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Cell growth and proliferation must be balanced during development to attain a final adult size with the appropriate proportions of internal organs to maximize fitness and reproduction. While multiple signaling pathways coordinate Drosophila development, it is unclear how multi-organ communication within and between tissues converge to regulate systemic growth. One such growth pathway, mediated by insulin-like peptides that bind to and activate the insulin receptor in multiple target tissues, is a primary mediator of organismal size. Here we uncover a signaling role for the NUAK serine/threonine kinase in muscle tissue that impinges upon insulin pathway activity to limit overall body size, including a reduction in the growth of individual organs. In skeletal muscle tissue, manipulation of NUAK or insulin pathway components influences sarcomere number concomitant with modulation of thin and thick filament lengths, possibly by modulating the localization of Lasp, a nebulin repeat protein known to set thin filament length. This mode of sarcomere remodeling does not occur in other mutants that also exhibit smaller muscles, suggesting that a sensing mechanism exists in muscle tissue to regulate sarcomere growth that is independent of tissue size control. [Display omitted] • NUAK overexpression in muscle tissue blunts insulin signaling and reduces organismal size. • Methuselah-like 8 (mthl8) is a new target of NUAK and FOXO-mediated transcription. • Reduced muscle growth can be uncoupled from alterations in sarcomere number and size. [ABSTRACT FROM AUTHOR]

Abstract: Pittsburgh compound B or [11C]PIB is an amyloid imaging agent which shows a clear differentiation between subjects with Alzheimer''s disease (AD) and controls. However the observed signal difference in other forms of dementia such as dementia with Lewy bodies (DLB) is smaller, and mild cognitively impaired (MCI) subjects and some healthy elderly normals may show intermediate levels of [11C]PIB binding. The cerebellum, a commonly used reference region for non-specific tracer uptake in [11C]PIB studies in AD may not be valid in Prion disorders or monogenic forms of AD. The aim of this work was to: 1—compare methods for generating parametric maps of [11C]PIB retention in tissue using a plasma input function in respect of their ability to discriminate between AD subjects and controls and 2—estimate the test–retest reproducibility in AD subjects. 12  AD subjects (5 of which underwent a repeat scan within 6 weeks) and 10 control subjects had 90 minute [11C]PIB dynamic PET scans, and arterial plasma input functions were measured. Parametric maps were generated with graphical analysis of reversible binding (Logan plot), irreversible binding (Patlak plot), and spectral analysis. Between group differentiation was calculated using Student''s t-test and comparisons between different methods were made using p values. Reproducibility was assessed by intraclass correlation coefficients (ICC). We found that the 75 min value of the impulse response function showed the best group differentiation and had a higher ICC than volume of distribution maps generated from Logan and spectral analysis. Patlak analysis of [11C]PIB binding was the least reproducible. [Copyright &y& Elsevier]

Abstract: The glacially carved central coast of Maine is incised by river systems with interconnecting channels, offshore-trending submarine ridges, and narrow passages between nearshore islands and headlands. The tidal range exceeds 3m, leading to complex and vigorous circulation patterns with strong flows in narrow channels, near river mouths, and between islands. The spongiform coastal morphology allows enhanced exchange between offshore waters, estuaries and internecine bays, resulting in rapid dispersal of nutrients, larvae and contaminants throughout the region. A fine-grid numerical circulation model has been used to examine the influences of the tides, river flows and winds on the dispersion of lobster larvae and pollutants in the nearshore and riverine environment. This paper describes the model application, presents a few salient features of the circulation patterns, and examines some implications for the coastal environment. For example, under realistic tides and variable southwest summer winds, about 80% of neutral near-surface particles introduced near the offshore islands (a proxy for stage IV lobster larvae from offshore sources) remain within a few km of the islands over a two-week period. On the other hand, a persistent, periodic sea breeze can remove more than two-thirds of the particles from the domain over the same period. Tidal mixing disperses pollutants entering the upper Kennebec River to the offshore and through internecine passages in about one week. [Copyright &y& Elsevier]

The efficacy of treatments for advanced, recurrent metastatic endometrial cancers (EC) remains limited. In-depth, high-dimensional immune profiling of recurrent EC subtypes is much needed in order to describe the immune composition within the tumor microenvironment. A 2:1 randomized phase 2 trial was conducted comparing the combination of cabozantinib and nivolumab (Arm A) versus nivolumab (Arm B) in women with recurrent measurable EC (NCT03367741). A third exploratory cohort (Arm C) included EC patients with the carcinosarcoma subtype, and patients who had prior immunotherapy (IO). Fresh baseline core biopsies were collected and processed into single-cell suspensions for high-dimensional CyTOF analysis with a 36-marker immune profiling panel. Immune composition was determined by unsupervised single-cell clustering using PhenoGraph and visualized by uniform manifold approximation and projection (UMAP). The differential abundance (DA) of unique immune cell subsets present in the baseline biopsies was determined using the diffcyt-DA-EdgeR method. Cabozantinib plus nivolumab demonstrates improved PFS and ORR compared to nivolumab in heavily pre-treated women with recurrent EC. Unsupervised clustering of CD45+ cells from baseline biopsies (n=40) using PhenoGraph resulted in 35 unique immune cell subsets defined their expression of lineage and activation/checkpoint markers (e.g. PD-1, PD-L1, TIGIT, 4-1BB, CD39, CD69 and others). Broadly, these PhenoGraph-defined subsets constitute the major immune populations including CD4 and CD8 T cells, regulatory T cells, γδ T cells, B cells, innate lymphoid/natural killer (NK) cells, and monocyte/macrophages and dendritic cells. In-depth CyTOF analysis of the tumor microenvironment identified a higher proportion of activated tissue-resident γδ T cells in patients who had prior IO and who benefit from the combination therapy (non-progressors, n=4; progressors, n=5; 6 log fold-change, adjusted P =0.001). We did not observe any statistically significant differences in the baseline immune composition between IO-naïve (Arm A and B) endometrioid (n=13), serous (n=7) and carcinosarcoma tumors (n=4). However, in comparison to endometrioid and serous tumors, carcinosarcoma tumors may trend towards a lower abundance (not significant) of CD45RA+CD27+CD28+ CD4 and CD8 T cells, and CD45RA+CD69- NK cells. All three histological subtypes had a similar abundance of activated, tissue-resident PD-1+TIGIT+CD69+CD103+ CD8 T cells. Microsatellite instability high (MSI-H; n=2; both endometrioid) tumors were excluded from our analysis. In comparison to nivolumab monotherapy, combination cabozantinib and nivolumab treatment improved PFS and ORR in recurrent EC patients. To our knowledge, this is the first study reporting in-depth immune profiling analysis of core biopsies from EC patients. The tumor immune microenvironment of EC is comprised of several immune populations with unique phenotypes related to their expression of activation and checkpoint markers. [ABSTRACT FROM AUTHOR]

