Astrogliosis marker 11C-SL25.1188 PET in traumatic brain injury with persistent symptoms.

Traumatic brain injury (TBI) is common but little is known why up to a third of patients have persisting symptoms. Astrogliosis, a pathophysiological response to brain injury, may be a potential therapeutic target, but demonstration of astrogliosis in the brain of humans with TBI and persistent symptoms is lacking. Astroglial marker monoamine oxidase B (MAO-B) total distribution volume (11C-SL25.1188 VT), an index of MAO-B density, was measured in 29 TBI and 29 similarly aged healthy control cases with 11C-SL25.1188 PET, prioritizing prefrontal cortex (PFC) and cortex proximal to cortical convexity. Correlations of PFC 11C-SL25.1188 VT with psychomotor and processing speed; and serum blood measures implicated in astrogliosis were determined. 11C-SL25.1188 VT was greater in TBI in PFC (P = 0.00064) and cortex (P = 0.00038). PFC 11C-SL25.1188 VT inversely correlated with Comprehensive Trail Making Test psychomotor and processing speed (r = -0.48, P = 0.01). In participants scanned within 2 years of last TBI, PFC 11C-SL25.1188 VT correlated with serum glial fibrillary acid protein (r = 0.51, P = 0.037) and total tau (r = 0.74, P = 0.001). Elevated 11C-SL25.1188 VT argues strongly for astrogliosis and therapeutics modifying astrogliosis towards curative phenotypes should be tested in TBI with persistent symptoms. Given substantive effect size, astrogliosis PET markers should be applied to stratify cases and/or assess target engagement for putative therapeutics targeting astrogliosis.

Microglia imaging in methamphetamine use disorder: a positron emission tomography study with the 18 kDa translocator protein radioligand [F-18]FEPPA.

Activation of brain microglial cells, microgliosis, has been linked to methamphetamine (MA)-seeking behavior, suggesting that microglia could be a new therapeutic target for MA use disorder. Animal data show marked brain microglial activation following acute high-dose MA, but microglial status in human MA users is uncertain, with one positron emission tomography (PET) investigation reporting massively and globally increased translocator protein 18 kDa (TSPO; [C-11](R)-PK11195) binding, a biomarker for microgliosis, in MA users. Our aim was to measure binding of a second-generation TSPO radioligand, [F-18]FEPPA, in brain of human chronic MA users. Regional total volume of distribution (VT ) of [F-18]FEPPA was estimated with a two-tissue compartment model with arterial plasma input function for 10 regions of interest in 11 actively using MA users and 26 controls. A RM-ANOVA corrected for TSPO rs6971 polymorphism was employed to test significance. There was no main effect of group on [F-18]FEPPA VT (P = .81). No significant correlations between [F-18]FEPPA VT and MA use duration, weekly dosage, blood MA concentrations, regional brain volumes, and self-reported craving were observed. Our preliminary findings, consistent with our earlier postmortem data, do not suggest substantial brain microgliosis in MA use disorder but do not rule out microglia as a therapeutic target in MA addiction. Absence of increased [F-18]FEPPA TSPO binding might be related to insufficient MA dose or blunting of microglial response following repeated MA exposure, as suggested by some animal data.

Fatty acid amide hydrolase is lower in young cannabis users.

We have recently shown that levels of fatty acid amide hydrolase (FAAH), the enzyme that metabolizes the endocannabinoid anandamide, are lower in the brains of adult cannabis users (CUs) (34 ± 11 years of age), tested during early abstinence. Here, we examine replication of the lower FAAH levels in a separate, younger cohort (23 ± 5 years of age). Eighteen healthy volunteers (HVs) and fourteen CUs underwent a positron emission tomography scan using the FAAH radioligand [11 C]CURB. Regional [11 C]CURB binding was calculated using an irreversible two-tissue compartment model with a metabolite-corrected arterial plasma input function. The FAAH C385A genetic polymorphism (rs324420) was included as a covariate. All CUs underwent a urine screen to confirm recent cannabis use and had serum cannabinoids measured. One CU screened negative for cannabinoids via serum and was removed from analysis. All HVs reported less than five lifetime cannabis exposures more than a month prior to study initiation. There was a significant effect of group (F1,26 = 4.31; P = .048) when two A/A (rs324420) HVs were removed from analysis to match the genotype of the CU group (n = 16 HVs, n = 13 CUs). Overall, [11 C]CURB λk3 was 12% lower in CU compared with HV. Exploratory correlations showed that lower brain [11 C]CURB binding was related to greater use of cannabis throughout the past year. We confirmed our previous report and extended these findings by detecting lower [11 C]CURB binding in a younger cohort with less cumulative cannabis exposure.

