dose (∼18.5 GBq) of HSA 131I-MIBG intravenously. The primary endpoint was the proportion of patients with at least a 50% reduction in baseline antihypertensive medication use lasting at least 6 mo. Secondary endpoints included objective tumor response as assessed by Response Evaluation Criteria in Solid Tumors version 1.0, biochemical tumor marker response, overall survival, and safety. Results: Of the 68 patients who received at least 1 therapeutic dose of HSA 131I-MIBG, 17 (25%; 95% confidence interval, 16%-37%) had a durable reduction in baseline antihypertensive medication use. Among 64 patients with evaluable disease, 59 (92%) had a partial response or stable disease as the best objective response within 12 mo. Decreases in elevated (≥1.5 times the upper limit of normal at baseline) serum chromogranin levels were observed, with confirmed complete and partial responses 12 mo after treatment in 19 of 28 patients (68%). The median overall survival was 36.7 mo (95% confidence interval, 29.9-49.1 mo). The most common treatment-emergent adverse events were nausea, myelosuppression, and fatigue. No patients had drug-related acute hypertensive events during or after the administration of HSA 131I-MIBG. Conclusion: HSA 131I-MIBG offers multiple benefits, including sustained blood pressure control and tumor response in PPGL patients.

ACR Appropriateness Criteria® Acute Nonlocalized Abdominal Pain.

The range of pathology in adults that can produce abdominal pain is broad and necessitates an imaging approach to evaluate many different organ systems. Although localizing pain prompts directed imaging/management, clinical presentations may vary and result in nonlocalized symptoms. This review focuses on imaging the adult population with nonlocalized abdominal pain, including patients with fever, recent abdominal surgery, or neutropenia. Imaging of the entire abdomen and pelvis to evaluate for infectious or inflammatory processes of the abdominal viscera and solid organs, abdominal and pelvic neoplasms, and screen for ischemic or vascular etiologies is essential for prompt diagnosis and treatment. Often the first-line modality, CT quickly evaluates the abdomen/pelvis, providing for accurate diagnoses and management of patients with abdominal pain. Ultrasound and tailored MRI protocols may be useful as first-line imaging studies, especially in pregnant patients. In the postoperative abdomen, fluoroscopy may help detect anastomotic leaks/abscesses. While often performed, abdominal radiographs may not alter management. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision include an extensive analysis of current medical literature from peer reviewed journals and the application of well-established methodologies (RAND/UCLA Appropriateness Method and Grading of Recommendations Assessment, Development, and Evaluation or GRADE) to rate the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances where evidence is lacking or equivocal, expert opinion may supplement the available evidence to recommend imaging or treatment.

Use of Eflornithine (DFMO) in the Treatment of Early Alzheimer's Disease: A Compassionate Use, Single-Case Study.

Background: Recent genome-wide association screening (GWAS) studies have linked Alzheimer's disease (AD) neuropathology to gene networks that regulate immune function. Kan et al. recently reported that Arg1 (an anti-inflammatory gene that codes for arginase-1) is expressed in parts of the brain associated with amyloidosis prior to the onset of neuronal loss, suggesting that chronic brain arginine deprivation promotes AD-related neuropathology. They blocked arginine catabolism in their mouse AD model by administration of eflornithine (DFMO) to juvenile animals, effectively blocking the expression of AD-related amyloid pathology as the mice aged. We report results from a single-case study in which DFMO was administered, for the first time, in an attempt to slow progression of AD in a single woman with multi-domain, amnestic MCI who was unable to tolerate an acetylcholinesterase inhibitor. Methods: Patient C.S. is a 74-year old female with a 5-year history of cognitive decline who was placed on DFMO (500 mg b.i.d.) for 12 months, with amyloid PET scans (baseline and 12-months), APOE genotyping and neuropsychological exams at baseline, 3, 9, and 12 months. Results: C.S. suffered continued cognitive decline over 12 months, including progressive worsening of orientation, social functions and ability to engage in IADL's. She also showed progressive decline on measures of episodic memory and executive function. Florbetapir PET imaging yielded elevated total neocortical SUVr scores at both baseline (SUVr = 1.55) and at 12 months (SUVr = 1.69). Conclusions: We report a first attempt at using DFMO to slow AD progression. This 12-month single-case trial did not halt continued amyloidosis nor cognitive decline. Although this trial was predicated on data reported by Kan et al. (2015) showing that DFMO administered to juvenile AD-prone mice led to diminished amyloid aggregation, this attempt to treat an older mild AD patient may not be a fair test of Kan et al.'s model and results. A future trial might seek to block amyloidosis in young adults who are autosomal gene carriers for early onset AD, or perhaps in adults who are very clearly in the pre-clinical disease stage. Trial Registration: This trial was registered as a Compassionate Use IND #128888 with the United States Food and Drug Administration (FDA).

