Subclonal Cancer Driver Mutations Are Prevalent in the Unresected Peritumoral Edema of Adult Diffuse Gliomas.

Adult diffuse gliomas commonly recur regardless of therapy. As recurrence typically arises from the peritumoral edema adjacent to the resected bulk tumor, the profiling of somatic mutations from infiltrative malignant cells within this critical, unresected region could provide important insights into residual disease. A key obstacle has been the inability to distinguish between next-generation sequencing (NGS) noise and the true but weak signal from tumor cells hidden among the noncancerous brain tissue of the peritumoral edema. Here, we developed and validated True2 sequencing to reduce NGS-associated errors to <1 false positive/100 kb panel positions while detecting 97.6% of somatic mutations with an allele frequency ≥0.1%. True2 was then used to study the tumor and peritumoral edema of 22 adult diffuse gliomas including glioblastoma, astrocytoma, oligodendroglioma, and NF1-related low-grade neuroglioma. The tumor and peritumoral edema displayed a similar mutation burden, indicating that surgery debulks these cancers physically but not molecularly. Moreover, variants in the peritumoral edema included unique cancer driver mutations absent in the bulk tumor. Finally, analysis of multiple samples from each patient revealed multiple subclones with unique mutations in the same gene in 17 of 22 patients, supporting the occurrence of convergent evolution in response to patient-specific selective pressures in the tumor microenvironment that may form the molecular foundation of recurrent disease. Collectively, True2 enables the detection of ultralow frequency mutations during molecular analyses of adult diffuse gliomas, which is necessary to understand cancer evolution, recurrence, and individual response to therapy. SIGNIFICANCE: True2 is a next-generation sequencing workflow that facilitates unbiased discovery of somatic mutations across the full range of variant allele frequencies, which could help identify residual disease vulnerabilities for targeted adjuvant therapies.

Counseling and support services for healthcare workers in German university hospitals during the pandemic-descriptive results of a Germany-wide cross-sectional survey.

Background: Due to the SARS-CoV-2 pandemic, healthcare workers (HCWs) are experiencing tremendous levels of emotional and physical stress. Hospitals are trying to help personnel cope with work-related pressure. The aim of this study was to assess HCWs' awareness and utilization of counseling and support services during the pandemic, HCWs' unmet counseling and support needs, and the type and content of these services. Methods: A cross-sectional online survey was conducted from January to June 2021 through the German national research organization Network University Medicine (NUM). All participating hospitals (6 in total) were asked to inform their employees about the study. Results: A total of 1,495 HCWs were included in the analysis. Of these, 42.8% (n = 637) were frontline HCWs (who had contact with COVID-19 patients), 23.1% (n = 344) were second-line HCWs (who only had contact with non-COVID-19 patients) and 34.1% (n = 508) had no contact with any patients. Participating hospitals offer various counseling and support services for their staff. The percentage of respondents who were unaware of available counseling and support services ranged from 5.0 to 42.0%. Depending on the type of counseling and support services, 23.0-53.6% of the respondents indicated that counseling and support services were provided but not used, while 1.7-11.6% indicated that, despite the need for them, such services were not available. HCWs' overall satisfaction with the provided counseling and support services and their unmet support needs differed by patient contact: Frontline HCWs reported more unmet needs for counseling and support than second-line HCWs, while second-line HCWs reported more unmet needs than HCWs without patient contact. Conclusion: The results indicate that hospitals should make more efforts to inform HCWs about available counseling and support services. Hospitals could also create networks where HCWs could share information about the type and content of services and their experiences with various counseling and support services. These steps would enable hospitals to respond more quickly and effectively to the problems facing HCWs during pandemics.

[Anxiety and substance abuse disorders-Focus on alcohol and cannabis]. / Angst- und Abhängigkeitserkrankungen ­ Fokus Alkohol und Cannabis.

