Interplay of tau and functional network connectivity in progressive supranuclear palsy: a [18F]PI-2620 PET/MRI study.

PURPOSE: Progressive supranuclear palsy (PSP) is primary 4-repeat tauopathy. Evidence spanning from imaging studies indicate aberrant connectivity in PSPs. Our goal was to assess functional connectivity network alterations in PSP patients and the potential link between regional tau-burden and network-level functional connectivity using the next-generation tau PET tracer [18F]PI-2620 and resting-state functional MRI (fMRI). MATERIAL AND METHODS: Twenty-four probable PSP patients (70.9 ± 6.9 years, 13 female), including 14 Richardson syndrome (RS) and 10 non-RS phenotypes, underwent [18F]PI-2620 PET/MRI imaging. Distribution volume ratios (DVRs) were estimated using non-invasive pharmacokinetic modeling. Resting-state fMRI was also acquired in these patients as well as in thirteen older non-AD MCI reference group (64 ± 9 years, 4 female). The functional network was constructed using 141 by 141 region-to-region functional connectivity metrics (RRC) and network-based statistic was carried out (connection threshold p < 0.001, cluster threshold pFDR < 0.05). RESULTS: In total, 9870 functional connections were analyzed. PSPs compared to aged non-AD MCI reference group expressed aberrant connectivity evidenced by the significant NBS network consisting of 89 ROIs and 118 connections among them (NBS mass 4226, pFDR < 0.05). Tau load in the right globus pallidus externus (GPe) and left dentate nucleus (DN) showed significant effects on functional network connectivity. The network linked with increased tau load in the right GPe was associated with hyperconnectivity of low-range intra-opercular connections (NBS mass 356, pFDR < 0.05), while the network linked with increased tau load in the left cerebellar DN was associated with cerebellar hyperconnectivity and cortico-cerebellar hypoconnectivity (NBS mass 517, pFDR < 0.05). CONCLUSIONS: PSP patients show altered functional connectivity. Network incorporating deep gray matter structures demonstrate hypoconnectivity, cerebellum hyperconnectivity, while cortico-cortical connections show variable changes. Tau load in the right GPe and left DN is associated with functional networks which strengthen low-scale intra-opercular and intra-cerebellar connections and weaken opercular-cerebellar connections. These findings support the concept of tau load-dependent functional network changes in PSP, by that providing evidence for downstream effects of neuropathology on brain functionality in this primary tauopathy.

Prefrontal and posterior parietal contributions to the perceptual awareness of touch.

Which brain regions contribute to the perceptual awareness of touch remains largely unclear. We collected structural magnetic resonance imaging scans and neurological examination reports of 70 patients with brain injuries or stroke in S1 extending into adjacent parietal, temporal or pre-/frontal regions. We applied voxel-based lesion-symptom mapping to identify brain areas that overlap with an impaired touch perception (i.e., hypoesthesia). As expected, patients with hypoesthesia (n = 43) presented lesions in all Brodmann areas in S1 on postcentral gyrus (BA 1, 2, 3a, 3b). At the anterior border to BA 3b, we additionally identified motor area BA 4p in association with hypoesthesia, as well as further ventrally the ventral premotor cortex (BA 6, BA 44), assumed to be involved in whole-body perception. At the posterior border to S1, we found hypoesthesia associated effects in attention-related areas such as the inferior parietal lobe and intraparietal sulcus. Downstream to S1, we replicated previously reported lesion-hypoesthesia associations in the parietal operculum and insular cortex (i.e., ventral pathway of somatosensory processing). The present findings extend this pathway from S1 to the insular cortex by prefrontal and posterior parietal areas involved in multisensory integration and attention processes.

Serotonin transporter gene promoter methylation status correlates with in vivo prefrontal 5-HTT availability and reward function in human obesity.

