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Episodic memory is a polygenic trait influenced by different molecular mechanisms. We used PET and a candidate gene approach to investigate how individual differences at the molecular level translate into between-person differences in episodic memory performance of elderly persons. Specifically, we examined the interactive effects between hippocampal dopamine D2 receptor (D2DR) availability and candidate genes relevant for hippocampus-related memory functioning. We show that the positive effects of high D2DR availability in the hippocampus on episodic memory are confined to carriers of advantageous genotypes of the brain-derived neurotrophic factor ( BDNF, rs6265) and the kidney and brain expressed protein ( KIBRA, rs17070145) polymorphisms. By contrast, these polymorphisms did not modulate the positive relationship between caudate D2DR availability and episodic memory.

Purpose Assess the agreement for two investigators between computed tomography (CT) and magnetic resonance imaging (MRI) for seven imaging features included in the iNPH Radscale, a radiological screening tool. Methods The study included 35 patients with idiopathic normal pressure hydrocephalus (iNPH) who were treated surgically from 2011 to 2015 at Uppsala University Hospital with preoperative CT and MRI performed with maximum 3 months between scans. Seven features were assessed: Evans’ index, temporal horn size, callosal angle, periventricular white matter changes, narrow high convexity sulci, focally enlarged sulci, and enlarged Sylvian fissures. All scans were assessed by two investigators who were blinded to each other’s results and to clinical data. Results The agreement between CT and MRI was almost perfect for Evans’ index, temporal horns, narrow sulci, and Sylvian fissures (kappa and intraclass correlation, 0.84–0.91, p ≤ 0.001). There was substantial to almost perfect agreement for callosal angle and focally enlarged sulci. The concordance between modalities was fair for changes in periventricular white matter. Conclusion CT and MRI are equally good for assessing radiological signs associated with iNPH except for periventricular white matter changes, as MRI has superior soft tissue contrast. The other imaging features can be evaluated consistently, and assessments are reproducible independent of modality. Therefore, the iNPH Radscale is applicable to both CT and MRI and may become an important tool for standardized evaluation in the workup in patients with suspected iNPH. Electronic supplementary material The online version of this article (10.1007/s00234-019-02273-2) contains supplementary material, which is available to authorized users.

Background and aims: Hereditary transthyretin amyloid (ATTRv) amyloidosis caused by the transthyretin (TTR) Val30Met (p.V50M) mutation is characterised by peripheral neuropathy, and central nervous ...

Introduction: Long-term outcomes linked to preterm (PT) births have generally found an increased amount of neuromotor-developmental delays and/or disabilities. Few studies have addressed how upper- ...

Evidence indicates that neoadjuvant chemotherapy (NAC) may promote antitumour immune responses by activating T cells. The tumour-draining sentinel node (SN) is a key site to study tumour-specific T cell activation, being the primary immunological barrier against the tumour. In this prospective study, we set out to elucidate the effects of NAC on T cell subsets in the SNs of patients with muscle-invasive urothelial bladder cancer. We found that CD8

Vigor reflects how motivated one is to respond to a stimulus. We previously showed that humans are more vigorous when more reward is available on average, and that this relationship is modulated by the dopamine precursor levodopa. Dopamine signalling and probabilistic reward learning degrade with age, so the relationship between vigor and reward should change with age. We test this and assess whether the relationship between vigor and reward correlates with D1 dopamine receptor availability measured using Positron Emission Tomography. We measured response times of 30 older and 30 younger subjects during an oddball discrimination task where rewards varied systematically between trial. Reward rate had a similar impact on the vigor of both groups. We observed a weak positive association across subjects between ventral striatal dopamine receptor availability and effect of average reward rate on response time, which was in the opposite direction to our prediction. Overall, the effect of reward on response vigor is similar between younger and older humans and is weakly sensitive to dopamine D1 receptor availability.

With increasing age, functional connectomes become dissimilar across normal individuals, reflecting heterogenous aging effects on functional connectivity (FC). We investigated the distribution of these effects across the connectome and their relationship with age-related differences in dopamine (DA) D1 receptor availability and gray matter density (GMD). With this aim, we determined aging effects on mean and interindividual variance of FC using fMRI in 30 younger and 30 older healthy subjects and mapped the contribution of each connection to the patterns of age-related similarity loss. Aging effects on mean FC accounted mainly for the dissimilarity between connectomes of younger and older adults, and were related, across brain regions, to aging effects on DA D1 receptor availability. Aging effects on the variance of FC indicated a global increase in variance with advancing age, explained connectome dissimilarity among older subjects and were related to aging effects on variance of GMD. The relationship between aging and the similarity of connectomes can thus be partly explained by age differences in DA modulation and gray matter structure. Supplementary Information The online version contains supplementary material available at 10.1007/s00429-020-02205-4.

Background and purpose In locally advanced prostate cancer (PC), androgen deprivation therapy (ADT) in combination with whole prostate radiotherapy (RT) is the standard treatment. ADT affects the prostate as well as the tumour on multiparametric magnetic resonance imaging (MRI) with decreased PC conspicuity and impaired localisation of the prostate lesion. Image texture analysis has been suggested to be of aid in separating tumour from normal tissue. The aim of the study was to investigate the impact of ADT on baseline defined MRI features in prostate cancer with the goal to investigate if it might be of use in radiotherapy planning. Materials and methods Fifty PC patients were included. Multiparametric MRI was performed before, and three months after ADT. At baseline, a tumour volume was delineated on apparent diffusion coefficient (ADC) maps with suspected tumour content and a reference volume in normal prostatic tissue. These volumes were transferred to MRIs after ADT and were analysed with first-order -and invariant Haralick -features. Results At baseline, the median value and several of the invariant Haralick features of ADC, showed a significant difference between tumour and reference volumes. After ADT, only ADC median value could significantly differentiate the two volumes. Conclusions Invariant Haralick -features could not distinguish between baseline MRI defined PC and normal tissue after ADT. First-order median value remained significantly different in tumour and reference volumes after ADT, but the difference was less pronounced than before ADT.