Anxiety disorders are frequent, with a 12-month prevalence of 14%, tend to be chronic, and display a high comorbidity with substance abuse disorders. Anxiety and substance abuse disorders are associated with a pronounced individual as well as socioeconomic burden. This article reviews the epidemiological, etiological, and clinical aspects of the dual diagnosis of anxiety and substance abuse disorders, with a particular focus on alcohol and cannabis. The treatment comprises nonpharmacological strategies, mainly cognitive behavioral therapy combined with elements of motivational interviewing (MI) and pharmacological management with antidepressants; however, the use of selective serotonin reuptake inhibitors (SSRI)/serotonin and noradrenaline reuptake inhibitors (SNRI) is not unreservedly recommended. The use of gabapentinoids requires careful risk-benefit consideration because of their potential for abuse and dependence in substance abuse disorders. Benzodiazepines are reserved exclusively for crisis management. Rapid diagnosis and treatment initiation targeting both disorders are essential for successful treatment of comorbid anxiety and substance abuse disorders.

More extensive hypometabolism and higher mortality risk in patients with right- than left-predominant neurodegeneration of the anterior temporal lobe.

BACKGROUND: Left-predominant neurodegeneration of the anterior temporal lobe (ATL) and the associated syndrome termed semantic variant primary progressive aphasia (svPPA) are well characterized. Less is known about right-predominant neurodegeneration of the ATL, which has been associated with the clinical syndrome named right temporal variant of frontotemporal dementia (rtvFTD). Here, we assessed glucose metabolism across the brain, cognitive performance, and mortality in patients with right-predominant neurodegeneration of the ATL. METHODS: Patients with predominant hypometabolism of the ATL on FDG PET (as a measure of neurodegeneration) were retrospectively identified and categorized into those with asymmetrical right, left, or symmetric bilateral involvement (N = 10, 17, and 8). We compared whole-brain, normalized regional glucose metabolism using SPM12, cognitive performance on the CERAD Neuropsychological Assessment Battery, and mortality risk (age- and sex-adjusted Cox proportional hazard model) between groups. RESULTS: Hypometabolism was most pronounced and extensive in patients with right-predominant neurodegeneration of the ATL. Beyond the right temporal lobe, right frontal and left temporal lobes were affected in these patients. Cognitive performance was similarly impaired in all three groups, with predominant naming and hippocampal-dependent memory deficits. Mortality risk was 6.1 times higher in patients with right- than left-predominant ATL neurodegeneration (p < 0.05). Median survival duration after PET was shortest in patients with right- and longest in patients with left-predominant ATL neurodegeneration (5.7 vs 8.3 years after examination). DISCUSSION: More extensive neurodegeneration and shorter survival duration in patients with right- than left-predominant neurodegeneration of the ATL might indicate that the former consult memory clinics at a later disease stage, when symptoms like naming and episodic memory deficits have already emerged. At the time of diagnosis, the shorter survival duration of patients with right- than left-predominant ATL neurodegeneration should be kept in mind when counseling patients and caregivers.

[Willingness to get vaccinated among hospital staff in Germany: What is the role of COVID-19 conspiracy assumptions?] / Impfbereitschaft von Krankenhauspersonal in Deutschland: Welche Rolle spielen Verschwörungsannahmen zu COVID-19?

BACKGROUND: A critical factor in achieving widespread immunity against COVID-19 is the willingness of previously unvaccinated individuals to get vaccinated. Medical staff play a key role in this, as they ensure healthcare during the pandemic and for many serve as a source of information about vaccinations. Among the factors that negatively influence the general willingness to get vaccinated are conspiracy assumptions and the spread of misinformation. OBJECTIVE: The willingness of hospital staff in Germany to get vaccinated and various influencing variables were examined to obtain indicators that could help increase the general willingness to get vaccinated. METHODS: Between January and June 2021, a voluntary and anonymous online survey conducted as part of the egePan joint project of the national network for university medicine (funded by the Federal Ministry of Education and Research) was used to assess the willingness to be vaccinated, individual social characteristics, the belief in conspiracy assumptions, and communication items in German hospitals. RESULTS: In comparison with the general population, physicians and scientific staff in particular indicated an increased willingness to get vaccinated. Conspiracy assumptions were not very widespread but most frequent among administrative and nursing staff. Conspiracy assumptions were negatively associated with the willingness to get vaccinated. Predictors for a higher willingness to get vaccinated were the perceived safety and effectiveness of vaccinations and a higher age. DISCUSSION: Since the perceived safety and effectiveness of vaccinations have a positive effect on the willingness to get vaccinated, educational work and transparent information transfer could counteract the spread of conspiracy assumptions and increase vaccination rates among hospital staff.

