Robin Bonomi

BACKGROUND: Chronic alcohol use leads to synaptic dysfunction in preclinical studies. However, whether in vivo synaptic density deficits are found in people with alcohol use disorder (AUD) remains unclear. METHODS: Thirty-two people with AUD ( n = 17 women; n = 15 men) and 29 control participants ( n = 17 women; n = 12 men)completed 1 PET brain imaging scan with the radiotracer [ ¹¹ C]UCB-J, which binds to SV2A, a marker of synaptic density. The levels of synaptic density were quantified by estimating the nondisplaceable binding potential ( BP _ND ) across 4 regions of interest: frontal cortex, striatum, hippocampus, and cerebellum. RESULTS: People with AUD were, on average (±SD), 43 ± 13 years of age, and most met the criteria for having mild or moderate AUD. The control participants were 37 ± 12 years of age. People with AUD had, on average, a 11% lower [ ¹¹ C]UCB-J BP _ND than did controls in the frontal cortex [ F _(1,62) = 13.074, P < 0.001], striatum [ F _(1,60) = 10.283, P = 0.002], and hippocampus [ F _(1,60) = 5.964, P = 0.018], trending in the same direction in the cerebellum [ F _(1,50) = 3.438, P = 0.070]. Among people with AUD, lower [ ¹¹ C]UCB-J BP _ND was significantly related to more drinks per drinking day, in the frontal cortex ( P = 0.022) and striatum ( P = 0.026). People with AUD performed worse on executive function than did controls ( P = 0.020), but this was not related to [ ¹¹ C]UCB-J BP _ND . CONCLUSION: Synaptic density deficits were evident, even in people with mild-to-moderate AUD, with larger deficits observed in those with greater drinking severity. These findings underscore the potential of synaptic restoration as a therapeutic target for AUD. FUNDING: NIH (U54AA027989, P01AA02747307, K01AA029706, and K24AA031345); UCB Pharma SA.

Histone deacetylases (HDACs), typically known for regulating gene expression, also play a major role in protein regulation outside of histone modification. Emerging evidence suggests the HDACs may be novel pharmacologic targets in complex disorders such as posttraumatic stress disorder (PTSD). Histone deacetylase 6 (HDAC6) regulates microtubule function and plays a role in stress-related cortisol signaling in serotonergic regions of the brain by maintaining the nuclear translocation of glucocorticoid receptors. Here, we report results of a translational positron emission tomography brain imaging study using a novel HDAC6-selective radiotracer, [¹⁸F]Bavarostat. In humans, we demonstrate significantly lower availability of HDAC6 in the amygdala of individuals with PTSD compared to non-trauma exposed controls. These proof-of-concept human findings are supported by rodent findings of reduced HDAC6 availability both in case-control groups and within-subject longitudinal analysis using a single prolonged stress model. Together, our translational findings demonstrate a potential role for HDAC6 in the pathophysiology of PTSD.

Over the past two decades, epigenetic regulation has become a rapidly growing and influential field in biology and medicine. One key mechanism involves the acetylation and deacetylation of lysine residues on histone core proteins and other critical proteins that regulate gene expression and cellular signaling. Although histone deacetylases (HDACs) have received significant attention, the roles of individual HDAC isoforms in the pathogenesis of psychiatric diseases still require further research. This is particularly true with regard to the sirtuins, class III HDACs. Sirtuins have unique functional activity and significant roles in normal neurophysiology, as well as in the mechanisms of addiction, mood disorders, and other neuropsychiatric abnormalities. This review aims to elucidate the differences in catalytic structure and function of the seven sirtuins as they relate to psychiatry.

Dynamic brain immune function in individuals with posttraumatic stress disorder is rarely studied, despite evidence of peripheral immune dysfunction. Positron emission tomography brain imaging using the radiotracer [ ¹¹ C]PBR28 was used to measure the 18-kDa translocator protein (TSPO), a microglial marker, at baseline and 3 h after administration of lipopolysaccharide (LPS), a potent immune activator. Data were acquired in 15 individuals with PTSD and 15 age-matched controls. The PTSD group exhibited a significantly lower magnitude LPS-induced increase in TSPO availability in an a priori prefrontal-limbic circuit compared to controls. Greater anhedonic symptoms in the PTSD group were associated with a more suppressed neuroimmune response. In addition, while a reduced granulocyte–macrophage colony-stimulating factor response to LPS was observed in the PTSD group, other measured cytokine responses and self-reported sickness symptoms did not differ between groups; these findings highlight group differences in central–peripheral immune system relationships. The results of this study provide evidence of a suppressed microglia-mediated neuroimmune response to a direct immune system insult in individuals with PTSD that is associated with the severity of symptoms. They also provide further support to an emerging literature challenging traditional concepts of microglial and immune function in psychiatric disease.

