Establishing brain states in neuroimaging data.

The definition of a brain state remains elusive, with varying interpretations across different sub-fields of neuroscience-from the level of wakefulness in anaesthesia, to activity of individual neurons, voltage in EEG, and blood flow in fMRI. This lack of consensus presents a significant challenge to the development of accurate models of neural dynamics. However, at the foundation of dynamical systems theory lies a definition of what constitutes the 'state' of a system-i.e., a specification of the system's future. Here, we propose to adopt this definition to establish brain states in neuroimaging timeseries by applying Dynamic Causal Modelling (DCM) to low-dimensional embedding of resting and task condition fMRI data. We find that ~90% of subjects in resting conditions are better described by first-order models, whereas ~55% of subjects in task conditions are better described by second-order models. Our work calls into question the status quo of using first-order equations almost exclusively within computational neuroscience and provides a new way of establishing brain states, as well as their associated phase space representations, in neuroimaging datasets.

Reduced cortical cerebral blood flow in antipsychotic-free first-episode psychosis and relationship to treatment response.

BACKGROUND: Altered cerebral blood flow (CBF) has been found in people at risk for psychosis, with first-episode psychosis (FEP) and with chronic schizophrenia (SCZ). Studies using arterial spin labelling (ASL) have shown reduction of cortical CBF and increased subcortical CBF in SCZ. Previous studies have investigated CBF using ASL in FEP, reporting increased CBF in striatum and reduced CBF in frontal cortex. However, as these people were taking antipsychotics, it is unclear whether these changes are related to the disorder or antipsychotic treatment and how they relate to treatment response. METHODS: We examined CBF in FEP free from antipsychotic medication (N = 21), compared to healthy controls (N = 22). Both absolute and relative-to-global CBF were assessed. We also investigated the association between baseline CBF and treatment response in a partially nested follow-up study (N = 14). RESULTS: There was significantly lower absolute CBF in frontal cortex (Cohen's d = 0.84, p = 0.009) and no differences in striatum or hippocampus. Whole brain voxel-wise analysis revealed widespread cortical reductions in absolute CBF in large cortical clusters that encompassed occipital, parietal and frontal cortices (Threshold-Free Cluster Enhancement (TFCE)-corrected <0.05). No differences were found in relative-to-global CBF in the selected region of interests and in voxel-wise analysis. Relative-to-global frontal CBF was correlated with percentage change in total Positive and Negative Syndrome Scale after antipsychotic treatment (r = 0.67, p = 0.008). CONCLUSIONS: These results show lower cortical absolute perfusion in FEP prior to starting antipsychotic treatment and suggest relative-to-global frontal CBF as assessed with magnetic resonance imaging could potentially serve as a biomarker for antipsychotic response.

Sickness behaviour and depression: An updated model of peripheral-central immunity interactions.

Current research into mood disorders indicates that circulating immune mediators participating in the pathophysiology of chronic somatic disorders have potent influences on brain function. This paradigm has brought to the fore the use of anti-inflammatory therapies as adjunctive to standard antidepressant therapy to improve treatment efficacy, particularly in subjects that do not respond to standard medication. Such new practice requires biomarkers to tailor these new therapies to those most likely to benefit but also validated mechanisms of action describing the interaction between peripheral immunity and brain function to optimize target intervention. These mechanisms are generally studied in preclinical models that try to recapitulate the human disease, MDD, through peripherally induced sickness behaviour. In this proposal paper, after an appraisal of the data in rodent models and their adherence to the data in clinical cohorts, we put forward a modified model of periphery-brain interactions that goes beyond the currently established view of microglia cells as the drivers of depression. Instead, we suggest that, for most patients with mild levels of peripheral inflammation, brain barriers are the primary actors in the pathophysiology of the disease and in treatment resistance. We then highlight data gaps in this proposal and suggest novel lines of research.

Metastability, fractal scaling, and synergistic information processing: What phase relationships reveal about intrinsic brain activity.