COVID-19 vaccination rates in hospitalized mentally ill patients compared to the general population in Germany: Results from the COVID Ψ Vac study.

BACKGROUND: Mental illness is known to come along with a large mortality gap compared to thegeneral population and it is a risk for COVID-19 related morbidity andmortality. Achieving high vaccination rates in people with mental illness is therefore important. Reports are conflicting on whether vaccination rates comparable to those of the general population can be achieved and which variables represent risk factors for nonvaccination in people with mental illness. METHODS: The COVID Ψ Vac study collected routine data on vaccination status, diagnostic groups, sociodemographics, and setting characteristics from in- and day-clinic patients of 10 psychiatric hospitals in Germany in August 2021. Logistic regression modeling was used to determine risk factors for nonvaccination. RESULTS: Complete vaccination rates were 59% (n = 776) for the hospitalized patients with mental illness versus 64% for the regionally and age-matched general population. Partial vaccination rates were 68% (n = 893) for the hospitalised patients with mental illness versus 67% for the respective general population and six percentage (n = 74) of this hospitalized population were vaccinated during the hospital stay. Rates showed a large variation between hospital sites. An ICD-10 group F1, F2, or F4 main diagnosis, younger age, and coercive accommodation were further risk factors for nonvaccination in the model. CONCLUSIONS: Vaccination rates were lower in hospitalized people with mental illness than in the general population. By targeting at-risk groups with low-threshold vaccination programs in all health institutions they get in contact with, vaccination rates comparable to those in the general population can be achieved.

[Post-COVID syndrome-Focus fatigue]. / Post-COVID-Syndrom ­ Fokus Fatigue.

The World Health Organization (WHO) defines post-coronavirus disease 2019 (COVID-19) as a condition which occurs in individuals with a history of probable or confirmed severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) infection 3 months after the onset of COVID-19 symptoms, lasts for at least 2 months and cannot be explained by an alternative diagnosis. Core symptoms of post-COVID syndrome are fatigue, dyspnea and cognitive dysfunction, which have an impact on everyday functional level. Neuropsychiatric late sequelae are common in COVID-19 patients, with incidence rates over 30%. Beside the abovementioned core symptoms, sleep disorders, depression and anxiety show increased incidences. According to current opinion, associated neuropsychiatric symptoms are subsumed under the term post-COVID syndrome but are also interpreted as comorbidities, which can promote the manifestation of a post-COVID syndrome. The key symptom fatigue shows symptom overlapping and comorbidity with psychiatric disorders. Imaging studies indicate an organic correlate of fatigue in post-COVID patients. Furthermore, psychosocial aspects and psychiatric comorbidities, such as depression and anxiety disorders as modulating and therefore potentially treatable factors were identified. Treatment of fatigue consists of pharmacological management with stimulants and antidepressants as well as nonpharmacological strategies, most notably cognitive behavioral therapy and exercise-focused interventions. The evidence for this comes from meta-analyses of tumor-associated or post-viral fatigue.

Molecular Imaging Findings on Acute and Long-Term Effects of COVID-19 on the Brain: A Systematic Review.