Phase 1 Study of High-Specific-Activity I-131 MIBG for Metastatic and/or Recurrent Pheochromocytoma or Paraganglioma.

Context: No therapies are approved for the treatment of metastatic and/or recurrent pheochromocytoma or paraganglioma (PPGL) in the United States. Objective: To determine the maximum tolerated dose (MTD) of high-specific-activity I-131 meta-iodobenzylguanidine (MIBG) for the treatment of metastatic and/or recurrent PPGL. Design: Phase 1, dose-escalating study to determine the MTD via a standard 3 + 3 design, escalating by 37 MBq/kg starting at 222 MBq/kg. Setting: Three centers. Patients: Twenty-one patients were eligible, received study drug, and were evaluable for MTD, response, and toxicity. Intervention: Open-label use of high-specific-activity I-131 MIBG therapy. Main Outcome Measures: Dose-limiting toxicities, adverse events, radiation absorbed dose estimates, radiographic tumor response, biochemical response, and survival. Results: The MTD was determined to be 296 MBq/kg on the basis of two observed dose-limiting toxicities at the next dose level. The highest mean radiation absorbed dose estimates were in the thyroid and lower large intestinal wall (each 1.2 mGy/MBq). Response was evaluated by total administered activity: four patients (19%), all of whom received >18.5 GBq of study drug, had radiographic tumor responses of partial response by Response Evaluation Criteria in Solid Tumors. Best biochemical responses (complete or partial response) for serum chromogranin A and total metanephrines were observed in 80% and 64% of patients, respectively. Overall survival was 85.7% at 1 year and 61.9% at 2 years after treatment. The majority (84%) of adverse events were considered mild or moderate in severity. Conclusions: These findings support further development of high-specific-activity I-131 MIBG for the treatment of metastatic and/or recurrent PPGL at an MTD of 296 MBq/kg.

ACR Appropriateness Criteria® Chronic Liver Disease.

Because liver fibrosis can be treated, it is important to diagnose liver fibrosis noninvasively and monitor response to treatment. Although ultrasound (grayscale and Doppler) can diagnose cirrhosis, it does so unreliably using morphologic and sonographic features and cannot diagnose the earlier, treatable stages of hepatic fibrosis. Transient elastography, ultrasound elastography with acoustic radiation force impulse, and MR elastography are modalities that can assess for hepatic fibrosis. Although all international organizations recommend ultrasound for screening for hepatocellular carcinoma, ultrasound is particularly limited for identifying hepatocellular carcinoma in patients with obesity, nonalcoholic fatty liver disease, and nodular cirrhotic livers. In these patient groups as well as patients who are on the liver transplant wait list, ultrasound is so limited that consideration can be made for screening for hepatocellular carcinoma with either MRI or multiphase CT. Additionally, patients who have been previously diagnosed with and treated for hepatocellular carcinoma require continued surveillance for recurrent hepatocellular carcinoma. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision include an extensive analysis of current medical literature from peer reviewed journals and the application of well-established methodologies (RAND/UCLA Appropriateness Method and Grading of Recommendations Assessment, Development, and Evaluation or GRADE) to rate the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances where evidence is lacking or equivocal, expert opinion may supplement the available evidence to recommend imaging or treatment.

ACR Appropriateness Criteria® Staging of Pancreatic Ductal Adenocarcinoma.

Pancreatic adenocarcinoma is associated with poor overall prognosis. Complete surgical resection is the only possible option for cure. As such, increasingly complex surgical techniques including sophisticated vascular reconstruction are being used. Continued advances in surgical techniques, in conjunction with use of combination systemic therapies, and radiation therapy have been suggested to improve outcomes. A key aspect to surgical success is reporting of pivotal findings beyond absence of distant metastases, such as tumor size, location, and degree of tumor involvement of specific vessels associated with potential perineural tumor spread. Multiphase contrast-enhanced multidetector CT and MRI are the imaging modalities of choice for pretreatment staging and presurgical determination of resectability. Imaging modalities such as endoscopic ultrasound and fluorine-18-2-fluoro-2-deoxy-D-glucose imaging with PET/CT are indicated for specific scenarios such as biopsy guidance and confirmation of distant metastases, respectively. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision include an extensive analysis of current medical literature from peer reviewed journals and the application of well-established methodologies (RAND/UCLA Appropriateness Method and Grading of Recommendations Assessment, Development, and Evaluation or GRADE) to rate the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances where evidence is lacking or equivocal, expert opinion may supplement the available evidence to recommend imaging or treatment.

ACR Appropriateness Criteria® Chronic Liver Disease.

