Biomarkers in Neuropsychiatry最新文献

In this review, we evaluate the role of fluid biomarkers related to neurodegenerative diseases. Such conditions present diagnostic challenges due to phenotypic heterogeneity, longitudinal evolution, overlap between diagnostic entities, and variability in progression. Biomarkers can potentially provide insight into diagnosis, progression, prognostication, and treatment efficacy. This review covers recent advances in fluid biomarkers including beta-amyloid, tau protein, neurofilament light chain, alpha-synuclein and glial fibrillary protein, and briefly touches upon imaging biomarkers. For each biomarker, we discuss the pathophysiological correlates, clinical uses, accuracy, and limitations.

Chronic traumatic encephalopathy (CTE) is a progressive neurodegenerative condition that occurs several years following repetitive mild concussive or sub concussive brain injuries. To date, it is a post-mortem diagnosis. Traumatic encephalopathy syndrome (TES) is a framework that was developed as a clinical predictor of CTE in living individuals. Development of biomarkers of CTE, detectable through imaging or bodily fluids will aid improve the diagnostic accuracy of CTE in life, and help develop prevention and therapeutic strategies. This article reviews biomarkers investigated to date, and discusses challenges and future avenues in this burgeoning field.

Alzheimer’s disease (AD) is an age-related neurodegenerative disease and the leading cause of dementia worldwide. AD is associated with several neuropathologic changes including the progressive accumulation of extracellular amyloid-β (Aβ) plaques, intracellular neurofibrillary tau tangles, neuroinflammation, cerebral small vessel disease and neurodegeneration, many of which are known to begin years before the onset of clinical symptoms. As such, there is a growing interest in developing biomarkers that can be used to detect these changes in the brains of at-risk individuals to facilitate earlier and more accurate diagnosis. This may allow for earlier intervention with disease-modifying therapies to slow the progression of irreversible neurodegeneration and improve quality of life. The current review seeks to provide a concise overview of the neuropathology and genetics underlying AD, and then summarize the most promising clinically available and experimental biomarkers of AD. These include structural neuroimaging, functional magnetic resonance imaging (fMRI), positron emission tomography (PET), cerebrospinal fluid (CSF), and blood-based assays. Multiple potential clinical uses for these biomarkers are then described, including screening at-risk populations for disease, aiding in differential diagnosis of dementia and mild cognitive impairment (MCI), monitoring the impact of lifestyle intervention and disease modifying therapies, identification and treatment of neuropsychiatric symptoms of dementia, and aiding in planning for end of life care. Finally, additional areas of future research are discussed, including replication of biomarker studies in more diverse patient cohorts, characterization of real-world clinical and psychological impacts of biomarker testing, as well as novel biomarkers currently under investigation.

Delirium is a neuropsychiatric disorder highly prevalent in the intensive care unit (ICU), especially among elderly patients. Symptoms develop suddenly over a short period of time in the form of a fluctuating mental state marked by severe inattention and disturbance in cognition. Dementia, on the other hand, develops over a long period of time as a result of a neurodegenerative disorder. In this review, we aim to identify overlapping biomarkers between delirium and dementia to have a better understanding of the underlying pathophysiological mechanisms relating these two disorders. Overlapping biomarkers included low levels of albumin and IGF-1, a presence of the APOE ε4 allele (APOE ε4 +), as well as higher levels of of AβN-40, S100β, procalcitonin, IL-1β, NfL, prolactin, creatinine, MMP-9, and homocysteine. We put forward several hypotheses on the convergence of the pathophysiology of these two disorders. It is plausible that ICU-acquired delirium arises as a sign of prodromal dementia or as a result of chronic systemic inflammation and concomitant neuroinflammation due to an increase in S100β proteins in the brain as a byproduct of chronic glial activation. Simultaneously, accumulation of creatinine may render the functioning of the kidneys sub-optimal, which can have deleterious effects on cognitive functioning, while lower serum albumin can increase the risk of Aβ accumulation in the brain and therefore increase the likelihood of delirium and future dementia. Moreover, homozygosity in the APOE ε4 allele coupled with elevated plasma CRP might increase the risk of delirium and trigger the onset of Alzheimer’s disease (AD). Therapeutic approaches targeting the above biomarkers need to be the subject of further investigation, especially among those exhibiting persistent delirium.

Complement system is one of the most important defense mechanisms of the innate immune system. In addition to their roles in immune regulation, complement proteins are also involved in neurodevelopment and adult brain plasticity. Complement dysregulation has been shown in neurodevelopmental disorders including schizophrenia and autism spectrum disorder as well as in mood disorders. A number of clinical as well as genetic studies suggest the role of complement proteins in the cortical thinning and excessive synaptic pruning frequently associated with schizophrenia. The changes in complement proteins are also associated with the pathophysiology of autism spectrum disorder, major depressive disorder and bipolar disorder, but warrant further research. In addition, rodent models suggest a strong case for complement system in anxiety-like behavior. In this article, we review the recent findings on the role of complement system in neuropsychiatric disorders. The possible uses for future complement targeted therapies are also discussed.

Extracellular vesicles (EVs) are tiny (<1 µm) membrane-bound vesicles released by all tissues (including the brain) that cross the blood-brain barrier and facilitate cell-to-cell communication within and among tissues. They represent the body’s “Twitter system,” rapidly disseminating packets of information throughout the brain and body. Not unlike Twitter, EVs convey short messages through their cargos (e.g., RNAs, proteins, lipids, and metabolites), which direct the molecular activity of recipient cells in both health and disease. Extracellular vesicles serve as mediators of brain function and represent a reservoir for CNS-specific biomarkers that can be sequestered from plasma to guide diagnosis and treatment, representing a new frontier in the molecular study of psychiatric illness and in the development of biomarkers. The EV field has immense potential to revolutionize diagnostic approaches in psychiatry, facilitate precision treatment, predict response, and discover much-needed novel therapeutics.

Background

Little is known whether cholesterol levels affect depression treatment outcomes. We aimed to study the association between baseline and changes in blood cholesterol levels with drug-specific antidepressant response and long-term prognosis in patients with major depressive disorder (MDD).

Methods

From the Danish site of the GENDEP trial, we included patients with MDD randomized to escitalopram or nortriptyline treatment. Total and free cholesterol, low-density lipoprotein (LDL), high-density lipoprotein (HDL), and depression severity using the Montgomery-Åsberg Depression rating scale (MADRS) were measured at baseline and after 26 weeks of treatment initiation. By linkage with nationwide registers, we analyzed psychiatric and cardiometabolic hospital contacts during the five years after the trial. We assessed the association of cholesterol levels with a) depression severity using linear and mixed effects regression analyses; and b) the register-based outcomes using Cox regression analyses.

Results

Among 78 patients (mean age 38 years, 74% women, mean MADRS score 28 [SD=4.5]), baseline cholesterol levels were not correlated with antidepressant response. Among 58 patients with measurements at week 0 and 26, cholesterol levels significantly increased in both treatment groups. Only in patients using escitalopram did the increase in total and free cholesterol and LDL correlate with improved antidepressant response. Baseline or changes in cholesterol were not associated with 5-year outcomes.

Limitations

Secondary analyses on a rather small sample.

Conclusion

This study provides clinical insight into potential drug-specific associations between increases in cholesterol levels and antidepressant response to escitalopram but not nortriptyline.