Abstract: The early motor manifestations of Parkinson’s disease (PD) reflect degeneration of nigrostriatal dopamine neurons projecting to the caudal putamen. However, extrastriatal dopamine and other monoamine systems are also involved, particularly in later disease. We used 18F-dopa PET in a cross-sectional study to characterize extrastriatal monoamine neuronal dysfunction in PD. 16 Controls and 41 patients underwent investigation. We found that 18F-dopa uptake was decreased in cortical motor areas, particularly the motor cortex, even in early disease. Frontal association areas were also affected in later disease but limbic areas were spared except for hypothalamus. The substantia nigra, midbrain raphe and locus coeruleus showed normal or increased 18F-dopa uptake until PD was advanced, indicating compensatory responses in intact monoamine neuron perikarya. The red nucleus, subthalamus, ventral thalamus and pineal gland were also eventually involved. These findings provide a further basis for understanding the complex pathophysiology of PD in vivo and complement pathological studies. [Copyright &y& Elsevier]

Abstract: Virus-specific CD4+ T cells contribute to effective virus control through a multiplicity of mechanisms including direct effector functions as well as “help” for B cell and CD8+ T cell responses. Here, we have used the lymphocytic choriomeningitis virus (LCMV) system to assess the minimal constraints of a dominant antiviral CD4+ T cell response. We report that the core epitope derived from the LCMV glycoprotein (GP) is 11 amino acids in length and provides optimal recognition by epitope-specific CD4+ T cells. Surprisingly, this epitope is also recognized by LCMV-specific CD8+ T cells and thus constitutes a unique viral determinant with dual MHC class I- and II-restriction. [Copyright &y& Elsevier]

• We propose a novel imaging method to study gait-related brain function. • We used a dual-injection paradigm and for each participant acquired two static FDG-PET scans. • There was a gait-related increase in glucose metabolism in discrete locomotor brain regions during walking relative to standing. • Our methods reduce participant burden making repeated study visits redundant. • Our methods could be employed in neurodegenerative disorders adversely affecting gait. Gait is an excellent indicator of physical, emotional, and mental health. Previous studies have shown that gait impairments in ageing are common, but the neural basis of these impairments are unclear. Existing methodologies are suboptimal and novel paradigms capable of capturing neural activation related to real walking are needed. In this study, we used a hybrid PET/MR system and measured glucose metabolism related to both walking and standing with a dual-injection paradigm in a single study session. For this study, 15 healthy older adults (10 females, age range: 60.5-70.7 years) with normal cognition were recruited from the community. Each participant received an intravenous injection of [18F]-2-fluoro-2-deoxyglucose (FDG) before engaging in two distinct tasks, a static postural control task (standing) and a walking task. After each task, participants were imaged. To discern independent neural functions related to walking compared to standing, we applied a bespoke dose correction to remove the residual 18F signal of the first scan (PET STAND) from the second scan (PET WALK) and proportional scaling to the global mean, cerebellum, or white matter (WM). Whole-brain differences in walking-elicited neural activity measured with FDG-PET were assessed using a one-sample t-test. In this study, we show that a dual-injection paradigm in healthy older adults is feasible with biologically valid findings. Our results with a dose correction and scaling to the global mean showed that walking, compared to standing, increased glucose consumption in the cuneus (Z = 7.03), the temporal gyrus (Z = 6.91) and the orbital frontal cortex (Z = 6.71). Subcortically, we observed increased glucose metabolism in the supraspinal locomotor network including the thalamus (Z = 6.55), cerebellar vermis and the brainstem (pedunculopontine/mesencephalic locomotor region). Exploratory analyses using proportional scaling to the cerebellum and WM returned similar findings. Here, we have established the feasibility and tolerability of a novel method capable of capturing neural activations related to actual walking and extended previous knowledge including the recruitment of brain regions involved in sensory processing. Our paradigm could be used to explore pathological alterations in various gait disorders. [ABSTRACT FROM AUTHOR]

Type I Interferons (IFN-I) mediate numerous immune interactions during viral infections, from the establishment of an antiviral state to invoking and regulating innate and adaptive immune cells that eliminate infection. While continuous IFN-I signaling plays critical roles in limiting virus replication during both acute and chronic infections, sustained IFN-I signaling also leads to chronic immune activation, inflammation and, consequently, immune exhaustion and dysfunction. Thus, an understanding of the balance between the desirable and deleterious effects of chronic IFN-I signaling will inform our quest for IFN-based therapies for chronic viral infections as well as other chronic diseases, including cancer. As such the factors involved in induction, propagation and regulation of IFN-I signaling, from the initial sensing of viral nucleotides within the cell to regulatory downstream signaling factors and resulting IFN-stimulated genes (ISGs) have received significant research attention. This review summarizes recent work on IFN-I signaling in chronic infections, and provides an update on therapeutic approaches being considered to counter such infections. [ABSTRACT FROM AUTHOR]