Because liver fibrosis can be treated, it is important to diagnose liver fibrosis noninvasively and monitor response to treatment. Although ultrasound (grayscale and Doppler) can diagnose cirrhosis, it does so unreliably using morphologic and sonographic features and cannot diagnose the earlier, treatable stages of hepatic fibrosis. Transient elastography, ultrasound elastography with acoustic radiation force impulse, and MR elastography are modalities that can assess for hepatic fibrosis. Although all international organizations recommend ultrasound for screening for hepatocellular carcinoma, ultrasound is particularly limited for identifying hepatocellular carcinoma in patients with obesity, nonalcoholic fatty liver disease, and nodular cirrhotic livers. In these patients, as well as patients who are on the liver transplant wait list, ultrasound is so limited that consideration can be made for screening for hepatocellular carcinoma with either MRI or multiphase CT. Additionally, patients who have been previously diagnosed with and treated for hepatocellular carcinoma require continued surveillance for recurrent hepatocellular carcinoma. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision include an extensive analysis of current medical literature from peer-reviewed journals and the application of well-established methodologies (RAND/UCLA Appropriateness Method and Grading of Recommendations Assessment, Development, and Evaluation or GRADE) to rate the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances where evidence is lacking or equivocal, expert opinion may supplement the available evidence to recommend imaging or treatment.

ACR Appropriateness Criteria® Suspected Liver Metastases.

Liver metastases are the most common malignant liver tumors. The accurate and early detection and characterization of liver lesions is the key to successful treatment strategies. Increasingly, surgical resection in combination with chemotherapy is effective in significantly improving survival if all metastases are successfully resected. MRI and multiphase CT are the primary imaging modalities in the assessment of liver metastasis, with the relative preference toward multiphase CT or MRI depending upon the clinical setting (ie, surveillance or presurgical planning). The optimization of imaging parameters is a vital factor in the success of either modality. PET/CT, intraoperative ultrasound are used to supplement CT and MRI. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision include an extensive analysis of current medical literature from peer-reviewed journals and the application of well-established methodologies (RAND/UCLA Appropriateness Method and Grading of Recommendations Assessment, Development, and Evaluation or GRADE) to rate the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances where evidence is lacking or equivocal, expert opinion may supplement the available evidence to recommend imaging or treatment.

Brain amyloid in preclinical Alzheimer's disease is associated with increased driving risk.

INTRODUCTION: Postmortem studies suggest that fibrillar brain amyloid places people at higher risk for hazardous driving in the preclinical stage of Alzheimer's disease (AD). METHODS: We administered driving questionnaires to 104 older drivers (19 AD, 24 mild cognitive impairment, and 61 cognitive normal) who had a recent 18F-florbetapir positron emission tomography scan. We examined associations of amyloid standardized uptake value ratios with driving behaviors: traffic violations or accidents in the past 3 years. RESULTS: The frequency of violations or accidents was curvilinear with respect to standardized uptake value ratios, peaking around a value of 1.1 (model r2  = 0.10, P = .002); moreover, this relationship was evident for the cognitively normal participants. DISCUSSION: We found that driving risk is strongly related to accumulating amyloid on positron emission tomography, and that this trend is evident in the preclinical stage of AD. Brain amyloid burden may in part explain the increased crash risk reported in older adults.

Role of PET/CT in Workup of Fever without a Source.

Fever without source is a febrile illness without localizing signs or initial obvious cause. Early workup will often include chest radiography and computed tomography (CT) of the abdomen and pelvis, with or without CT of the chest. To evaluate localizing signs or symptoms or to further evaluate findings from initial studies, targeted imaging according to body part can be performed by using radiography, ultrasonography, CT, or magnetic resonance (MR) imaging. Nuclear medicine studies can provide imaging of the whole body and may be helpful when the clinical and conventional imaging workup findings are negative or equivocal in identifying a source of fever. Nuclear medicine studies can be used to detect pathologic changes early in a disease course, even in the absence of an anatomic abnormality. Gallium 67 scintigraphy, indium 111- and technetium 99m-labeled leukocyte scintigraphy, and fluorine 18 fluorodeoxyglucose positron emission tomography (PET)/CT studies are all useful in the evaluation of fever, but the radiopharmaceutical cost for PET/CT is much lower than that for radiolabeled leukocyte studies. The increased use of bundled payments for inpatient admissions requires updated cost evaluations for the preferred nuclear medicine study. For inpatients in whom the findings from the initial clinical workup and imaging studies are nondiagnostic, PET/CT examination may be preferable to radiolabeled leukocyte studies because of its high sensitivity and lower cost. Negative findings at PET/CT can be helpful in excluding a suspected site of infection, and positive findings at PET/CT can be helpful in confirming a suspected site of infection or in identifying an unexpected cause of fever. (©)RSNA, 2016.

Acute Lower Gastrointestinal Bleeding: Temporal Factors Associated With Positive Findings on Catheter Angiography After (99m)Tc-Labeled RBC Scanning.

