Introducing neurofilament light chain measure in psychiatry: current evidence, opportunities, and pitfalls

The recent introduction of new-generation immunoassay methods allows the reliable quantification of structural brain markers in peripheral matrices. Neurofilament light chain (NfL), a neuron-specific cytoskeletal component released in extracellular matrices after neuroaxonal impairment, is considered a promising blood marker of active brain pathology. Given its sensitivity to a wide range of neuropathological alterations, NfL has been suggested for the use in clinical practice as a highly sensitive, but unspecific tool to quantify active brain pathology. While large efforts have been put in characterizing its clinical profile in many neurological conditions, NfL has received far less attention as a potential biomarker in major psychiatric disorders. Therefore, we briefly introduce NfL as a marker of neuroaxonal injury, systematically review recent findings on cerebrospinal fluid and blood NfL levels in patients with primary psychiatric conditions and highlight the opportunities and pitfalls. Current evidence suggests an elevation of blood NfL levels in patients with major depression, bipolar disorder, psychotic disorders, anorexia nervosa, and substance use disorders compared to physiological states. However, blood NfL levels strongly vary across diagnostic entities, clinical stage, and patient subgroups, and are influenced by several demographic, clinical, and analytical factors, which require accurate characterization. Potential clinical applications of NfL measure in psychiatry are seen in diagnostic and prognostic algorithms, to exclude neurodegenerative disease, in the assessment of brain toxicity for different pharmacological compounds, and in the longitudinal monitoring of treatment response. The high inter-individual variability of NfL levels and the lack of neurobiological understanding of its release are some of the main current limitations. Overall, this primer aims to introduce researchers and clinicians to NfL measure in the psychiatric field and to provide a conceptual framework for future research directions

Introducing neurofilament light chain measure in psychiatry: current evidence, opportunities, and pitfalls

The recent introduction of new-generation immunoassay methods allows the reliable quantification of structural brain markers in peripheral matrices. Neurofilament light chain (NfL), a neuron-specific cytoskeletal component released in extracellular matrices after neuroaxonal impairment, is considered a promising blood marker of active brain pathology. Given its sensitivity to a wide range of neuropathological alterations, NfL has been suggested for the use in clinical practice as a highly sensitive, but unspecific tool to quantify active brain pathology. While large efforts have been put in characterizing its clinical profile in many neurological conditions, NfL has received far less attention as a potential biomarker in major psychiatric disorders. Therefore, we briefly introduce NfL as a marker of neuroaxonal injury, systematically review recent findings on cerebrospinal fluid and blood NfL levels in patients with primary psychiatric conditions and highlight the opportunities and pitfalls. Current evidence suggests an elevation of blood NfL levels in patients with major depression, bipolar disorder, psychotic disorders, anorexia nervosa, and substance use disorders compared to physiological states. However, blood NfL levels strongly vary across diagnostic entities, clinical stage, and patient subgroups, and are influenced by several demographic, clinical, and analytical factors, which require accurate characterization. Potential clinical applications of NfL measure in psychiatry are seen in diagnostic and prognostic algorithms, to exclude neurodegenerative disease, in the assessment of brain toxicity for different pharmacological compounds, and in the longitudinal monitoring of treatment response. The high inter-individual variability of NfL levels and the lack of neurobiological understanding of its release are some of the main current limitations. Overall, this primer aims to introduce researchers and clinicians to NfL measure in the psychiatric field and to provide a conceptual framework for future research directions

Molecular correlates of trait anxiety: expanding biomarker discovery from protein expression to turnover

Depression and anxiety disorders affect a great number of people in the world. Although remarkable efforts have been devoted to understanding the clinical and biological basis of these disorders, progress has been relatively slow. Furthermore, no laboratory test currently is available for diagnosis of anxiety and depression. These disorders are mainly diagnosed empirically on the basis of a doctor’s personal observations and experiences. Hence, discovery of biomarkers for these psychiatric disorders deserves much scientific attention. The animal models investigated in the present study represent high, low, and normal anxiety-like phenotypes (HAB, LAB, NAB) and were established by selective inbreeding. To compare the protein expression levels between different animal lines, living animals were metabolically labeled with the 15N stable isotope and then investigated by quantitative mass spectrometry. In addition, metabolomic studies were performed to shed light on pathways affected in the trait anxiety mouse model. A number of proteins and metabolites were found to be significantly altered in their expression levels between the three mouse lines. Both protein and metabolite information was used for in silico network analysis to find pathways pertinent to the pathobiology of anxiety disorders. Another focus of this thesis was the development of new methodologies for the metabolic labeling approach. This includes improved identification of labeled proteins and the analysis of protein turnover. The latter represents another important aspect in the field of proteomics and adds a dynamic dimension to the field. The method allows the detection of protein expression alterations at a much earlier stage. The newly developed ProTurnyer (Protein Turnover Analyzer) algorithm is able to calculate in a high throughput manner turnover for individual proteins

Structural connectivity and subcellular changes after antidepressant doses of ketamine and Ro 25-6981 in the rat: an MRI and immuno-labeling study