Within-person, moment-to-moment, variability in behavior increases with advancing adult age, potentially reflecting the influence of reduced structural and neurochemical brain integrity, especially that of the dopaminergic system. We examined the role of dopamine D2 receptor (D2DR) availability, grey-, and white-matter integrity, for between-person differences in cognitive variability in a large sample of healthy older adults (n = 181; 64–68 years) from the Cognition, Brain, and Aging (COBRA) study. Intra-individual variability (IIV) in cognition was measured as across-trial variability in participants’ response times for tasks assessing perceptual speed and working memory, as well as for a control task of motor speed. Across the whole sample, no associations of D2DR availability, or grey- and white-matter integrity, to IIV were observed. However, within-person variability in cognition was increased in two subgroups of individuals displaying low mean-level cognitive performance, one of which was characterized by low subcortical and cortical D2DR availability. In this latter group, fronto-striatal D2DR availability correlated negatively with within-person variability in cognition. This finding suggests that the influence of D2DR availability on cognitive variability may be more easily disclosed among individuals with low dopamine-system integrity, highlighting the benefits of large-scale studies for delineating heterogeneity in brain-behavior associations in older age.

The hippocampal longitudinal axis has been linked to dissociated functional networks relevant to episodic memory. However, the organization of axis-dependent networks and their relation to episodic memory in aging remains less explored. Moreover, age-related deterioration of the dopamine (DA) system, affecting memory and functional network properties, might constitute a source of reduced specificity of hippocampal networks in aging. Here, we characterized axis-dependent large-scale hippocampal resting-state networks, their relevance to episodic memory, and links to DA in older individuals (n = 170, 64–68 years). Partial least squares identified 2 dissociated networks differentially connected to the anterior and posterior hippocampus. These overlapped with anterior–temporal/posterior–medial networks in young adults, indicating preserved organization of axis-dependent connectivity in old age. However, axis-specific networks were overall unrelated to memory and hippocampal DA D2 receptor availability (D2DR) measured with [11C]-raclopride positron emission tomography. Further analyses identified a memory-related network modulated by hippocampal D2DR, equally connected to anterior–posterior regions. This network included medial frontal, posterior parietal, and striatal areas. The results add to the current understanding of large-scale hippocampal connectivity in aging, demonstrating axis-dependent connectivity with dissociated anterior and posterior networks, as well as a primary role in episodic memory of connectivity shared by regions along the hippocampalaxis.

PURPOSE: Nearly half of penile cancers are related to human papillomavirus (HPV) infection. Investigations of tumor- and HPV-specific T cell reactivity in regional lymph nodes (LNs) from patients with penile cancer are warranted. MATERIALS AND METHODS: In this study, single-cell suspensions from LNs and peripheral blood from 11 patients with penile cancer were stained with antibodies for lymphocyte markers and analyzed by fluorescence-activated cell sorting (FACS). DNA was extracted from the tumor tissue and HPV status was investigated by PCR. RESULTS: T-cell reactivity against autologous tumor-extract and against the HPV-vaccine Gardasil® was tested by flow-cytometric assay of specific cell-mediated immune response in activated whole blood (FASCIA). CD4+/CD8+ ratios were significantly lower in HPV positive LNs (p

Purpose: Resectability assessment of patients with colorectal liver metastases is based on computed tomography and liver magnetic resonance imaging. Addition of fluorine-18-fluorodeoxyglucose positron emission tomography/computed tomography has been recommended, but the impact of the added information remains unclear. The primary aim of this study was to determine how preoperative positron emission tomography/computed tomography changed management in patients with potentially resectable colorectal liver metastases. The secondary aim was to investigate whether findings on positron emission tomography/computed tomography correlated to metastatic disease in cases with extended surgery and influenced oncological outcomes. Methods: A retrospective observational study of the impact of adding positron emission tomography/computed tomography to conventional imaging in the surgical decision-making of colorectal liver metastases. All patients with colorectal liver metastases diagnosed by conventional imaging were included and assessed by a multidisciplinary team conference at Umeå University Hospital between June 2013 and December 2017. Eligibility criteria were all patients with potentially resectable colorectal liver metastases. Patients who underwent preoperative positron emission tomography/computed tomography in addition to conventional radiology were compared with those who underwent conventional imaging only. Results: 151/220 patients underwent preoperative positron emission tomography/computed tomography. Findings on positron emission tomography/computed tomography changed the management in 10.6% of the patients. Eight patients were excluded from surgery after detection by positron emission tomography/computed tomography of extrahepatic disease. Eight patients underwent more extended surgery than initially planned due to positron emission tomography/computed tomography. Five of these positron emission tomography-positive resected sites were verified by pathology as metastatic disease. No difference in overall survival was seen following surgical resection in patients with and without a preoperative positron emission tomography/computed tomography. Conclusions: Preoperative positron emission tomography/computed tomography resulted in a changed surgical management in 10.6% of cases in a selected cohort.

In the effort of developing new immunotherapies, the sentinel node (SN) has proven a promising source from which to harness an effective antitumour T cell response. However, tumour immune escape, a process in which regulatory T cells (Tregs) play a central role, remains a major limiting factor. Therefore, there is a clear need to increase the knowledge of Treg function and signalling in sentinel nodes. Here, we set out to explore whether the proteome in SN-resident T cells is altered by the tumour and to identify key proteins in SN T cell signalling, focusing on Tregs. Five patients with muscle-invasive urothelial bladder cancer were prospectively included. Mass spectrometry was performed on two patients, with validation and functional studies being performed on three additional patients and four healthy donors. At cystectomy, SN, non-SN lymph nodes and peripheral blood samples were collected from the patients and T cell subsets isolated through flow cytometry before downstream experiments. Proteomic analysis indicated that growth and immune signalling pathways are upregulated in SN-resident Tregs. Furthermore, centrality analysis identified the cytokine IL-16 to be central in the SN-Treg signalling network. We show that tumour-released factors, through activating caspase-3, increase Treg IL-16 processing into bioactive forms, reinforcing Treg suppressive capacity. In conclusion, we provide evidence that Tregs exposed to secreted factors from bladder tumours show increased immune and growth signalling and altered IL-16 processing which translates to enhanced Treg suppressive function, indicating altered IL-16 signalling as a novel tumour immune escape mechanism.

The finding of reduced activity in the default mode network (DMN) during externally focused cognitive control has been highly influential to our understanding of human brain function, but ‘deactivations’ have also prompted major questions of interpretation. Using hybrid functional PET-MR imaging, this study shows that fMRI task activations and deactivations do not reflect antagonistic patterns of synaptic metabolism. FMRI activations were accompanied by concomitant increases in metabolism during cognitive control, but, unlike the BOLD response, metabolism in the core DMN did not change between rest and task. Metabolic increases along the borders of the DMN during task performance further revealed a set of regions that guide engagement and suppression of neighboring networks during cognitive control. Collectively, dissociations between metabolism and BOLD signal specific to the DMN reveal functional heterogeneity in this network and demonstrate that BOLD deactivations during cognitive control should not be interpreted to reflect reduced synaptic activity.