Stress-induced cortical dopamine response is altered in subjects at clinical high risk for psychosis using cannabis.

Stress and cannabis use are risk factors for the development of psychosis. We have previously shown that subjects at clinical high risk for psychosis (CHR) exhibit a higher striatal dopamine response to stress compared with healthy volunteers (HV), with chronic cannabis use blunting this response. However, it is unknown if this abnormal dopamine response extends to the prefrontal cortex (PFC). Here, we investigated dorsolateral PFC (dlPFC) and medial PFC (mPFC) dopamine release using [11 C]FLB457 positron emission tomography (PET) and a validated stress task. Thirty-three participants completed two PET scans (14 CHR without cannabis use, eight CHR regular cannabis users [CHR-CUs] and 11 HV) while performing a Sensory Motor Control Task (control scan) and the Montreal Imaging Stress Task (stress scan). Stress-induced dopamine release (ΔBPND ) was defined as percent change in D2/3 receptor binding potential between both scans using a novel correction for injected mass of [11 C]FLB457. ΔBPND was significantly different between groups in mPFC (F(2,30) = 5.40, .010), with CHR-CUs exhibiting lower ΔBPND compared with CHR (.008). Similarly, salivary cortisol response (ΔAUCI ) was significantly lower in CHR-CU compared with CHR (F(2,29) = 5.08, .013; post hoc .018) and positively associated with ΔBPND . Furthermore, CHR-CUs had higher attenuated psychotic symptoms than CHR following the stress task, which were negatively associated with ΔBPND . Length of cannabis use was negatively associated with ΔBPND in mPFC when controlling for current cannabis use. Given the global trend to legalize cannabis, this study is important as it highlights the effects of regular cannabis use on cortical dopamine function in high-risk youth.

GABA levels and TSPO expression in people at clinical high risk for psychosis and healthy volunteers: a PET-MRS study.

BACKGROUND: γ-Aminobutyric acidergic (GABAergic) dysfunction and immune activation have been implicated in the pathophysiology of schizophrenia. Preclinical evidence suggests that inflammation-related abnormalities may contribute to GABAergic alterations in the brain, but this has never been investigated in vivo in humans. In this multimodal imaging study, we quantified cerebral GABA plus macromolecule (GABA+) levels in antipsychotic-naive people at clinical high risk for psychosis and in healthy volunteers. We investigated for the first time the association between GABA+ levels and expression of translocator protein 18 kDa (TSPO; a marker of microglial activation) using positron emission tomography (PET). METHODS: Thirty-five people at clinical high risk for psychosis and 18 healthy volunteers underwent 3 T proton magnetic resonance spectroscopy to obtain GABA+ levels in the medial prefrontal cortex (mPFC). A subset (29 people at clinical high risk for psychosis and 15 healthy volunteers) also underwent a high-resolution [18F]FEPPA PET scan to quantify TSPO expression. Each participant was genotyped for the TSPO rs6971 polymorphism. RESULTS: We found that GABA+ levels were significantly associated with TSPO expression in the mPFC (F1,40 = 10.45, p = 0.002). We found no significant differences in GABA+ levels in the mPFC (F1,51 = 0.00, p > 0.99) between people at clinical high risk for psychosis and healthy volunteers. We found no significant correlations between GABA+ levels or residuals of the association with TSPO expression and the severity of prodromal symptoms or cognition. LIMITATIONS: Given the cross-sectional nature of this study, we could determine no cause-and-effect relationships for GABA alterations and TSPO expression. CONCLUSION: Our findings suggest that TSPO expression is negatively associated with GABA+ levels in the prefrontal cortex, independent of disease status.

Cortical stress regulation is disrupted in schizophrenia but not in clinical high risk for psychosis.

