Introducing a gatekeeping system for amyloid status assessment in mild cognitive impairment.

BACKGROUND: In patients with mild cognitive impairment (MCI), enhanced cerebral amyloid-ß plaque burden is a high-risk factor to develop dementia with Alzheimer's disease (AD). Not all patients have immediate access to the assessment of amyloid status (A-status) via gold standard methods. It may therefore be of interest to find suitable biomarkers to preselect patients benefitting most from additional workup of the A-status. In this study, we propose a machine learning-based gatekeeping system for the prediction of A-status on the grounds of pre-existing information on APOE-genotype 18F-FDG PET, age, and sex. METHODS: Three hundred and forty-two MCI patients were used to train different machine learning classifiers to predict A-status majority classes among APOE-ε4 non-carriers (APOE4-nc; majority class: amyloid negative (Aß-)) and carriers (APOE4-c; majority class: amyloid positive (Aß +)) from 18F-FDG-PET, age, and sex. Classifiers were tested on two different datasets. Finally, frequencies of progression to dementia were compared between gold standard and predicted A-status. RESULTS: Aß- in APOE4-nc and Aß + in APOE4-c were predicted with a precision of 87% and a recall of 79% and 51%, respectively. Predicted A-status and gold standard A-status were at least equally indicative of risk of progression to dementia. CONCLUSION: We developed an algorithm allowing approximation of A-status in MCI with good reliability using APOE-genotype, 18F-FDG PET, age, and sex information. The algorithm could enable better estimation of individual risk for developing AD based on existing biomarker information, and support efficient selection of patients who would benefit most from further etiological clarification. Further potential utility in clinical routine and clinical trials is discussed.

The validation status of blood biomarkers of amyloid and phospho-tau assessed with the 5-phase development framework for AD biomarkers.

PURPOSE: The development of blood biomarkers that reflect Alzheimer's disease (AD) pathophysiology (phosphorylated tau and amyloid-ß) has offered potential as scalable tests for dementia differential diagnosis and early detection. In 2019, the Geneva AD Biomarker Roadmap Initiative included blood biomarkers in the systematic validation of AD biomarkers. METHODS: A panel of experts convened in November 2019 at a two-day workshop in Geneva. The level of maturity (fully achieved, partly achieved, preliminary evidence, not achieved, unsuccessful) of blood biomarkers was assessed based on the Biomarker Roadmap methodology and discussed fully during the workshop which also evaluated cerebrospinal fluid (CSF) and positron emission tomography (PET) biomarkers. RESULTS: Plasma p-tau has shown analytical validity (phase 2 primary aim 1) and first evidence of clinical validity (phase 3 primary aim 1), whereas the maturity level for Aß remains to be partially achieved. Full and partial achievement has been assigned to p-tau and Aß, respectively, in their associations to ante-mortem measures (phase 2 secondary aim 2). However, only preliminary evidence exists for the influence of covariates, assay comparison and cut-off criteria. CONCLUSIONS: Despite the relative infancy of blood biomarkers, in comparison to CSF biomarkers, much has already been achieved for phases 1 through 3 - with p-tau having greater success in detecting AD and predicting disease progression. However, sufficient data about the effect of covariates on the biomarker measurement is lacking. No phase 4 (real-world performance) or phase 5 (assessment of impact/cost) aim has been tested, thus not achieved.

2020 update on the clinical validity of cerebrospinal fluid amyloid, tau, and phospho-tau as biomarkers for Alzheimer's disease in the context of a structured 5-phase development framework.

PURPOSE: In the last decade, the research community has focused on defining reliable biomarkers for the early detection of Alzheimer's disease (AD) pathology. In 2017, the Geneva AD Biomarker Roadmap Initiative adapted a framework for the systematic validation of oncological biomarkers to cerebrospinal fluid (CSF) AD biomarkers-encompassing the 42 amino-acid isoform of amyloid-ß (Aß42), phosphorylated-tau (P-tau), and Total-tau (T-tau)-with the aim to accelerate their development and clinical implementation. The aim of this work is to update the current validation status of CSF AD biomarkers based on the Biomarker Roadmap methodology. METHODS: A panel of experts in AD biomarkers convened in November 2019 at a 2-day workshop in Geneva. The level of maturity (fully achieved, partly achieved, preliminary evidence, not achieved, unsuccessful) of CSF AD biomarkers was assessed based on the Biomarker Roadmap methodology before the meeting and presented and discussed during the workshop. RESULTS: By comparison to the previous 2017 Geneva Roadmap meeting, the primary advances in CSF AD biomarkers have been in the area of a unified protocol for CSF sampling, handling and storage, the introduction of certified reference methods and materials for Aß42, and the introduction of fully automated assays. Additional advances have occurred in the form of defining thresholds for biomarker positivity and assessing the impact of covariates on their discriminatory ability. CONCLUSIONS: Though much has been achieved for phases one through three, much work remains in phases four (real world performance) and five (assessment of impact/cost). To a large degree, this will depend on the availability of disease-modifying treatments for AD, given these will make accurate and generally available diagnostic tools key to initiate therapy.