Dynamic functional connectivity (dFC) in resting-state fMRI holds promise to deliver candidate biomarkers for clinical applications. However, the reliability and interpretability of dFC metrics remain contested. Despite a myriad of methodologies and resulting measures, few studies have combined metrics derived from different conceptualizations of brain functioning within the same analysis - perhaps missing an opportunity for improved interpretability. Using a complexity-science approach, we assessed the reliability and interrelationships of a battery of phase-based dFC metrics including tools originating from dynamical systems, stochastic processes, and information dynamics approaches. Our analysis revealed novel relationships between these metrics, which allowed us to build a predictive model for integrated information using metrics from dynamical systems and information theory. Furthermore, global metastability - a metric reflecting simultaneous tendencies for coupling and decoupling - was found to be the most representative and stable metric in brain parcellations that included cerebellar regions. Additionally, spatiotemporal patterns of phase-locking were found to change in a slow, non-random, continuous manner over time. Taken together, our findings show that the majority of characteristics of resting-state fMRI dynamics reflect an interrelated dynamical and informational complexity profile, which is unique to each acquisition. This finding challenges the interpretation of results from cross-sectional designs for brain neuromarker discovery, suggesting that individual life-trajectories may be more informative than sample means.

GABA-A receptor differences in schizophrenia: a positron emission tomography study using [11C]Ro154513.

A loss of GABA signaling is a prevailing hypothesis for the pathogenesis of schizophrenia. Preclinical studies indicate that blockade of the α5 subtype of the GABA receptor (α5-GABAARs) leads to behavioral phenotypes associated with schizophrenia, and postmortem evidence indicates lower hippocampal α5-GABAARs protein and mRNA levels in schizophrenia. However, it is unclear if α5-GABAARs are altered in vivo or related to symptoms. We investigated α5-GABAARs availability in antipsychotic-free schizophrenia patients and antipsychotic-medicated schizophrenia patients using [11C]Ro15-4513 PET imaging in a cross-sectional, case-control study design. Thirty-one schizophrenia patients (n = 10 antipsychotic free) and twenty-nine matched healthy controls underwent a [11C]Ro15-4513 PET scan and MRI. The α5 subtype GABA-A receptor availability was indexed using [11C]Ro15-4513 PET imaging. Dynamic PET data were analyzed using the two-tissue compartment model with an arterial plasma input function and total volume of distribution (VT) as the outcome measure. Symptom severity was assessed using the PANSS scale. There was significantly lower [11C]Ro15-4513 VT in the hippocampus of antipsychotic-free patients, but not in medicated patients (p = 0.64), relative to healthy controls (p < 0.05; effect size = 1.4). There was also a significant positive correlation between [11C]Ro15-4513 VT and total PANSS score in antipsychotic-free patients (r = 0.72; p = 0.044). The results suggest that antipsychotic-free patients with schizophrenia have lower α5-GABAARs levels in the hippocampus, consistent with the hypothesis that GABA hypofunction underlies the pathophysiology of the disorder.

The translocator protein (TSPO) is prodromal to mitophagy loss in neurotoxicity.

Dysfunctional mitochondria characterise Parkinson's Disease (PD). Uncovering etiological molecules, which harm the homeostasis of mitochondria in response to pathological cues, is therefore pivotal to inform early diagnosis and therapy in the condition, especially in its idiopathic forms. This study proposes the 18 kDa Translocator Protein (TSPO) to be one of those. Both in vitro and in vivo data show that neurotoxins, which phenotypically mimic PD, increase TSPO to enhance cellular redox-stress, susceptibility to dopamine-induced cell death, and repression of ubiquitin-dependent mitophagy. TSPO amplifies the extracellular signal-regulated protein kinase 1 and 2 (ERK1/2) signalling, forming positive feedback, which represses the transcription factor EB (TFEB) and the controlled production of lysosomes. Finally, genetic variances in the transcriptome confirm that TSPO is required to alter the autophagy-lysosomal pathway during neurotoxicity.

Increased serum peripheral C-reactive protein is associated with reduced brain barriers permeability of TSPO radioligands in healthy volunteers and depressed patients: implications for inflammation and depression.

