Molecular imaging in neuropsychiatry

This volume, entitled ‘Molecular Imaging in Neuropsychiatry’, focuses on state of the art molecular imaging methods, as applied to the most challenging diagnostic and therapeutic issues in psychology and neurology, and demonstrates the critical role of molecular brain imaging in understanding neurobiological mechanisms and in potentially informing the development of more effective treatments. The topics range from neurodevelopmental to mood disorders, addictions, to the non-motor symptoms of movement disorders.

The past two decades have witnessed remarkable advances in radiotracer chemistry for positron emission tomography (PET), as well as methodological advances for magnetic resonance spectroscopy (MRS) that provides complementary information to PET imaging. Radiotracer development has made possible the investigation of enzymes, neurotransmitter synthesis/metabolism, transporters, and receptors for a variety of neurotransmitters and neuromodulators (including second messengers and neuropeptides) in the living brain. A major focus over the past decade has been in vivo imaging of neurodegenerative disease mechanisms that previously could be studied only at post-mortem examination, including inflammation, beta-amyloid, and Tau proteins (Hammoud, 2016; Mathis, Lopresti, Ikonomovic, & Klunk, 2017). MRS provides a unique opportunity to study amino acid neurotransmitters (GABA, glutamate), and measures of neuronal metabolism and oxidative stress. Recent advances include edited MRS, which has resulted in more precise quantification of neurotransmitters and metabolites at lower field strength that can be performed even in multi-site studies, as well as high field strength MRS imaging (Godlewska, Clare, Cowen, & Emir, 2017; Mikkelsen et al., 2017).

In parallel to advances in PET radiotracer chemistry, developments in instrumentation have substantially improved the spatial resolution of PET. The high-resolution research tomograph is a dedicated human brain PET scanner with a resolution of 2.3–3.4 mm (de Jong et al., 2007; Wienhard et al., 2002). The development of dual modality imaging has been another major innovation in instrumentation, including PET/computed tomography scanners and PET/magnetic resonance imaging (MRI) scanners. Sequential imaging of structure and function (PET/CT, PET/MRI) and, more recently, simultaneous acquisition of structure/circuitry and function (PET/MRI; Bailey et al., 2017). Simultaneous PET/MRI is an important opportunity to study pharmacologic and/or behaviour induced changes in neural circuitry and specific neurobiological mechanisms.

The review by Hwang, Mohamed, and Brasic (2017) describes the complementary contributions of PET and MRS to the understanding of the pathophysiology of autism spectrum disorders (ASD), where molecular imaging studies are critical to inform the development of treatments for cognitive dysfunction and neuropsychiatric symptoms. The authors discuss the challenges of conducting neuroimaging research in ASD. They present the major MRS and PET neuroimaging findings, including their own important contributions. MRS studies of GABA and glutamate and PET studies of dopamine, serotonin, glucose metabolism, and cerebral blood flow are reviewed. The results presented underscore the need to understand the neurobiology of ASD across the lifespan, as well as to relate the molecular imaging findings to symptomatology in larger patient samples.

While chronic schizophrenia has been a major focus of the molecular imaging research, the study of individuals at clinical high risk for schizophrenia has been more limited. Schifani et al. (2017) have performed innovative molecular imaging studies of early psychosis, including studying individuals at clinical high risk for schizophrenia and first episode psychosis. This challenging area of research is critical to identify molecular targets that may alter the early course of psychosis and may have implications for understanding the co-morbidity between psychosis and substance use that may have a negative impact on psychosis risk and course. In their review, the authors focus on imaging of extra-striatal dopamine, neuroinflammation, glutamate, GABA, and endocannabinoids. Importantly, they discuss future applications to study novel mechanisms such as other endocannabinoid targets, synaptic density, and nociceptin receptors, based on recent advances in radiotracer chemistry.

The role of the hypothalamic-pituitary-adrenocortical (HPA) axis is well established in post-traumatic stress disorder (PTSD), and has been appreciated recently in substance use disorders and their co-morbidity with PTSD. As PET radiotracer development for the HPA axis has been challenging, human studies have focused on peripheral biomarkers (e.g. cortisol, corticotrophin releasing factor). Tollefson, Himes, and Narendran (2017) have performed mechanistically novel molecular imaging studies in substance use. They review the pre-clinical evidence for HPA axis dysfunction in substance use disorders and PTSD, as well as the stress and anti-stress systems in the brain, with a focus on the anti-stress peptide, nociceptin. The nociceptin receptor (NOP-1A) has been implicated in alcohol use disorders and PTSD in animal models. The NOP-1A receptor can now be studied in the living human brain with a recently developed PET radiotracer. Further, the NOP-1A receptor can be evaluated as a potential therapeutic target in vivo. The authors present their promising results and discuss future applications of this novel radiotracer to understanding substance use disorders and PTSD co-morbidity.