Normal brain aging is a multidimensional process that includes deterioration in various brain structures and functions, with large heterogeneity in patterns and rates of decline. Sex differences have been reported for various cognitive and brain parameters, but little is known in relation to neuromodulatory aspects of brain aging. We examined sex differences in dopamine D2-receptor (D2DR) availability in relation to episodic memory, but also, grey-matter volumes, white-matter lesions, and cerebral perfusion in healthy older adults (n = 181, age: 64–68 years) from the Cognition, Brain, and Aging study. Women had higher D2DR availability in midbrain and left caudate and putamen, as well as superior episodic memory performance. Controlling for left caudate D2DR availability attenuated sex differences in memory performance. In men, lower left caudate D2DR levels were associated with lower cortical perfusion and higher burden of white-matter lesions, as well as with episodic memory performance. However, sex was not a significant moderator of the reported links to D2DR levels. Our findings suggest that sex differences in multiple associations among DA receptor availability, vascular factors, and structural connectivity contribute to sex differences in episodic memory. Future longitudinal studies need to corroborate these patterns by lead-lag associations. This manuscript is part of the Special Issue entitled ‘Cognitive Neuroscience of Healthy and Pathological Aging’ edited by Drs. M. N. Rajah, S. Belleville, and R. Cabeza. This article is part of the Virtual Special Issue titled COGNITIVE NEUROSCIENCE OF HEALTHY AND PATHOLOGICAL AGING. The full issue can be found on ScienceDirect at https://www.sciencedirect.com/journal/neurobiology-of-aging/special-issue/105379XPWJP .

Background: Cachexia and sarcopenia are associated with poor survival after colorectal cancer (CRC) diagnosis. Computed tomography (CT) can be used to measure aspects of cachexia including sarcopenia, myosteatosis and the amount of subcutaneous and visceral adipose tissue. The aim of this study was to relate CT-based body composition variables with survival outcomes in CRC. Material and methods: In this population-based, retrospective cohort study, CT scans of 974 patients with pathological stages I-IV CRCs, collected at or very near diagnosis (years 2000-2016), were used to measure cross-sectional fat and muscle tissue areas. Body composition variables based on these measurements were assessed in relation to tumor stage and site and cancer-specific survival in stages I-III CRC (n = 728) using Cox proportional hazards models and Kaplan-Meier estimators. Results: Sarcopenia was associated with decreased cancer-specific survival, especially in patients with stages I-II tumors. The hazard ratio (HR) for the lowest versus highest tertile of skeletal muscle index (SMI) was 1.67; 95% confidence interval (CI), 1.08-2.58 for all stages, and HR 2.22; 95% CI 1.06-4.68, for stages I-II. Myosteatosis was also associated with decreased cancer-specific survival [(HR 2.03; 95% CI 1.20-3.34 for the lowest versus the highest tertile of skeletal muscle radiodensity (SMR)]. SMI and SMR were lower in patients with right-sided CRC, independent of age and sex. No adipose tissue measurement was significantly associated with cancer-specific survival. Conclusion: In concordance with previous studies, sarcopenia and myosteatosis were associated with decreased cancer-specific survival. The strong association between sarcopenia and poor cancer-specific survival in early-stage disease could have clinical implications for personalizing therapy decisions, including nutritional support.

Purpose To enable the evaluation of locoregional disease in the on-going RECTOPET (REctal Cancer Trial on PET/MRI/CT) study; a methodology to match mesorectal imaging findings to histopathology is presented, along with initial observations. Methods FDG-PET/MRI examinations were performed in twenty-four consecutively included patients with rectal adenocarcinoma. In nine patients, of whom five received neoadjuvant treatment, a postoperative MRI of the surgical specimen was performed. The pathological cut-out was performed according to clinical routine with the addition of photo documentation of each slice of the surgical specimen, meticulously marking the location, size, and type of pathology of each mesorectal finding. This allowed matching individual nodal structures from preoperative MRI, via the specimen MRI, to histopathology. Results Preoperative MRI identified 197 mesorectal nodal structures, of which 92 (47%) could be anatomically matched to histopathology. Of the matched nodal structures identified in both MRI and histopathology, 25% were found to be malignant. These malignant structures consisted of lymph nodes (43%), tumour deposits (48%), and extramural venous invasion (9%). One hundred eleven nodal structures (55%) could not be matched anatomically. Of these, 97 (87%) were benign lymph nodes, and 14 (13%) were malignant nodal structures. Five were malignant lymph nodes, and nine were tumour deposits, all of which had a short axis diameter Conclusions We designed a method able to anatomically match and study the characteristics of individual mesorectal nodal structures, enabling further research on the impact of each imaging modality. Initial observations suggest that small malignant nodal structures assessed as lymph nodes in MRI often comprise other forms of mesorectal tumour spread. Trial registration Clinical Trials Identifier:NCT03846882.

ObjectiveTo determine whether neurofilament light chain protein in CSF (cNfL), a sensitive biomarker of neuroaxonal damage, reflects disease severity or can predict survival in Parkinson disease (PD).MethodsWe investigated whether disease severity, phenotype, or survival in patients with new-onset PD correlates with cNfL concentrations around the time of diagnosis in the population-based New Parkinsonism in Umeå (NYPUM) study cohort (n = 99). A second, larger new-onset PD cohort (n = 194) was used for independent validation. Association of brain pathology with the cNfL concentration was examined with striatal dopamine transporter imaging and repeated diffusion tensor imaging at baseline and 1 and 3 years.ResultsHigher cNfL in the early phase of PD was associated with greater severity of all cardinal motor symptoms except tremor in both cohorts and with shorter survival and impaired olfaction. cNfL concentrations above the median of 903 ng/L conferred an overall 5.8 times increased hazard of death during follow-up. After adjustment for age and sex, higher cNfL correlated with striatal dopamine transporter uptake deficits and lower fractional anisotropy in diffusion tensor imaging of several axonal tracts.ConclusionscNfL shows usefulness as a biomarker of disease severity and to predict survival in PD. The present results indicate that the cNfL concentration reflects the intensity of the neurodegenerative process, which could be important in future clinical trials.Classification of evidenceThis study provides Class II evidence that in patients with PD, cNfL concentrations are associated with more severe disease and shorter survival.