The relationship between peripheral and central immunity and how these ultimately may cause depressed behaviour has been the focus of a number of imaging studies conducted with Positron Emission Tomography (PET). These studies aimed at testing the immune-mediated model of depression that proposes a direct effect of peripheral cytokines and immune cells on the brain to elicit a neuroinflammatory response via a leaky blood-brain barrier and ultimately depressive behaviour. However, studies conducted so far using PET radioligands targeting the neuroinflammatory marker 18 kDa translocator protein (TSPO) in patient cohorts with depression have demonstrated mild inflammatory brain status but no correlation between central and peripheral immunity. To gain a better insight into the relationship between heightened peripheral immunity and neuroinflammation, we estimated blood-to-brain and blood-to-CSF perfusion rates for two TSPO radiotracers collected in two separate studies, one large cross-sectional study of neuroinflammation in normal and depressed cohorts (N = 51 patients and N = 25 controls) and a second study where peripheral inflammation in N = 7 healthy controls was induced via subcutaneous injection of interferon (IFN)-α. In both studies we observed a consistent negative association between peripheral inflammation, measured with c-reactive protein P (CRP), and radiotracer perfusion into and from the brain parenchyma and CSF. Importantly, there was no association of this effect with the marker of BBB leakage S100ß, that was unchanged. These results suggest a different model of peripheral-to-central immunity interaction whereas peripheral inflammation may cause a reduction in BBB permeability. This effect, on the long term, is likely to disrupt brain homeostasis and induce depressive behavioural symptoms.

Neural diffusivity and pre-emptive epileptic seizure intervention.

The propagation of epileptic seizure activity in the brain is a widespread pathophysiology that, in principle, should yield to intervention techniques guided by mathematical models of neuronal ensemble dynamics. During a seizure, neural activity will deviate from its current dynamical regime to one in which there are significant signal fluctuations. In silico treatments of neural activity are an important tool for the understanding of how the healthy brain can maintain stability, as well as of how pathology can lead to seizures. The hope is that, contained within the mathematical foundations of such treatments, there lie potential strategies for mitigating instabilities, e.g. via external stimulation. Here, we demonstrate that the dynamic causal modelling neuronal state equation generalises to a Fokker-Planck formalism if one extends the framework to model the ways in which activity propagates along the structural connections of neural systems. Using the Jacobian of this generalised state equation, we show that an initially unstable system can be rendered stable via a reduction in diffusivity-i.e., by lowering the rate at which neuronal fluctuations disperse to neighbouring regions. We show, for neural systems prone to epileptic seizures, that such a reduction in diffusivity can be achieved via external stimulation. Specifically, we show that this stimulation should be applied in such a way as to temporarily mirror the activity profile of a pathological region in its functionally connected areas. This counter-intuitive method is intended to be used pre-emptively-i.e., in order to mitigate the effects of the seizure, or ideally even prevent it from occurring in the first place. We offer proof of principle using simulations based on functional neuroimaging data collected from patients with idiopathic generalised epilepsy, in which we successfully suppress pathological activity in a distinct sub-network prior to seizure onset. Our hope is that this technique can form the basis for future real-time monitoring and intervention devices that are capable of treating epilepsy in a non-invasive manner.

[18F]Florbetapir PET/MR imaging to assess demyelination in multiple sclerosis.

PURPOSE: We evaluated myelin changes throughout the central nervous system in Multiple Sclerosis (MS) patients by using hybrid [18F]florbetapir PET-MR imaging. METHODS: We included 18 relapsing-remitting MS patients and 12 healthy controls. Each subject performed a hybrid [18F]florbetapir PET-MR and both a clinical and cognitive assessment. [18F]florbetapir binding was measured as distribution volume ratio (DVR), through the Logan graphical reference method and the supervised cluster analysis to extract a reference region, and standard uptake value (SUV) in the 70-90 min interval after injection. The two quantification approaches were compared. We also evaluated changes in the measures derived from diffusion tensor imaging and arterial spin labeling. RESULTS: [18F]florbetapir DVRs decreased from normal-appearing white matter to the centre of T2 lesion (P < 0.001), correlated with fractional anisotropy and with mean, axial and radial diffusivity within T2 lesions (coeff. = -0.15, P < 0.001, coeff. = -0.12, P < 0.001 and coeff. = -0.16, P < 0.001, respectively). Cerebral blood flow was reduced in white matter damaged areas compared to white matter in healthy controls (-10.9%, P = 0.005). SUV70-90 and DVR are equally able to discriminate between intact and damaged myelin (area under the curve 0.76 and 0.66, respectively; P = 0.26). CONCLUSION: Our findings demonstrate that [18F]florbetapir PET imaging can measure in-vivo myelin damage in patients with MS. Demyelination in MS is not restricted to lesions detected through conventional MRI but also involves the normal appearing white matter. Although longitudinal studies are needed, [18F]florbetapir PET imaging may have a role in clinical settings in the management of MS patients.