Objective: Our aim was to assess with positron emission tomography (PET) the temporal and spatial inter-relationships between levels of cortical microglial activation and the aggregated amyloid-β and tau load in mild cognitive impairment (MCI) and early Alzheimer's disease (AD). Methods: Six clinically probable AD and 20 MCI subjects had inflammation ( 11 C- (R) -PK11195), amyloid ( 11 C-PiB) and tau ( 18 F-flortaucipir) PET, magnetic resonance imaging (MRI) and a neuropsychological assessment. Parametric images of tracer binding were interrogated at a voxel level and by region of interest analyses. Results: 55% of MCI and 83% of AD subjects had a high amyloid-β load. We have previously reported that clusters of correlated amyloid and inflammation levels are present in cortex. Here we found no correlation between levels of inflammation ( 11 C- (R) -PK11195 BP ND ) and tau ( 18 F-flortaucipir SUVR) or MMSE scores in high amyloid-β cases. Interpretation: While correlated levels of amyloid-β and inflammation can be seen in MCI, we did not detect an association between levels of cortical tau tangles and inflammation in our series of high amyloid-β cases. High levels of inflammation could be seen in amyloid-β positive MCI cases where 18 F-flortaucipir signals were low suggesting microglial activation precedes tau tangle formation. Inflammation levels were higher in high amyloid-β MCI than in early AD cases, compatible with it initially playing a protective role. [ABSTRACT FROM AUTHOR]

Background The majority of patients diagnosed with idiopathic rapid eye movement sleep behaviour disorder (iRBD) progress over time to a Lewy-type α-synucleinopathy such as Parkinson's disease or dementia with Lewy bodies. This in vivo molecular imaging study aimed to investigate if extrastriatal monoaminergic systems are affected in iRBD patients and if this coincides with neuroinflammation. Methods We studied twenty-one polysomnography-confirmed iRBD patients with 18 F-DOPA and 11 C-PK11195 positron emission tomography (PET) to investigate extrastriatal monoaminergic function and microglial activation. Twenty-nine healthy controls (n = 9 18 F-DOPA and n = 20 11 C-PK11195) were also investigated. Analyses were performed within predefined regions of interest and at voxel-level with Statistical Parametric Mapping. Results Regions of interest analysis detected monoaminergic dysfunction in iRBD thalamus with a 15% mean reduction of 18 F-DOPA Ki values compared to controls (mean difference = −0.00026, 95% confidence interval [−0.00050 to −0.00002], p-value = 0.03). No associated thalamic changes in 11 C-PK11195 binding were observed. Other regions sampled showed no 18 F-DOPA or 11 C-PK11195 PET differences between groups. Voxel-level interrogation of 11 C-PK11195 binding identified areas with significantly increased binding within the occipital lobe of iRBD patients. Conclusion Thalamic monoaminergic dysfunction in iRBD patients may reflect terminal dysfunction of projecting neurons from the locus coeruleus and dorsal raphe nucleus, two structures that regulate REM sleep and are known to be involved in the early phase of PD. The observation of significantly raised microglial activation in the occipital lobe of these patients might suggest early local Lewy-type α-synuclein pathology and possibly an increased risk for later cognitive dysfunction. [ABSTRACT FROM AUTHOR]

Parkinson's disease (PD) is characterized by degeneration of dopaminergic neurons in the substantia nigra leading to slowness and stiffness of limb movement with rest tremor. Using ubiquitin proteasome system inhibitors, rodent models have shown nigrostriatal degeneration and motor impairment. We translated this model to the Göttingen minipig by administering lactacystin into the medial forebrain bundle (MFB). Minipigs underwent positron emission tomography (PET) imaging with (+)-α-[ 11 C]dihydrotetrabenazine ([ 11 C]DTBZ), a marker of vesicular monoamine transporter 2 availability, at baseline and three weeks after the unilateral administration of 100 μg lactacystin into the MFB. Compared to their baseline values, minipigs injected with lactacystin showed on average a 36% decrease in ipsilateral striatal binding potential corresponding to impaired presynaptic dopamine terminals. Behaviourally, minipigs displayed asymmetrical motor disability with spontaneous rotations in one of the animals. Immunoreactivity for tyrosine hydroxylase (TH) and HLA-DR-positive microglia confirmed asymmetrical reduction in nigral TH-positive neurons with an inflammatory response in the lactacystin-injected minipigs. In conclusion, direct injection of lactacystin into the MFB of minipigs provides a model of PD with reduced dopamine neurotransmission, TH-positive neuron reduction, microglial activation and behavioural deficits. This large animal model could be useful in studies of symptomatic and neuroprotective therapies with translatability to human PD. [ABSTRACT FROM AUTHOR]