Probabilistic reward learning reflects the ability to adapt choices based on probabilistic feedback. The dopaminergically innervated corticostriatal circuit in the brain plays an important role in supporting successful probabilistic reward learning. Several components of the corticostriatal circuit deteriorate with age, as it does probabilistic reward learning. We showed previously that D1 receptor availability in NAcc predicts the strength of anticipatory value signaling in vmPFC, a neural correlate of probabilistic learning that is attenuated in older participants and predicts probabilistic reward learning performance. We investigated how white matter integrity in the pathway between nucleus accumbens (NAcc) and ventromedial prefrontal cortex (vmPFC) relates to the strength of anticipatory value signaling in vmPFC in younger and older participants. We found that in a sample of 22 old and 23 young participants, fractional anisotropy in the pathway between NAcc and vmPFC predicted the strength of value signaling in vmPFC independently from D1 receptor availability in NAcc. These findings provide tentative evidence that integrity in the dopaminergic and white matter pathways of corticostriatal circuitry supports the expression of value signaling in vmPFC which supports reward learning, however, the limited sample size calls for independent replication. These and future findings could add to the improved understanding of how corticostriatal integrity contributes to reward learning ability.

Purpose To examine the relationship between the number of tumour draining sentinel nodes (SNs) and pathoanatomical outcomes, in muscle-invasive bladder cancer (MIBC), in patients undergoing neoadjuvant chemotherapy (NAC) and radical cystectomy (RC). Materials and Methods In an ongoing prospective multicenter study, we included 230 patients with suspected urothelial MIBC from ten Swedish urological centers. All underwent TURb and clinical staging. From the cohort, 116 patients with urothelial MIBC; cT2-cT4aN0M0, underwent radical cystectomy (RC) and lymphadenectomy with SN-detection (SNd). 83 patients received cisplatin-based NAC and 33 were NAC-naïve. The number and locations of detected SNs and non-SNs were recorded for each patient. The NAC treated patients were categorized by pathoanatomical outcomes post-RC into three groups: complete responders (CR), stable disease (SD) and progressive disease (PD). Selected covariates with possible impact on SN-yield were tested in uni -and multivariate analyses for NAC-treated patients only. Results In NAC treated patients, the mean number of SNs was significantly higher in CR patients (3.3) and SD patients (3.6) compared with PD patients (1.4) (p = 0.034). In a linear multivariate regression model, the number of harvested nodes was the only independent variable that affected the number of SNs (p = 0.0004). Conclusions The number of tumor-draining SNs in NAC-treated patients was significantly lower in patients with progressive disease.

Background and purposeThe idiopathic normal pressure hydrocephalus (iNPH) Radscale was developed to standardize the evaluation of radiological signs in iNPH. The purpose of this study was to estimate the diagnostic accuracy of the iNPH Radscale in a sample of "true positive" and "true negative" cases.MethodsSeventy-five patients with definite iNPH, i.e. who had improved at clinical follow-up one year after ventriculoperitoneal shunt surgery, were compared with 55 asymptomatic individuals from the general population. A radiologist assessed the seven radiological features of the iNPH Radscale in computed tomography of the brain in the patients (preoperatively) and controls.ResultsThe iNPH Radscale score was significantly higher in the iNPH group (Median = 10, interquartile range 9-11) than in the control group (Median = 1, interquartile range 1-2) (p ConclusionsIn this study, iNPH Radscale could accurately discriminate between patients with definite iNPH and asymptomatic individuals over 65 years old. According to the results, a diagnosis of iNPH is very likely in patients with an iNPH Radscale score above 8 and corresponding clinical symptoms. On the other hand, the diagnosis should be questioned when the iNPH Radscale score is below the cut-off level of 4. We conclude that the iNPH Radscale could work as a diagnostic screening tool to detect iNPH. Whether the scale also can be used to predict shunt outcome needs further studies.

Dopamine (DA) modulates corticostriatal connections. Studies in which imaging of the DA system is integrated with functional imaging during cognitive performance have yielded mixed findings. Some work has shown a link between striatal DA (measured by PET) and fMRI activations, whereas others have failed to observe such a relationship. One possible reason for these discrepant findings is differences in task demands, such that a more demanding task with greater prefrontal activations may yield a stronger association with DA. Moreover, a potential DA–BOLD association may be modulated by task performance. We studied 155 (104 normal-performing and 51 low-performing) healthy older adults (43% females) who underwent fMRI scanning while performing a working memory (WM)n-back task along with DA D2/3PET assessment using [11C]raclopride. Using multivariate partial-least-squares analysis, we observed a significant pattern revealing positive associations of striatal as well as extrastriatal DA D2/3receptors to BOLD response in the thalamo–striatal–cortical circuit, which supports WM functioning. Critically, the DA–BOLD association in normal-performing, but not low-performing, individuals was expressed in a load-dependent fashion, with stronger associations during 3-back than 1-/2-back conditions. Moreover, normal-performing adults expressing upregulated BOLD in response to increasing task demands showed a stronger DA–BOLD association during 3-back, whereas low-performing individuals expressed a stronger association during 2-back conditions. This pattern suggests a nonlinear DA–BOLD performance association, with the strongest link at the maximum capacity level. Together, our results suggest that DA may have a stronger impact on functional brain responses during more demanding cognitive tasks.SIGNIFICANCE STATEMENTDopamine (DA) is a major neuromodulator in the CNS and plays a key role in several cognitive processes via modulating the blood oxygenation level-dependent (BOLD) signal. Some studies have shown a link between DA and BOLD, whereas others have failed to observe such a relationship. A possible reason for the discrepancy is differences in task demands, such that a more demanding task with greater prefrontal activations may yield a stronger association with DA. We examined the relationship of DA to BOLD response during working memory under three load conditions and found that the DA–BOLD association is expressed in a load-dependent fashion. These findings may help explain the disproportionate impairment evident in more effortful cognitive tasks in normal aging and in those suffering dopamine-dependent neurodegenerative diseases (e.g., Parkinson's disease).