Determinants of treatment response in first-episode psychosis: an 18F-DOPA PET study.

Psychotic illnesses show variable responses to treatment. Determining the neurobiology underlying this is important for precision medicine and the development of better treatments. It has been proposed that dopaminergic differences underlie variation in response, with striatal dopamine synthesis capacity (DSC) elevated in responders and unaltered in non-responders. We therefore aimed to test this in a prospective cohort, with a nested case-control comparison. 40 volunteers (26 patients with first-episode psychosis and 14 controls) received an 18F-DOPA Positron Emission Tomography scan to measure DSC (Kicer) prior to antipsychotic treatment. Clinical assessments (Positive and Negative Syndrome Scale, PANSS, and Global Assessment of Functioning, GAF) occurred at baseline and following antipsychotic treatment for a minimum of 4 weeks. Response was defined using improvement in PANSS Total score of >50%. Patients were followed up for at least 6 months, and remission criteria applied. There was a significant effect of group on Kicer in associative striatum (F(2, 37) = 7.9, p = 0.001). Kicer was significantly higher in responders compared with non-responders (Cohen's d = 1.55, p = 0.01) and controls (Cohen's d = 1.31, p = 0.02). Kicer showed significant positive correlations with improvements in PANSS-positive (r = 0.64, p < 0.01), PANSS negative (rho = 0.51, p = 0.01), and PANSS total (rho = 0.63, p < 0.01) ratings and a negative relationship with change in GAF (r = -0.55, p < 0.01). Clinical response is related to baseline striatal dopaminergic function. Differences in dopaminergic function between responders and non-responders are present at first episode of psychosis, consistent with dopaminergic and non-dopaminergic sub-types in psychosis, and potentially indicating a neurochemical basis to stratify psychosis.

Widespread microglial activation in multiple system atrophy.

BACKGROUND: The pattern and role of microglial activation in multiple system atrophy is largely unclear. The objective of this study was to use [11 C](R)-PK11195 PET to determine the extent and correlation of activated microglia with clinical parameters in MSA patients. METHODS: Fourteen patients with the parkinsonian phenotype of MSA (MSA-P) with a mean disease duration of 2.9 years (range 2-5 years) were examined with [11 C](R)-PK11195 PET and compared with 10 healthy controls. RESULTS: Patients with the parkinsonian phenotype of MSA showed a significant (P ≤ 0.01) mean increase in binding potentials compared with healthy controls in the caudate nucleus, putamen, pallidum, precentral gyrus, orbitofrontal cortex, presubgenual anterior cingulate cortex, and the superior parietal gyrus. No correlations between binding potentials and clinical parameters were found. CONCLUSIONS: In early clinical stages of the parkinsonian phenotype of MSA, there is widespread microglial activation as a marker of neuroinflammatory changes without correlation to clinical parameters in our patient population. © 2019 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

Frontostriatal functional connectivity and striatal dopamine synthesis capacity in schizophrenia in terms of antipsychotic responsiveness: an [18F]DOPA PET and fMRI study.

BACKGROUND: Given that only a subgroup of patients with schizophrenia responds to first-line antipsychotic drugs, a key clinical question is what underlies treatment response. Observations that prefrontal activity correlates with striatal dopaminergic function, have led to the hypothesis that disrupted frontostriatal functional connectivity (FC) could be associated with altered dopaminergic function. Thus, the aim of this study was to investigate the relationship between frontostriatal FC and striatal dopamine synthesis capacity in patients with schizophrenia who had responded to first-line antipsychotic drug compared with those who had failed but responded to clozapine. METHODS: Twenty-four symptomatically stable patients with schizophrenia were recruited from Seoul National University Hospital, 12 of which responded to first-line antipsychotic drugs (first-line AP group) and 12 under clozapine (clozapine group), along with 12 matched healthy controls. All participants underwent resting-state functional magnetic resonance imaging and [18F]DOPA PET scans. RESULTS: No significant difference was found in the total PANSS score between the patient groups. Voxel-based analysis showed a significant correlation between frontal FC to the associative striatum and the influx rate constant of [18F]DOPA in the corresponding region in the first-line AP group. Region-of-interest analysis confirmed the result (control group: R2 = 0.019, p = 0.665; first-line AP group: R2 = 0.675, p < 0.001; clozapine group: R2 = 0.324, p = 0.054) and the correlation coefficients were significantly different between the groups. CONCLUSIONS: The relationship between striatal dopamine synthesis capacity and frontostriatal FC is different between responders to first-line treatment and clozapine treatment in schizophrenia, indicating that a different pathophysiology could underlie schizophrenia in patients who respond to first-line treatments relative to those who do not.