The importance of the GABA-benzodiazepine receptor complex and its subtypes are increasingly recognised in addiction. Using the α1/α5 benzodiazepine receptor PET radioligand [ 11 C]Ro15 4513, we previously showed reduced binding in the nucleus accumbens and hippocampus in abstinent alcohol dependence. We proposed that reduced [ 11 C]Ro15 4513 binding in the nucleus accumbens was a marker of addiction whilst the reduction in hippocampus and positive relationship with memory was a consequence of chronic alcohol abuse. To examine this further we assessed [ 11 C]Ro15 4513 binding in another addiction, opiate dependence, and used spectral analysis to estimate contributions of α1 and α5 subtypes to [ 11 C]Ro15 4513 binding in opiate and previously acquired alcohol-dependent groups. Opiate substitute maintained opiate-dependent men ( n = 12) underwent an [ 11 C]Ro15 4513 PET scan and compared with matched healthy controls ( n = 13). We found a significant reduction in [ 11 C]Ro15 4513 binding in the nucleus accumbens in the opiate-dependent compared with the healthy control group. There was no relationship between [ 11 C]Ro15 4513 binding in the hippocampus with memory. We found that reduced [ 11 C]Ro15 4513 binding was associated with reduced α5 but not α1 subtypes in the opiate-dependent group. This was also seen in an alcohol-dependent group where an association between memory performance and [ 11 C]Ro15 4513 binding was primarily driven by α5 and not α1 subtype. We suggest that reduced α5 levels in the nucleus accumbens are associated with addiction since we have now shown this in dependence to two pharmacologically different substances, alcohol and opiates. [ABSTRACT FROM AUTHOR]

Background: Endocannabinoids are involved in normal cognition, and dysfunction in cannabinoid-receptor-mediated neurotransmission has been suggested in a variety of neurological and psychiatric pathologies. The type 1 cannabinoid receptor (CB1) is widely expressed in the human central nervous system. The objective of this study was to quantify the test–retest reproducibility of measures of the PET ligand [11C]MePPEP in order to assess the stability of CB1-receptor quantification in humans in vivo. Methods: Fifteen healthy subjects (eight females; median age 32years, range 25 to 65years) had a 90-minute PET scan on two occasions after injection of a median dose of [11C]MePPEP of 364MBq. Metabolite-corrected arterial plasma input functions were obtained for all scans. Eight ROIs, reflecting different levels of receptor densities/concentrations, were defined automatically: hippocampus, anterior cingulate gyrus, inferior frontal gyrus, caudate nucleus, globus pallidus, nucleus accumbens, thalamus, and pons. We used seven quantification methods: reversible compartmental models with one and two tissue classes, two and four rate constants, and a variable blood volume term (2kbv; 4kbv); model-free (spectral) analyses with and without regularisation, including one with voxel-wise quantification; the simplified reference tissue model (SRTM) with pons as a pseudo-reference region; and modified standard uptake values (mSUVs) calculated for the period of ~30–60min after injection. Percentage test–retest change and between-subject variability were both assessed, and test–retest reliability was quantified by the intraclass correlation coefficient (ICC). The ratio of binding estimates pallidum:pons served as an indicator of a method's ability to reflect binding heterogeneity. Results: Neither the SRTM nor the 4kbv model produced reliable measures, with ICCs around zero. Very good (>0.75) or excellent (>0.80) ICCs were obtained with the other methods. The most reliable were spectral analysis parametric maps (average across regions±standard deviation 0.83±0.03), rank shaping regularised spectral analysis (0.82±0.05), and the 2kbv model (0.82±0.09), but mSUVs were also reliable for most regions (0.79±0.13). Mean test–retest changes among the five well-performing methods ranged from 12±10% for mSUVs to 16% for 2kbv. Intersubject variability was high, with mean between-subject coefficients of variation ranging from 32±13% for mSUVs to 45% for 2kbv. The highest pallidum:pons ratios of binding estimates were achieved by mSUV (4.2), spectral analysis-derived parametric maps (3.6), and 2kbv (3.6). Conclusion: Quantification of CB1 receptor availability using [11C]MePPEP shows good to excellent reproducibility with several kinetic models and model-free analyses, whether applied on a region-of-interest or voxelwise basis. Simple mSUV measures were also reliable for most regions, but do not allow fully quantitative interpretation. [11C]MePPEP PET is well placed as a tool to investigate CB1-receptor mediated neurotransmission in health and disease. [ABSTRACT FROM AUTHOR]

Abstract: Previous positron emission tomography (PET) studies in refractory temporal lobe epilepsy (TLE) using the non-selective opioid receptor antagonist [11C]diprenorphine (DPN) did not detect any changes in mesial temporal structures, despite known involvement of the hippocampus in seizure generation. Normal binding in smaller hippocampi is suggestive of increased receptor concentration in the remaining grey matter. Correction for partial-volume effect (PVE) has not been used in previous DPN PET studies. Here, we present PVE-corrected DPN-PET data quantifying post-ictal and interictal opioid receptor availability in humans with mTLE. Eight paired datasets of post-ictal and interictal DPN PET scans and eleven test/retest control datasets were available from a previously published study on opioid receptor changes in TLE following seizures (Hammers et al., 2007a). Five of the eight participants with TLE had documented hippocampal sclerosis. Data were re-analyzed using regions of interest and a novel PVE correction method (structural functional synergistic-resolution recovery (SFS-RR); (Shidahara et al., 2012)). Data were denoised, followed by application of SFS-RR, with anatomical information derived via precise anatomical segmentation of the participants' MRI (MAPER; (Heckemann et al., 2010)). [11C]diprenorphine volume-of-distribution (VT) was quantified in six regions of interest. Post-ictal increases were observed in the ipsilateral fusiform gyri and lateral temporal pole. A novel finding was a post-ictal increase in [11C]DPN VT relative to the interictal state in the ipsilateral parahippocampal gyrus, not observed in uncorrected datasets. As for voxel-based (SPM) analyses, correction for global VT values was essential in order to demonstrate focal post-ictal increases in [11C]DPN VT. This study provides further direct human in vivo evidence for changes in opioid receptor availability in TLE following seizures, including changes that were not evident without PVE correction. Denoising, resolution recovery and precise anatomical segmentation can extract valuable information from PET studies that would be missed with conventional post-processing procedures. [Copyright &y& Elsevier]