ObjectiveTo examine mortality and associated risk factors, including possible effects of mild cognitive impairment, imaging, and CSF abnormalities, in a community-based population with incident parkinsonism and Parkinson disease.MethodsOne hundred eighty-two patients with new-onset, idiopathic parkinsonism were diagnosed from January 2004 through April 2009, in a catchment area of 142,000 inhabitants in Sweden. Patients were comprehensively investigated according to a multimodal research protocol and followed prospectively for up to 13.5 years. A total of 109 patients died. Mortality rates in the general Swedish population were used to calculate standardized mortality ratio and expected survival, and Cox proportional hazard models were used to investigate independent predictors of mortality.ResultsThe standardized mortality ratio for all patients was 1.84 (95% confidence interval 1.50–2.22, p < 0.001). Patients with atypical parkinsonism (multiple system atrophy or progressive supranuclear palsy) had the highest mortality. In early Parkinson disease, a mild cognitive impairment diagnosis, freezing of gait, hyposmia, reduced dopamine transporter activity in the caudate, and elevated leukocytes in the CSF were significantly associated with shorter survival.ConclusionAlthough patients presenting with idiopathic parkinsonism have reduced survival, the survival is highly dependent on the type and characteristics of the parkinsonian disorder. Patients with Parkinson disease presenting with normal cognitive function seem to have a largely normal life expectancy. The finding of a subtle CSF leukocytosis in patients with Parkinson disease with short survival may have clinical implications.

Summary Tissue-resident memory T (TRM) cells are CD8+ T lymphocytes that reside in the tissues, including tumours. This T cell subset possesses a magnitude of cytotoxicity, but its epigenetic regulation has not been studied. Here, we investigate the impact of perforin DNA methylation in TRM cells and correlate it with their functional potential. Fifty-three urothelial urinary bladder cancer (UBC) patients were recruited prospectively. The DNA methylation status of the perforin gene (PRF1) locus in TRM cells was investigated by pyrosequencing. Flow cytometry with ViSNE analysis and in-vitro stimulation were used to evaluate TRM cell phenotypes. We discovered that tumour TRM cells have low DNA methylation in the PRF1 locus (32·9% methylation), which corresponds to increased numbers of perforin-expressing TRM cells. Surprisingly, programmed cell death 1 (PD-1) expression is high in tumour TRM cells, suggesting exhaustion. Following interleukin-15 and T cell receptor stimulation, perforin and T-bet expressions are enhanced, indicating that TRM cells from tumours are not terminally exhausted. Moreover, a high number of TRM cells infiltrating the tumours corresponds to lower tumour stage in patients. In conclusion, TRM cells from UBC tumours are epigenetically cytotoxic with signs of exhaustion. This finding identifies TRM cells as potential new targets for cancer immunotherapy.

Background: Urinary bladder cancer is a common malignancy worldwide. Environmental factors and chronic inflammation are correlated with the disease risk. Diagnosis is performed by transurethral resection of the bladder, and patients with muscle invasive disease preferably proceed to radical cystectomy, with or without neoadjuvant chemotherapy. The anti-tumour immune responses, known to be initiated in the tumour and draining lymph nodes, may play a major role in future treatment strategies. Thus, increasing the knowledge of tumour-associated immunological processes is important. Activated CD4(+) T cells differentiate into four main separate lineages: Th1, Th2, Th17 and Treg, and they are recognized by their effector molecules IFN-gamma, IL-13, IL-17A, and the transcription factor Foxp3, respectively. We have previously demonstrated signature CpG sites predictive for lineage commitment of these four major CD4(+ )T cell lineages. Here, we investigate the lineage commitment specifically in tumour, lymph nodes and blood and relate them to the disease stage and response to neoadjuvant chemotherapy. Results: Blood, tumour and regional lymph nodes were obtained from patients at time of transurethral resection of the bladder and at radical cystectomy. Tumour-infiltrating CD4(+ )lymphocytes were significantly hypomethylated in all four investigated lineage loci compared to CD4(+) lymphocytes in lymph nodes and blood (lymph nodes vs rumour-infiltrating lymphocytes: IFNG -4229 bp p amp;lt; 0.0001, IL13 -11 bp p amp;lt; 0.05, IL17A -122 bp p amp;lt; 0.01 and FOXP3 -77 bp pamp;gt; 0.05). Examination of individual lymph nodes displayed different methylation signatures, suggesting possible correlation with future survival. More advanced post-cystectomy tumour stages correlated significantly with increased methylation at the IFNG -4229 bp locus. Patients with complete response to neoadjuvant chemotherapy displayed significant hypomethylation in CD4(+ )T cells for all four investigated loci, most prominently in IFNG p amp;lt; 0.0001. Neoadjuvant chemotherapy seemed to result in a relocation of Th1-committed CD4(+) T cells from blood, presumably to the tumour, indicated by shifts in the methylation patterns, whereas no such shifts were seen for lineages corresponding to IL13, IL17A and FOXP3. Conclusion: Increased lineage commitment in CD4(+) T cells, as determined by demethylation in predictive CpG sites, is associated with lower post-cystectomy tumour stage, complete response to neoadjuvant chemotherapy and overall better outcome, suggesting epigenetic profiling of CD4(+) T cell lineages as a useful readout for clinical staging. Funding Agencies|Swedish Cancer foundation; Wallenberg foundation; Swedish Medical Research Council; Regionala forskningsradet i Uppsala-Orebroregionen (RFR in Uppsala-Orebro); Swedish Research Council; Cancer Research Foundation in Norrland, Umea, Sweden; Stiftelsen Emil Anderssons fond for medicinsk forskning, Sundsvall, Sweden

Altered white matter microstructure is commonly found in children born preterm (PT), especially those born at an extremely low gestational age (GA). These children also commonly show disturbed motor function. This study explores the relation between white matter alterations and upper-limb movement segmentation in 41 children born PT (19 girls), and 41 children born at term (18 girls) at 8 years. The PT group was subdivided into extremely PT (E-PT; GA = 25-27 weeks, N = 10), very PT (V-PT; GA = 28-32 weeks, N = 13), and moderately PT (M-PT; GA = 33-35 weeks, N = 18). Arm/hand preference (preferred/non-preferred) was determined through object interactions and the brain hemispheres were designated accordingly. White matter alterations were assessed using diffusion tensor imaging in nine areas, and movement segmentation of the body-parts head, shoulder, elbow, and wrist were registered during a unimanual goal-directed task. Increased movement segmentation was demonstrated consistently on the preferred side in the E-PT group compared with the term born group. Also compared with the term born peers, the E-PT group demonstrated reduced fractional anisotropy (FA) in the cerebral peduncle (targeting the corticospinal tract) in the hemisphere on the non-preferred side and in the splenium of corpus callosum. In contrast, in the anterior internal capsule on the preferred side, the E-PT group had increased FA. Lower FA in the cerebral peduncle, but higher FA in the anterior internal capsule, was associated with increased movement segmentation across body-parts in a contralateral manner. The results suggest that impaired development of sensorimotor tracts in E-PT children could explain a sub-optimal spatiotemporal organization of upper-limb movements. Hum Brain Mapp 38:5051-5068, 2017. © 2017 Wiley Periodicals, Inc.