Neuroinflammation in schizophrenia: meta-analysis of in vivo microglial imaging studies.

BACKGROUND: Converging lines of evidence implicate an important role for the immune system in schizophrenia. Microglia are the resident immune cells of the central nervous system and have many functions including neuroinflammation, axonal guidance and neurotrophic support. We aimed to provide a quantitative review of in vivo PET imaging studies of microglia activation in patients with schizophrenia compared with healthy controls. METHODS: Demographic, clinical and imaging measures were extracted from each study and meta-analysis was conducted using a random-effects model (Hedge's g). The difference in 18-kDa translocator protein (TSPO) binding between patients with schizophrenia and healthy controls, as quantified by either binding potential (BP) or volume of distribution (VT), was used as the main outcome. Sub-analysis and sensitivity analysis were carried out to investigate the effects of genotype, ligand and illness stage. RESULTS: In total, 12 studies comprising 190 patients with schizophrenia and 200 healthy controls met inclusion criteria. There was a significant elevation in tracer binding in schizophrenia patients relative to controls when BP was used as an outcome measure, (Hedge's g = 0.31; p = 0.03) but no significant differences when VT was used (Hedge's g = -0.22; p = 0.29). CONCLUSIONS: In conclusion, there is evidence for moderate elevations in TSPO tracer binding in grey matter relative to other brain tissue in schizophrenia when using BP as an outcome measure, but no difference when VT is the outcome measure. We discuss the relevance of these findings as well as the methodological issues that may underlie the contrasting difference between these outcomes.

From homeostasis to behavior: Balanced activity in an exploration of embodied dynamic environmental-neural interaction.

In recent years, there have been many computational simulations of spontaneous neural dynamics. Here, we describe a simple model of spontaneous neural dynamics that controls an agent moving in a simple virtual environment. These dynamics generate interesting brain-environment feedback interactions that rapidly destabilize neural and behavioral dynamics demonstrating the need for homeostatic mechanisms. We investigate roles for homeostatic plasticity both locally (local inhibition adjusting to balance excitatory input) as well as more globally (regional "task negative" activity that compensates for "task positive", sensory input in another region) balancing neural activity and leading to more stable behavior (trajectories through the environment). Our results suggest complementary functional roles for both local and macroscale mechanisms in maintaining neural and behavioral dynamics and a novel functional role for macroscopic "task-negative" patterns of activity (e.g., the default mode network).

Protein synthesis is associated with high-speed dynamics and broad-band stability of functional hubs in the brain.

L-[1-11C]leucine PET can be used to measure in vivo protein synthesis in the brain. However, the relationship between regional protein synthesis and on-going neural dynamics is unclear. We use a graph theoretical approach to examine the relationship between cerebral protein synthesis (rCPS) and both static and dynamical measures of functional connectivity (measured using resting state functional MRI, R-fMRI). Our graph theoretical analysis demonstrates a significant positive relationship between protein turnover and static measures of functional connectivity. We compared these results to simple measures of metabolism in the cortex using [18F]FDG PET). Whilst some relationships between [18F]FDG binding and graph theoretical measures was present, there remained a significant relationship between protein turnover and graph theoretical measures, which were more robustly explained by L-[1-11C]Leucine than [18F]FDG PET. This relationship was stronger in dynamics at a faster temporal resolution relative to dynamics measured over a longer epoch. Using a Dynamic connectivity approach, we also demonstrate that broad-band dynamic measures of Functional Connectivity (FC), are inversely correlated with protein turnover, suggesting greater stability of FC in highly interconnected hub regions is supported by protein synthesis. Overall, we demonstrate that cerebral protein synthesis has a strong relationship independent of tissue metabolism to neural dynamics at the macroscopic scale.

