Abstract Background Neutrophil granulocytes are important parts of the defence against bacterial infections. Their action is a two-edged sword, the mediators killing the intruding bacteria are at the same time causing tissue damage. Neutrophil activation is part of the dysregulated immune response to infection defining sepsis and neutrophil elastase is one of the powerful proteases causing both effects and damage. Inhibition of neutrophil elastase has been tried in sepsis and ARDS, so far with inconclusive results. Methods We used positron emission tomography (PET) combined with computed tomography (CT) and the selective and specific neutrophil elastase inhibitor PET-tracer [11C]GW457427 ([11C]NES), in an intensive care unit porcine Escherichia coli sepsis model with the primary aim to visualise the biodistribution of neutrophil elastase in the initial acute phase of the septic reaction. Repeated PET–CT investigations were performed before and after induction of sepsis. Results At baseline [11C]NES uptake was found in the bone marrow, spleen and liver. The uptake in the bone marrow was markedly increased two hours into the sepsis, whereas in spleen and liver the uptake was not as markedly changed compared to baseline. At 4 h after the sepsis induction [11C]NES in the bone marrow decreased while the uptake increased in the spleen, liver and lungs. Conclusion The neutrophil elastase PET-tracer [11C]NES is a novel and unique instrument to study the acute innate neutrophil immune response in sepsis and associated vital organ failure. We here present images and quantitative data of the neutrophil elastase distribution the first hours of acute experimental sepsis. Surprisingly, a pronounced increase of neutrophil elastase was found in the bone marrow 2 h into the sepsis reaction followed at 4 h by increase in the liver, spleen and lungs and a concomitant reduction of the tracer uptake in bone marrow.

Gamma-aminobutyric acid (GABA) and glutamate are implicated in the antidepressant effects of repetitive transcranial magnetic stimulation (rTMS), though findings from magnetic resonance spectroscopy (MRS) are inconsistent. Furthermore, the relationship between GABAA-receptor availability and rTMS outcomes remains largely unexplored. In this study, GABA and glutamate levels in the dorsal anterior cingulate cortex (dACC) were measured using a 1H-MRS MEGA-PRESS sequence in 42 patients with bipolar or unipolar depression, both before and after a sham-controlled, double-blind clinical trial involving intermittent theta-burst stimulation (iTBS) over the dorsomedial prefrontal cortex. A subset of 28 patients also underwent [11C]flumazenil positron emission tomography (PET) to measure whole-brain GABAA-receptor availability and mean receptor availability in the nucleus accumbens and dACC. Depressive symptoms were assessed using the self-rated Montgomery Åsberg Depression Rating Scale (MADRS-S). The results indicated no significant changes in neurotransmitter levels or GABAA-receptor availability post-iTBS in either the active or sham conditions. However, changes in MADRS-S scores after active iTBS were positively correlated with changes in GABA levels in the dACC (r(13) = 0.54, p = 0.04) and baseline GABAA-receptor availability in the nucleus accumbens (r(11) = 0.66, p = 0.02). These correlations were absent in the sham group. The findings suggest that a reduction in GABA within targeted frontostriatal circuits can be part of the antidepressant mechanism of iTBS, challenging previous research. Additionally, they indicate a potential predictive role for frontostriatal GABAA-receptor availability in the treatment of depression using dorsomedial prefrontal iTBS.

Abstract Background [11C]metomidate, a methyl ester analogue of etomidate, is used for positron emission tomography of adrenocortical cancer, and has been tested in recent clinical trials for lateralization in primary aldosteronism (PA). However, in PA, visualization as well as uptake quantification are hampered by the tracer’s rather high non-specific liver uptake, and its overall clinical usefulness is also limited by the short 20-minute half-life of carbon-11. Therefore, we evaluated para-chloro-2-[18F]fluoroethyl-etomidate, [18F]CETO, a fluorine-18 (T1/2=109.8 min) analogue, as a potential new adrenocortical PET tracer. The aim of this study was to assess radiation dosimetry of [18F]CETO. Results [18F]CETO showed a high uptake in adrenal glands, still increasing at 5 h post injection. Adrenal glands (absorbed dose coefficients 0.100 ± 0.032 mGy/MBq in males and 0.124 ± 0.013 mGy/MBq in females) received the highest absorbed dose. The effective dose coefficient was 20 µSv/MBq. Conclusions [18F]CETO has a favourable biodistribution in humans for adrenal imaging. The effective dose for a typical clinical PET examination with 200 MBq [18F]CETO is 4 mSv. Trial registration ClinicalTrials.gov, NCT05361083 Retrospectively registered 29 April 2022. at, URL: https://clinicaltrials.gov/ct2/show/NCT05361083.