Objective: The reference Logan plot is a tool for determining the non-displaceable binding potential for dynamic PET exams using tracers with reversible bindings. Dynamic frame protocols affect noise in PET images and short frames can lead to quantitative uncertainties and noise-induced reconstruction bias. The aim of this study was to analyze the effect of frame binning on 11C-Raclopride striatal binding potential from reference Logan analysis. Methods: 12 healthy volunteers were scanned in list mode using 11C-raclopride, and the image data were reconstructed into 9 different frame binning schemes whereof 3 clinical schemes. Reconstruction was performed with 3 different algorithms, one based on filtered back projection (FBP) and two based on ordered subset expectation maximization (OSEM); one including resolution recovery. Logan plots were used for calculating the non-displaceable binding potential. Variation in binding potential was evaluated using Students t-tests. Results: It was found that frame lengths of up to 60 s gave significantly different results compared to the reference clinical protocol for OSEM, both with and without resolution recovery (maximum deviation: 10.3 % for the 15 s protocol). For FBP, frame lengths of up to 30 s gave significantly different results with a maximum deviation of 2.8 %. The higher sampling dependence of OSEM compared to FBP is likely due to noise-dependent bias in the OSEM algorithm, most apparent at high noise levels. Conclusions: Bias related to OSEM reconstruction of high-noise data is an important factor for dynamic PET protocols. Time frames of 120 s or more generate the most stable values for the striatum binding potential with the reference Logan plot for 11C-Raclopride brain PET.

The aim of this study was to evaluate the detection rate of bone metastases and the added value ofA total of 66 untreated patients with high-risk PC with ACE-PET/CT and planar BS findings within 3 months of each other were retrospectively enrolled. Findings were compared and verified with follow-up data after an average of 26 months.The rate of detection of bone metastases was superior with ACE-PET/CT compared to BS (p0.01). Agreement between the methods and between BS and follow-up was moderate (Cohen's kappa coefficient of 0.64 and 0.66, respectively). Agreement between ACE-PET/CT and follow-up was excellent (kappa coefficient of 0.95). Therapy was changed in 11% of patients due to ACE-PET/CT results.ACE-PET/CT performed better than planar BS in detection of bone metastases in high-risk PC. ACE-PET/CT findings influenced clinical management.

In vivo dopamine D2-receptor availability is frequently assessed with (11)C-raclopride and positron emission tomography. Due to low signal-to-noise ratios for (11)C-raclopride in areas with low D2 receptor densities, the ligand has been considered unreliable for measurements outside the dopamine-dense striatum. Intriguingly, recent studies show that extrastriatal (11)C-raclopride binding potential (BP(ND)) values are (i) reliably higher than in the cerebellum (where D2-receptor levels are negligible), (ii) correlate with behavior in the expected direction, and (iii) showed good test–retest reliability in a sample of younger adults. The present work demonstrates high seven-month test–retest reliability of striatal and extrastriatal (11)C-raclopride BP(ND) values in healthy, older adults (n = 27, age: 64–78 years). Mean (11)C-raclopride BP(ND) values were stable between test sessions in subcortical nuclei, and in frontal and temporal cortices (p > 0.05). Across all structures analyzed, intraclass correlation coefficients were high (0.85–0.96), absolute variability was low (mean: 4–8%), and coefficients of variance ranged between 9 and 25%. Furthermore, regional (11)C-raclopride BP(ND) values correlated with previously determined (18)F-fallypride BP(ND) values (ρ = 0.97 and 0.92 in correlations with and without striatal values, respectively, p

Episodic memory is a polygenic trait influenced by different molecular mechanisms. We used PET and a candidate gene approach to investigate how individual differences at the molecular level translate into between-person differences in episodic memory performance of elderly persons. Specifically, we examined the interactive effects between hippocampal dopamine D2 receptor (D2DR) availability and candidate genes relevant for hippocampus-related memory functioning. We show that the positive effects of high D2DR availability in the hippocampus on episodic memory are confined to carriers of advantageous genotypes of the brain-derived neurotrophic factor (

There is much evidence that dopamine is vital for cognitive functioning in aging. Here we tested the hypothesis that aerobic exercise and fitness influence dopaminergic neurotransmission in the striatum, and in turn performance on offline working-memory updating tasks. Dopaminergic neurotransmission was measured by positron emission tomography (PET) and the non-displacable binding potential (BP

This Strategic Research Agenda identifies current challenges and needs in healthcare, illustrates how biomedical imaging and derived data can help to address these, and aims to stimulate dedicated research funding efforts.Medicine is currently moving towards a more tailored, patient-centric approach by providing personalised solutions for the individual patient. Innovation in biomedical imaging plays a key role in this process as it addresses the current needs for individualised prevention, treatment, therapy response monitoring, and image-guided surgery.The use of non-invasive biomarkers facilitates better therapy prediction and monitoring, leading to improved patient outcomes. Innovative diagnostic imaging technologies provide information about disease characteristics which, coupled with biological, genetic and -omics data, will contribute to an individualised diagnosis and therapy approach.In the emerging field of theranostics, imaging tools together with therapeutic agents enable the selection of best treatments and allow tailored therapeutic interventions.For prenatal monitoring, the use of innovative imaging technologies can ensure an early detection of malfunctions or disease.The application of biomedical imaging for diagnosis and management of lifestyle-induced diseases will help to avoid disease development through lifestyle changes.Artificial intelligence and machine learning in imaging will facilitate the improvement of image interpretation and lead to better disease prediction and therapy planning.As biomedical imaging technologies and analysis of existing imaging data provide solutions to current challenges and needs in healthcare, appropriate funding for dedicated research is needed to implement the innovative approaches for the wellbeing of citizens and patients. ispartof: INSIGHTS INTO IMAGING vol:10 issue:1 ispartof: location:Germany status: published