Clinical validity of increased cortical uptake of [18F]flortaucipir on PET as a biomarker for Alzheimer's disease in the context of a structured 5-phase biomarker development framework.

PURPOSE: In 2017, the Geneva Alzheimer's disease (AD) Biomarker Roadmap initiative adapted the framework of the systematic validation of oncological diagnostic biomarkers to AD biomarkers, with the aim to accelerate their development and implementation in clinical practice. With this work, we assess the maturity of [18F]flortaucipir PET and define its research priorities. METHODS: The level of maturity of [18F]flortaucipir was assessed based on the AD Biomarker Roadmap. The framework assesses analytical validity (phases 1-2), clinical validity (phases 3-4), and clinical utility (phase 5). RESULTS: The main aims of phases 1 (rationale for use) and 2 (discriminative ability) have been achieved. [18F]Flortaucipir binds with high affinity to paired helical filaments of tau and has favorable kinetic properties and excellent discriminative accuracy for AD. The majority of secondary aims of phase 2 were fully achieved. Multiple studies showed high correlations between ante-mortem [18F]flortaucipir PET and post-mortem tau (as assessed by histopathology), and also the effects of covariates on tracer binding are well studied. The aims of phase 3 (early detection ability) were only partially or preliminarily achieved, and the aims of phases 4 and 5 were not achieved. CONCLUSION: Current literature provides partial evidence for clinical utility of [18F]flortaucipir PET. The aims for phases 1 and 2 were mostly achieved. Phase 3 studies are currently ongoing. Future studies including representative MCI populations and a focus on healthcare outcomes are required to establish full maturity of phases 4 and 5.

Combined Early and Late [68Ga]PSMA-HBED-CC PET Scans Improve Lesion Detectability in Biochemical Recurrence of Prostate Cancer with Low PSA Levels.

PURPOSE: Our aim was to evaluate the benefit of early (1 h post-injection (p.i.)) and late (3 h p.i.) [68Ga]PSMA-HBED-CC positron emission tomography (PET)/x-ray computed tomography (CT) imaging for detection of biochemical recurrence (BCR) of prostate cancer (PCa). PROCEDURES: Seventy patients with BCR of the PCa and prostate-specific antigen (PSA) levels of less than 2.0 µg/l were subjected to [68Ga]PSMA-HBED-CC PET (mean injected activity 180 MBq). While early imaging contained whole body scans, late imaging was confined to the pelvis and the lower abdomen. Uptake in suspicious lesions was analyzed by peak and maximum standardized uptake values (SUVpeak/max). Tumor-to-background ratios were calculated for all lesions in which the liver served as reference organ. The Wilcoxon matched-pair signed-rank test was used to compare the uptake in suspicious lesions between early and late imaging. Follow-up data were used to validate the existence of the additionally detected lesions. RESULTS: Forty-four of the 70 patients thus examined were interpreted as PSMA-positive in early and/or late scans while 26 remained without suspicion of PSMA tracer uptake. A total of 70 suspicious lesions were analyzed. Ten tumor-suspicious lesions from seven different patients were better or exclusively visible in the late measurements while three tumor-suspicious lesions from three different patients were better or exclusively visible in the early images. A validation by follow-up data was possible for 11 of these 13 additionally detected lesions. In direct comparison between early and late imaging, the mean SUVmax in PSMA-positive lesions was 74 % higher (p < 0.001) and the mean SUVpeak was 36 % higher (p = 0.001) in the late scans. The SUVmean in the reference regions was decreasing in the late measurements, whereas the mean TBR increased by a factor of 3 (p < 0.001). Taking confirmed lesions only into account, we estimated a 10 % gain in additionally detected PSMA-positive lesions (7/70) within the patient cohort. CONCLUSIONS: The time period between injection and data acquisition influences the detection rate of [68Ga]PSMA-HBED-CC PET/CT. In biochemical recurrence with low PSA levels, late [68Ga]PSMA-HBED-CC PET/CT imaging offers frequent advantages with regard to lesion contrast.