Introduction: Gamma-aminobutyric acid (GABA) deficiency is suggested in depressive disorders, along with alterations in cortical excitability. However, whether these excitability changes are related to GABAA receptor availability is largely unknown. Our aim was to assess the correlation between these measures in depressed patients and healthy controls. Methods: Twenty-eight patients with a major depressive episode, measured before and after participating in a clinical trial with repetitive transcranial magnetic stimulation (TMS), and 15 controls underwent [11C]flumazenil positron emission tomography to assess GABAA receptor availability and paired pulse TMS (ppTMS) to evaluate cortical excitability. Both whole-brain voxel-wise GABAA receptor availability and mean values from left hand motor cortex and left paracentral lobule were correlated to the ppTMS outcomes: short-interval intracortical inhibition reflecting GABAA receptor activity, long-interval intracortical inhibition representing GABAB receptor activity, intracortical facilitation reflecting glutamate N-methyl-D-aspartate-receptor activity, as well as the resting motor threshold (rMT), considered a global measure of corticospinal excitability. Results: No significant differences in baseline GABAA receptor availability or cortical excitability were found between patients and controls. Additionally, no correlations were observed between baseline measurements of GABAA receptor availability and TMS outcomes. Changes in GABAA receptor availability in the hand motor cortex, between pre- and post-assessments, were inversely related to pre-post changes in hand rMT. Conclusion: We found that a change in GABAA receptor availability was inversely related to a change in rMT, suggesting a link between GABA deficiency and increased rMT previously observed in depressive episodes. The results highlight the complex mechanisms governing cortical excitability measures and offer new insight into their properties during the depressive state.

Traumatic brain injury (TBI) or repeated sport-related concussions (rSRC) may lead to long-term memory impairment. Diffusion tensor imaging (DTI) is helpful to reveal global white matter damage but may underestimate focal abnormalities. We investigated the distribution of post-injury regional white matter changes after TBI and rSRC. Six patients with moderate/severe TBI, and 12 athletes with rSRC were included ≥6 months post-injury, and 10 (age-matched) healthy controls (HC) were analyzed. The Repeatable Battery for the Assessment of Neuropsychological Status was performed at the time of DTI. Major white matter pathways were tracked using q-space diffeomorphic reconstruction and analyzed for global and regional changes with a controlled false discovery rate. TBI patients displayed multiple classic white matter injuries compared with HC (p < 0.01). At the regional white matter analysis, the left frontal aslant tract, anterior thalamic radiation, and the genu of the corpus callosum displayed focal changes in both groups compared with HC but with different trends. Both TBI and rSRC displayed worse memory performance compared with HC (p < 0.05). While global analysis of DTI-based parameters did not reveal common abnormalities in TBI and rSRC, abnormalities to the fronto-thalamic network were observed in both groups using regional analysis of the white matter pathways. These results may be valuable to tailor individualized rehabilitative approaches for post-injury cognitive impairment in both TBI and rSRC patients.

