Cerebral Glucose Metabolism Is a Valuable Predictor of Survival in Patients with Lewy Body Diseases.

OBJECTIVE: Patients with Lewy body diseases have an increased risk of dementia, which is a significant predictor for survival. Posterior cortical hypometabolism on [18F]fluorodeoxyglucose positron emission tomography (PET) precedes the development of dementia by years. We therefore examined the prognostic value of cerebral glucose metabolism for survival. METHODS: We enrolled patients diagnosed with Parkinson's disease (PD), Parkinson's disease with dementia, or dementia with Lewy bodies who underwent [18F]fluorodeoxyglucose PET. Regional cerebral metabolism of each patient was analyzed by determining the expression of the PD-related cognitive pattern (Z-score) and by visual PET rating. We analyzed the predictive value of PET for overall survival using Cox regression analyses (age- and sex-corrected) and calculated prognostic indices for the best model. RESULTS: Glucose metabolism was a significant predictor of survival in 259 included patients (n = 118 events; hazard ratio: 1.4 [1.2-1.6] per Z-score; hazard ratio: 1.8 [1.5-2.2] per visual PET rating score; both p < 0.0001). Risk stratification with visual PET rating scores yielded a median survival of 4.8, 6.8, and 12.9 years for patients with severe, moderate, and mild posterior cortical hypometabolism (median survival not reached for normal cortical metabolism). Stratification into 5 groups based on the prognostic index revealed 10-year survival rates of 94.1%, 78.3%, 34.7%, 0.0%, and 0.0%. INTERPRETATION: Regional cerebral glucose metabolism is a significant predictor of survival in Lewy body diseases and may allow an earlier survival prediction than the clinical milestone "dementia." Thus, [18F]fluorodeoxyglucose PET may improve the basis for therapy decisions, especially for invasive therapeutic procedures like deep brain stimulation in Parkinson's disease. ANN NEUROL 2024;96:539-550.

Combining PSMA-PET and PROMISE to re-define disease stage and risk in patients with prostate cancer: a multicentre retrospective study.

BACKGROUND: Prostate-specific membrane antigen (PSMA)-PET was introduced into clinical practice in 2012 and has since transformed the staging of prostate cancer. Prostate Cancer Molecular Imaging Standardized Evaluation (PROMISE) criteria were proposed to standardise PSMA-PET reporting. We aimed to compare the prognostic value of PSMA-PET by PROMISE (PPP) stage with established clinical nomograms in a large prostate cancer dataset with follow-up data for overall survival. METHODS: In this multicentre retrospective study, we used data from patients of any age with histologically proven prostate cancer who underwent PSMA-PET at the University Hospitals in Essen, Münster, Freiburg, and Dresden, Germany, between Oct 30, 2014, and Dec 27, 2021. We linked a subset of patient hospital records with patient data, including mortality data, from the Cancer Registry North-Rhine Westphalia, Germany. Patients from Essen University Hospital were randomly assigned to the development or internal validation cohorts (2:1). Patients from Münster, Freiburg, and Dresden University Hospitals were included in an external validation cohort. Using the development cohort, we created quantitative and visual PPP nomograms based on Cox regression models, assessing potential PPP predictors for overall survival, with least absolute shrinkage and selection operator penalty for overall survival as the primary endpoint. Performance was measured using Harrell's C-index in the internal and external validation cohorts and compared with established clinical risk scores (International Staging Collaboration for Cancer of the Prostate [STARCAP], European Association of Urology [EAU], and National Comprehensive Cancer Network [NCCN] risk scores) and a previous nomogram defined by Gafita et al (hereafter referred to as GAFITA) using receiver operating characteristic (ROC) curves and area under the ROC curve (AUC) estimates. FINDINGS: We analysed 2414 male patients (1110 included in the development cohort, 502 in the internal cohort, and 802 in the external validation cohort), among whom 901 (37%) had died as of data cutoff (June 30, 2023; median follow-up of 52·9 months [IQR 33·9-79·0]). Predictors in the quantitative PPP nomogram were locoregional lymph node metastases (molecular imaging N2), distant metastases (extrapelvic nodal metastases, bone metastases [disseminated or diffuse marrow involvement], and organ metastases), tumour volume (in L), and tumour mean standardised uptake value. Predictors in the visual PPP nomogram were distant metastases (extrapelvic nodal metastases, bone metastases [disseminated or diffuse marrow involvement], and organ metastases) and total tumour lesion count. In the internal and external validation cohorts, C-indices were 0·80 (95% CI 0·77-0·84) and 0·77 (0·75-0·78) for the quantitative nomogram, respectively, and 0·78 (0·75-0·82) and 0·77 (0·75-0·78) for the visual nomogram, respectively. In the combined development and internal validation cohort, the quantitative PPP nomogram was superior to STARCAP risk score for patients at initial staging (n=139 with available staging data; AUC 0·73 vs 0·54; p=0·018), EAU risk score at biochemical recurrence (n=412; 0·69 vs 0·52; p<0·0001), and NCCN pan-stage risk score (n=1534; 0·81 vs 0·74; p<0·0001) for the prediction of overall survival, but was similar to GAFITA nomogram for metastatic hormone-sensitive prostate cancer (mHSPC; n=122; 0·76 vs 0·72; p=0·49) and metastatic castration-resistant prostate cancer (mCRPC; n=270; 0·67 vs 0·75; p=0·20). The visual PPP nomogram was superior to EAU at biochemical recurrence (n=414; 0·64 vs 0·52; p=0·0004) and NCCN across all stages (n=1544; 0·79 vs 0·73; p<0·0001), but similar to STARCAP for initial staging (n=140; 0·56 vs 0·53; p=0·74) and GAFITA for mHSPC (n=122; 0·74 vs 0·72; p=0·66) and mCRPC (n=270; 0·71 vs 0·75; p=0·23). INTERPRETATION: Our PPP nomograms accurately stratify high-risk and low-risk groups for overall survival in early and late stages of prostate cancer and yield equal or superior prediction accuracy compared with established clinical risk tools. Validation and improvement of the nomograms with long-term follow-up is ongoing (NCT06320223). FUNDING: Cancer Registry North-Rhine Westphalia.