Molecular imaging techniques such as PET and SPECT have been used to shed light on how coronavirus disease 2019 (COVID-19) affects the human brain. We provide a systematic review that summarizes the current literature according to 5 predominant topics. First, a few case reports have suggested reversible cortical and subcortical metabolic alterations in rare cases with concomitant para- or postinfectious encephalitis. Second, imaging findings in single patients with the first manifestations of parkinsonism in the context of COVID-19 resemble those in neurodegenerative parkinsonism (loss of nigrostriatal integrity), but scarceness of data and a lack of follow-up preclude further etiologic conclusions (e.g., unmasking/hastening of neurodegeneration vs. infectious or parainfectious parkinsonism). Third, several case reports and a few systematic studies have addressed focal symptoms and lesions, most notably hyposmia. The results have been variable, although some studies found regional hypometabolism of regions related to olfaction (e.g., orbitofrontal and mesiotemporal). Fourth, a case series and systematic studies in inpatients with COVID-19-related encephalopathy (acute to subacute stage) consistently found a frontoparietal-dominant neocortical dysfunction (on imaging and clinically) that proved to be grossly reversible in most cases until 6 mo. Fifth, studies on post-COVID-19 syndrome have provided controversial results. In patients with a high level of self-reported complaints (e.g., fatigue, memory impairment, hyposmia, and dyspnea), some authors found extensive areas of limbic and subcortical hypometabolism, whereas others found no metabolic alterations on PET and only minor cognitive impairments (if any) on neuropsychologic assessment. Furthermore, we provide a critical appraisal of studies with regard to frequent methodologic issues and current pathophysiologic concepts. Finally, we devised possible applications of PET and SPECT in the clinical work-up of diagnostic questions related to COVID-19.

Functional Selectivity of Coumarin Derivates Acting via GPR55 in Neuroinflammation.

Anti-neuroinflammatory treatment has gained importance in the search for pharmacological treatments of different neurological and psychiatric diseases, such as depression, schizophrenia, Parkinson's disease, and Alzheimer's disease. Clinical studies demonstrate a reduction of the mentioned diseases' symptoms after the administration of anti-inflammatory drugs. Novel coumarin derivates have been shown to elicit anti-neuroinflammatory effects via G-protein coupled receptor GPR55, with possibly reduced side-effects compared to the known anti-inflammatory drugs. In this study, we, therefore, evaluated the anti-inflammatory capacities of the two novel coumarin-based compounds, KIT C and KIT H, in human neuroblastoma cells and primary murine microglia. Both compounds reduced PGE2-concentrations likely via the inhibition of COX-2 synthesis in SK-N-SH cells but only KIT C decreased PGE2-levels in primary microglia. The examination of other pro- and anti-inflammatory parameters showed varying effects of both compounds. Therefore, the differences in the effects of KIT C and KIT H might be explained by functional selectivity as well as tissue- or cell-dependent expression and signal pathways coupled to GPR55. Understanding the role of chemical residues in functional selectivity and specific cell- and tissue-targeting might open new therapeutic options in pharmacological drug development and might improve the treatment of the mentioned diseases by intervening in an early step of their pathogenesis.

Detection of circulating tumor DNA without a tumor-informed search using next-generation sequencing is a prognostic biomarker in pancreatic ductal adenocarcinoma.

The confounding effects of next-generation sequencing (NGS) noise on detection of low frequency circulating tumor DNA (ctDNA) without a priori knowledge of solid tumor mutations has limited the applications of circulating cell-free DNA (ccfDNA) in clinical oncology. Here, we use a 118 gene panel and leverage ccfDNA technical replicates to eliminate NGS-associated errors while also enhancing detection of ctDNA from pancreatic ductal adenocarcinomas (PDACs). Pre-operative ccfDNA and tumor DNA were acquired from 14 patients with PDAC (78.6% stage II-III). Post-operative ccfDNA was also collected from 11 of the patients within 100 days of surgery. ctDNA detection was restricted to variants corresponding to pathogenic mutations in PDAC present in both replicates. PDAC-associated pathogenic mutations were detected in pre-operative ccfDNA in four genes (KRAS, TP53, SMAD4, ALK) from five patients. Of the nine ctDNA variants detected (variant allele frequency: 0.08%-1.59%), five had a corresponding mutation in tumor DNA. Pre-operative detection of ctDNA was associated with shorter survival (312 vs. 826 days; χ2=5.4, P = 0.021). Guiding ctDNA detection in pre-operative ccfDNA based on mutations present in tumor DNA yielded a similar survival analysis. Detection of ctDNA in the post-operative ccfDNA with or without tumor-informed guidance was not associated with outcomes. Therefore, the detection of PDAC-derived ctDNA during a broad and untargeted survey of ccfDNA with NGS may be a valuable, non-invasive, prognostic biomarker to integrate into the clinical assessment and management of patients prior to surgery.