Test-retest reproducibility of quantitative binding measures of [11C]Ro15-4513, a PET ligand for GABAA receptors containing alpha5 subunits.

INTRODUCTION: Alteration of γ-aminobutyric acid "A" (GABAA) receptor-mediated neurotransmission has been associated with various neurological and psychiatric disorders. [11C]Ro15-4513 is a PET ligand with high affinity for α5-subunit-containing GABAA receptors, which are highly expressed in limbic regions of the human brain (Sur et al., 1998). We quantified the test-retest reproducibility of measures of [11C]Ro15-4513 binding derived from six different quantification methods (12 variants). METHODS: Five healthy males (median age 40 years, range 38-49 years) had a 90-min PET scan on two occasions (median interval 12 days, range 11-30 days), after injection of a median dose of 441 MegaBequerels of [11C]Ro15-4513. Metabolite-corrected arterial plasma input functions (parent plasma input functions, ppIFs) were generated for all scans. We quantified regional binding using six methods (12 variants), some of which were region-based (applied to the average time-activity curve within a region) and others were voxel-based: 1) Models requiring arterial ppIFs - regional reversible compartmental models with one and two tissue compartments (2kbv and 4kbv); 2) Regional and voxelwise Logan's graphical analyses (Logan et al., 1990), which required arterial ppIFs; 3) Model-free regional and voxelwise (exponential) spectral analyses (SA; (Cunningham and Jones, 1993)), which also required arterial ppIFs; 4) methods not requiring arterial ppIFs - voxelwise standardised uptake values (Kenney et al., 1941), and regional and voxelwise simplified reference tissue models (SRTM/SRTM2) using brainstem or alternatively cerebellum as pseudo-reference regions (Lammertsma and Hume, 1996; Gunn et al., 1997). To compare the variants, we sampled the mean values of the outcome parameters within six bilateral, non-reference grey matter regions-of-interest. Reliability was quantified in terms of median absolute percentage test-retest differences (MA-TDs; preferentially low) and between-subject coefficient of variation (BS-CV, preferentially high), both compounded by the intraclass correlation coefficient (ICC). These measures were compared between variants, with particular interest in the hippocampus. RESULTS: Two of the six methods (5/12 variants) yielded reproducible data (i.e. MA-TD <10%): regional SRTMs and voxelwise SRTM2s, both using either the brainstem or the cerebellum; and voxelwise SA. However, the SRTMs using the brainstem yielded a lower median BS-CV (7% for regional, 7% voxelwise) than the other variants (8-11%), resulting in lower ICCs. The median ICCs across six regions were 0.89 (interquartile range 0.75-0.90) for voxelwise SA, 0.71 (0.64-0.84) for regional SRTM-cerebellum and 0.83 (0.70-0.86) for voxelwise SRTM-cerebellum. The ICCs for the hippocampus were 0.89 for voxelwise SA, 0.95 for regional SRTM-cerebellum and 0.93 for voxelwise SRTM-cerebellum. CONCLUSION: Quantification of [11C]Ro15-4513 binding shows very good to excellent reproducibility with SRTM and with voxelwise SA which, however, requires an arterial ppIF. Quantification in the α5 subunit-rich hippocampus is particularly reliable. The very low expression of the α5 in the cerebellum (Fritschy and Mohler, 1995; Veronese et al., 2016) and the substantial α1 subunit density in this region may hamper the application of reference tissue methods.

Measuring specific receptor binding of a PET radioligand in human brain without pharmacological blockade: The genomic plot.