[Dementia with Lewy bodies: old and new knowledge-Part 2: treatment]. / Demenz mit Lewy-Körpern: alte und neue Erkenntnisse ­ Teil 2: Behandlung.

BACKGROUND: The treatment of patients with dementia with Lewy bodies (DLB) is multifaceted, as motor symptoms, cognitive symptoms, behavioral and psychological symptoms can occur in different constellations. In addition, the use of certain medications is limited (e.g., neuroleptics). OBJECTIVE: To summarize the main recent findings on the treatment of DLB. RESULTS: To date, there is no approved therapeutic option for the treatment of patients with DLB in Germany; moreover, the evidence base for pharmacological and non-pharmacological treatment is sparse. The currently consented treatment options are based on the treatment of motor symptoms in the same way as the treatment of Parkinson's disease and for behavioral symptoms based on the treatment for Alzheimer's disease. DISCUSSION: The treatment of DLB with its various symptoms is difficult and often can only be adequately achieved for the patient in close cooperation with a specialist.

[Dementia with Lewy bodies: old and new knowledge - Part 1: clinical aspects and diagnostics]. / Demenz mit Lewy-Körpern: alte und neue Erkenntnisse ­ Teil 1: Klinik und Diagnostik.

BACKGROUND: Dementia with Lewy bodies (DLB) is the second most common neurodegenerative dementia after Alzheimer's disease. Patients with DLB often have a poor prognosis, with worse outcomes than patients with Alzheimer's disease in terms of important parameters, such as quality of life, caregiver burden, health-related costs, frequency of hospital and nursing home admissions, shorter time to severe dementia, and lower survival. The DLB is frequently misdiagnosed and often undertreated. Therefore, it is critical to diagnose DLB as early as possible to ensure optimal care and treatment. OBJECTIVE: The aim of this review article is to summarize the main recent findings on diagnostic tools, epidemiology and genetics of DLB. RESULTS: Precise clinical diagnostic criteria exist for DLB that enable an etiologic assignment. Imaging techniques are used as standard in DLB, especially also to exclude non-neurodegenerative causes. In particular, procedures in nuclear medicine have a high diagnostic value. DISCUSSION: The diagnosis is primarily based on clinical symptoms, although the development of in vivo neuroimaging and biomarkers is changing the scope of clinical diagnosis as well as research into this devastating disease.

Towards Improving the Efficacy of PSMA-Targeting Radionuclide Therapy for Late-Stage Prostate Cancer-Combination Strategies.