Impact of age and sex correction on the diagnostic performance of dopamine transporter SPECT.

PURPOSE: The specific binding ratio (SBR) of 123I-FP-CIT (FP-CIT) in the putamen decreases with age by about 5% per decade and most likely is about 10% higher in females. However, the clinical utility of age and sex correction of the SBR is still a matter of debate. This study tested the impact of age and sex correction on the diagnostic performance of the putamen SBR in three independent patient samples. METHODS: Research sample: 207 healthy controls (HC) and 438 Parkinson's disease (PD) patients. Clinical sample A: 183 patients with neurodegenerative parkinsonian syndrome (PS) and 183 patients with non-neurodegenerative PS from one site. Clinical sample B: 84 patients with neurodegenerative PS and 38 patients with non-neurodegenerative PS from another site. Correction for age and sex of the putamen SBR was based on linear regression in the HC or non-neurodegenerative PS, separately in each sample. The area under the ROC curve (AUC) was used as performance measure. RESULTS: The putamen SBR was higher in females compared to males (PPMI: 14%, p < 0.0005; clinical sample A: 7%, p < 0.0005; clinical sample B: 6%, p = 0.361). Age-related decline of the putamen SBR ranged between 3.3 and 10.4% (p ≤ 0.019). In subjects ≥ 50 years, age and sex explained < 10% of SBR between-subjects variance. Correction of the putamen SBR for age and sex resulted in slightly decreased AUC in the PPMI sample (0.9955 versus 0.9969, p = 0.025) and in clinical sample A (0.9448 versus 0.9519, p = 0.057). There was a small, non-significant AUC increase in clinical sample B (0.9828 versus 0.9743, p = 0.232). CONCLUSION: These findings do not support age and sex correction of the putaminal FP-CIT SBR in the diagnostic workup of parkinsonian syndromes. This most likely is explained by the fact that the proportion of between-subjects variance caused by age and sex is considerably below the symptom threshold of about 50% reduction in neurodegenerative PS.

Intrinsic Alertness Is Impaired in Patients with Nigrostriatal Degeneration: A Prospective Study with Reference to [123I]FP-CIT SPECT and [18F]FDG PET.

BACKGROUND: Variations in alertness and attention are common in Lewy body diseases (LBD) and among the core features of dementia with Lewy bodies (DLB). Dopamine transporter SPECT is an accurate biomarker of nigrostriatal degeneration (NSD) in LBD. OBJECTIVE: The present study investigated performance on a computerized alertness test as a potential measure of attention in patients with NSD compared to patients without NSD. METHODS: Thirty-six patients with cognitive impairment plus at least one core feature of DLB referred for [123I]FP-CIT SPECT imaging were prospectively recruited. Performance in a computerized test of intrinsic alertness was compared between patients with and those without NSD as assessed by [123I]FP-CIT SPECT. RESULTS: Reaction times to auditory stimuli (adjusted for age, sex, and education) were significantly longer in patients with NSD compared to those with a normal [123I]FP-CIT SPECT scan (p < 0.05). Statistical analyses revealed no significant differences comparing reaction times to visual stimuli or dispersion of reaction times between groups. Exploratory analysis in a subgroup of patients with available [18F]FDG PET revealed that longer reaction times were associated with decreased glucose metabolism in the prefrontal cortex (statistical parametric mapping, adjusted for age and sex; p < 0.005, cluster extent > 50 voxels). CONCLUSION: Computerized assessment of auditory reaction times is able to detect alertness deficits in patients with NSD and might help to measure alertness deficits in patients with LBD and NSD. Future studies in larger samples are needed to evaluate the diagnostic utility of computerized alertness assessment for the differential diagnosis of LBD.

[123I]FP-CIT SPECT in Clinically Uncertain Parkinsonism Predicts Survival: A Data-Driven Analysis.