Abstract: 18F-flutemetamol is a positron emission tomography (PET) tracer for in vivo amyloid imaging. The ability to classify amyloid scans in a binary manner as ‘normal’ versus ‘Alzheimer-like’, is of high clinical relevance. We evaluated whether a supervised machine learning technique, support vector machines (SVM), can replicate the assignments made by visual readers blind to the clinical diagnosis, which image components have highest diagnostic value according to SVM and how 18F-flutemetamol-based classification using SVM relates to structural MRI-based classification using SVM within the same subjects. By means of SVM with a linear kernel, we analyzed 18F-flutemetamol scans and volumetric MRI scans from 72 cases from the 18F-flutemetamol phase 2 study (27 clinically probable Alzheimer''s disease (AD), 20 amnestic mild cognitive impairment (MCI), 25 controls). In a leave-one-out approach, we trained the 18F-flutemetamol based classifier by means of the visual reads and tested whether the classifier was able to reproduce the assignment based on visual reads and which voxels had the highest feature weights. The 18F-flutemetamol based classifier was able to replicate the assignments obtained by visual reads with 100% accuracy. The voxels with highest feature weights were in the striatum, precuneus, cingulate and middle frontal gyrus. Second, to determine concordance between the gray matter volume- and the 18F-flutemetamol-based classification, we trained the classifier with the clinical diagnosis as gold standard. Overall sensitivity of the 18F-flutemetamol- and the gray matter volume-based classifiers were identical (85.2%), albeit with discordant classification in three cases. Specificity of the 18F-flutemetamol based classifier was 92% compared to 68% for MRI. In the MCI group, the 18F-flutemetamol based classifier distinguished more reliably between converters and non-converters than the gray matter-based classifier. The visual read-based binary classification of 18F-flutemetamol scans can be replicated using SVM. In this sample the specificity of 18F-flutemetamol based SVM for distinguishing AD from controls is higher than that of gray matter volume-based SVM. [Copyright &y& Elsevier]

Abstract: Post-mortem studies of multiple system atrophy (MSA) patients have shown widespread subcortical neurodegeneration. In this study, we have used 18F-dopa PET, a marker of monoaminergic nerve terminal function, to explore in vivo changes in striatal and extrastriatal dopamine, noradrenaline, and serotonin transmission for a cohort of patients with MSA with predominant parkinsonism. Fourteen patients with MSA, ten patients with idiopathic Parkinson''s disease (PD) matched for disease duration, and ten healthy controls were studied with 18F-dopa PET. Regions of interest (ROIs) were placed to sample 18F-dopa uptake in thirteen structures and mean activity was compared between groups. The MSA patients showed significantly decreased 18F-dopa uptake in putamen, caudate nucleus, ventral striatum, globus pallidus externa and red nucleus compared to controls, whereas PD patients only had decreased 18F-dopa uptake in putamen, caudate nucleus, and ventral striatum. MSA cases with orthostatic hypotension had lower 18F-dopa uptake in the locus coeruleus than patients without this symptom. In conclusion, 18F-dopa PET showed more widespread basal ganglia dysfunction in MSA than in PD with similar disease duration, and extrastriatal loss of monoaminergic innervation could be detected in the red nucleus and locus coeruleus. In contrast to PD, there was no evidence of early compensatory increases in regional 18F-dopa uptake. [Copyright &y& Elsevier]

Abstract: More than 50% of patients with Parkinson''s disease (PD) are expected to show abnormalities with their weight in a process that starts several years before the diagnosis. The serotonergic (5-HT) system has been proposed to regulate appetite and the 5-HT transporter (SERT) is a key modulator of 5-HT metabolism. Here, we hypothesized that a dysfunctional 5-HT system could be responsible for alterations of weight in PD and we sought to investigate this in vivo. Thirty four PD patients had Body Mass Index (BMI) changes monitored over a 12-month period and one positron emission tomography (PET) brain scan with 11C-DASB, a selective marker of SERT availability, during their second clinical assessment. Results were compared with those of a group of 10 normal controls. Half (17) of the PD patients showed abnormal BMI changes over the 12-month period; 12 lost while 5 gained weight. PD patients with abnormal BMI changes showed significantly raised 11C-DASB binding in rostral raphe nuclei, hypothalamus, caudate nucleus and ventral striatum compared to cases with no significant BMI changes. 11C-DASB binding in other regions was similarly decreased in the PD BMI subgroups compared to normal controls. BMI gainers showed significantly raised 11C-DASB binding in anterior cingulate cortex (ACC) compared to BMI losers. Our findings suggest that abnormal BMI changes over a 12-month period are linked with relatively raised SERT availability in PD on an overall background of decreased 5-HT function. The regions implicated are the rostral raphe nuclei and its connections to limbic and cognitive areas. It is conceivable that 5-HT agents could help alleviate abnormal changes in BMI in PD. [Copyright &y& Elsevier]