PURPOSE OF REVIEW: [177Lu]Lu-PSMA-617 is a radiopharmaceutical that emits beta-minus radiation and targets prostate-specific membrane antigen (PSMA)-positive prostate cancer. Despite its clinical success, there are still patients not showing sufficient response rates. This review compiles latest studies aiming at therapy improvement in [177Lu]Lu-PSMA-617-naïve and -resistant patients by alternative or combination treatments. RECENT FINDINGS: A variety of agents to combine with [177Lu]Lu-PSMA-617 are currently under investigation including alpha radiation-emitting pharmaceuticals, radiosensitizers, taxane chemotherapeutics, androgen receptor pathway inhibitors, immune checkpoint inhibitors, and external beam radiation. Actinium-225 (225Ac)-labeled PSMA-targeting inhibitors are the most studied pharmaceuticals for combination therapy or as an alternative for treatment after progression under [177Lu]Lu-PSMA-617 therapy. Alpha emitters seem to have a potential of achieving a response to PSMA-targeting radionuclide therapy in both initial non-responders or responders to [177Lu]Lu-PSMA-617 later developing treatment resistance. Emerging evidence for immunostimulatory effects of radiopharmaceuticals and first prospective studies support the combination of [177Lu]Lu-PSMA-617 and immune checkpoint inhibition for late-stage prostate cancer.

Widespread white matter oedema in subacute COVID-19 patients with neurological symptoms.

While neuropathological examinations in patients who died from COVID-19 revealed inflammatory changes in cerebral white matter, cerebral MRI frequently fails to detect abnormalities even in the presence of neurological symptoms. Application of multi-compartment diffusion microstructure imaging (DMI), that detects even small volume shifts between the compartments (intra-axonal, extra-axonal and free water/CSF) of a white matter model, is a promising approach to overcome this discrepancy. In this monocentric prospective study, a cohort of 20 COVID-19 inpatients (57.3 ± 17.1 years) with neurological symptoms (e.g. delirium, cranial nerve palsies) and cognitive impairments measured by the Montreal Cognitive Assessment (MoCA test; 22.4 ± 4.9; 70% below the cut-off value <26/30 points) underwent DMI in the subacute stage of the disease (29.3 ± 14.8 days after positive PCR). A comparison of whole-brain white matter DMI parameters with a matched healthy control group (n = 35) revealed a volume shift from the intra- and extra-axonal space into the free water fraction (V-CSF). This widespread COVID-related V-CSF increase affected the entire supratentorial white matter with maxima in frontal and parietal regions. Streamline-wise comparisons between COVID-19 patients and controls further revealed a network of most affected white matter fibres connecting widespread cortical regions in all cerebral lobes. The magnitude of these white matter changes (V-CSF) was associated with cognitive impairment measured by the MoCA test (r = -0.64, P = 0.006) but not with olfactory performance (r = 0.29, P = 0.12). Furthermore, a non-significant trend for an association between V-CSF and interleukin-6 emerged (r = 0.48, P = 0.068), a prominent marker of the COVID-19 related inflammatory response. In 14/20 patients who also received cerebral 18F-FDG PET, V-CSF increase was associated with the expression of the previously defined COVID-19-related metabolic spatial covariance pattern (r = 0.57; P = 0.039). In addition, the frontoparietal-dominant pattern of neocortical glucose hypometabolism matched well to the frontal and parietal focus of V-CSF increase. In summary, DMI in subacute COVID-19 patients revealed widespread volume shifts compatible with vasogenic oedema, affecting various supratentorial white matter tracts. These changes were associated with cognitive impairment and COVID-19 related changes in 18F-FDG PET imaging.

Evaluation of the cerebrovascular reactivity in patients with Moyamoya Angiopathy by use of breath-hold fMRI: investigation of voxel-wise hemodynamic delay correction in comparison to [15O]water PET.