BACKGROUND: Dopamine transporter SPECT is an established method to investigate nigrostriatal integrity in case of clinically uncertain parkinsonism. OBJECTIVE: The present study explores whether a data-driven analysis of [123I]FP-CIT SPECT is able to stratify patients according to mortality after SPECT. METHODS: Patients from our clinical registry were included if they had received [123I]FP-CIT SPECT between 10/2008 and 06/2016 for diagnosis of parkinsonism and if their vital status could be determined in 07/2017. Specific binding ratios (SBR) of the whole striatum, its asymmetry (asymmetry index, AI; absolute value), and the rostrocaudal gradient of striatal binding (C/pP: caudate SBR divided by posterior putamen SBR) were used as input for hierarchical clustering of patients. We tested differences in survival between these groups (adjusted for age) with a Cox proportional hazards model. RESULTS: Data from 518 patients were analyzed. Median follow-up duration was 3.3 years [95% C.I. 3.1 to 3.7]. Three subgroups identified by hierarchical clustering were characterized by relatively low striatal SBR, high AI, and low C/pP (group 1), low striatal SBR, high AI, and high C/pP (group 2), and high striatal SBR, low AI, and low C/pP (group 3). Mortality was significantly higher in group 1 compared to each of the other two groups (p = 0.029 and p = 0.003, respectively). CONCLUSION: Data-driven analysis of [123I]FP-CIT SPECT identified a subgroup of patients with significantly increased mortality during follow-up. This suggests that [123I]-FP-CIT SPECT might not only serve as a diagnostic tool to verify nigrostriatal degeneration but also provide valuable prognostic information.

Automated voxel- and region-based analysis of gray matter and cerebrospinal fluid space in primary dementia disorders.

PURPOSE: Previous studies showed voxel-based volumetry as a helpful tool in detecting pathologic brain atrophy. Aim of this study was to investigate whether the inclusion of CSF volume improves the imaging based diagnostic accuracy using combined automated voxel- and region-based volumetry. METHODS: In total, 120 individuals (30 healthy elderly, 30 frontotemporal dementia (FTD), 30 Alzheimer's dementia (AD) and 30 Lewy body dementia (LBD) patients) were analyzed with voxel-based morphometry and compared to a reference group of 360 healthy elderly controls. Abnormal GM and CSF volumes were visualized via z-scores. Volumetric results were finally evaluated by ROC analyses. RESULTS: Based on the volume of abnormal GM and CSF voxels high accuracy was shown in separating dementia from normal ageing (AUC 0.93 and 0.91, respectively) within 5 different brain regions per hemisphere (frontal, medial temporal, temporal, parietal, occipital). Accuracy for separating FTD and AD was higher based on CSF volume (FTD: AUC 0.80 vs. 0.75 in frontal regions; AD: AUC 0.78 vs. 0.68 in parietal regions based on CSF and GM respectively). CONCLUSIONS: Differentiation of dementia patients from normal ageing persons shows high accuracy when based on automatic volumetry alone. Evaluating volumes of abnormal CSF performed better than volumes of abnormal GM, especially in AD and FTD patients.

The stochastic nature of errors in next-generation sequencing of circulating cell-free DNA.

Challenges with distinguishing circulating tumor DNA (ctDNA) from next-generation sequencing (NGS) artifacts limits variant searches to established solid tumor mutations. Here we show early and random PCR errors are a principal source of NGS noise that persist despite duplex molecular barcoding, removal of artifacts due to clonal hematopoiesis of indeterminate potential, and suppression of patterned errors. We also demonstrate sample duplicates are necessary to eliminate the stochastic noise associated with NGS. Integration of sample duplicates into NGS analytics may broaden ctDNA applications by removing NGS-related errors that confound identification of true very low frequency variants during searches for ctDNA without a priori knowledge of specific mutations to target.

Anxiety in Late Life: An Update on Pathomechanisms.