Abstract: Post-mortem and neuroimaging studies in Parkinson''s disease (PD) have shown involvement of the brain serotoninergic, noradrenergic and cholinergic pathways alongside the characteristic degeneration of nigrostriatal dopamine neurons. The rate of progression of the degenerative process in these extrastriatal areas is still unclear. We used 18F-dopa PET, a marker of aromatic aminoacid decarboxylase activity in monoaminergic neurons, to assess longitudinal changes in tracer uptake in brain noradrenergic, serotoninergic and extrastriatal dopaminergic structures over a 3-year period in a group of early PD patients. Ten PD patients had 18F-dopa PET twice: at baseline and again after 37.1±21.5months follow up. A standard object map was used to extract tracer influx constants (Ki) in 11 striatal and extrastriatal regions. Progressive decreases in 18F-dopa Ki occurred over the follow-up period in the majority of the investigated areas, the fastest annual declines occurring in putamen (8.1%), locus coeruleus (7.8%), and globus pallidus interna (7.7%). Caudate and hypothalamus showed 6.3% and 6.1% annual Ki declines, respectively. At baseline, some structures showed increased levels of 18F-dopa uptake in PD compared to controls (internal pallidum, locus coeruleus), indicating possible compensatory upregulation of monoamine turnover. These increased levels had normalised (globus pallidus interna) or become subnormal (locus coeruleus) at follow-up suggesting exhaustion of these mechanisms within the first years of disease. Loss of monoaminergic function in extrastriatal regions, as reflected by18F-dopa PET, is delayed and occurs independently from nigrostriatal degeneration. When assessing the efficacy of novel neuroprotective agents on nigrostriatal dysfunction in PD, 18F-dopa PET could provide supplementary information concerning function of extrastriatal monoaminergic structures. [Copyright &y& Elsevier]

Abstract: Thirty Parkinson''s disease (PD) patients were divided into three equal groups according to their disease duration while 10 normal healthy volunteers matched for age and sex served as a control group. Striatal and extrastriatal serotonergic function was studied with 11C-DASB PET, a marker of serotonin transporter availability. 11C-DASB binding was correlated with disease disability and exposure to dopaminergic therapy. We found significant 11C-DASB binding reductions in striatal, brainstem, and cortical regions in PD but no correlations were evident between 11C-DASB binding and UPDRS scores, Hoehn &Yahr staging, disease duration and level of exposure to dopaminergic therapy. Our results suggest that progressive non-linear serotonergic dysfunction occurs in PD but it does not determine levels of disability. Additionally, chronic exposure to dopaminergic therapy does not appear to influence SERT binding. [Copyright &y& Elsevier]

Abstract: PET studies in parkin-linked parkinsonism have generally been performed to assess striatal dopaminergic dysfunction and very little is known about the involvement of other monoaminergic structures in these patients. Measurements of 18F-dopa uptake into serotonergic and noradrenergic structures provide an indication of the functional integrity of these nerve terminals. We used 18F-dopa PET to assess changes in brain monoaminergic function associated with parkin mutations. Twelve patients with parkin-linked parkinsonism and 12 asymptomatic parkin heterozygotes were included in the study. Eleven healthy controls, 12 patients with idiopathic Parkinson''s disease (IPD), and four patients with PINK1 mutations were also investigated for comparison. parkin patients and IPD patients were matched for striatal dopaminergic dysfunction, as measured by 18F-dopa uptake. Compared to controls, parkin patients showed significant 18F-dopa reductions in the caudate, putamen, ventral striatum, locus coeruleus, midbrain raphe, and pallidum. The same structures showed reduced uptake in IPD patients, who additionally had significant reductions in hypothalamus, ventral anterior thalamus, and pineal gland. Direct comparison of parkin with IPD patients showed that hypothalamus was targeted in IPD and midbrain raphe in parkin disease. Patients with PINK1 mutation and several parkin heterozygotes also showed monoaminergic dysfunction. These findings suggest that parkin patients and IPD patients with similar striatal dysfunction have different patterns of monoaminergic involvement, with more widespread dysfunction in IPD. [Copyright &y& Elsevier]

Abstract: We used 11C-raclopride PET, a marker of D2 dopamine receptor binding, and statistical parametric mapping (SPM) to localise cortical D2 receptor dysfunction in individual Huntington''s disease (HD) gene carriers (16 symptomatic and 11 premanifest subjects) and assess its clinical significance. 62.5% of symptomatic HD patients and 54.5% of premanifest carriers showed cortical reductions in D2 binding. The most frequent decreases in cortical binding in individual HD subjects were seen in temporal and frontal areas. Symptomatic HD subjects with decreased cortical D2 binding had worse scores on neuropsychological tests assessing attention and executive functions than subjects without cortical dopamine dysfunction, notwithstanding comparable reduction in striatal D2 binding and motor disability. Our results indicate that cortical dopaminergic dysfunction is common in both symptomatic and premanifest HD gene carriers. It is an early event in HD pathophysiology and could contribute to the impairment in neuropsychological performance in these patients. [Copyright &y& Elsevier]

Abstract: [11C](R)PK11195-PET is a marker of activated microglia while [11C]PIB-PET detects raised amyloid load. Here we studied in vivo the distributions of amyloid load and microglial activation in Alzheimer''s disease (AD) and their relationship with cognitive status. Thirteen AD subjects had [11C](R)PK11195-PET and [11C]PIB-PET scans. Ten healthy controls had [11C](R)PK11195-PET and 14 controls had [11C]PIB-PET scans. Region-of-interest analysis of [11C](R)PK11195-PET detected significant 20–35% increases in microglial activation in frontal, temporal, parietal, occipital and cingulate cortices (p <0.05) of the AD subjects. [11C]PIB-PET revealed significant two-fold increases in amyloid load in these same cortical areas (p <0.0001) and SPM (statistical parametric mapping) analysis confirmed the localisation of these increases to association areas. MMSE scores in AD subjects correlated with levels of cortical microglial activation but not with amyloid load. The inverse correlation between MMSE and microglial activation is compatible with a role of microglia in neuronal damage. [Copyright &y& Elsevier]