Primary Objective Traumatic brain injury (TBI) and sports-related concussion (SRC) may result in chronic functional and neuroanatomical changes. We tested the hypothesis that neuroimaging findings (cerebral blood flow (CBF), cortical thickness, and H-1-magnetic resonance (MR) spectroscopy (MRS)) were associated to cognitive function, TBI severity, and sex. Research Design Eleven controls, 12 athletes symptomatic following >= 3SRCs and 6 patients with moderate-severe TBI underwent MR scanning for evaluation of cortical thickness, brain metabolites (MRS), and CBF using pseudo-continuous arterial spin labeling (ASL). Cognitive screening was performed using the RBANS cognitive test battery. Main Outcomes and Results RBANS-index was impaired in both injury groups and correlated with the injury severity, although not with any neuroimaging parameter. Cortical thickness correlated with injury severity (p = 0.02), while neuronal density, using the MRS marker ((NAA+NAAG)/Cr, did not. On multivariate analysis, injury severity (p = 0.0003) and sex (p = 0.002) were associated with CBF. Patients with TBI had decreased gray (p = 0.02) and white matter (p = 0.02) CBF compared to controls. CBF was significantly lower in total gray, white matter and in 16 of the 20 gray matter brain regions in female but not male athletes when compared to female and male controls, respectively. Conclusions Injury severity correlated with CBF, cognitive function, and cortical thickness. CBF also correlated with sex and was reduced in female, not male, athletes. Chronic CBF changes may contribute to the persistent injury mechanisms in TBI and rSRC.

[11C]Metomidate positron emission tomography (PET) is currently used for staging of adrenocortical carcinoma and for lateralization in primary aldosteronism (PA). Due to the short half-life of carbon-11 and a high non-specific liver uptake of [11C]metomidate there is a need for improved adrenal imaging methods. In a previous pre-clinical study para-chloro-2-[18F]fluoroethyletomidate has been proven to be a specific adrenal tracer. The objective is to perform a first evaluation of para-chloro-2-[18F]fluoroethyletomidate positron emission computed tomography ([18F]CETO-PET/CT) in patients with adrenal tumours and healthy volunteers. Fifteen patients underwent [18F]CETO-PET/CT. Five healthy volunteers were recruited for test-retest analysis and three out of the five underwent additional [15O]water PET/CT to measure adrenal blood flow. Arterial blood sampling and tracer metabolite analysis was performed. The kinetics of [18F]CETO were assessed and simplified quantitative methods were validated by comparison to outcome measures of tracer kinetic analysis. Uptake of [18F]CETO was low in the liver and high in adrenals. Initial metabolization was rapid, followed by a plateau. The kinetics of [18F]CETO in healthy adrenals and all adrenal pathologies, except for adrenocortical carcinoma, were best described by an irreversible single-tissue compartment model. Standardized uptake values (SUV) correlated well with the uptake rate constant K1. Both K1 and SUV were highly correlated to adrenal blood flow in healthy controls. Repeatability coefficients of K1, SUV65–70, and SUV120 were 25, 22, and 17 ClinicalTrials.gov , NCT05361083 Retrospectively registered 29 April 2022. at, https://clinicaltrials.gov/ct2/show/NCT05361083

Background In a Phase I study treatment with the serum amyloid P component (SAP) depleter miridesap followed by monoclonal antibody to SAP (dezamizumab) showed removal of amyloid from liver, spleen and kidney in patients with systemic amyloidosis. We report results from a Phase 2 study and concurrent immuno-positron emission tomography (PET) study assessing efficacy, pharmacodynamics, pharmacokinetics, safety and cardiac uptake (of dezamizumab) following the same intervention in patients with cardiac amyloidosis. Methods Both were uncontrolled open-label studies. After SAP depletion with miridesap, patients received ≤ 6 monthly doses of dezamizumab in the Phase 2 trial (n = 7), ≤ 2 doses of non-radiolabelled dezamizumab plus [ 89 Zr]Zr-dezamizumab (total mass dose of 80 mg at session 1 and 500 mg at session 2) in the immuno-PET study (n = 2). Primary endpoints of the Phase 2 study were changed from baseline to follow-up (at 8 weeks) in left ventricular mass (LVM) by cardiac magnetic resonance imaging and safety. Primary endpoint of the immuno-PET study was [ 89 Zr]Zr-dezamizumab cardiac uptake assessed via PET. Results Dezamizumab produced no appreciable or consistent reduction in LVM nor improvement in cardiac function in the Phase 2 study. In the immuno-PET study, measurable cardiac uptake of [ 89 Zr]Zr-dezamizumab, although seen in both patients, was moderate to low. Uptake was notably lower in the patient with higher LVM. Treatment-associated rash with cutaneous small-vessel vasculitis was observed in both studies. Abdominal large-vessel vasculitis after initial dezamizumab dosing (300 mg) occurred in the first patient with immunoglobulin light chain amyloidosis enrolled in the Phase 2 study. Symptom resolution was nearly complete within 24 h of intravenous methylprednisolone and dezamizumab discontinuation; abdominal computed tomography imaging showed vasculitis resolution by 8 weeks. Conclusions Unlike previous observations of visceral amyloid reduction, there was no appreciable evidence of amyloid removal in patients with cardiac amyloidosis in this Phase 2 trial, potentially related to limited cardiac uptake of dezamizumab as demonstrated in the immuno-PET study. The benefit-risk assessment for dezamizumab in cardiac amyloidosis was considered unfavourable after the incidence of large-vessel vasculitis and development for this indication was terminated. Trial registration NCT03044353 (2 February 2017) and NCT03417830 (25 January 2018).