Post-traumatic stress disorder is a prevalent disorder within the USA and worldwide with a yearly diagnosis rate of 2–4% and affecting women more than men. One of the primary methods for study of this stress disorder relies on animal models as there are few noninvasive methods and few replicated peripheral biomarkers for use in humans. One area of active research in psychiatric neuroscience is the field of epigenetics – how the chemical modifications of the genetic code regulate behavior. The dynamic changes in histone acetylation and deacetylation in the brain are not fully reflected by the study of peripheral biomarker. In this review, we aim to examine the role of histone acetylation and deacetylation in memory formation and fear memory learning. The studies discussed here focus largely on the role of histone deacetylases (HDACs) in animal models of trauma and fear response. Many studies used HDAC inhibitors to elucidate the effects after inhibition of these enzymes after trauma or stress. These studies of memory processing and cued fear extinction in animal can often shed light on human disorders of cued fear responses and memory dysregulation after stress or trauma such as in PTSD. These results provide strong evidence for a role of these enzymes in PTSD in humans. The few clinical studies that exist with HDAC inhibitors also suggest a fundamental role of these enzymes in the neurobiology of the stress response. Further study of these enzymes in both clinical and pre-clinical settings may help elucidate the neurobiology of stress-related pathology like PTSD and provide a foundation for novel therapy to treat these disorders.

In the latest World Health Organization classification of brain tumors, gliomatosis cerebri has been redefined to varying subsets of diffuse gliomas; however, the term is still used to describe gliomas with infiltrative growth into three or more cerebral lobes. These tumors are frequently misdiagnosed and difficult to treat due to their atypical presentation using structural imaging modalities including computed tomography and T1/T2-weighted magnetic resonance imaging (MRI). In this retrospective case series, we compared clinical MRI to amino acid positron emission tomography (PET) to assess the potential value of PET in the assessment of the extent of tumor involvement and in monitoring disease progression. We report the clinical course and serial multimodal imaging findings of four patients. Each patient presented at varying points in disease progression with widespread glioma brain involvement and was evaluated at least once by amino acid PET using alpha-[ ¹¹ C]methyl-L-tryptophan ([ ¹¹ C]-AMT). Increased uptake of [ ¹¹ C]-AMT was detected in a subset of non-enhancing brain lesions and detected tumor invasion before MRI signs of tumor in some regions. Increased uptake of [ ¹¹ C]-AMT was also detected in tumorous regions not detected by perfusion MRI or MR spectroscopy. Metabolic response to treatment was also observed in two patients. Overall, these data are consistent with and expand upon previous reports using other amino acid PET tracers in gliomatosis and show the potential added value of this imaging modality to clinical MRI in the detection and monitoring of these diffusely infiltrative tumors.

Several studies demonstrated that glioblastoma multiforme progression and recurrence is linked to epigenetic regulatory mechanisms. Sirtuin 1 (SIRT1) plays an important role in glioma progression, invasion, and treatment response and is a potential therapeutic target. The aim of this study is to test the feasibility of 2-[¹⁸F]BzAHA for quantitative imaging of SIRT1 expression–activity and monitoring pharmacologic inhibition in a rat model of intracerebral glioma. Sprague Dawley rats bearing 9L (N = 12) intracerebral gliomas were injected with 2-[¹⁸F]BzAHA (300–500 µCi/animal i.v.) and dynamic positron-emission tomography (PET) imaging was performed for 60 min. Then, SIRT1 expression in 9L tumors (N = 6) was studied by immunofluorescence microscopy (IF). Two days later, rats with 9L gliomas were treated either with SIRT1 specific inhibitor EX-527 (5 mg/kg, i.p.; N = 3) or with histone deacetylases class IIa specific inhibitor MC1568 (30 mg/kg, i.p.; N = 3) and 30 min later were injected i.v. with 2-[¹⁸F]BzAHA. PET-computerized tomography-magnetic resonance (PET/CT/MR) images acquired after EX-527 and MC1568 treatments were co-registered with baseline images. Standard uptake values (SUVs) of 2-[¹⁸F]BzAHA in 9L tumors measured at 20 min post-radiotracer administration were 1.11 ± 0.058 and had a tumor-to-brainstem SUV ratio of 2.73 ± 0.141. IF of 9L gliomas revealed heterogeneous upregulation of SIRT1, especially in hypoxic and peri-necrotic regions. Significant reduction in 2-[¹⁸F]BzAHA SUV and distribution volume in 9L tumors was observed after administration of EX-527, but not MC1568. PET/CT/MRI with 2-[¹⁸F]BzAHA can facilitate studies to elucidate the roles of SIRT1 in gliomagenesis and progression, as well as to optimize therapeutic doses of novel SIRT1 inhibitors.

Sirtuin 1 (SIRT1) is a class III histone deacetylase that plays significant roles in the regulation of lifespan, metabolism, memory, and circadian rhythms and in the mechanisms of many diseases. However, methods of monitoring the pharmacodynamics of SIRT1-targeted drugs are limited to blood sampling because of the invasive nature of biopsies. For the noninvasive monitoring of the spatial and temporal dynamics of SIRT1 expression–activity in vivo by PET–CT–MRI, we developed a novel substrate-type radiotracer, [¹⁸F]-2-fluorobenzoylaminohexanoicanilide (2-[¹⁸F]BzAHA). PET–CT–MRI studies in rats demonstrated increased accumulation of 2-[¹⁸F]BzAHA-derived radioactivity in the hypothalamus, hippocampus, nucleus accumbens, and locus coeruleus, consistent with autoradiographic and immunofluorescent (IMF) analyses of brain-tissue sections. Pretreatment with the SIRT1 specific inhibitor, EX-527 (5 mg/kg, ip), resulted in about a 20% reduction of 2-[¹⁸F]BzAHA-derived-radioactivity accumulation in these structures. In vivo imaging of SIRT1 expression–activity should facilitate studies that improve the understanding of SIRT1-mediated regulation in the brain and aid in the development and clinical translation of SIRT1-targeted therapies.