Abstract: A mild to moderate reduction in dopamine, noradrenaline and serotonin levels alongside a progressive loss of hypocretin cells and melanin hormone concentrating cells has been reported in the hypothalamus of PD at postmortem. Hypothalamic uptake of 18F-dopa PET, an in vivo marker of dysfunction of monoaminergic neurons, is also significantly reduced in these patients. These data indicate a general impairment of hypothalamic function in PD. Dopamine receptors play an important role in the regulation of hypothalamic pathways. To date, possible changes in hypothalamic D2 receptor availability have not been investigated in PD. The objective in this study was to assess dopamine D2 receptor availability in hypothalamus of patients with idiopathic Parkinson''s disease (PD) using positron emission tomography (PET) with 11C-raclopride (RAC). We evaluated D2 binding in RAC PET images of 14 PD patients using both region of interest (ROI) analysis and a voxel based approach. ROIs for the hypothalamus were traced on the subject''s MRI co-registered to the PET image. 11C-raclopride binding potentials (BP) for hypothalamus were obtained by applying ROIs onto parametric images. Findings were compared with those of 9 normal controls. We found a significant reduction in the mean hypothalamic RAC BP of the PD patients compared with the normal controls (0.2714±0.06 vs. 0.3861±0.04; mean±SD; p =0.0005). ROI results were confirmed with statistical parametric mapping (SPM). Individual hypothalamic BP values of PD patients did not correlate with age, disease duration, disease severity and levodopa equivalent dose. It remains to be ascertained whether the reductions in hypothalamic D2 receptor availability seen in PD are disease related, the results of chronic exposure to levodopa or both. Our results provide further evidence of dopaminergic dysfunction in the hypothalamus in PD, and this may contribute to the development of sleep, endocrine and autonomic disorders. [Copyright &y& Elsevier]

Abstract: The basal ganglia and thalamus are involved in processing all physiological behaviors and affected by many diseases. Accurate localization is a crucial issue in neuroimaging, particularly when working with groups of normalized images in a standard stereotaxic space. Here, manual delineation of the central structures (thalamus; nucleus caudatus and accumbens; putamen, pallidum, substantia nigra) was performed on 30 high resolution MRIs of healthy young adults (15 female, median age 31 years) in native space. Protocol inter-rater reliabilities were quantified as structure overlap (similarity indices, SIs). Structural volumes were calculated in native space, and after spatial normalization to stereotaxic space (MNI/ICBM152) and in relation to hemispheric volumes. Spatial extents relative to the anterior commissure (AC) were extracted. The 30 resulting atlases were then used to create probabilistic maps in stereotaxic space. Inter-rater SIs were high at 0.85–0.92 except for the nucleus accumbens. In native space, caudate, nucleus accumbens and putamen were significantly larger on the left, and the globus pallidus larger in males. After normalizing for brain volume, the nucleus accumbens, putamen and thalamus were larger on the left, with the gender difference in the globus pallidus still detectable. Some of these volume differences translated into significantly different distances from the AC. The probabilistic maps showed that overall the central structures'' boundaries are relatively unchanged after spatial normalization. We present a comprehensive assessment of thalamic and basal ganglia volumetric and geometric data in both native and stereotaxic spaces. Probabilistic maps in MNI/ICBM152 space will allow accurate localization in group analyses. [Copyright &y& Elsevier]

Abstract: [11C]diprenorphine (DPN) is a non-subtype selective opioid receptor PET ligand with slow kinetics and no region devoid of specific binding. Parametric maps are desirable but have to overcome high noise at the voxel level. We obtained parameter values, parametric map image quality, test–retest reproducibility and reliability (using intraclass correlation coefficients (ICCs)) for conventional spectral analysis and a derived method (rank shaping), compared them with values obtained through sampling of volumes of interest (VOIs) on the dynamic data sets and tested whether smaller amounts of radioactivity injected maintained reliability. Ten subjects were injected twice with either ∼185 MBq or ∼135 MBq of [11C]DPN, followed by dynamic PET for 90 min. Data were movement corrected with a frame-to-frame co-registration method. Arterial plasma input functions corrected for radiolabelled metabolites were created. There was no overall effect of movement correction except for one subject with substantial movement whose test–retest differences decreased by ∼50%. Actual parametric values depended heavily on the cutoff for slow frequencies (between 0.0008 s−1 and 0.00063 s−1). Image quality was satisfactory for restricted base ranges when using conventional spectral analysis. The rank shaping method allowed maximising of this range but had similar bias. VOI-based methods had the widest dynamic range between regions. Average percentage test–retest differences were smallest for the parametric maps with restricted base ranges; similarly ICCs were highest for these (up to 0.86) but unacceptably low for VOI-derived VD estimates at the low doses of injected radioactivity (0.24/0.04). Our data can inform the choice of methodology for a given biological problem. [Copyright &y& Elsevier]

Abstract: [11C]-(R)-PK11195 is presently the most widely used radiotracer for the monitoring of microglia activity in the central nervous system (CNS). Microglia, the resident immune cells of the brain, play a critical role in acute and chronic diseases of the central nervous system and in host defence against neoplasia. The purpose of this investigation was to evaluate the reliability and sensitivity of five kinetic modelling methods for the formation of parametric maps from dynamic [11C]-(R)-PK11195 studies. The methods we tested were the simplified reference tissue model (SRTM), basis pursuit, a simple target-to-reference ratio, the Logan plot and a wavelet based Logan plot. For the reliability assessment, the test–retest data consisted of four Alzheimer’s patients that were scanned twice at approximately a six-week interval. For the sensitivity assessment, comparison of [11C]-(R)-PK11195 binding in Huntington’s disease (HD) patients and normal subjects was performed using a group contrast to localize significant increases in mean pixel volume of distribution (VD) in HD. In all instances, a reference region kinetic extracted by a supervised clustering technique was used as input function. Reliability was assessed by use of the intra-class correlation coefficient (ICC) across a wide set of anatomical regions and it was found that the wavelet-based Logan plot, basis pursuit and SRTM gave the highest ICC values on average. The same methods produced the highest z-scores resulting from increases in mean striatal VD in HD patients compared with controls. The reference-to-target ratio and the Logan graphical approach were significantly less reliable and less sensitive. [Copyright &y& Elsevier]