Anxiety disorders are common, yet clinically underrecognized in late life, with estimated prevalence rates ranging from 1.2 to 15%. They are highly comorbid with depression, sleep disorders, and substance use disorders, may accelerate cognitive decline, and potentially catalyze morbidity and mortality risk in the elderly. Thus, a more detailed knowledge about the underlying mechanisms of late-life anxiety disorders is urgently warranted. Age-related genetic, neuroimaging, neuroendocrine, and neuropsychological markers as well as late-life specific psychosocial aspects, particularly loss and isolation, have been identified as prominent pathogenetically relevant and thus potentially targetable factors. Personalized treatments based on individual biological and biographic markers, innovative therapeutic approaches, and preventive strategies have great potential to alleviate the high individual and societal burden of late-life anxiety disorders.

Diagnostic performance of the specific uptake size index for semi-quantitative analysis of I-123-FP-CIT SPECT: harmonized multi-center research setting versus typical clinical single-camera setting.

INTRODUCTION: The specific uptake size index (SUSI) of striatal FP-CIT uptake is independent of spatial resolution in the SPECT image, in contrast to the specific binding ratio (SBR). This suggests that the SUSI is particularly appropriate for multi-site/multi-camera settings in which camera-specific effects increase inter-subject variability of spatial resolution. However, the SUSI is sensitive to inter-subject variability of striatum size. Furthermore, it might be more sensitive to errors of the estimate of non-displaceable FP-CIT binding. This study compared SUSI and SBR in the multi-site/multi-camera (MULTI) setting of a prospective multi-center study and in a mono-site/mono-camera (MONO) setting representative of clinical routine. METHODS: The MULTI setting included patients with Parkinson's disease (PD, n = 438) and healthy controls (n = 207) from the Parkinson Progression Marker Initiative. The MONO setting included 122 patients from routine clinical patient care in whom FP-CIT SPECT had been performed with the same double-head SPECT system according to the same acquisition and reconstruction protocol. Patients were categorized as "neurodegenerative" (n = 84) or "non-neurodegenerative" (n = 38) based on follow-up data. FP-CIT SPECTs were stereotactically normalized to MNI space. SUSI and SBR were computed for caudate, putamen, and whole striatum using unilateral ROIs predefined in MNI space. SUSI analysis was repeated in native patient space in the MONO setting. The area (AUC) under the ROC curve for identification of PD/"neurodegenerative" cases was used as performance measure. RESULTS: In both settings, the highest AUC was achieved by the putamen (minimum over both hemispheres), independent of the semi-quantitative method (SUSI or SBR). The putaminal SUSI provided slightly better performance with ROI analysis in MNI space compared to patient space (AUC = 0.969 vs. 0.961, p = 0.129). The SUSI (computed in MNI space) performed slightly better than the SBR in the MULTI setting (AUC = 0.993 vs. 0.991, p = 0.207) and slightly worse in the MONO setting (AUC = 0.969 vs. AUC = 0.976, p = 0.259). There was a trend toward larger AUC difference between SUSI and SBR in the MULTI setting compared to the MONO setting (p = 0.073). Variability of voxel intensity in the reference region was larger in misclassified cases compared to correctly classified cases for both SUSI and SBR (MULTI setting: p = 0.007 and p = 0.012, respectively). CONCLUSIONS: The SUSI is particularly useful in MULTI settings. SPECT images should be stereotactically normalized prior to SUSI analysis. The putaminal SUSI provides better diagnostic performance than the SUSI of the whole striatum. Errors of the estimate of non-displaceable count density in the reference region can cause misclassification by both SUSI and SBR, particularly in borderline cases. These cases might be identified by visual checking FP-CIT uptake in the reference region for particularly high variability.

Update on PET imaging biomarkers in the diagnosis of neuropsychiatric disorders.