The dopamine (DA) system plays an important role in cognition. Accordingly, normal variation in DA genes has been found to predict individual differences in cognitive performance. However, little is known of the impact of genetic differences on the link between empirical indicators of the DA system and cognition in humans. The present work used PET with11C-raclopride to assess DA D2-receptor binding potential (BP) and links to episodic memory, working memory, and perceptual speed in 179 healthy adults aged 64–68 years. Previously, the T-allele of a DA D2-receptor single-nucleotide polymorphism, C957T, was associated with increased apparent affinity of11C-raclopride, giving rise to higher BP values despite similar receptor density values between allelic groups. Consequently, we hypothesized that11C-raclopride BP measures inflated by affinity rather than D2-receptor density in T-allele carriers would not be predictive of DA integrity and therefore prevent finding an association between11C-raclopride BP and cognitive performance. In accordance with previous findings, we show that11C-raclopride BP was increased in T-homozygotes. Importantly,11C-raclopride BP was only associated with cognitive performance in groups with low or average ligand affinity (C-allele carriers of C957T, n = 124), but not in the high-affinity group (T-homozygotes, n = 55). The strongest11C-raclopride BP–cognition associations and the highest level of performance were found in C-homozygotes. These findings show that genetic differences modulate the link between BP and cognition and thus have important implications for the interpretation of DA assessments with PET and11C-raclopride in multiple disciplines ranging from cognitive neuroscience to psychiatry and neurology.

Background 68Ga-labeled Glu-NH-CO-NH-Lys(Ahx)-HBED-CC ([68Ga]PSMA-11) has been increasingly used to image prostate cancer using positron emission tomography (PET)/computed tomography (CT) both during diagnosis and treatment planning. It has been shown to be of clinical value for patients both in the primary and secondary stages of prostate cancer. The aim of this study was to determine the effective dose and organ doses from injection of [68Ga]PSMA-11 in a cohort of low-risk prostate cancer patients. Methods Six low-risk prostate cancer patients were injected with 133–178 MBq [68Ga]PSMA-11 and examined with four PET/CT acquisitions from injection to 255 min post-injection. Urine was collected up to 4 h post-injection, and venous blood samples were drawn at 45 min, 85 min, 175 min, and 245 min post-injection. Kidneys, liver, lungs, spleen, salivary and lacrimal glands, and total body where delineated, and cumulated activities and absorbed organ doses calculated. The software IDAC-Dose 2.1 was used to calculate absorbed organ doses according to the International Commission on Radiological Protection (ICRP) publication 107 using specific absorbed fractions published in ICRP 133 and effective dose according to ICRP Publication 103. We also estimated the absorbed dose to the eye lenses using Monte Carlo methods. Results [68Ga]PSMA-11 was rapidly cleared from the blood and accumulated preferentially in the kidneys and the liver. The substance has a biological half-life in blood of 6.5 min (91%) and 4.4 h (9%). The effective dose was calculated to 0.022 mSv/MBq. The kidneys received approximately 40 mGy after an injection with 160 MBq [68Ga]PSMA-11 while the lacrimal glands obtained an absorbed dose of 0.12 mGy per administered MBq. Regarding the eye lenses, the absorbed dose was low (0.0051 mGy/MBq). Conclusion The effective dose for [68Ga]PSMA-11 is 0.022 mSv/MBq, where the kidneys and lacrimal glands receiving the highest organ dose.

Objective The aging brain undergoes several changes, including reduced vascular, structural, and dopamine (DA) system integrity. Such brain changes have been associated with age‐related cognitive deficits. However, their relative importance, interrelations, and links to risk factors remain elusive. Methods The present work used magnetic resonance imaging and positron emission tomography with 11C‐raclopride to jointly examine vascular parameters (white‐matter lesions and perfusion), DA D2‐receptor availability, brain structure, and cognitive performance in healthy older adults (n = 181, age: 64–68 years) from the Cognition, Brain, and Aging (COBRA) study. Results Covariance was found among several brain indicators, where top predictors of cognitive performance included caudate and hippocampal integrity (D2DR availability and volumes), and cortical blood flow and regional volumes. White‐matter lesion burden was negatively correlated with caudate DA D2‐receptor availability and white‐matter microstructure. Compared to individuals with smaller lesions, individuals with confluent lesions (exceeding 20 mm in diameter) had reductions in cortical and hippocampal perfusion, striatal and hippocampal D2‐receptor availability, white‐matter microstructure, and reduced performance on tests of episodic memory, sequence learning, and processing speed. Higher cardiovascular risk as assessed by treatment for hypertension, systolic blood pressure, overweight, and smoking was associated with lower frontal cortical perfusion, lower putaminal D2DR availability, smaller grey‐matter volumes, a larger number of white‐matter lesions, and lower episodic memory performance. Interpretation Taken together, these findings suggest that reduced cardiovascular health is associated with poorer status for brain variables that are central to age‐sensitive cognitive functions, with emphasis on DA integrity.

The dopamine D2/3 system is fundamental for sensory, motor, emotional, and cognitive aspects of behavior. Small-scale human histopathological and animal studies show high density of D2/3 dopamine receptors (D2/3DR) in striatum, but also demonstrate the existence of such receptors across cortical and limbic regions. Assessment of D2/3DR BPND in the extrastriatal regions with [11C]raclopride has long been considered unreliable due to the relatively low density of D2/3DR outside the striatum. We describe the distribution and interregional links of D2/3DR availability measured with PET and [11C]raclopride across the human brain in a large sample (N = 176; age range 64–68 years). Structural equation modeling revealed that D2/3DR availability can be organized according to anatomical (nigrostriatal, mesolimbic, mesocortical) and functional (limbic, associative, sensorimotor) dopamine pathways. D2/3DR availability in corticolimbic functional subdivisions showed differential associations to corresponding striatal subdivisions, extending animal and pharmacological work. Our findings provide evidence on the dimensionality and organization of [11C]raclopride D2/3DR availability in the living human brain that conforms to known dopaminergic pathways. Electronic supplementary material The online version of this article (10.1007/s00429-019-01938-1) contains supplementary material, which is available to authorized users.