Abstract: Idiopathic Parkinson''s disease (PD) is a neurodegenerative disorder associated with akinesia, tremor and rigidity. While the characteristic Lewy body pathology targets pigmented and other brainstem nuclei at post-mortem, activated microglia are found in both subcortical and cortical areas. [11C](R)-PK11195 is a positron emission tomography (PET) marker of peripheral benzodiazepine sites (PBBS), which are selectively expressed by activated microglia. We examined 18 PD patients clinically and with [11C](R)-PK11195 and [18F]-dopa PET. Compared to 11 normal controls, the PD patients showed significantly increased mean levels of [11C](R)-PK11195 binding in the pons, basal ganglia and frontal and temporal cortical regions. Eight PD patients were examined longitudinally, and their [11C](R)-PK11195 signal remained stable over 2 years. Levels of microglial activation did not correlate with clinical severity or putamen [18F]-dopa uptake. Our in vivo findings confirm that widespread microglial activation is associated with the pathological process in PD. The absence of significant longitudinal changes suggests that microglia are activated early in the disease process, and levels then remain relatively static, possibly driving the disease via cytokine release. [Copyright &y& Elsevier]

Noradrenergic neurotransmission may play an important role in tremor modulation through its innervation of key structures of the central tremor circuits. Here, Parkinson's disease (PD) patients with (PDT+) or without (PDT-) rest tremor had 11C-methylreboxetine(11C-MeNER) positron emission tomography (PET) to test the hypothesis that noradrenaline terminal function was relatively preserved in PDT+ compared to PDT-. Sixty-five PD patients and 28 healthy controls (HC) were scanned with 11C-MeNER PET. Patients were categorized as PDT+ if subscores in UPDRS-III item 3 or MDS-UPDRS-III item 17 was ≥2; remaining were categorized as PDT-. Simplified reference tissue model 2 distribution volume ratios (DVR) for 11C-MeNER were calculated for thalamus, dorsal and median raphe, locus coeruleus (LC) and red nucleus using time activity curves (TACs) obtained from volumes of interest (VOI). Data were statistically interrogated with a general linear mixed model using 'region', and 'group' as factors and the interaction of 'region x group' was examined. Tremor positive PD patients had a significantly higher mean 11C-MeNER DVR compared to PDT- in LC and thalamus. The PDT+ mean LC DVR was similar to that of HC. PDT+ mean 11C-MeNER DVRs were significantly lower than HC in the dorsal raphe while the PDT- group showed significantly lower mean 11C-MeNER DVR across all regions compared to HC. While both PD T+ and PD T- groups showed a significant loss of noradrenaline terminal function compared to controls, noradrenergic neurons were relatively preserved in PDT+ in LC and thalamus. The greater loss of noradrenergic transporters in PDT- in LC and thalamus compared with PDT+ is in line with earlier in-vitro studies and could potentially contribute to their tremor negative phenotype. • Noradrenaline is associated with rest tremor in Parkinson's disease. • Noradrenaline is preserved in tremor predominant Parkinson's Disease. • Patients without tremor show loss of noradrenaline in locus coeruleus and thalamus. [ABSTRACT FROM AUTHOR]

Alpha-synuclein (a-syn) can aggregate and form toxic oligomers and insoluble fibrils which are the main component of Lewy bodies. Intra-neuronal Lewy bodies are a major pathological characteristic of Parkinson's disease (PD). These fibrillar structures can act as seeds and accelerate the aggregation of monomeric a-syn. Indeed, recent studies show that injection of preformed a-syn fibrils (PFF) into the rodent brain can induce aggregation of the endogenous monomeric a-syn resulting in neuronal dysfunction and eventual cell death. We injected 8 μg of murine a-syn PFF, or soluble monomeric a-syn into the right striatum of rats. The animals were monitored behaviourally using the cylinder test, which measures paw asymmetry, and the corridor task that measures lateralized sensorimotor response to sugar treats. In vivo PET imaging was performed after 6, 13 and 22 weeks using [11C]DTBZ, a marker of the vesicular monoamine 2 transporter (VMAT2), and after 15 and 22 weeks using [11C]UCB-J, a marker of synaptic SV2A protein in nerve terminals. Histology was performed at the three time points using antibodies against dopaminergic markers, aggregated a-syn, and MHCII to evaluate the immune response. While the a-syn PFF injection caused only mild behavioural changes, [11C]DTBZ PET showed a significant and progressive decrease of VMAT2 binding in the ipsilateral striatum. This was accompanied by a small progressive decrease in [11C]UCB-J binding in the same area. In addition, our histological analysis revealed a gradual spread of misfolded a-syn pathology in areas anatomically connected to striatum that became bilateral with time. The striatal a-syn PFF injection resulted in a progressive unilateral degeneration of dopamine terminals, and an early and sustained presence of MHCII positive ramified microglia in the ipsilateral striatum and substantia nigra. Our study shows that striatal injections of a-syn fibrils induce progressive pathological synaptic dysfunction prior to cell death that can be detected in vivo with PET. We confirm that intrastriatal injection of a-syn PFFs provides a model of progressive a-syn pathology with loss of dopaminergic and synaptic function accompanied by neuroinflammation, as found in human PD. • Intrastriatal α-Synuclein fibrils induce nigrostriatal degeneration. • α-Synuclein pathology induced early and sustained MHCII expression. • α-Synuclein fibrils injection results in hyperactivity and mild sensorimotor defects. • rats with α-Synuclein pathology show progressive decrease in [11C]DTBZ PET striatal binding. • α-Synuclein pathology induced decreased synaptic density measured by [11C]UCB-J PET. [ABSTRACT FROM AUTHOR]