PURPOSE OF REVIEW: To give an update on recent imaging studies probing positron emission tomography (PET) as a tool for improving biomarker-guided diagnosis of neuropsychiatric disorders. RECENT FINDINGS: Several studies confirmed the value of imaging of regional neuronal activity and imaging of dopaminergic, serotonergic, and other neuroreceptor function in the diagnostic process of neuropsychiatric disorders, particularly schizophrenia, depression/bipolar disorder, substance use disorders, obsessive compulsive disorders (OCD), and attention-deficit/hyperactivity disorder. Additionally, imaging brain microglial activation using translocator protein 18 kDa (TSPO) radiotracer allows for unique in-vivo insights into pathophysiological neuroinflammatory changes underlying schizophrenia, affective disorders, and OCD. SUMMARY: The role of PET imaging in the biomarker-guided diagnostic process of neuropsychiatric disorders has been increasingly acknowledged in recent years. Future prospective studies are needed to define the value of PET imaging for diagnosis, treatment decisions, and prognosis in neuropsychiatric disorders.

Update on PET in neurodegenerative and neuroinflammatory disorders manifesting on a behavioural level: imaging for differential diagnosis.

PURPOSE OF REVIEW: To give an update on recent findings concerning the use of PET for differential diagnosis in neurodegenerative and neuroinflammatory disorders manifesting on a behavioural level. RECENT FINDINGS: Although accurate differential diagnosis of dementia can be achieved by imaging disease-specific patterns of cerebral glucose metabolism with [F]fluorodeoxyglucose ([F]FDG)-PET, the diagnostic impact of [F]FDG-PET in primary psychiatric disorders is limited. Amyloid-beta PET provides an incremental value beyond [F]FDG-PET in the differential diagnosis of dementia and was proposed as a biomarker defining the so-called Alzheimer continuum. Recently developed tau-specific tracers might also aid in the diagnostic process (biological definition of Alzheimer's disease together with amyloid-beta). Surpassing the diagnostic accuracy of other techniques, such as MRI, [F]FDG-PET has also gained widespread clinical use for diagnosis and follow-up of paraneoplastic and autoimmune disorders of the central nervous system (CNS) as an important differential diagnosis for rapid progressive dementia and subacute onset of psychiatric syndromes. SUMMARY: Molecular neuroimaging with PET is an established method for the differential diagnosis of neurodegenerative and autoimmune CNS disorders manifesting on a behavioural level with significant therapeutic and prognostic impact. Future prospective studies are needed to define the value of tau imaging for diagnosis and prognosis in neurodegenerative disorders.

Amyloid imaging for differential diagnosis of dementia: incremental value compared to clinical diagnosis and [18F]FDG PET.

PURPOSE: Cerebral beta-amyloid and regional glucose metabolism assessed by positron emission tomography (PET) are used as diagnostic biomarkers for Alzheimer's disease (AD). The present study validates the incremental diagnostic value of amyloid PET in addition to clinical diagnosis and [18F]FDG PET in a real-life memory clinic population. METHODS: Of 138 consecutive patients with cognitive impairment who received combined [18F]FDG and [11C]PIB PET, 84 were diagnosed with major neurocognitive disorder (DSM-5) and included. Baseline clinical and [18F]FDG PET diagnoses were independently established with and without access to amyloid PET results and were dichotomized into AD or non-AD disorders. The incremental value of amyloid PET was evaluated in terms of: (1) the change in clinical and [18F]FDG PET diagnoses, (2) the change in agreement between clinical and [18F]FDG PET diagnoses, and (3) diagnostic accuracy using an interdisciplinary consensus diagnosis after an extended follow-up (2.4 ± 1.3 years after PET) as the reference. RESULTS: After disclosure of the amyloid PET results, clinical and [18F]FDG PET diagnoses changed in 23% and 18% of patients, respectively, and agreement between both ratings increased from 62% to 86% (p < 0.001). The accuracy of clinical and [18F]FDG PET diagnoses improved from 71% to 89% (p < 0.01) and from 76% to 94% (p < 0.001), respectively. The additional value of amyloid PET was rather uniform in relation to age at onset and consistency with appropriate use criteria. CONCLUSION: Amyloid PET provides significant incremental diagnostic value beyond clinical and [18F]FDG PET diagnoses of AD. Given the high diagnostic accuracy of combined clinical and amyloid PET assessment, further studies are needed to clarify the role of an additional [18F]FDG PET scan in these patients.