While alterations in striatal dopamine in psychosis and stress have been well studied, the role of dopamine in prefrontal cortex is poorly understood. To date, no study has investigated the prefrontocortical dopamine response to stress in the psychosis spectrum, even though the dorsolateral and medial prefrontal cortices are key regions in cognitive and emotional regulation, respectively. The present study uses the high-affinity dopamine D2/3 receptor radiotracer 11C-FLB457 and PET together with a validated psychosocial stress challenge to investigate the dorsolateral and medial prefrontocortical dopamine response to stress in schizophrenia and clinical high risk for psychosis. Forty participants completed two 11C-FLB457 PET scans (14 antipsychotic-free schizophrenia, 14 clinical high risk for psychosis and 12 matched healthy volunteers), one while performing a Sensory Motor Control Task (control) and another while performing the Montreal Imaging Stress Task (stress). Binding potential (BPND) was estimated using Simplified Reference Tissue Model with cerebellar cortex as reference region. Dopamine release was defined as per cent change in BPND between control and stress scans (ΔBPND) using a novel correction for injected mass. Salivary cortisol response (ΔAUCI) was assessed throughout the tasks and its relationship with dopamine release examined. 11C-FLB457 binding at control conditions was significantly different between groups in medial [F(2,37) = 7.98, P = 0.0013] and dorsolateral [F(2,37) = 6.97, P = 0.0027] prefrontal cortex with schizophrenia patients having lower BPND than participants at clinical high risk for psychosis and healthy volunteers, but there was no difference in ΔBPND among groups [dorsolateral prefrontal cortex: F(2,37) = 1.07, P = 0.35; medial prefrontal cortex: F(2,37) = 0.54, P = 0.59]. We report a positive relationship between ΔAUCI and 11C-FLB457 ΔBPND in dorsolateral and medial prefrontal cortex in healthy volunteers (r = 0.72, P = 0.026; r = 0.76, P = 0.014, respectively) and in participants at clinical high risk for psychosis (r = 0.76, P = 0.0075; r = 0.72, P = 0.018, respectively), which was absent in schizophrenia (r = 0.46, P = 1.00; r = 0.19, P = 1.00, respectively). Furthermore, exploratory associations between ΔBPND or ΔAUCI and stress or anxiety measures observed in clinical high risk for psychosis were absent in schizophrenia. These findings provide first direct evidence of a disrupted prefrontocortical dopamine-stress regulation in schizophrenia.

TSPO expression and brain structure in the psychosis spectrum.

Psychosis is associated with abnormal structural changes in the brain including decreased regional brain volumes and abnormal brain morphology. However, the underlying causes of these structural abnormalities are less understood. The immune system, including microglial activation, has been implicated in the pathophysiology of psychosis. Although previous studies have suggested a connection between peripheral proinflammatory cytokines and structural brain abnormalities in schizophrenia, no in-vivo studies have investigated whether microglial activation is also linked to brain structure alterations previously observed in schizophrenia and its putative prodrome. In this study, we investigated the link between mitochondrial 18 kDa translocator protein (TSPO) and structural brain characteristics (i.e. regional brain volume, cortical thickness, and hippocampal shape) in key brain regions such as dorsolateral prefrontal cortex and hippocampus of a large group of participants (N = 90) including individuals at clinical high risk (CHR) for psychosis, first-episode psychosis (mostly antipsychotic-naïve) patients, and healthy volunteers. The participants underwent structural brain MRI scan and [18F]FEPPA positron emission tomography (PET) targeting TSPO. A significant [18F]FEPPA binding-by-group interaction was observed in morphological measures across the left hippocampus. In first-episode psychosis, we observed associations between [18F]FEPPA VT (total volume of distribution) and outward and inward morphological alterations, respectively, in the dorsal and ventro-medial portions of the left hippocampus. These associations were not significant in CHR or healthy volunteers. There was no association between [18F]FEPPA VT and other structural brain characteristics. Our findings suggest a link between TSPO expression and alterations in hippocampal morphology in first-episode psychosis.

Neuroimaging and clinical features in adults with a 22q11.2 deletion at risk of Parkinson's disease.

The recurrent 22q11.2 deletion is a genetic risk factor for early-onset Parkinson's disease. Adults with the associated 22q11.2 deletion syndrome (22q11.2DS) may exhibit phenotypes that could help identify those at highest risk and reveal disease trajectories. We investigated clinical and neuroimaging features relevant to Parkinson's disease in 26 adults: 13 with 22q11.2DS at genetic risk of Parkinson's disease (mean age = 41.5 years, standard deviation = 9.7), 12 healthy age and sex-matched controls, and a 22q11.2DS patient with l-DOPA-responsive early-onset Parkinson's disease. Neuroimaging included transcranial sonography and positron emission tomography using 11C-dihydrotetrabenazine (11C-DTBZ), a radioligand that binds to the presynaptic vesicular monoamine transporter. The 22q11.2DS group without Parkinson's disease demonstrated significant motor and olfactory deficits relative to controls. Eight (61.5%) were clinically classified with parkinsonism. Transcranial sonography showed a significantly larger mean area of substantia nigra echogenicity in the 22q11.2DS risk group compared with controls (P = 0.03). The 22q11.2DS patient with Parkinson's disease showed the expected pattern of severely reduced striatal 11C-DTBZ binding. The 22q11.2DS group without Parkinson's disease however showed significantly elevated striatal 11C-DTBZ binding relative to controls (∼33%; P < 0.01). Results were similar within the 22q11.2DS group for those with (n = 7) and without (n = 6) psychotic illness. These findings suggest that manifestations of parkinsonism and/or evolution to Parkinson's disease in this genetic at-risk population may include a hyperdopaminergic mechanism. Adequately powered longitudinal studies and animal models are needed to evaluate the relevance of the observed clinical and imaging phenotypes to Parkinson's disease and other disorders that are more prevalent in 22q11.2DS, such as schizophrenia.