Smoking is a cause of serious disease in smokers. Electronic cigarettes, delivering aerosolized nicotine, offer adult smokers a potentially less harmful alternative to combustible cigarettes. This explorative PET/CT study investigated the distribution and deposition of inhaled [11C]nicotine using the mybluTM e-cigarette with two nicotine formulations, freebase and lactate salt. Fifteen healthy adult smokers participated in the two-part study to assess the distribution and accumulation of [11C]nicotine in the respiratory pathways and brain. Time-activity data for the respiratory pathways, lungs, oesophagus and brain were derived. 31–36% of both inhaled tracer formulations accumulated in the lung within 15–35 s. [11C]Nicotinefreebase exhibited higher uptake and deposition in the upper respiratory pathways. For [11C]nicotinelactate, brain deposition peaked at 4–5%, with an earlier peak and a steeper decline. A different kinetic profile was obtained for [11C]nicotinelactate with lower tracer uptake and accumulation in the upper respiratory pathways and an earlier peak and a steeper decline in lung and brain. Using nicotine lactate formulations in e-cigarettes may thus contribute to greater adult smoker acceptance and satisfaction compared to freebase formulations, potentially aiding a transition from combustible cigarettes and an acceleration of tobacco harm reduction initiatives.

Traumatic brain injury (TBI) and repeated sports-related concussions (rSRCs) are associated with an increased risk for neurodegeneration. Autopsy findings of selected cohorts of long-term TBI survivors and rSRC athletes reveal increased tau aggregation and a persistent neuroinflammation. To assess in vivo tau aggregation and neuroinflammation in young adult TBI and rSRC cohorts, we evaluated 9 healthy controls (mean age 26 ± 5 years; 4 males, 5 females), 12 symptomatic athletes (26 ± 7 years; 6 males, 6 females) attaining ≥3 previous SRCs, and 6 moderate-to severe TBI patients (27 ± 7 years; 4 males, 2 females) in a combined positron emission tomography (PET)/magnetic resonance (MR) scanner ≥6 months post-injury. Dual PET tracers, [18F]THK5317 for tau aggregation and [11C]PK11195 for neuroinflammation/microglial activation, were investigated on the same day. The Repeated Battery Assessment of Neurological Status (RBANS) scores, used for cognitive evaluation, were lower in both the rSRC and TBI groups (p < 0.05). Neurofilament-light (NF-L) levels were increased in plasma and cerebrospinal fluid (CSF; p < 0.05), and serum tau levels lower, in TBI although not in rSRC. In rSRC athletes, PET imaging showed increased neuroinflammation in the hippocampus and tau aggregation in the corpus callosum. In TBI patients, tau aggregation was observed in thalami, temporal white matter and midbrain; widespread neuroinflammation was found e.g. in temporal white matter, hippocampus and corpus callosum. In mixed-sex cohorts of young adult athletes with persistent post-concussion symptoms and in TBI patients, increased tau aggregation and neuroinflammation are observed at ≥6 months post-injury using PET. Studies with extended clinical follow-up, biomarker examinations and renewed PET imaging are needed to evaluate whether these findings progress to a neurodegenerative disorder or if spontaneous resolution is possible.