OBJECTIVE: The objective of the study was to determine if time to positive (TTP), defined as the time from the start of (99m)Tc-labeled RBC scanning to the appearance of a radionuclide blush (considered to be a positive finding for acute lower gastrointestinal bleeding [LGIB]), and lag time (LT), defined as the time from the appearance of a radionuclide blush to the start of catheter angiography (CA), affected the yield of CA for the detection of acute LGIB. MATERIALS AND METHODS: TTP and LT were retrospectively evaluated in 120 patients who had positive findings for acute LGIB on (99m)Tc-labeled RBC scanning and subsequently underwent CA for the diagnosis and localization of gastrointestinal bleeding. Two nuclear medicine fellowship-trained radiologists independently reviewed the (99m)Tc-labeled RBC scans. Two fellowship-trained interventional radiologists independently reviewed the angiograms. All data were analyzed using SAS software. RESULTS: When a TTP threshold of ≤ 9 minutes was used, the sensitivity, specificity, positive predictive value, and negative predictive value for a positive CA study were 92%, 35%, 27%, and 94%, respectively. In addition, the odds of detecting bleeding on CA increased 6.1-fold with a TTP of ≤ 9 minutes relative to a TTP of > 9 minutes (p = 0.020). A significant inverse relationship was found between LT and a positive CA study (p = 0.041). CONCLUSION: TTP and LT impact the rate of positive CA studies. A TTP threshold of ≤ 9 minutes allows the detection of almost all patients who would benefit from CA for treatment and allows a reduction in unnecessary negative CA studies. The likelihood of positive findings on CA decreases with a delay in the performance of CA.

ACR Appropriateness Criteria Crohn Disease.

Crohn disease is a chronic inflammatory disorder involving the gastrointestinal tract, characterized by episodic flares and times of remission. Underlying structural damage occurs progressively, with recurrent bouts of inflammation. The diagnosis and management of this disease process is dependent on several clinical, laboratory, imaging, endoscopic, and histologic factors. In recent years, with the maturation of CT enterography, and MR enterography, imaging has played an increasingly important role in relation to Crohn Disease. In addition to these specialized examination modalities, ultrasound and routine CT have potential uses. Fluoroscopy, radiography, and nuclear medicine may be less beneficial depending on the clinical scenario. The imaging modality best suited to evaluating this disease may change, depending on the target population, severity of presentation, and specific clinical situation. This document presents seven clinical scenarios (variants) in both the adult and pediatric populations and rates the appropriateness of the available imaging options. They are summarized in a consolidated table, and the underlying rationale and supporting literature are presented in the accompanying narrative. The ACR Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed every three years by a multidisciplinary expert panel. The guideline development and review include an extensive analysis of current medical literature from peer-reviewed journals and the application of a well established consensus methodology (modified Delphi) to rate the appropriateness of imaging and treatment procedures by the panel. In those instances in which evidence is lacking or not definitive, expert opinion may be used to recommend imaging or treatment.

Disruption of cholinergic neurotransmission exacerbates Aß-related cognitive impairment in preclinical Alzheimer's disease.

Disruption in cholinergic neurotransmission is one of the earliest neuropathological changes in preclinical Alzheimer's disease (AD) and may be associated with abnormal beta-amyloid (Aß) accumulation. Therefore, disruption of cholinergic neurotransmission with scopolamine may unmask otherwise undetectable cognitive deficits in preclinical AD. To compare the effects of low-dose (0.20 mg s.c.) scopolamine on cognition between Aß+ and Aß- cognitively normal (CN) older adults using the Groton Maze Learning Test (GMLT). CN older adults completed the GMLT predose and then received scopolamine (0.20 mg) subcutaneously. Participants were reassessed 1-, 3-, 5-, 7-, and 8-hours post dose. All participants underwent positron emission tomography neuroimaging for Aß using (18)F-florbetapir within 6 weeks of their baseline visit. Rhode Island Hospital Clinical Research Center, Providence, USA. CN older adults (n = 63), with a family history of AD and subjective memory complaints were enrolled (15 were classified as Aß+ and 48 were classified as Aß-). Cognition was assessed using the computerized GMLT at all predose and post-dose time points. At 5-hours post dose, the Aß+ group performed significantly worse than the Aß- group on all measures of learning efficiency and working memory and/or executive function (Cohen's d = 1.13-1.56). When participants were classified as having an abnormal response to scopolamine (based on change score at 5-hours post dose >0), 100% were correctly classified as Aß+ and 67% as Aß-. The results of this study suggest that diminished cholinergic tone likely occurs in preclinical AD, and as such, the use of a cholinergic stress test to perturb an already compromised neurotransmitter system may be an effective way of identifying CN older adults who are in this preclinical stage of AD.