Microglial activation in Parkinson's disease using [18F]-FEPPA.

BACKGROUND: Neuroinflammatory processes including activated microglia have been reported to play an important role in Parkinson's disease (PD). Increased expression of translocator protein (TSPO) has been observed after brain injury and inflammation in neurodegenerative diseases. Positron emission tomography (PET) radioligand targeting TSPO allows for the quantification of neuroinflammation in vivo. METHODS: Based on the genotype of the rs6791 polymorphism in the TSPO gene, we included 25 mixed-affinity binders (MABs) (14 PD patients and 11 age-matched healthy controls (HC)) and 27 high-affinity binders (HABs) (16 PD patients and 11 age-matched HC) to assess regional differences in the second-generation radioligand [18F]-FEPPA between PD patients and HC. FEPPA total distribution volume (V T) values in cortical as well as subcortical brain regions were derived from a two-tissue compartment model with arterial plasma as an input function. RESULTS: Our results revealed a significant main effect of genotype on [18F]-FEPPA V T in every brain region, but no main effect of disease or disease × genotype interaction in any brain region. The overall percentage difference of the mean FEPPA V T between HC-MABs and HC-HABs was 32.6% (SD = 2.09) and for PD-MABs and PD-HABs was 43.1% (SD = 1.21). CONCLUSIONS: Future investigations are needed to determine the significance of [18F]-FEPPA as a biomarker of neuroinflammation as well as the importance of the rs6971 polymorphism and its clinical consequence in PD.

Salience network and parahippocampal dopamine dysfunction in memory-impaired Parkinson disease.

OBJECTIVE: Patients with Parkinson disease (PD) and mild cognitive impairment (MCI) are vulnerable to dementia and frequently experience memory deficits. This could be the result of dopamine dysfunction in corticostriatal networks (salience, central executive networks, and striatum) and/or the medial temporal lobe. Our aim was to investigate whether dopamine dysfunction in these regions contributes to memory impairment in PD. METHODS: We used positron emission tomography imaging to compare D2 receptor availability in the cortex and striatal (limbic and associative) dopamine neuron integrity in 4 groups: memory-impaired PD (amnestic MCI; n = 9), PD with nonamnestic MCI (n = 10), PD without MCI (n = 11), and healthy controls (n = 14). Subjects were administered a full neuropsychological test battery for cognitive performance. RESULTS: Memory-impaired patients demonstrated more significant reductions in D2 receptor binding in the salience network (insular cortex and anterior cingulate cortex [ACC] and the right parahippocampal gyrus [PHG]) compared to healthy controls and patients with no MCI. They also presented reductions in the right insula and right ACC compared to nonamnestic MCI patients. D2 levels were correlated with memory performance in the right PHG and left insula of amnestic patients and with executive performance in the bilateral insula and left ACC of all MCI patients. Associative striatal dopamine denervation was significant in all PD patients. INTERPRETATION: Dopaminergic differences in the salience network and the medial temporal lobe contribute to memory impairment in PD. Furthermore, these findings indicate the vulnerability of the salience network in PD and its potential role in memory and executive dysfunction.

Similar striatal D2/D3 dopamine receptor availability in adults with Tourette syndrome compared with healthy controls: A [(11) C]-(+)-PHNO and [(11) C]raclopride positron emission tomography imaging study.