Value of bone marrow biopsy in Hodgkin lymphoma patients staged by FDG PET: results from the German Hodgkin Study Group trials HD16, HD17, and HD18.

Background: Bone marrow (BM) involvement defines advanced-stage Hodgkin lymphoma and thus has impact on the assignment to treatment. Our aim was to evaluate whether the established BM biopsy may be omitted in patients if 18F-fluorodeoxyglucose positron emission tomography (PET) scanning is carried out during staging. Patients and methods: Our analysis set consisted of 832 Hodgkin lymphoma patients from the German Hodgkin Study Group trials HD16, HD17, and HD18 who underwent both PET scanning and BM biopsy before treatment. All PET studies were centrally reviewed and BM was categorized as showing focal involvement or not. Results: Taking BM biopsy as reference standard, baseline PET showed a negative predictive value of 99.9% [95% confidence interval (CI) 99.2% to 100%] with true-negative results in 702 of 703 cases. The sensitivity of PET for detecting BM involvement was 95.0% (95% CI 75.1% to 99.9%) as it could identify 19 out of 20 patients with positive BM biopsy. Moreover, PET found 110 additional subjects with focal BM lesions who would have been considered negative by biopsy. Conclusions: When compared with BM biopsy, PET was able to detect focal BM lesions in a large number of additional patients. This indicates that conventional BM biopsy may substantially underestimate the actual incidence of BM involvement. Given the high negative predictive value, baseline PET scanning can safely be used to exclude BM involvement in Hodgkin lymphoma. BM biopsy should be considered only in such patients in whom PET-detected lesions lead to a change of treatment protocol. Registered trials: The trials included in this analysis were registered at ClinicalTrials.gov: HD16-NCT00736320, HD17-NCT01356680, and HD18-NCT00515554.

European Association of Nuclear Medicine and European Academy of Neurology recommendations for the use of brain 18 F-fluorodeoxyglucose positron emission tomography in neurodegenerative cognitive impairment and dementia: Delphi consensus.

BACKGROUND AND PURPOSE: Recommendations for using fluorodeoxyglucose positron emission tomography (FDG-PET) to support the diagnosis of dementing neurodegenerative disorders are sparse and poorly structured. METHODS: Twenty-one questions on diagnostic issues and on semi-automated analysis to assist visual reading were defined. Literature was reviewed to assess study design, risk of bias, inconsistency, imprecision, indirectness and effect size. Critical outcomes were sensitivity, specificity, accuracy, positive/negative predictive value, area under the receiver operating characteristic curve, and positive/negative likelihood ratio of FDG-PET in detecting the target conditions. Using the Delphi method, an expert panel voted for/against the use of FDG-PET based on published evidence and expert opinion. RESULTS: Of the 1435 papers, 58 papers provided proper quantitative assessment of test performance. The panel agreed on recommending FDG-PET for 14 questions: diagnosing mild cognitive impairment due to Alzheimer's disease (AD), frontotemporal lobar degeneration (FTLD) or dementia with Lewy bodies (DLB); diagnosing atypical AD and pseudo-dementia; differentiating between AD and DLB, FTLD or vascular dementia, between DLB and FTLD, and between Parkinson's disease and progressive supranuclear palsy; suggesting underlying pathophysiology in corticobasal degeneration and progressive primary aphasia, and cortical dysfunction in Parkinson's disease; using semi-automated assessment to assist visual reading. Panellists did not support FDG-PET use for pre-clinical stages of neurodegenerative disorders, for amyotrophic lateral sclerosis and Huntington disease diagnoses, and for amyotrophic lateral sclerosis or Huntington-disease-related cognitive decline. CONCLUSIONS: Despite limited formal evidence, panellists deemed FDG-PET useful in the early and differential diagnosis of the main neurodegenerative disorders, and semi-automated assessment helpful to assist visual reading. These decisions are proposed as interim recommendations.

[The importance of molecular imaging (PET) in the diagnostics of dementia]. / Bedeutung molekularer Bildgebung (PET) in der Diagnostik von Demenzerkrankungen.