PET studies allow in vivo imaging of the density of brain receptor species. The PET signal, however, is the sum of the fraction of radioligand that is specifically bound to the target receptor and the non-displaceable fraction (i.e. the non-specifically bound radioligand plus the free ligand in tissue). Therefore, measuring the non-displaceable fraction, which is generally assumed to be constant across the brain, is a necessary step to obtain regional estimates of the specific fractions. The nondisplaceable binding can be directly measured if a reference region, i.e. a region devoid of any specific binding, is available. Many receptors are however widely expressed across the brain, and a true reference region is rarely available. In these cases, the nonspecific binding can be obtained after competitive pharmacological blockade, which is often contraindicated in humans. In this work we introduce the genomic plot for estimating the nondisplaceable fraction using baseline scans only. The genomic plot is a transformation of the Lassen graphical method in which the brain maps of mRNA transcripts of the target receptor obtained from the Allen brain atlas are used as a surrogate measure of the specific binding. Thus, the genomic plot allows the calculation of the specific and nondisplaceable components of radioligand uptake without the need of pharmacological blockade. We first assessed the statistical properties of the method with computer simulations. Then we sought ground-truth validation using human PET datasets of seven different neuroreceptor radioligands, where nonspecific fractions were either obtained separately using drug displacement or available from a true reference region. The population nondisplaceable fractions estimated by the genomic plot were very close to those measured by actual human blocking studies (mean relative difference between 2% and 7%). However, these estimates were valid only when mRNA expressions were predictive of protein levels (i.e. there were no significant post-transcriptional changes). This condition can be readily established a priori by assessing the correlation between PET and mRNA expression.

Increased PK11195-PET binding in normal-appearing white matter in clinically isolated syndrome.

The most accurate predictor of the subsequent development of multiple sclerosis in clinically isolated syndrome is the presence of lesions at magnetic resonance imaging. We used in vivo positron emission tomography with (11)C-(R)-PK11195, a biomarker of activated microglia, to investigate the normal-appearing white matter and grey matter of subjects with clinically isolated syndrome to explore its role in the development of multiple sclerosis. Eighteen clinically isolated syndrome and eight healthy control subjects were recruited. Baseline assessment included: history, neurological examination, expanded disability status scale, magnetic resonance imaging and PK11195-positron emission tomography scans. All assessments except the PK11195-positron emission tomography scan were repeated over 2 years. SUPERPK methodology was used to measure the binding potential relative to the non-specific volume, BPND. We show a global increase of normal-appearing white matter PK11195 BPND in clinically isolated syndrome subjects compared with healthy controls (P = 0.014). Clinically isolated syndrome subjects with T2 magnetic resonance imaging lesions had higher PK11195 BPND in normal-appearing white matter (P = 0.009) and their normal-appearing white matter PK11195 BPND correlated with the Expanded Disability Status Scale (P = 0.007; r = 0.672). At 2 years those who developed dissemination in space or multiple sclerosis, had higher PK11195 BPND in normal-appearing white matter at baseline (P = 0.007 and P = 0.048, respectively). Central grey matter PK11195 BPND was increased in subjects with clinically isolated syndrome compared to healthy controls but no difference was found in cortical grey matter PK11195 BPND. Microglial activation in clinically isolated syndrome normal-appearing white matter is diffusely increased compared with healthy control subjects and is further increased in those who have magnetic resonance imaging lesions. Furthermore microglial activation in clinically isolated syndrome normal-appearing white matter is also higher in those subjects who developed multiple sclerosis at 2 years. Our finding, if replicated in a larger study, could be of prognostic value and aid early treatment decisions in clinically isolated syndrome.

Increased central microglial activation associated with peripheral cytokine levels in premanifest Huntington's disease gene carriers.

Previous studies have shown activation of the immune system and altered immune response in Huntington's disease (HD) gene carriers. Here, we hypothesized that peripheral and central immune responses could be concurrent pathophysiological events and represent a global innate immune response to the toxic effects of mutant huntingtin in HD gene carriers. We sought to investigate our hypothesis using [(11)C]PK11195 PET as a translocator protein (TSPO) marker of central microglial activation, together with assessment of peripheral plasma cytokine levels in a cohort of premanifest HD gene carriers who were more than a decade from predicted symptomatic conversion. Data were also compared to those from a group of healthy controls matched for age and gender. We found significantly increased peripheral plasma IL-1ß levels in premanifest HD gene carriers compared to the group of normal controls (P=0.018). Premanifest HD gene carriers had increased TSPO levels in cortical, basal ganglia and thalamic brain regions (P<0.001). Increased microglial activation in somatosensory cortex correlated with higher plasma levels of IL-1ß (rs=0.87, P=0.013), IL-6 (rs=0.85, P=0.013), IL-8 (rs=0.68, P=0.045) and TNF-α (rs=0.79; P=0.013). Our findings provide first in vivo evidence for an association between peripheral and central immune responses in premanifest HD gene carriers, and provide further supporting evidence for the role of immune dysfunction in the pathogenesis of HD.