Pharmacological and anatomical evidence implicates striatal dopamine receptors in Tourette syndrome (TS). Nevertheless, results of positron emission tomography (PET) studies of the dopamine system in TS have been inconsistent. We investigated striatal D2/3 dopamine receptors in TS using the radioligands [(11) C]raclopride and [(11) C]-(+)-PHNO, an agonist that binds preferentially to D3 receptors, thus allowing higher sensitivity and measurement of receptors in a high affinity state. Eleven adults with TS and 11 matched healthy control (HC) participants underwent [(11) C]raclopride and [(11) C]-(+)-PHNO PET scans. General linear model was used for voxelwise contrasts of striatal binding potentials (BPND ) between TS and HC participants. Analysis of variance was performed to investigate main effect of radioligand. In addition, BPND values were extracted for ventral, motor, and associative striatum. Finally, we examined the relationship between BPND measures and symptom severity in TS participants. Main effects analyses showed that [(11) C]-(+)-PHNO BPND was higher in ventral striatum, whereas [(11) C]raclopride BPND was higher in motor and associative striatum. There were no significant group differences between TS and HC. Furthermore, TS and HC participants had similar [(11) C]-(+)-PHNO and [(11) C]raclopride BPND in the three striatal subregions. Moreover, there was no significant correlation between BPND and symptom severity. TS and HC participants had similar striatal D2/3 receptor availability measures. These results challenge the assumption that striatal dopamine receptors have a major role in the pathophysiology of TS. Consistent with previous findings, [(11) C]-(+)-PHNO localized preferentially to ventral striatal, D3 receptor-rich regions, in contrast to [(11) C]raclopride, which localized preferentially in the dorsal striatum.

Monoamine Oxidase-A Occupancy by Moclobemide and Phenelzine: Implications for the Development of Monoamine Oxidase Inhibitors.

BACKGROUND: Monoamine oxidase inhibitors (MAOIs) are being developed for major depressive disorder, Alzheimer's, and Parkinson's Disease. Newer MAOIs have minimal sensitivity to tyramine, but a key limitation for optimizing their development is that standards for in vivo monoamine oxidase-A (MAO-A) occupancy in humans are not well established. The objectives were to determine the dose-occupancy relationship of moclobemide and the occupancy of phenelzine at typical clinical dosing. METHODS: Major depressive episode (MDE) subjects underwent [(11)C]harmine positron emission tomography scanning prior to and following 6 weeks of treatment with moclobemide or phenelzine. RESULTS: Mean brain MAO-A occupancies were 74.23±8.32% for moclobemide at 300-600 mg daily (n = 11), 83.75±5.52% for moclobemide at 900-1200 mg daily (n = 9), and 86.82±6.89% for phenelzine at 45-60 mg daily (n = 4). The regional dose-occupancy relationship of moclobemide fit a hyperbolic function [F(x) = a(x/[b + x]); F(1,18) = 5.57 to 13.32, p = 0.002 to 0.03, mean 'a': 88.62±2.38%, mean 'b': 69.88±4.36 mg]. Multivariate analyses of variance showed significantly greater occupancy of phenelzine (45-60mg) and higher-dose moclobemide (900-1200 mg) compared to lower-dose moclobemide [300-600 mg; F(7,16) = 3.94, p = 0.01]. CONCLUSIONS: These findings suggest that for first-line MDE treatment, daily moclobemide doses of 300-600mg correspond to a MAO-A occupancy of 74%, whereas for treatment-resistant MDE, either phenelzine or higher doses of moclobemide correspond to a MAO-A occupancy of at least 84%. Therefore, novel MAO inhibitor development should aim for similar thresholds. The findings provide a rationale in treatment algorithm design to raise moclobemide doses to inhibit more MAO-A sites, but suggest switching from high-dose moclobemide to phenelzine is best justified by binding to additional targets.

[¹¹C]-(+)-PHNO PET imaging of dopamine D(2/3) receptors in Parkinson's disease with impulse control disorders.