Due to the expanding older population and increasing prevalence of dementia and currently lacking curative therapy but potentially conceivable availability of molecular-specific treatment to delay the progression of cognitive decline, the early diagnosis of cognitive deficits and their etiological differential diagnosis becomes increasingly more important. The advances in nuclear medicine diagnostics in the field of neurodegenerative diseases within the last few years have been substantial. In this article the relevance of these technologies in the diagnostic process of dementia is described.

[Lutetium-177-PSMA radioligand therapy : Consensus within the framework of GKV-funded care between the university hospitals in Aachen, Bonn, Düsseldorf, Essen, and Cologne and the MDK Nordrhein]. / Lutetium-177-PSMA-Radioligandentherapie : Konsensus im Rahmen der GKV-finanzierten Versorgung zwischen den Hochschulkliniken in Aachen, Bonn, Düsseldorf, Essen und Köln und dem MDK Nordrhein.

In the last 3 years, Lutetium-177 prostate-specific membrane antigen radioligand therapy (Lu-177-PSMA-RLT) has received increasing attention in nuclear medicine as a new form of treatment for castration-resistant metastatic prostate cancer. This therapy combines the radionuclide Lutetium-177, which has been therapeutically used in nuclear medicine for many years, with a molecular target of the transmembrane prostate-specific membrane antigen expressed by prostate cancer cells. Since there are no prospective randomized studies on Lu-177-PSMA-RLT and the question of reimbursement has repeatedly been the subject of review by the MDK Nordrhein (Medischenische Dienst der Krankenversicherung), there was a desire because of the increasing number of patients being treated to clarify under which circumstances Lu-177-PSMA-RLT can be reimbursed by German statutory health insurance. The goals of this article are to help treating physicians understand how this new therapy option works, to integrate it in the overall therapy concept for castration-resistant metastatic prostate cancer, and, above all, to use Lu-177-PSMA-RLT-based on the current data-at the right place in the therapy sequence of castration-resistant metastatic prostate cancer.

Retention efficacy and release of radioiodine in fume hoods.

Procedures to determine the release of hazardous gaseous substances including radioactive iodine are covered by different norms such as the European standard EN 14175 and the German national standard DIN 25466. The detection of sulphur hexafluoride (SF6) is required to comply with the prescribed methodology. The detection limit of this test is 4.5·10-7 mol/m3 in exhaust air. This detection limit would represent a very high activity in the region of 0.27 TBq/m3 leading to an unacceptable risk. We therefore developed a test using a filter system, consisting of a combination of filters capable of separating various chemical forms of airborne radioiodine. Air samples were collected directly in front of the fume hood and in the laboratory beside two different fume hoods of a similar construction with a final activated carbon filter for retention of radioiodine. Particular attention was therefore paid to air samples taken after passage over the filters. Significant differences in the degree of retention of iodine were found between the two fume hoods investigated. In one test a malfunction of the fume hood was demonstrated. In this case 0.148 × 10-3% of the total released activity per m3 air was found 1 cm in front of the hood sash. A remarkably high fraction of the activity released in the fume hood (1.3 × 10-3%/m3 air) was measured after the activated carbon filter. In the ambient air, values of up to 8.6 × 10-6% pro m3 laboratory air sampled were measured, despite a 6-8-fold air exchange. The selected procedure is a factor of 1011 (Schomäcker et al., 2001) more sensitive than the standard recommended methods (EN 14175). The standard test prescribed by the DIN/EN failed to reveal any inadequacy in the protective function of the radionuclide hood with respect to radioiodine retention.

Exhalation of 131I after radioiodine therapy: Dosimetric considerations based on measurements in exhaled air.

It is well known that a considerable amount of radioiodine is exhaled after radioiodine therapy (RIT) leading to unwanted radiation exposure through inhalation for non-involved persons. This study focuses on the amount of exhalation in the breath-out air of RIT-patients and the dosimetric consequences. Furthermore, the correlation between radioiodine uptake and exhalation was investigated. The radioiodine species were collected in a filter system and quantified over time by measurements with a scintillation counter. The dosimetric implications were then studied for different exposure scenarios. Of the activity administered to the patient, approximately 10-3% (50-110 ppm) is exhaled. The radioiodine inhalation taking place following exhalation in the vicinity yields doses of up to 500 µSv (children, staying with the patient immediately after application and for the next 8 h). Three days after administration the doses are significantly reduced. This study lays emphasis on previous assumptions that exhalation depends on thyroid storage. Regardless of the type of thyroid disease, the predominant form exhaled is organic radioiodine. The amount of exhaled radioiodine is small but from the point of view of radiation protection, by no means negligible immediately after administration. Radiation doses received by incorporation of exhaled radioiodine can easily exceed 100 µSv soon after administration of radioiodine. Three days after RIT the radioactivity can still be measured in the exhaled air but even at maximum, the annual doses lie far below 10 µSv and are thus comparatively low.