The mechanisms underlying increased vulnerability to depression during hormonal transitions in women (pregnancy, post-partum, and perimenopause/menopause) are not well understood. Zsido, Villringer, and Sacher (2017) review the clinical and neurobiological evidence for such vulnerability. Then, they focus on the application of molecular brain imaging to understand sex differences in brain circuitry and neurochemistry (serotonin metabolism, transporters and receptors, monoamine oxidase-A) in mood disorders, as well as study hormonal transitions, including their innovative research on post-partum depression. The authors discuss the compelling need for carefully controlled studies to measure sex differences, as well as within-subject studies to measure hormonal fluctuations. The authors discuss methodological issues and make important practical recommendations for the conduct of post-partum and perimenopause molecular imaging studies, based on their unique research experience.

Mathias, Monette, Harper, and Forester (2017) discuss the applications of MRS to understanding mood disorders in late life, which are associated with increased mortality, morbidity, and risk of dementia. MRS studies have made important insights into mechanisms such as oxidative stress, mitochondrial dysfunction, inflammation, and neurotransmitter dysfunction that may represent a neurobiological link between mood disorders and cognitive decline, and may serve as biomarkers of these processes. The authors and their colleagues have performed innovative MRS studies in late life depression and geriatric bipolar disorder, including evaluating unique neurobiological mechanisms of antidepressants or effects of novel treatments. These studies have shown that the biochemical alterations may have utility for diagnosis and treatment response in these conditions, and that studies in older age cohorts require further investigation.

Parkinson’s disease (PD) is the second most common chronic, progressive, neurodegenerative disease. In addition to the potentially disabling motor symptoms, PD patients are also at risk for non-motor symptoms, including depression, anxiety, apathy, cognitive impairment, and impulse control behaviours (ICBs) as a side-effect of dopamine replacement therapy. The neurobiological basis of neuropsychiatric symptoms and cognitive deficits are not well understood, but molecular imaging provides a window into these symptoms in the early stages of PD at which point strategies for intervention and prevention may be more effective. Stark and Claassen (2017) provide a comprehensive review of dopamine receptors imaging in PD with a focus on ICBs, including their important research. The review highlights advances in striatal and extrastriatal PET radiotracer development that have been applied to PD and ICBs, as well as applications of these radiotracers to measure medication or behaviour induced changes in endogenous dopamine concentrations. The authors also explain how findings using dopamine radiotracers and experimental designs inform or contrast with current models explaining the role of the striatum and basal ganglia structures in learning, compulsive behaviours, and other behavioural symptoms.

The review by Valli and Strafella (2017) is an example of a significant development of PET radiotracers for imaging abnormal proteins involved in neurodegenerative disease, the Tau protein. While the exact position of Tau in the cascade of events ultimately leading to neuronal death is still controversial in Alzheimer’s disease (Goudsmit, 2016), several neurodegenerative conditions, including corticobasal degeneration (CBD), progressive supranuclear palsy (PSP), and fronto-temporal dementia (FTD), are pathologically characterized by the accumulation of Tau in oligomers of various isoforms (Bennett et al., 1998). These disorders often cause parkinsonism with additional behavioural, mood or cognitive symptoms beyond that which are typically found in idiopathic Parkinson’s disease, and these non-motor symptoms are frequently disabling and difficult to treat. Valli and Strafella have made major contributions to applying molecular imaging methods to understand the neurobiology of cognitive and behavioural symptoms in PD. They provide a thorough overview of the strengths and potential weaknesses of various Tau radiotracers used in the detection, classification, and tracking of progression in these atypical parkinsonian disorders. Learning from the pitfalls of earlier Tau radiotracers, the authors explain the potential advantages of newer tracers, which might lead to additional mechanistic insights in Tau-based movement disorders, and allow development and assessment of new neuroprotective therapies.

We wish to acknowledge the important contributions of the post-baccalaureate and post-doctoral colleagues who have authored the papers with outstanding mentors. There are many great opportunities for innovative, clinically oriented molecular imaging research for these future, outstanding independent investigators.

Disclosure statement

No potential conflict of interest was reported by the authors.