PURPOSE: Patients with Moyamoya Angiopathy (MMA) require hemodynamic assessment to evaluate the risk of stroke. Hemodynamic evaluation by use of breath-hold-triggered fMRI (bh-fMRI) was proposed as a readily available alternative to the diagnostic standard [15O]water PET. Recent studies suggest voxel-wise hemodynamic delay correction in hypercapnia-triggered fMRI. The aim of this study was to evaluate the effect of delay correction of bh-fMRI in patients with MMA and to compare the results with [15O]water PET. METHODS: bh-fMRI data sets of 22 patients with MMA were evaluated without and with voxel-wise delay correction within different shift ranges and compared to the corresponding [15O]water PET data sets. The effects were evaluated combined and in subgroups of data sets with most severely impaired CVR (apparent steal phenomenon), data sets with territorial time delay, and data sets with neither steal phenomenon nor delay between vascular territories. RESULTS: The study revealed a high mean cross-correlation (r = 0.79, p < 0.001) between bh-fMRI and [15O]water PET. The correlation was strongly dependent on the choice of the shift range. Overall, no shift range revealed a significantly improved correlation between bh-fMRI and [15O]water PET compared to the correlation without delay correction. Delay correction within shift ranges with positive high high cutoff revealed a lower agreement between bh-fMRI and PET overall and in all subgroups. CONCLUSION: Voxel-wise delay correction, in particular with shift ranges with high cutoff, should be used critically as it can lead to false-negative results in regions with impaired CVR and a lower correlation to the diagnostic standard [15O]water PET.

Cognitive impairment and altered cerebral glucose metabolism in the subacute stage of COVID-19.

During the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic, neurological symptoms increasingly moved into the focus of interest. In this prospective cohort study, we assessed neurological and cognitive symptoms in hospitalized coronavirus disease-19 (COVID-19) patients and aimed to determine their neuronal correlates. Patients with reverse transcription-PCR-confirmed COVID-19 infection who required inpatient treatment primarily because of non-neurological complications were screened between 20 April 2020 and 12 May 2020. Patients (age > 18 years) were included in our cohort when presenting with at least one new neurological symptom (defined as impaired gustation and/or olfaction, performance < 26 points on a Montreal Cognitive Assessment and/or pathological findings on clinical neurological examination). Patients with ≥2 new symptoms were eligible for further diagnostics using comprehensive neuropsychological tests, cerebral MRI and 18fluorodeoxyglucose (FDG) PET as soon as infectivity was no longer present. Exclusion criteria were: premorbid diagnosis of cognitive impairment, neurodegenerative diseases or intensive care unit treatment. Of 41 COVID-19 inpatients screened, 29 patients (65.2 ± 14.4 years; 38% female) in the subacute stage of disease were included in the register. Most frequently, gustation and olfaction were disturbed in 29/29 and 25/29 patients, respectively. Montreal Cognitive Assessment performance was impaired in 18/26 patients (mean score 21.8/30) with emphasis on frontoparietal cognitive functions. This was confirmed by detailed neuropsychological testing in 15 patients. 18FDG PET revealed pathological results in 10/15 patients with predominant frontoparietal hypometabolism. This pattern was confirmed by comparison with a control sample using voxel-wise principal components analysis, which showed a high correlation (R2 = 0.62) with the Montreal Cognitive Assessment performance. Post-mortem examination of one patient revealed white matter microglia activation but no signs of neuroinflammation. Neocortical dysfunction accompanied by cognitive decline was detected in a relevant fraction of patients with subacute COVID-19 initially requiring inpatient treatment. This is of major rehabilitative and socioeconomic relevance.

Hemodynamic evaluation of patients with Moyamoya Angiopathy: comparison of resting-state fMRI to breath-hold fMRI and [15O]water PET.

PURPOSE: Patients with Moyamoya Angiopathy (MMA) require hemodynamic evaluation to assess the risk of stroke. Assessment of cerebral blood flow with [15O]water PET and acetazolamide challenge is the diagnostic standard for the evaluation of the cerebral perfusion reserve (CPR). Estimation of the cerebrovascular reactivity (CVR) by use of breath-hold-triggered fMRI (bh-fMRI) as an index of CPR has been proposed as a reliable and more readily available approach. Recent findings suggest the use of resting-state fMRI (rs-fMRI) which requires minimum patient compliance. The aim of this study was to compare rs-fMRI to bh-fMRI and [15O]water PET in patients with MMA. METHODS: Patients with MMA underwent rs-fMRI and bh-fMRI in the same MRI session. Maps of the CVR gained by both modalities were compared retrospectively by calculating the correlation between the mean CVR of 12 volumes of interest. Additionally, the rs-maps of a subgroup of patients were compared to CPR-maps gained by [15O]water PET. RESULTS: The comparison of the rs-maps and the bh-maps of 24 patients revealed a good correlation (Pearson's r = 0.71 ± 0.13; preoperative patients: Pearson's r = 0.71 ± 0.17; postoperative patients: Pearson's r = 0.71 ± 0.11). The comparison of 7 rs-fMRI data sets to the corresponding [15O]water PET data sets also revealed a high level of agreement (Pearson's r = 0.80 ± 0.19). CONCLUSION: The present analysis indicates that rs-fMRI might be a promising non-invasive method with almost no patient cooperation needed to evaluate the CVR. Further prospective studies are required.