The effectiveness of wastewater treatment in nuclear medicine: Performance data and radioecological considerations.

For planned and ongoing storage of liquid radioactive waste in a designated plant for a nuclear medicine therapy ward (decontamination system/decay system), detailed knowledge of basic parameters such as the amount of radioactivity and the necessary decay time in the plant is required. The design of the plant at the Department of Nuclear Medicine of the University of Cologne, built in 2001, was based on assumptions about the individual discharge of activity from patients, which we can now retrospectively validate. The decontamination factor of the plant is at present in the order of 10-9 for 131I. The annual discharges have been continuously reduced over the period of operation and are now in the region of a few kilobecquerels. This work emphasizes the high efficacy of the decontamination plant to reduce the amount of radioactivity released from the nuclear medicine ward into the environment to almost negligible levels.

Influence of iodine supply on the radiation-induced DNA-fragmentation.

The protective effect of stable iodide against radiation on thyroid cells was investigated. One physiological effect of stable iodine is well-rooted: stable iodine leads to a reduced thyroid uptake of radioactive iodine. This work wants to focus on an intrinsic effect of stable iodine by which DNA-damage in cells is prevented. To investigate this intrinsic effect thyroid cells (FRTL-5) were externally irradiated by use of a linear accelerator (LINAC) applying energy doses of 0.01 Gy-400 Gy and by incubation with various activity concentrations of 131I (0.1-50 MBq/ml for 24 h). We added stable iodine (NaI) to the cells prior to external irradiation and investigated the effect of the concentration of stable iodine (1, 5, 15 µg/ml). In order to clarify whether thyroid cells have a distinctive and iodine-dependent reaction to ionizing radiation, keratinocytes (HaCaT) without NIS were exposed in the same way. As indicators for the cellular reaction, the extent of DNA fragmentation was determined (Roche, Mannheim, Germany). Both cell types showed distinct ability for apoptosis as proven with camptothecin. The addition of "cold" iodine from 1 to 15 µg/ml without irradiation ("negative control") did not change the response in both cell types. Plausibly, the radio-sensitivity of both cell types did increase markedly with increasing radiation dose but the radiation effect is diminished if iodine is added to the thyroid cells beforehand. The DNA-damage in thyroid cells after addition of cold iodine is reduced by a factor of 2-3. The skin cells did not show an significant change of radio-sensitivity depending on the presence of cold iodine. Elementary iodine possibly acts as a radical scavenger and thus markedly reduces the secondary radiation damage caused by the formation of cytotoxic radicals. This intrinsic radioprotective effect of iodine is seen only in cells with NIS.

Concordance in the interpretation of PET after chemotherapy in advanced stage Hodgkin lymphoma.

UNLABELLED: The aim was to analyze the degree of agreement between the central review panel and the local PET interpretation within the HD15 trial and its impact on subsequent treatment and progression free survival. PATIENTS, METHODS: The analysis set consisted of 739 patients with residues ≥ 2.5 cm after 6 or 8 cycles of BEACOPPesc from the HD15 trial performed by the German Hodgkin Study Group. The recommendation for or against further radiotherapy was based on the central [(18)F]FDG-PET interpretation. Central PET interpretation was compared to the local PET interpretation and concordance was measured using Cohen's Kappa coefficient. Prognostic impact of the analysis of concordance between local and central PET interpretations was evaluated using progression free survival (PFS); groups were compared with the log rank test. RESULTS: The central panel rated 548 of 739 patients (74%) as PET negative. Of these, 513 were also rated as PET negative in the local PET interpretation. PET positivity was seen by central reviewers in the remaining 191 patients (26%), in concordance with local reviewers in 155 cases. Even though substantial agreement was found (Cohen's Kappa 0.81), the interpretation of the central PET review panel led to a different therapeutic recommendation in 71/739 (10%) patients. PFS was equally high in groups in which the therapeutic regime had been changed on the basis of the central panel decision. CONCLUSION: High concordance is found between local and central reviewers with regard to PET interpretation in residual tissue after intense chemotherapy. The existence of the central PET review panel allows the identification of additional patients as PET negative so that radiotherapy can be safely omitted (35 of 548 patients = 4.7%).