Dopamine agonist medications with high affinity for the D3 dopamine receptor are commonly used to treat Parkinson's disease, and have been associated with pathological behaviors categorized under the umbrella of impulse control disorders (ICD). The aim of this study was to investigate whether ICD in Parkinson's patients are associated with greater D3 dopamine receptor availability. We used positron emission tomography (PET) radioligand imaging with the D3 dopamine receptor preferring agonist [¹¹C]-(+)-propyl-hexahydro-naphtho-oxazin (PHNO) in Parkinson's patients with (n = 11) and without (n = 21) ICD, and age-, sex-, and education-matched healthy control subjects (n = 18). Contrary to hypotheses, [¹¹C]-(+)-PHNO binding in D3 -rich brain areas was not elevated in Parkinson's patients with ICD compared with those without; instead, [¹¹C]-(+)-PHNO binding in ventral striatum was 20% lower (P = 0.011), correlating with two measures of ICD severity (r = -0.8 and -0.9), which may reflect higher dopamine tone in ventral striatum. In dorsal striatum, where [¹¹C]-(+)-PHNO binding is associated with D2 receptor levels, [¹¹C]-(+)-PHNO binding was elevated across patients compared with controls. We conclude that although D3 dopamine receptors have been linked to the occurrence of ICD in Parkinson's patients. Our findings do not support the hypothesis that D3 receptor levels are elevated in Parkinson's patients with ICD. We also did not find ICD-related abnormalities in D2 receptor levels. Our findings argue against the possibility that differences in D2/3 receptor levels can account for the development of ICD in PD; however, we cannot rule out that differences in dopamine levels (particularly in ventral striatum) may be involved.

Combined insular and striatal dopamine dysfunction are associated with executive deficits in Parkinson's disease with mild cognitive impairment.

The ability to dynamically use various aspects of cognition is essential to daily function, and reliant on dopaminergic transmission in cortico-striatal circuitry. Our aim was to investigate both striatal and cortical dopaminergic changes in patients with Parkinson's disease with mild cognitive impairment, who represent a vulnerable group for the development of dementia. We hypothesized severe striatal dopamine denervation in the associative (i.e. cognitive) region and cortical D2 receptor abnormalities in the salience and executive networks in Parkinson's disease with mild cognitive impairment compared with cognitively normal patients with Parkinson's disease and healthy control subjects. We used positron emission tomography imaging with dopaminergic ligands (11)C-dihydrotetrabenazine, to investigate striatal dopamine neuron integrity in the associative subdivision and (11)C-FLB 457, to investigate cortical D2 receptor availability in patients with Parkinson's disease (55-80 years of age) with mild cognitive impairment (n = 11), cognitively normal patients with Parkinson's disease (n = 11) and age-matched healthy control subjects (n = 14). Subjects were administered a neuropsychological test battery to assess cognitive status and determine the relationship between dopaminergic changes and cognitive performance. We found that patients with mild cognitive impairment had severe striatal dopamine depletion in the associative (i.e. cognitive) subdivision as well as reduced D2 receptor availability in the bilateral insula, a key cognitive hub, compared to cognitively normal patients and healthy subjects after controlling for age, disease severity and daily dopaminergic medication intake. Associative striatal dopamine depletion was predictive of D2 receptor loss in the insula of patients with Parkinson's disease with mild cognitive impairment, demonstrating interrelated striatal and cortical changes. Insular D2 levels also predicted executive abilities in these patients as measured using a composite executive z-score obtained from neuropsychological testing. Furthermore we assessed cortical thickness to ensure that D2 receptor changes were not confounded by brain atrophy. There was no difference between groups in cortical thickness in the insula, or any other cortical region of interest. These findings suggest that striatal dopamine denervation combined with insular D2 receptor loss underlie mild cognitive impairment in Parkinson's disease and in particular decline in executive function. Furthermore, these findings suggest a crucial and direct role for dopaminergic modulation in the insula in facilitating cognitive function.

Quantitative imaging of neuroinflammation in human white matter: a positron emission tomography study with translocator protein 18 kDa radioligand, [18F]-FEPPA.

The ability to quantify translocator protein 18 kDa (TSPO) in white matter (WM) is important to understand the role of neuroinflammation in neurological disorders with WM involvement. This article aims to extend the utility of TSPO imaging in WM using a second-generation radioligand, [18F]-FEPPA, and high-resolution research tomograph (HRRT) positron emission tomography (PET) camera system. Four WM regions of interests (WM-ROI), relevant to the study of aging and neuroinflammatory diseases, were examined. The corpus callosum, cingulum bundle, superior longitudinal fasciculus, and posterior limb of internal capsule were delineated automatically onto subject's T1 -weighted magnetic resonance image using a diffusion tensor imaging-based WM template. The TSPO polymorphism (rs6971) stratified individuals to three genetic groups: high-affinity binders (HAB), mixed-affinity binders (MAB), and low-affinity binders. [18F]-FEPPA PET scans were acquired on 32 healthy subjects and analyzed using a full kinetic compartment analysis. The two-tissue compartment model showed moderate identifiability (coefficient of variation 15-19%) for [18F]-FEPPA total volume distribution (VT ) in WM-ROIs. Noise affects VT variability, although its effect on bias was small (6%). In a worst-case scenario, ≤6% of simulated data did not fit reliably. A simulation of increased TSPO density exposed minimal effect on variability and identifiability of [18F]-FEPPA VT in WM-ROIs. We found no association between age and [18F]-FEPPA VT in WM-ROIs. The VT values were 15% higher in HAB than in MAB, although the difference was not statistically significant. This study provides evidence for the utility and limitations of [18F]-FEPPA PET to measure TSPO expression in WM.