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.

Deep Brain Stimulation of the Medial Forebrain Bundle in a Rodent Model of Depression: Exploring Dopaminergic Mechanisms with Raclopride and Micro-PET.

BACKGROUND: Deep brain stimulation (DBS) of the medial forebrain bundle (MFB) can reverse depressive-like symptoms clinically and in experimental models of depression, but the mechanisms of action are unknown. OBJECTIVES: This study investigated the role of dopaminergic mechanisms in MFB stimulation-mediated behavior changes, in conjunction with raclopride administration and micropositron emission tomography (micro-PET). METHODS: Flinders Sensitive Line (FSL) rats were allocated into 4 groups: FSL (no treatment), FSL+ (DBS), FSL.R (FSL with raclopride), and FSL.R+ (FSL with raclopride and DBS). Animals were implanted with bilateral electrodes targeting the MFB and given 11 days access to raclopride in the drinking water with or without concurrent continuous bilateral DBS over the last 10 days. Behavioral testing was conducted after stimulation. A PET scan using [18F]desmethoxyfallypride was performed to determine D2 receptor availability before and after raclopride treatment. Changes in gene expression in the nucleus accumbens and the hippocampus were assessed using quantitative polymerase chain reaction. RESULTS: Micro-PET imaging showed that raclopride administration blocked 36% of the D2 receptor in the striatum, but the relative level of blockade was reduced/modulated by stimulation. Raclopride treatment enhanced depressive-like symptoms in several tasks, and the MFB DBS partially reversed the depressive-like phenotype. The raclopride-treated MFB DBS animals had increased levels of mRNA coding for dopamine receptor D1 and D2 suggestive of a stimulation-mediated increase in dopamine receptors. CONCLUSION: Data suggest that chronic and continuous MFB DBS could act via the modulation of the midbrain dopaminergic transmission, including impacting on the postsynaptic dopamine receptor profile.

Neuropsychological impairment in adults with moyamoya angiopathy: preoperative assessment and correlation to MRI and H215O PET.

Patients with moyamoya angiopathy (MMA) are known to have an increased risk of impaired executive function (dysexecutive cognitive syndrome (DCS)). Numbers of moyamoya patients with DCS vary strongly in the literature; evidence of a correlation to affected vascular territories is low. This study aims to identify cognitive impairment in adult moyamoya patients and to correlate findings with imaging results. In addition, the predictive value of individual tests for the identification of DCS was analyzed. Neuropsychological test data of 41 adult moyamoya patients was analyzed for a possible correlation with territorial hypoperfusion on H215O PET with acetazolamide (ACZ) challenge (cerebrovascular reserve-CVR) and infarction patterns observed in MRI. Each vascular territory was analyzed separately and correlated to neuropsychological test results and to the presence of DCS. In total, 41.5% of patients presented with DCS. Significant association of DCS and affection of the right middle cerebral artery (MCA) territory was seen for insufficient CVR in PET (p = 0.030) and for patients with infarctions seen in MRI (p = 0.014). Analysis of individual neuropsychological test results confirmed the main association with the right MCA territory, as well as some association with the right anterior cerebral artery (ACA) territory. Analysis of a subgroup of patients with chronic disease on MRI (presence of large post-infarction gliosis and brain atrophy in affected territories) revealed a significantly higher risk for DCS (85% affected) than non-chronic patients (21% affected) (p < 0.001). Analysis of neuropsychological test data in this moyamoya cohort reveals DCS in 41.5% of all patients. Correlation between DCS and an impairment of CVR seen in PET and/or infarctions seen in MRI was significant for the right MCA territory. Patients with chronic disease had a significantly higher risk for DCS than non-chronic patients (p < 0.001).

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.

Amyloid load but not regional glucose metabolism predicts conversion to Alzheimer's dementia in a memory clinic population.