A polymorphism in the promoter region of the human serotonin transporter (5-HTT)-coding SLC6A4 gene (5-HTTLPR) has been implicated in moderating susceptibility to stress-related psychopathology and to possess regulatory functions on human in vivo 5-HTT availability. However, data on a direct relation between 5-HTTLPR and in vivo 5-HTT availability have been inconsistent. Additional factors such as epigenetic modifications of 5-HTTLPR might contribute to this association. This is of particular interest in the context of obesity, as an association with 5-HTTLPR hypermethylation has previously been reported. Here, we tested the hypothesis that methylation rates of 14 cytosine-phosphate-guanine (CpG) 5-HTTLPR loci, in vivo central 5-HTT availability as measured with [11C]DASB positron emission tomography (PET) and body mass index (BMI) are related in a group of 30 obese (age: 36±10 years, BMI>35 kg/m2) and 14 normal-weight controls (age 36±7 years, BMI<25 kg/m2). No significant association between 5-HTTLPR methylation and BMI overall was found. However, site-specific elevations in 5-HTTLPR methylation rates were significantly associated with lower 5-HTT availability in regions of the prefrontal cortex (PFC) specifically within the obese group when analyzed in isolation. This association was independent of functional 5-HTTLPR allelic variation. In addition, negative correlative data showed that CpG10-associated 5-HTT availability determines levels of reward sensitivity in obesity. Together, our findings suggest that epigenetic mechanisms rather than 5-HTTLPR alone influence in vivo 5-HTT availability, predominantly in regions having a critical role in reward processing, and this might have an impact on the progression of the obese phenotype.

Hunger and disinhibition but not cognitive restraint are associated with central norepinephrine transporter availability.

The relationship between food-intake related behaviours measured by the Three-Factor Eating Questionnaire (TFEQ) and in vivo norepinephrine transporter (NET) availability has not been explored yet. We investigated ten obese individuals (body mass index (BMI) 42.4 ± 3.7 kg/m2) and ten normal-weight healthy controls (HC, BMI 23.9 ± 2.5 kg/m2) with (S,S)-[11C]-O-methylreboxetine ([11C]MRB) positron emission tomography (PET). All participants completed the TFEQ, which measures cognitive restraint, disinhibition and hunger. Image analysis required magnetic resonance imaging data sets onto which volumes-of-interests were drawn. Tissue time activity curves (TACs) were obtained from the dynamic PET data followed by kinetic modeling of these regional brain TACs applying the multilinear reference tissue model (2 parameters) with the occipital cortex as reference region. Obese individuals scored significantly higher on the hunger subscale of the TFEQ. Correlative data analysis showed that a higher degree of hunger correlated negatively with the NET availability of the insular cortex in both obese individuals and HC; however, this finding was more pronounced in obesity. Further, for obese individuals, a negative correlation between disinhibition and NET BPND of the locus coeruleus was detected. In conclusion, these initial data provide in vivo imaging support for the involvement of the central NE system in maladaptive eating behaviors such as susceptibility to hunger.

Emotional eating and in vivo norepinephrine transporter availability in obesity: A [11 C]MRB PET pilot study.

OBJECTIVE: Emotional eating (EE) has been linked to norepinephrine dysfunction. Therefore, we aimed to investigate the relationship between EE and norepinephrine transporter (NET) availability. METHOD: Ten severely obese individuals (body mass index (BMI) 42.4 ± 3.7 kg/m2 ) and ten non-obese, healthy controls (BMI 23.9 ± 2.5 kg/m2 ) matched for age and sex were studied using (S,S)-[11 C]-O-methylreboxetine ([11 C]MRB) positron emission tomography (PET). Kinetic modeling of regional tissue time activity curves was performed using multilinear reference tissue model 2 (MRTM2, with the occipital cortex as a reference region) to estimate binding potential based on individual PET-MR coregistration. To test for associations of EE and NET availability, participants completed the EE subscale of the Dutch Eating Behavior Questionnaire before scanning. RESULTS: Obese individuals and non-obese, healthy controls did not significantly differ regarding EE scores and regional NET availability. For obese individuals only, correlative data analyses pointed to a sinoidal distribution pattern as a higher degree of EE related to lower NET availability in the locus coeruleus and to higher NET availability in the left thalamus. DISCUSSION: These results indicate that central in vivo NET availability is altered in EE of individuals with obesity. © 2016 Wiley Periodicals, Inc.(Int J Eat Disord 2017; 50:152-156).