The Gamma-aminobutyric acid (GABA) and glutamate (Glu) neurotransmitter systems are implicated in depression. While previous studies found reduced GABA levels, and a tendency towards reduced Glu, using proton (1H) magnetic resonance spectroscopy (1H-MRS), little is known about GABAA receptor availability in depression. Here, the aim was to characterize GABA and Glu-levels in dorsal anterior cingulate cortex (dACC), whole-brain GABAA availability, and their relationship in patients with depression compared to healthy controls. Forty-two patients and 45 controls underwent 1H-MRS using a MEGA-PRESS sequence to quantify dACC GABA+ and Glu (contrasted against creatine [Cr]). Immediately preceding the 1H-MRS, a subsample of 28 patients and 15 controls underwent positron emission tomography (PET) with [11C]Flumazenil to assess whole-brain GABAA receptor availability. There were no differences in dACC GABA+/Cr or Glu/Cr ratios between patients and controls. The same was true for whole-brain GABAA receptor availability. However, there was a significant negative relationship between GABA+/Cr ratio and receptor availability in ACC, in a whole-brain voxel-wise analysis across patients and controls, controlling for group or depressive symptoms. This relatively large study did not support the GABA-deficit hypothesis in depression, but shed light on GABA-system functioning, suggesting a balance between neurotransmitter concentration and receptor availability in dACC.

Cross-sectional studies have indicated potential for positron emission tomography (PET) in imaging tau pathology in Alzheimer’s disease (AD); however, its prognostic utility remains unproven. In a longitudinal, multi-modal, prognostic study of cognitive decline, 20 patients with a clinical biomarker-based diagnosis in the AD spectrum (mild cognitive impairment or dementia and a positive amyloid-beta PET scan) were recruited from the Cognitive Clinic at Karolinska University Hospital. The participants underwent baseline neuropsychological assessment, PET imaging with [ 18 F]THK5317, [ 11 C]PIB and [ 18 F]FDG, magnetic resonance imaging, and in a subgroup cerebrospinal fluid (CSF) sampling, with clinical follow-up after a median 48 months (interquartile range = 32:56). In total, 11 patients declined cognitively over time, while 9 remained cognitively stable. The accuracy of baseline [ 18 F]THK5317 binding in temporal areas was excellent at predicting future cognitive decline (area under the receiver operating curve 0.84–1.00) and the biomarker levels were strongly associated with the rate of cognitive decline (β estimate −33.67 to −31.02, p < 0.05). The predictive accuracy of the other baseline biomarkers was poor (area under the receiver operating curve 0.58–0.77) and their levels were not associated with the rate of cognitive decline (β estimate −4.64 to 15.78, p > 0.05). Baseline [ 18 F]THK5317 binding and CSF tau levels were more strongly associated with the MMSE score at follow-up than at baseline ( p < 0.05). These findings support a temporal dissociation between tau deposition and cognitive impairment, and suggest that [ 18 F]THK5317 predicts future cognitive decline better than other biomarkers. The use of imaging markers for tau pathology could prove useful for clinical prognostic assessment and screening before inclusion in relevant clinical trials.

Objective To study the macrostructural and microstructural MRI correlates of brain astrocytosis, measured with 11C-deuterium-L-deprenyl (11C-DED)–PET, in familial autosomal-dominant Alzheimer disease (ADAD). Methods The total sample (n = 31) comprised ADAD mutation carriers (n = 10 presymptomatic, 39.2 ± 10.6 years old; n = 3 symptomatic, 55.5 ± 2.0 years old) and noncarriers (n = 18, 44.0 ± 13.7 years old) belonging to families with mutations in either the presenilin-1 or amyloid precursor protein genes. All participants underwent structural and diffusion MRI and neuropsychological assessment, and 20 participants (6 presymptomatic and 3 symptomatic mutation carriers and 11 noncarriers) also underwent 11C-DED-PET. Results Vertex-wise interaction analyses revealed a differential relationship between carriers and noncarriers in the association between 11C-DED binding and estimated years to onset (EYO) and between cortical mean diffusivity (MD) and EYO. These differences were due to higher 11C-DED binding in presymptomatic carriers, with lower binding in symptomatic carriers compared to noncarriers, and to lower cortical MD in presymptomatic carriers, with higher MD in symptomatic carriers compared to noncarriers. Using a vertex-wise local correlation approach, 11C-DED binding was negatively correlated with cortical MD and positively correlated with cortical thickness. Conclusions Our proof-of-concept study is the first to show that microstructural and macrostructural changes can reflect underlying neuroinflammatory mechanisms in early stages of Alzheimer disease (AD). The findings support a role for neuroinflammation in AD pathogenesis, with potential implications for the correct interpretation of neuroimaging biomarkers as surrogate endpoints in clinical trials.