Neurofilament light-chain (NfL) and 18 kDa translocator protein in early psychosis and its putative high-risk.

Evidence of elevated peripheral Neurofilament light-chain (NfL) as a biomarker of neuronal injury can be utilized to reveal nonspecific axonal damage, which could reflect altered neuroimmune function. To date, only a few studies have investigated NfL as a fluid biomarker in schizophrenia primarily, though none in its putative prodrome (Clinical High-Risk, CHR) or in untreated first-episode psychosis (FEP). Further, it is unknown whether peripheral NfL is associated with 18 kDa translocator protein (TSPO), a validated neuroimmune marker. In this secondary study, we investigated for the first time (1) serum NfL in early stages of psychosis including CHR and FEP as compared to healthy controls, and (2) examined its association with brain TSPO, using [18F]FEPPA positron emission tomography (PET). Further, in the exploratory analyses, we aimed to assess associations between serum NfL and symptom severity in patient group and cognitive impairment in the combined cohort. A large cohort of 84 participants including 27 FEP (24 antipsychotic-naive), 41 CHR (34 antipsychotic-naive) and 16 healthy controls underwent structural brain MRI and [18F]FEPPA PET scan and their blood samples were obtained and assessed for serum NfL concentrations. We found no significant differences in serum NfL levels across clinical groups, controlling for age. We also found no significant association between NfL levels and brain TSPO in the entire cohort. We observed a negative association between serum NfL and negative symptom severity in CHR. Our findings suggest that neither active neuroaxonal deterioration as measured with NfL nor associated neuroimmune activation (TSPO) is clearly identifiable in an early mostly untreated psychosis sample including its putative high-risk.

18F-Flortaucipir (AV1451) imaging identifies grey matter atrophy in retired athletes.

BACKGROUND: The long-term consequences of concussions may include pathological neurodegeneration as seen in Alzheimer's disease (AD) and chronic traumatic encephalopathy (CTE). Tau-PET showed promise as a method to detect tau pathology of CTE, but more studies are needed OBJECTIVE: This study aimed (1) to assess the association of imaging evidence of tau pathology with brain volumes in retired athletes and (2) to examine the relationship between tau-PET and neuropsychological functioning. METHODS: Former contact sport athletes were recruited through the Canadian Football League Alumni Association or the Canadian Concussion Centre clinic. Athletes completed MRI, [18F]flortaucipir tau-PET, and a neuropsychological battery. Memory composite was created by averaging the Rey Auditory Verbal Learning Test and Rey Visual Design Learning Test z-scores. Grey matter (GM) volumes were age/intracranial volume corrected using normal control MRIs. Tau-PET % positivity in GM was calculated as the number of positive voxels (≥ 1.3 standardized uptake value ratio (SUVR)/total voxels). RESULTS: 47 retired contact sport athletes negative for AD (age:51 ± 14; concussions/athlete:15 ± 2) and 54 normal controls (age:50 ± 13) were included. Tau-PET positive voxels had significantly lower GM volumes, compared to tau-PET negative voxels (- 0.37 ± 0.41 vs. - 0.31 ± 0.37, paired p = .006). There was a significant relationship between GM tau-PET % positivity and memory composite score (r = - .366, p = .02), controlled for age, PET scanner, and PET scan duration. There was no relationship between tau-PET measures and concussion number, or years of sport played. CONCLUSION: A higher tau-PET signal was associated with reduced GM volumes and lower memory scores. Tau-PET may be useful for identifying those at risk for neurodegeneration.

Convergent effects of acute stress and glucocorticoid exposure upon MAO-A in humans.