Impact of attenuation correction on clinical [(18)F]FDG brain PET in combined PET/MRI.

BACKGROUND: In PET/MRI, linear photon attenuation coefficients for attenuation correction (AC) cannot be directly derived, and cortical bone is, so far, usually not considered. This results in an underestimation of the average PET signal in PET/MRI. Recently introduced MR-AC methods predicting bone information from anatomic MRI or proton density-weighted zero-time imaging may solve this problem in the future. However, there is an ongoing debate if the current error is acceptable for clinical use and/or research. METHODS: We examined this feature for [(18)F] fluorodeoxyglucose (FDG) brain PET in 13 patients with clinical signs of dementia or movement disorders who subsequently underwent PET/CT and PET/MRI on the same day. Multiple MR-AC approaches including a CT-derived AC were applied. RESULTS: The resulting PET data was compared to the CT-derived standard regarding the quantification error and its clinical impact. On a quantitative level, -11.9 to +2 % deviations from the CT-AC standard were found. These deviations, however, did not translate into a systematic diagnostic error. This, as overall patterns of hypometabolism (which are decisive for clinical diagnostics), remained largely unchanged. CONCLUSIONS: Despite a quantitative error by the omission of bone in MR-AC, clinical quality of brain [(18)F]FDG is not relevantly affected. Thus, brain [(18)F]FDG PET can already, even now with suboptimal MR-AC, be utilized for clinical routine purposes, even though the MR-AC warrants improvement.

Sex differences in serotonin-hypothalamic connections underpin a diminished sense of emotional well-being with increasing body weight.

BACKGROUND/OBJECTIVES: The neurobiological mechanisms linking obesity to emotional distress related to weight remain largely unknown. PARTICIPANTS/METHODS: Here we combined positron emission tomography, using the serotonin transporter (5-HTT) radiotracer [(11)C]-3-amino-4-(2-dimethylaminomethylphenylsulfanyl)-benzonitrile, with functional connectivity magnetic resonance imaging, the Beck Depression Inventory (BDI-II) and the Impact of Weight on Quality of Life-Lite questionnaire (IWQOL-Lite) to investigate the role of central serotonin in the severity of depression (BDI-II), as well as in the loss of emotional well-being with body weight (IWQOL-Lite). RESULTS: In a group of lean to morbidly obese individuals (n=28), we found sex differences in the 5-HTT availability-related connectivity of the hypothalamus. Males (n=11) presented a strengthened connectivity to the lateral orbitofrontal cortex, whereas in females (n=17) we found strengethened projections to the ventral striatum. Both regions are known as reward regions involved in mediating the emotional response to food. Their resting-state activity correlated positively to the body mass index (BMI) and IWQOL-Lite scores, suggesting that each region in both sexes also underpins a diminished sense of emotional well-being with body weight. Contrarily to males, we found that in females also the BDI-II positively correlated with the BMI and by trend with the activity in ventral striatum, suggesting that in females an increased body weight may convey to other mood dimensions than those weight-related ones included in the IWQOL-Lite. CONCLUSIONS: This study suggests sex differences in serotonin-hypothalamic connections to brain regions of the reward circuitry underpinning a diminished sense of emotional well-being with an increasing body weight.

The central nervous norepinephrine network links a diminished sense of emotional well-being to an increased body weight.

OBJECTIVES: The neurobiological mechanisms linking obesity to emotional distress remain largely undiscovered. METHODS: In this pilot study, we combined positron emission tomography, using the norepinephrine transporter (NET) tracer [(11)C]-O-methylreboxetine, with functional connectivity magnetic resonance imaging, the Beck depression inventory (BDI), and the impact of weight on quality of life-Lite questionnaire (IWQOL-Lite), to investigate the role of norepinephrine in the severity of depression (BDI), as well as in the loss of emotional well-being with body weight (IWQOL-Lite). RESULTS: In a small group of lean-to-morbidly obese individuals (n=20), we show that an increased body mass index (BMI) is related to a lowered NET availability within the hypothalamus, known as the brain's homeostatic control site. The hypothalamus displayed a strengthened connectivity in relation to the individual hypothalamic NET availability to the anterior insula/frontal operculum, as well as the medial orbitofrontal cortex, assumed to host the primary and secondary gustatory cortex, respectively (n=19). The resting-state activity in these two regions was correlated positively to the BMI and IWQOL-Lite scores, but not to the BDI, suggesting that the higher the resting-state activity in these regions, and hence the higher the BMI, the stronger the negative impact of the body weight on the individual's emotional well-being was. CONCLUSIONS: This pilot study suggests that the loss in emotional well-being with weight is embedded within the central norepinephrine network.