[F-18]THK5317 is a PET tracer for in-vivo imaging of tau associated with Alzheimer's disease (AD). This work aimed to evaluate optimal timing for standardized uptake value ratio (SUVR) measures with [F-18]THK5317 and automated generation of SUVR-1 and relative cerebral blood flow (R-1) parametric images. Nine AD patients and nine controls underwent 90 min [F-18]THK5317 scans. SUVR-1 was calculated at transient equilibrium (TE) and for seven different 20 min intervals and compared with distribution volume ratio (DVR; reference Logan). Cerebellar grey matter (MRI) was used as reference region. A supervised cluster analysis (SVCA) method was implemented to automatically generate a reference region, directly from the dynamic PET volume without the need of a structural MRI scan, for computation of SUVR-1 and R-1 images for a scan duration matching the optimal timing. TE was reached first in putamen, frontal- and parietal cortex at 22 +/- 4 min for AD patients and in putamen at 20 +/- 0 min in controls. Over all regions and subjects, SUVR20-40-1 correlated best with DVR-1, R-2 = 0.97. High correlation was found between values generated using MRI- and SVCA-based reference (R-2 = 0.93 for SUVR20-40-1; R-2 = 0.94 for R-1). SUVR20-40 allows for accurate semi-quantitative assessment of tau pathology and SVCA may be used to obtain a reference region for calculation of both SUVR-1 and R-1 with 40 min scan duration.

The aim of this study is to assess the impact of age at onset on the prognostic value of Alzheimer’s biomarkers in a large sample of patients with mild cognitive impairment (MCI). We measured Aβ42, t-tau, hippocampal volume on magnetic resonance imaging (MRI) and cortical metabolism on fluorodeoxyglucose–positron emission tomography (FDG-PET) in 188 MCI patients followed for at least 1 year. We categorised patients into earlier and later onset (EO/LO). Receiver operating characteristic curves and corresponding areas under the curve (AUCs) were performed to assess and compar the biomarker prognostic performances in EO and LO groups. Linear Model was adopted for estimating the time-to-progression in relation with earlier/later onset MCI groups and biomarkers. In earlier onset patients, all the assessed biomarkers were able to predict cognitive decline (p < 0.05), with FDG-PET showing the best performance. In later onset patients, all biomarkers but t-tau predicted cognitive decline (p < 0.05). Moreover, FDG-PET alone in earlier onset patients showed a higher prognostic value than the one resulting from the combination of all the biomarkers in later onset patients (earlier onset AUC 0.935 vs later onset AUC 0.753, p < 0.001). Finally, FDG-PET showed a different prognostic value between earlier and later onset patients (p = 0.040) in time-to-progression allowing an estimate of the time free from disease. FDG-PET may represent the most universal tool for the establishment of a prognosis in MCI patients and may be used for obtaining an onset-related estimate of the time free from disease.