PURPOSE: The value of imaging regional glucose metabolism with [18F]FDG PET for the prediction of progression from mild cognitive impairment (MCI) to Alzheimer's dementia (AD) is controversial. The predictive value of imaging with [18F]FDG PET was therefore tested and compared with that of imaging beta-amyloid load with [11C]PIB PET in the same memory clinic population of MCI patients. METHODS: Thirty-nine patients with MCI who had undergone [18F]FDG as well as [11C]PIB PET were identified from a single-centre clinical registry. [18F]FDG and [11C]PIB PET images were rated as positive or negative for the presence of regional hypometabolism typical of AD and beta-amyloid deposition, respectively. Raters were blinded to the clinical information. Patients were followed clinically for 2.7 ± 1.2 years after PET. Cox proportional hazards models, adjusted for age and sex, were used to test the predictive value of [18F]FDG PET, [11C]PIB PET, and both in combination. RESULTS: [18F]FDG PET did not significantly predict conversion to AD (p > 0.1). By contrast, models including [11C]PIB PET only (p < 0.05) or both [18F]FDG and [11C]PIB PET (p < 0.05) significantly predicted conversion to AD. The hazard ratio for AD in patients with a positive [11C]PIB scan was 10.2 (95% confidence interval 1.3-78.1). The results were confirmed by analysis of semiquantitative measures using normalized [18F]FDG uptake and [11C]PIB standardized uptake value ratios in AD-typical regions as continuous predictors. CONCLUSION: In contrast to [11C]PIB PET, [18F]FDG PET did not predict conversion from MCI to AD in this clinical patient sample. Therefore, amyloid PET should be preferred for individual prediction and patient counselling in clinical practice.

Performance of 111In-labelled PSMA ligand in patients with nodal metastatic prostate cancer: correlation between tracer uptake and histopathology from lymphadenectomy.

PURPOSE: Intraoperative identification of lymph node (LN) metastases (LNM) detected on preoperative PSMA PET/CT may be facilitated by PSMA radioguided surgery with the use of a gamma probe. We evaluated the uptake of 111In-labelled PSMA ligand DKFZ-617 (referred to as 111In-PSMA-617) in unaffected LN and LNM at the level of single LN. METHODS: Six patients with prostate cancer (PCa) with suspicion of LNM on preoperative PSMA PET/CT underwent 111In-PSMA-617-guided lymphadenectomy (LA; four salvage LA and two primary LA). 111In-PSMA-617 (109 ± 5 MBq). was injected Intravenously 48 h prior to surgery Template LAs were performed in small subregions: common, external, obturator and internal iliac vessels, and presacral and retroperitoneal subregions (n = 4). Samples from each subregion were isolated aiming at the level of single LN. Uptake was measured ex situ using a germanium detector. Receiver operating characteristic (ROC) analysis was performed based on 111In-PSMA-617 uptake expressed as standardized uptake values normalized to lean body mass (SUL). RESULTS: Overall 310 LN (mean 52 ± 19.7) were removed from 74 subregions (mean 12 ± 3.7). Of the 310 LN, 35 turned out to be LNM on histopathology. Separation of the samples from all subregions resulted in 318 single specimens: 182 PCa-negative LN samples with 275 LN, 35 single LNM samples, 3 non-nodal PCa tissue samples and 98 fibrofatty tissue samples. The median SULs of nonaffected LN (0.16) and affected LN (13.2) were significantly different (p < 0.0001). Based on 38 tumour-containing and 182 tumour-free specimens, ROC analysis revealed an area under the curve of 0.976 (95% CI 0.95-1.00, p < 0.0001). Using a SUL cut-off value of 1.136, sensitivity, specificity, positive predictive value, negative predictive value and accuracy in discriminating affected from nonaffected LN were 92.1% (35/38), 98.9% (180/182), 94.6% (35/37), 98.4% (180/183) and 97.7% (215/220), respectively. CONCLUSION: Ex situ analysis at the level of single LN showed that 111In-PSMA-617 had excellent ability to discriminate between affected and nonaffected LN in our patients with PCa. This tracer characteristic is a prerequisite for in vivo real-time measurements during surgery.

Antidepressant treatment effects on dopamine transporter availability in patients with major depression: a prospective 123I-FP-CIT SPECT imaging genetic study.