Ketamine has rapid and robust antidepressant effects. However, unwanted psychotomimetic effects limit its widespread use. Hence, several studies examined whether GluN2B-subunit selective NMDA antagonists would exhibit a better therapeutic profile. Although preclinical work has revealed some of the mechanisms of action of ketamine at cellular and molecular levels, the impact on brain circuitry is poorly understood. Several neuroimaging studies have examined the functional changes in the brain induced by acute administration of ketamine and Ro 25-6981 (a GluN2B-subunit selective antagonist), but the changes in the microstructure of gray and white matter have received less attention. Here, the effects of ketamine and Ro 25-6981 on gray and white matter integrity in male Sprague-Dawley rats were determined using diffusion-weighted magnetic resonance imaging (DWI). In addition, DWI-based structural brain networks were estimated and connectivity metrics were computed at the regional level. Immunohistochemical analyses were also performed to determine whether changes in myelin basic protein (MBP) and neurofilament heavy-chain protein (NF200) may underlie connectivity changes. In general, ketamine and Ro 25-6981 showed some opposite structural alterations, but both compounds coincided only in increasing the fractional anisotropy in infralimbic prefrontal cortex and dorsal raphe nucleus. These changes were associated with increments of NF200 in deep layers of the infralimbic cortex (together with increased MBP) and the dorsal raphe nucleus. Our results suggest that the synthesis of NF200 and MBP may contribute to the formation of new dendritic spines and myelination, respectively. We also suggest that the increase of fractional anisotropy of the infralimbic and dorsal raphe nucleus areas could represent a biomarker of a rapid antidepressant response.Funding: Open Access funding provided thanks to the CRUE-CSIC agreement with Springer Nature. This work was supported by grants from the Instituto de Salud Carlos III, Subdirección General de Evaluación y Fomento de la Investigación (PI13/00038, PI16/00217 and PI19/00170 to A.A.) that were co-funded by the European Regional Development Fund (‘A way to build Europe’); Generalitat Valenciana, Conselleria d’ Educació, Investigació, Cultura i Esport (GV/2018/049 to A.B-S.); Ministerio de Ciencia, Innovación y Universidades (RTI2018-097534-B-I00 to F.P.-C.). Funding from the Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Instituto de Salud Carlos III is also acknowledged

Concussion: a detailed overview from impact to recovery and discussion of related sequelae

Thesis (M.A.)--Boston UniversityA concussion is the transient alteration of consciousness immediately following application, either direct or indirect, of traumatic biomechanical forces to the head. It is a widespread and likely underreported disorder affecting millions of people in the US every year. In the past, concussions have often been trivialized by coaches, trainers, parents, and athletes as “bumps to the head” rather than truly serious injuries. Now, however, mounting evidence of the severe long-term consequences of concussion is stimulating public interest in the issue. This has spurred research in recent years and our understanding of the injury construct of concussion has advanced accordingly, although several areas of uncertainty remain regarding the potential future consequences of single or multiple concussions. A greater understanding of the underlying mechanisms of concussion in humans may help ameliorate the negative conditions of those millions suffering from concussion and its sequelae. This paper details this complex disorder from impact to recovery, including underlying physiological mechanisms, and discusses its potential long- term consequences. The need for advancement in concussion prevention strategies is discussed as a primary goal for the future. Education, institution of new guidelines and legislation concerning youth sports, advances in equipment, and rule/policy changes in professional sports are discussed as potential areas for improvement. However, action in these areas will not solve the problem on its own. An overall cultural shift needs to occur in order to emphasize the severity of concussions in general. Additionally, support and early recognition of long-term sequelae of repeat concussion would be helpful in limiting the number of negative outcomes in concussion patients

Mechanisms involved in chronic neuropathic pain after avulsion injury

PhDMotor vehicle accidents are the most common cause of injuries involving avulsion of spinal roots from the brachial or lumbosacral plexuses. This results in chronic intractable pain that is refractory to pharmacotherapy. This is largely due to lack of information on underlying mechanisms, and lack of an established animal model to test drug treatments. This thesis has: 1) compared the neuroanatomical effects of dorsal root rhizotomy (DRR) and avulsion (DRA) in the spinal cord. DRR is commonly used to model avulsion injury but unlike avulsion it does not damage the spinal cord, as often happens clinically. 2) Developed a behavioural model of spinal root avulsion injury (SRA). 3) Evaluated the behavioural effects of drugs prescribed to treat neuropathic pain or those used clinically to treat other conditions like motoneuron disease or spinal cord injury. DRA produced a greater and prolonged glial, inflammatory, vascular response and cell loss than DRR. SRA produced thermal and mechanical hypersensitivity in the affected hind-paw. Neurodegenerative and neuroinflammatory responses were observed in both the avulsed and adjacent spinal segments, but produced no changes in the neuronal phenotype adjacent dorsal root ganglion neurons, suggesting that the evoked behaviour is mediated by central mechanisms. Administration of amitriptyline or carbamazepine reduced behavioural hypersensitivity in SRA, confirming their limited clinical efficacy in treatment of avulsion injury. Minocycline and riluzole produced therapeutic efficacy. Both compounds prevented the establishment of behavioural hypersensitivity, which correlated histologically with microglial inhibition, although riluzole was transiently effective. Additionally, minocycline reversed the hypersensitivity, an effect that persisted beyond drug washout, whereas riluzole had a limited effect that only lasted whilst the drug was administered. This thesis provides insight into the mechanisms of avulsion-induced neuropathic pain. The establishment of a behaviourally reproducible avulsion model provides a platform to test new pharmacological candidates for treatment, such as minocycline

11th European Headache Federation Congress jointly with 31st Congress of the Italian Society for the Study of Headaches : Rome, Italy. 01-03 December 2017

. Aims of the study were explore the relationship between peripheral chromatic and central visual dysfunction evaluating also the presence of functional receptor impairment in patients with migraine, with and without aura examined interictally