Visualizing inflammation activity in rheumatoid arthritis with Tc-99 m anti-CD4-mAb fragment scintigraphy.

PURPOSE: T-cell-located CD4 antigen represents one of the therapeutic targets in rheumatoid arthritis (RA). However, up to now there is no established imaging tool to visualize this target in vivo. The aim of our study was to assess the safety and tolerability of a technetium-99m labelled murine anti-human CD4 IgG1-Fab fragment ([(99m)Tc]-anti-CD4-Fab, [(99m)Tc]-EP1645) in patients with active synovitis due to RA, and to evaluate its potential as a marker of disease activity. METHODS: In the present phase I proof of principle study five patients with RA were examined. Planar scans of the whole body, hands, and feet were taken 30 min up to 24h after application of 550 ± 150 MBq [(99m)Tc]-anti-CD4-Fab, followed by visual analyses, comparison with clinical data in 68 joints per patient and semiquantitative analysis of hand and wrist joints. RESULTS: Neither infusion related adverse events nor adverse events during follow up were observed. No increase in human anti-murine antibody titres was seen. All patients had positive scans in almost 70% of clinically affected joints. Positive scans were also found in 8% of joints without evidence of swelling or tenderness. CONCLUSION: Scintigraphy with [(99m)Tc]-anti-CD4-Fab is a promising technique for evaluation of inflammatory activity in patients with RA, pre-therapeutical evaluation of CD4 status and therapy control. Tracer uptake in clinically inconspicuous joints strongly indicates diagnostic potential of [(99m)Tc]-anti-CD4-Fab. Whether this technique is eligible as a prognostic factor in RA needs to be analysed in further studies as well as the pathophysiological background of clinically affected joints lacking tracer uptake.

EEG source analysis of epileptiform activity using a 1 mm anisotropic hexahedra finite element head model.

The major goal of the evaluation in presurgical epilepsy diagnosis for medically intractable patients is the precise reconstruction of the epileptogenic foci, preferably with non-invasive methods. This paper evaluates whether surface electroencephalography (EEG) source analysis based on a 1 mm anisotropic finite element (FE) head model can provide additional guidance for presurgical epilepsy diagnosis and whether it is practically feasible in daily routine. A 1 mm hexahedra FE volume conductor model of the patient's head with special focus on accurately modeling the compartments skull, cerebrospinal fluid (CSF) and the anisotropic conducting brain tissues was constructed using non-linearly co-registered T1-, T2- and diffusion-tensor-magnetic resonance imaging data. The electrodes of intra-cranial EEG (iEEG) measurements were extracted from a co-registered computed tomography image. Goal function scan (GFS), minimum norm least squares (MNLS), standardized low resolution electromagnetic tomography (sLORETA) and spatio-temporal current dipole modeling inverse methods were then applied to the peak of the averaged ictal discharges EEG data. MNLS and sLORETA pointed to a single center of activity. Moving and rotating single dipole fits resulted in an explained variance of more than 97%. The non-invasive EEG source analysis methods localized at the border of the lesion and at the border of the iEEG electrodes which mainly received ictal discharges. Source orientation was towards the epileptogenic tissue. For the reconstructed superficial source, brain conductivity anisotropy and the lesion conductivity had only a minor influence, whereas a correct modeling of the highly conducting CSF compartment and the anisotropic skull was found to be important. The proposed FE forward modeling approach strongly simplifies meshing and reduces run-time (37 ms for one forward computation in the model with 3.1 million unknowns), corroborating the practical feasibility of the approach.