Combined PET/MRI: Multi-modality Multi-parametric Imaging Is Here: Summary Report of the 4th International Workshop on PET/MR Imaging; February 23-27, 2015, Tübingen, Germany.

This paper summarises key themes and discussions from the 4th international workshop dedicated to the advancement of the technical, scientific and clinical applications of combined positron emission tomography (PET)/magnetic resonance imaging (MRI) systems that was held in Tübingen, Germany, from February 23 to 27, 2015. Specifically, we summarise the three days of invited presentations from active researchers in this and associated fields augmented by round table discussions and dialogue boards with specific topics. These include the use of PET/MRI in cardiovascular disease, paediatrics, oncology, neurology and multi-parametric imaging, the latter of which was suggested as a key promoting factor for the wider adoption of integrated PET/MRI. Discussions throughout the workshop and a poll taken on the final day demonstrated that attendees felt more strongly that PET/MRI has further advanced in both technical versatility and acceptance by clinical and research-driven users from the status quo of last year. Still, with only minimal evidence of progress made in exploiting the true complementary nature of the PET and MRI-based information, PET/MRI is still yet to achieve its potential. In that regard, the conclusion of last year's meeting "the real work has just started" still holds true.

Current status and future role of brain PET/MRI in clinical and research settings.

Hybrid PET/MRI systematically offers a complementary combination of two modalities that has often proven itself superior to the single modality approach in the diagnostic work-up of many neurological and psychiatric diseases. Emerging PET tracers, technical advances in multiparametric MRI and obvious workflow advantages may lead to a significant improvement in the diagnosis of dementia disorders, neurooncological diseases, epilepsy and neurovascular diseases using PET/MRI. Moreover, simultaneous PET/MRI is well suited to complex studies of brain function in which fast fluctuations of brain signals (e.g. related to task processing or in response to pharmacological interventions) need to be monitored on multiple levels. Initial simultaneous studies have already demonstrated that these complementary measures of brain function can provide new insights into the functional and structural organization of the brain.

Volume of interest-based [18F]fluorodeoxyglucose PET discriminates MCI converting to Alzheimer's disease from healthy controls. A European Alzheimer's Disease Consortium (EADC) study.

An emerging issue in neuroimaging is to assess the diagnostic reliability of PET and its application in clinical practice. We aimed at assessing the accuracy of brain FDG-PET in discriminating patients with MCI due to Alzheimer's disease and healthy controls. Sixty-two patients with amnestic MCI and 109 healthy subjects recruited in five centers of the European AD Consortium were enrolled. Group analysis was performed by SPM8 to confirm metabolic differences. Discriminant analyses were then carried out using the mean FDG uptake values normalized to the cerebellum computed in 45 anatomical volumes of interest (VOIs) in each hemisphere (90 VOIs) as defined in the Automated Anatomical Labeling (AAL) Atlas and on 12 meta-VOIs, bilaterally, obtained merging VOIs with similar anatomo-functional characteristics. Further, asymmetry indexes were calculated for both datasets. Accuracy of discrimination by a Support Vector Machine and the AAL VOIs was tested against a validated method (PALZ). At the voxel level SMP8 showed a relative hypometabolism in the bilateral precuneus, and posterior cingulate, temporo-parietal and frontal cortices. Discriminant analysis classified subjects with an accuracy ranging between .91 and .83 as a function of data organization. The best values were obtained from a subset of 6 meta-VOIs plus 6 asymmetry values reaching an area under the ROC curve of .947, significantly larger than the one obtained by the PALZ score. High accuracy in discriminating MCI converters from healthy controls was reached by a non-linear classifier based on SVM applied on predefined anatomo-functional regions and inter-hemispheric asymmetries. Data pre-processing was automated and simplified by an in-house created Matlab-based script encouraging its routine clinical use. Further validation toward nonconverter MCI patients with adequately long follow-up is needed.

The patient as a radioactive source: an intercomparison of survey meters for measurements in nuclear medicine.