We investigated if sleep deprivation (SD) and electroconvulsive therapy (ECT) affect striatal dopamine transporter (DAT) availability assessed by single-photon emission computed tomography (SPECT) and 123I-FP-CIT, if dopamine transporter gene (SLC6A3; DAT) variation modifies aforementioned parameters, and if SD response or SD-induced DAT changes correlate with ECT response. Sixteen patients with major depression (MDD) referred for ECT and 12 matched controls were prospectively recruited for imaging and SLC6A3 VNTR genotyping. After withdrawal from any psychiatric medication, 123I-FP-CIT-SPECT was acquired at baseline, after SD and after ECT series. Striatal DAT availability was assessed by volume-of-interest analysis of SPECT data. Eleven patients underwent combined treatment with SD and ECT (five ECT responders and six non-responders). Per-protocol analyses yielded no significant effect of SD or ECT on striatal DAT availability using repeated-measures ANOVA. However, intention-to-treat analysis indicated a significant decrease of striatal DAT availability due to SD (paired t test, p < 0.01). Stratification by SLC6A3 VNTR genotype suggested the 9R allele to drive this effect. In an exploratory analysis, SD-induced change in DAT availability of the left caudate nucleus predicted ECT response. This study revealed a treatment effect of SD on striatal DAT availability-possibly depending on SLC6A3 VNTR genotype. This and the observed association between SD-induced change of striatal DAT availability and response to ECT may help to identify treatment mechanisms and response predictors useful for precision medicine approaches in the treatment of MDD.

Regional neuronal activity in patients with relapsing remitting multiple sclerosis.

OBJECTIVES: Although interferon-beta is an established drug for relapsing remitting multiple sclerosis (RRMS), its impact on neuronal activity is not well understood. METHODS: We investigated 15 patients with RRMS by [18 F]fluorodeoxyglucose positron emission tomography (FDG-PET) to assess cerebral metabolic rate of glucose (CMRglc ) before interferon-beta therapy. Further, we performed clinical and neuropsychological investigations. In nine patients, these investigations were repeated after 6 months of therapy. Ten healthy controls were also studied. RESULTS: We found no significant differences in absolute CMRglc between patients and controls, or in patients before and during treatment. However, during treatment, relative regional glucose metabolism (rCMRlglc ) was decreased in cerebellum and increased in parts of left inferior parietal, temporo-occipital, frontal cortical areas, left striatum and right insula. In untreated patients, higher fatigue was associated with lower rCMRlglc in portions of left posterior cingulate cortex, and higher depression was associated with lower rCMRlglc within the left superior temporal sulcus. In the pooled sample, higher depression was associated with higher rCMRlglc in parts of the right precuneus. CONCLUSIONS: Our results indicate effects of IFN-beta treatment on cerebellar, cortical and subcortical neuronal function. Moreover, more severe fatigue and depression in untreated patients seem to be associated with reduced neuronal activity in left posterior cingulate cortex and left superior temporal cortex, respectively.

Biological imaging for individualized therapy in radiation oncology: part I physical and technical aspects.

Recently, there has been an increase in the imaging modalities available for radiotherapy planning and radiotherapy prognostic outcome: dual energy computed tomography (CT), dynamic contrast enhanced CT, dynamic contrast enhanced magnetic resonance imaging (MRI), diffusion-weighted MRI, positron emission tomography-CT, dynamic contrast enhanced ultrasound, MR spectroscopy and positron emission tomography-MR. These techniques enable more precise gross tumor volume definition than CT alone and moreover allow subvolumes within the gross tumor volume to be defined which may be given a boost dose or an individual voxelized dose prescription may be derived. With increased plan complexity care must be taken to immobilize the patient in an accurate and reproducible manner. Moreover the physical and technical limitations of the entire treatment planning chain need to be well characterized and understood, interdisciplinary collaboration ameliorated (physicians and physicists within nuclear medicine, radiology and radiotherapy) and image protocols standardized.

Biological imaging for individualized therapy in radiation oncology: part II medical and clinical aspects.

Positron emission tomography and multiparametric MRI provide crucial information concerning tumor extent and normal tissue anatomy. Moreover, they are able to visualize biological characteristics of the tumor, which can be considered in the radiation treatment planning and monitoring. In this review we discuss the impact of biological imaging positron emission tomography and multiparametric MRI for radiation oncology, based on the data of the literature and on the experience of our own institution in this field.