Significance The brain’s dopaminergic pathways are crucially important for adaptive behavior. They are thought to enable us to approach rewards and stay away from punishments. During learning, dopaminergic reward prediction errors are thought to reinforce previously rewarded actions, so they become easier to repeat. This dopaminergic activity could lead to a systematic bias by which rewarded actions are more readily learned than rewarded inactions. We present two findings. First, dopamine receptors in cortex, dorsal striatum, and nucleus accumbens provide distinct sources of variance in the human brain. Second, the boost in an individual’s learning rate from previously rewarded actions is dependent on the dopamine receptor density in dorsal striatum, a central structure in the dopaminergic circuit., Learning to act to obtain reward and inhibit to avoid punishment is easier compared with learning the opposite contingencies. This coupling of action and valence is often thought of as a Pavlovian bias, although recent research has shown it may also emerge through instrumental mechanisms. We measured this learning bias with a rewarded go/no-go task in 60 adults of different ages. Using computational modeling, we characterized the bias as being instrumental. To assess the role of endogenous dopamine (DA) in the expression of this bias, we quantified DA D1 receptor availability using positron emission tomography (PET) with the radioligand [11C]SCH23390. Using principal-component analysis on the binding potentials in a number of cortical and striatal regions of interest, we demonstrated that cortical, dorsal striatal, and ventral striatal areas provide independent sources of variance in DA D1 receptor availability. Interindividual variation in the dorsal striatal component was related to the strength of the instrumental bias during learning. These data suggest at least three anatomical sources of variance in DA D1 receptor availability separable using PET in humans, and we provide evidence that human dorsal striatal DA D1 receptors are involved in the modulation of instrumental learning biases.

Introduction: Interns' experiences communicating with and writing referrals to hospital radiology departments are important for patient safety, image quality, and decision-making in the diagnostic ...

PURPOSE: To determine whether sentinel node detection (SNd) in muscle-invasive urothelial bladder cancer (MIBC) can be performed in patients undergoing neoadjuvant chemotherapy (NAC) and determine whether SNd is feasible in all pT stages, including pT0. BACKGROUND: Previous published series of SNd in MIBC have not included patients undergoing NAC, and systematic reports of pT0 patients w/wo NAC were absent. Translational immunological tumor research on MIBC focusing on SNd, in the era of NAC, requires technical feasibility. Additionally, SNd in MIBC requests further evaluations as a method for nodal staging. MATERIALS AND METHODS: Ninety-nine patients with suspected urothelial MIBC were prospectively selected from six urological centers. After TUR-B and primary staging, 65 MIBC patients qualified for radical cystectomy. Precystectomy staging was cT2a-T4aN0M0, including 47 NAC patients and 18 chemo-naïve patients. All 65 patients underwent intraoperative SNd by peritumoral injection of 80 Mbq Technetium and Geiger probe detection. Postcystectomy staging was pT0-T4aN0-N2M0. SNs were defined by two calculations, SNdef1 and SNdef2. RESULTS: Totally 1063 lymph nodes were removed (total SNs; 222-227). NAC patients with pT0 (n = 24) displayed a true positive detection in 91.7 % by either SNdef, with a median of 3.0 SNs. NACpT >0 patients had a true positive detection in 87 % (SNdef1) and 91.3 % (SNdef2). In a univariate analysis, patient group neither NAC nor tumor downstaging influenced detection rates, regardless of SN definition. In total eight patients, 4/22 metastatic nodes were SNs while 18/22 were non-SNs. CONCLUSIONS: Sentinel node detection in MIBC is feasible also in NAC patients, regardless of pT stage. SNd played no role in nodal staging.

The dopamine (DA) system plays an important role in cognition. Accordingly, normal variation in DA genes has been found to predict individual differences in cognitive performance. However, little is known of the impact of genetic differences on the link between empirical indicators of the DA system and cognition in humans. The present work used PET with

Published: 25 September 2017 Evidence suggests that associations between the neurotransmitter dopamine and cognition are nonmonotonic and open to modulation by various other factors. The functional implications of a given level of dopamine may therefore differ from person to person. By applying latent-profile analysis to a large (n = 181) sample of adults aged 64-68 years, we probabilistically identified 3 subgroups that explain the multivariate associations between dopamine D2/3R availability (probed with C-11-raclopride-PET, in cortical, striatal, and hippocampal regions) and cognitive performance (episodic memory, working memory, and perceptual speed). Generally, greater receptor availability was associated with better cognitive performance. However, we discovered a subgroup of individuals for which high availability, particularly in striatum, was associated with poor performance, especially for working memory. Relative to the rest of the sample, this subgroup also had lower education, higher body-mass index, and lower resting-state connectivity between caudate nucleus and dorsolateral prefrontal cortex. We conclude that a smaller subset of individuals induces a multivariate non-linear association between dopamine D2/3R availability and cognitive performance in this group of older adults, and discuss potential reasons for these differences that await further empirical scrutiny. Swedish Research Council [446-2013-7189] et al.

Available online: 21 July 2018 Between-person differences in cognitive performance in older age are associated with variations in physical activity. The neurotransmitter dopamine (DA) contributes to cognitive performance, and the DA system deteriorates with advancing age. Animal data and a patient study suggest that physical activity modulates DA receptor availability, but data from healthy humans are lacking. In a cross-sectional study with 178 adults aged 64-68 years, we investigated links among self-reported physical activity, D(2/3)DA receptor (D2/3DR) availability, and cognitive performance. D2/3DR availability was measured with [C-11]raclopride positron emission tomography at rest. We used structural equation modeling to obtain latent factors for processing speed, episodic memory, working memory, physical activity, and D2/3DR availability in caudate, putamen, and hippocampus. Physical activity intensity was positively associated with D2/3DR availability in caudate, but not putamen and hippocampus. Frequency of physical activity was not related to D2/3DR availability. Physical activity intensity was positively related to episodic memory and working memory. D2/3DR availability in caudate and hippocampus was positively related to episodic memory. Taken together, our results suggest that striatal DA availability might be a neurochemical correlate of episodic memory that is also associated with physical activity. Swedish Research Council [446-2013-7189] FORTE [2013-2277] Umea University Umea University-Karolinska Institute Strategic Neuroscience program Knut and Alice Wallenberg Foundation gs5:Torsten and Ragnar Soderberg Foundation Alexander von Humboldt Research award Swedish Brain Power Swedish Brain Foundation Vasterbotten County Council Max Planck Society German Research Foundation (DFG)