In this work, the radiation exposure in nuclear medicine is evaluated by measuring dose rates in the proximity of patients and those in close contact to sources like capsules and syringes. A huge number of different survey meters (SMs) are offered commercially. This topic has recently gained interest since dosemeters and active personal dosemeters (APD) for the new dose quantities (ambient and directional dose equivalent) have become available. One main concern is the practical use of SMs and APD in daily clinical routines. Therefore, the radiation field of four common radiopharmaceuticals containing (18)F, (90)Y, (99m)Tc and (131)I in radioactive sources or after application to the patient was determined. Measurements were carried out with different SMs and for several distances. Dose rates decline significantly with the distance to the patient, and with some restrictions, APD can be used as SMs.

The Road Ahead to Cure Alzheimer's Disease: Development of Biological Markers and Neuroimaging Methods for Prevention Trials Across all Stages and Target Populations.

Alzheimer's disease (AD) is a slowly progressing non-linear dynamic brain disease in which pathophysiological abnormalities, detectable in vivo by biological markers, precede overt clinical symptoms by many years to decades. Use of these biomarkers for the detection of early and preclinical AD has become of central importance following publication of two international expert working group's revised criteria for the diagnosis of AD dementia, mild cognitive impairment (MCI) due to AD, prodromal AD and preclinical AD. As a consequence of matured research evidence six AD biomarkers are sufficiently validated and partly qualified to be incorporated into operationalized clinical diagnostic criteria and use in primary and secondary prevention trials. These biomarkers fall into two molecular categories: biomarkers of amyloid-beta (Aß) deposition and plaque formation as well as of tau-protein related hyperphosphorylation and neurodegeneration. Three of the six gold-standard ("core feasible) biomarkers are neuroimaging measures and three are cerebrospinal fluid (CSF) analytes. CSF Aß1-42 (Aß1-42), also expressed as Aß1-42 : Aß1-40 ratio, T-tau, and P-tau Thr181 & Thr231 proteins have proven diagnostic accuracy and risk enhancement in prodromal MCI and AD dementia. Conversely, having all three biomarkers in the normal range rules out AD. Intermediate conditions require further patient follow-up. Magnetic resonance imaging (MRI) at increasing field strength and resolution allows detecting the evolution of distinct types of structural and functional abnormality pattern throughout early to late AD stages. Anatomical or volumetric MRI is the most widely used technique and provides local and global measures of atrophy. The revised diagnostic criteria for "prodromal AD" and "mild cognitive impairment due to AD" include hippocampal atrophy (as the fourth validated biomarker), which is considered an indicator of regional neuronal injury. Advanced image analysis techniques generate automatic and reproducible measures both in regions of interest, such as the hippocampus and in an exploratory fashion, observer and hypothesis-indedendent, throughout the entire brain. Evolving modalities such as diffusion-tensor imaging (DTI) and advanced tractography as well as resting-state functional MRI provide useful additionally useful measures indicating the degree of fiber tract and neural network disintegration (structural, effective and functional connectivity) that may substantially contribute to early detection and the mapping of progression. These modalities require further standardization and validation. The use of molecular in vivo amyloid imaging agents (the fifth validated biomarker), such as the Pittsburgh Compound-B and markers of neurodegeneration, such as fluoro-2-deoxy-D-glucose (FDG) (as the sixth validated biomarker) support the detection of early AD pathological processes and associated neurodegeneration. How to use, interpret, and disclose biomarker results drives the need for optimized standardization. Multimodal AD biomarkers do not evolve in an identical manner but rather in a sequential but temporally overlapping fashion. Models of the temporal evolution of AD biomarkers can take the form of plots of biomarker severity (degree of abnormality) versus time. AD biomarkers can be combined to increase accuracy or risk. A list of genetic risk factors is increasingly included in secondary prevention trials to stratify and select individuals at genetic risk of AD. Although most of these biomarker candidates are not yet qualified and approved by regulatory authorities for their intended use in drug trials, they are nonetheless applied in ongoing clinical studies for the following functions: (i) inclusion/exclusion criteria, (ii) patient stratification, (iii) evaluation of treatment effect, (iv) drug target engagement, and (v) safety. Moreover, novel promising hypothesis-driven, as well as exploratory biochemical, genetic, electrophysiological, and neuroimaging markers for use in clinical trials are being developed. The current state-of-the-art and future perspectives on both biological and neuroimaging derived biomarker discovery and development as well as the intended application in prevention trials is outlined in the present publication.