A biphasic model for cortical microstructural changes in sporadic preclinical Alzheimer's disease (AD) has been recently proposed (Montal 2017). Stage 1 subjects showed decreased cortical mean diffusivity (MD), potentially related to brain inflammation (Weston 2015), whereas Stage 2 subjects, and especially the mild cognitive impairment and demented patients, showed increased cortical MD. The main objective of this work was to study the presence of early brain inflammation through 11C-deuterium-L-deprenyl (Deprenyl) PET (Rodriguez-Vieitez 2016) and to assess its relationship with cortical MD decreases in a familial autosomal-dominant AD cohort. We included 10 asymptomatic mutation carriers (AMC), 3 symptomatic mutation carriers (SMC) and 18 age-gender matched non-carriers (NC). All subjects had structural MRI, and a subset (6 AMC, 3 SMC and 11 NC) also had Deprenyl PET. Structural images were processed with Freesurfer v6, and used for the diffusion and PET pipelines. Diffusion imaging was processed surface-based as previously described (Montal 2017). Deprenyl PET was processed as previously described (Rodriguez-Vieitez 2016). Then, Deprenyl PET binding values were projected to the brain cortical surface using PetSurfer. First, we studied the effect of the interaction between estimated years to symptom onset (EYO) and mutation status (carrier/non-carrier) on cortical MD and Deprenyl PET. Second, we performed cortical MD and Deprenyl PET group comparisons between AMC and NC, and between SMC and NC. Finally, we assessed the local relationship between Deprenyl PET and cortical MD in a vertex-wise analysis. The interaction analyses showed that the relationship between cortical MD and EYO, and between Deprenyl PET and EYO differs between carriers and non-carriers. Specifically, the AMC presented decreased mean diffusivity (Fig. 1) and increased Deprenyl binding (Fig. 2), whereas the SMC presented increased MD (Fig. 3) and no Deprenyl binding changes with respect to the NC. Finally, the vertex-wise analyses showed a local inverse relationship between Deprenyl PET and cortical MD (Fig. 4).

The range of onset ages within some PSEN1 families is wide, and a few cases of reduced penetrance of PSEN1 mutations have been reported. However, published data on reduced penetrance have been limited to clinical histories, often collected retrospectively and lacking biomarker information. We present a case of reduced penetrance of the PSEN1 H163Y mutation in a carrier prospectively followed for 22 years.

Assessments of brain glucose metabolism (18F-FDG-PET) and cerebral amyloid burden (11C-PiB-PET) in mild cognitive impairment (MCI) have shown highly variable performances when adopted to predict progression to dementia due to Alzheimer's disease (ADD). This study investigates, in a clinical setting, the separate and combined values of 18F-FDG-PET and 11C-PiB-PET in ADD conversion prediction with optimized data analysis procedures. Respectively, we investigate the accuracy of an optimized SPM analysis for 18F-FDG-PET and of standardized uptake value ratio semiquantification for 11C-PiB-PET in predicting ADD conversion in 30 MCI subjects (age 63.57±7.78 years). Fourteen subjects converted to ADD during the follow-up (median 26.5 months, inter-quartile range 30 months). Receiver operating characteristic analyses showed an area under the curve (AUC) of 0.89 and of 0.81 for, respectively, 18F-FDG-PET and 11C-PiB-PET. 18F-FDG-PET, compared to 11C-PiB-PET, showed higher specificity (1.00 versus 0.62, respectively), but lower sensitivity (0.79 versus 1.00). Combining the biomarkers improved classification accuracy (AUC = 0.96). During the follow-up time, all the MCI subjects positive for both PET biomarkers converted to ADD, whereas all the subjects negative for both remained stable. The difference in survival distributions was confirmed by a log-rank test (p = 0.002). These results indicate a very high accuracy in predicting MCI to ADD conversion of both 18F-FDG-PET and 11C-PiB-PET imaging, the former showing optimal performance based on the SPM optimized parametric assessment. Measures of brain glucose metabolism and amyloid load represent extremely powerful diagnostic and prognostic biomarkers with complementary roles in prodromal dementia phase, particularly when tailored to individual cases in clinical settings.

The enzyme phosphodiesterase 10A (PDE10A) is abundant in striatal medium spiny neurons, where it regulates postsynaptic dopamine signaling. It has been implicated in the pathophysiology of schizophrenia in animal models and is investigated as a potential pharmacological target. Thinning of the prefrontal cortex is common in schizophrenia, but how this relates to PDE10A expression is unknown. Here we compared, for the first time, the striatal non-displaceable binding potential (BPND) of the new validated PDE10A ligand [11C]Lu AE92686 between patients with schizophrenia and healthy controls. Furthermore we aimed to assess the correlation of PDE10A BPND to cortical thickness.