Monoamine oxidase-A (MAO-A), a key brain enzyme which metabolizes monoamines, is implicated in the pathophysiology of stress-related illnesses, including major depressive disorder, addiction, and violent behavior. Chronic stressors and glucocorticoid-administration typically associate with elevated MAO-A levels/activity. However, the relationship of shorter stress or glucocorticoid exposures and MAO-A levels/activity is not well established. Our objectives are to assess effects of acute stress upon MAO-A V(T,) an index of MAO-A density, in human brain and acute glucocorticoid exposure upon MAO-A levels in human neuronal and glial cell lines. Twelve healthy, non-smoking participants aged 18-50 underwent [(11)C]harmine positron emission tomography to measure brain MAO-A V(T) on two different days: One under acute psychosocial stress (via Trier Social Stress and Montreal Imaging Stress Tasks) and one under a non-stress condition. MAO-A density (by Western blot) and activity (by [(14)C]-5-HT metabolism and liquid scintillation spectroscopy) were measured in human neuronal and glial cell lines after 4 h exposure to dexamethasone. We observed a significant reduction in whole-brain MAO-A binding as reflected by reductions in 10 of 11 brain regions. Acute dexamethasone exposure in neuronal and glial cells significantly decreased MAO-A activity and protein levels. We observed a highly consistent relationship between acute stressors and glucocorticoid administration and decreased MAO-A binding, activity and protein levels. Since MAO-A metabolizes monoamines, this phenomenon may explain why acute stressors benefit healthy animals even though chronic stress is associated with illness.

Higher binding of the dopamine D3 receptor-preferring ligand [11C]-(+)-propyl-hexahydro-naphtho-oxazin in methamphetamine polydrug users: a positron emission tomography study.

Positron emission tomography (PET) findings suggesting lower D2-type dopamine receptors and dopamine concentration in brains of stimulant users have prompted speculation that increasing dopamine signaling might help in drug treatment. However, this strategy needs to consider the possibility, based on animal and postmortem human data, that dopaminergic activity at the related D3 receptor might, in contrast, be elevated and thereby contribute to drug-taking behavior. We tested the hypothesis that D3 receptor binding is above normal in methamphetamine (MA) polydrug users, using PET and the D3-preferring ligand [11C]-(+)-propyl-hexahydro-naphtho-oxazin ([11C]-(+)-PHNO). Sixteen control subjects and 16 polydrug users reporting MA as their primary drug of abuse underwent PET scanning after [11C]-(+)-PHNO. Compared with control subjects, drug users had higher [11C]-(+)-PHNO binding in the D3-rich midbrain substantia nigra (SN; +46%; p<0.02) and in the globus pallidus (+9%; p=0.06) and ventral pallidum (+11%; p=0.1), whereas binding was slightly lower in the D2-rich dorsal striatum (approximately -4%, NS; -12% in heavy users, p=0.01) and related to drug-use severity. The [11C]-(+)-PHNO binding ratio in D3-rich SN versus D2-rich dorsal striatum was 55% higher in MA users (p=0.004), with heavy but not moderate users having ratios significantly different from controls. [11C]-(+)-PHNO binding in SN was related to self-reported "drug wanting." We conclude that the dopamine D3 receptor, unlike the D2 receptor, might be upregulated in brains of MA polydrug users, although lower dopamine levels in MA users could have contributed to the finding. Pharmacological studies are needed to establish whether normalization of D3 receptor function could reduce vulnerability to relapse in stimulant abuse.

Prefrontal dopaminergic receptor abnormalities and executive functions in Parkinson's disease.

The main pattern of cognitive impairments seen in early to moderate stages of Parkinson's disease (PD) includes deficits of executive functions. These nonmotor complications have a significant impact on the quality of life and day-to-day activities of PD patients and are not effectively managed by current therapies, a problem which is almost certainly due to the fact that the disease extends beyond the nigrostriatal system. To investigate the role of extrastriatal dopamine in executive function in PD, PD patients and a control group were studied with positron-emission-tomography using a high-affinity dopamine D2/D3 receptor tracer, [(11) C]FLB-457. All participants were scanned twice while performing an executive task and a control task. Patients were off medication for at least 12 h. The imaging analysis revealed that parkinsonian patients had lower [(11) C]FLB-457 binding than control group independently of task conditions across different brain regions. Cognitive assessment measures were positively correlated with [(11) C]FLB-457 binding in the bilateral dorsolateral prefrontal cortex and anterior cingulate cortex only in control group, but not in PD patients. Within the control group, during the executive task (as compared to control task), there was evidence of reduced [(11) C]FLB-457 binding (indicative of increased dopamine release) in the right orbitofrontal cortex. In contrast, PD patients did not show any reduction in binding during the executive task (as compared with control task). These findings suggest that PD patients present significant abnormalities in extrastriatal dopamine associated with executive processing. These observations provide important insights on the pathophysiology of cognitive dysfunction in PD.