Aimed to decipher the levels of metabolites, metabolomics can now advance to unraveling their functionalities in various contexts. Here, the authors present the metabolite medicine concept, integrating classical metabolomics methods with advanced computational and structural tools to facilitate functional studies. The levels of metabolites are strictly regulated in metabolomic networks1, giving rise to a dynamically-stable metabolome homeostasis, termed metabolostasis. Consistently, the abrogation of these functions is often associated with pathological outcomes. Thus, inborn error of metabolism (IEM) disorders arise from congenital mutations in genes encoding metabolic enzymes, often resulting in aberrant accumulation of various metabolites. Recently, the accumulated metabolites in several IEM conditions have been suggested to self-assemble into ordered cytotoxic structures, which may account for the pathological phenotypes4. Similarly, crystallization of metabolites, such as uric acid and calcium oxalate, is known to be associated with various pathologies, including gout and kidney stones, respectively6. The involvement of diverse metabolites in different types of cancer is also beginning to unfold, designating these molecules as oncometabolites7. Other conditions, such as neurodegenerative and cardiovascular diseases, have also been shown to involve de-regulation of metabolite levels. However, in spite of the numerous indications for the important role metabolites play in physiology and pathology, in most cases, their exact functions are still unknown, emphasizing the need to decipher the mechanisms underlying these conditions. Such an understanding will allow to identify whether a given metabolite plays a causative role in a specific pathology, or whether its aberrant levels are merely a side effect.The ability to accurately determine the composition and concentrations of large sets of metabolites at varying physiological and pathological states had transformed our understanding of biological processes. The roles played by metabolites are highly diverse, including, among others, structural functions, regulation of signal transduction, feedback mechanisms and generation of photonic systems 8. Metabolomics analysis includes two complementary approaches. Untargeted metabolomics methods identify changes in the metabolites and their relative differences between samples, yet the lack of quality control measures, such as internal standards and calibration curves, often results in reduced accuracy. In parallel, targeted metabolomics provides an accurate account of the levels of the tested metabolites, but is limited to a pre-determined set of molecules. The combination of both methodologies in iterative cycles allows confident quantitation of the relevant metabolites, thereby facilitating both discovery and hypothesis-driven research9. Semi-targeted methods have therefore been developed to combine the advantages of both approaches. These methodologies have provided comprehensive data sets describing the levels of numerous metabolites under various physiological and pathological conditions. Metabolomics increasingly employs a data science approach due to the vast amount of data acquired in each individual experiment and the total volume of high-quality biological and medical data. Metabolite abundances directly reflect biological perturbations originating from collective modifications of the genome, transcriptome, and proteome. Moreover, many of the most common human diseases involve disrupted metabolism at the level of the organism and/or the individual cell, bearing a clear effect on metabolites level. As a result, metabolomics is extensively utilized to develop precision medicine applications, providing specific diagnosis and personalized treatment tools for various pathological conditions characterized by phenotypic heterogeneity, including dermatomyositis, pulmonary vascular disease, and liver pathologies12. However, in spite of this vast amount of experimental findings, the role of each metabolite under a given set of conditions is far from being understood. The next challenge of the metabolomics field would therefore be to go beyond the simplistic lists of metabolites to deciphering their functions. This leap will provide insights into the basic mechanisms underlying diverse types of disease conditions, thereby advancing future efforts for developing novel therapeutics.Following the advancements achieved through genomics and proteomics, the realization of the significant roles of metabolites has led to the establishment of metabolomics as an emerging methodology. Taking a systemic approach, metabolomics allows to simultaneously quantify large cohorts of metabolites in a given samplevia an inclusive infrastructure that implements analytical, microscopy and crystallographic techniques together with bioinformatics and computational methodologies , which offers quantitative analysis of metabolites with unparalleled sensitivity and selectivity. The use of a tandem mass spectrometer (MS/MS) provides highly sensitive data and structural information, allowing to better decipher given compounds. Moreover, to overcome sample complexity and allow for metabolite separation prior to detection, the coupling of liquid chromatography (LC) to MS/MS (LC-MS/MS) is required to facilitate metabolite identification and quantitation17. Moreover, recently it was shown that metabolites have the ability to self-assemble and form supramolecular fibrillar amyloid structures which could provide another dimension for the epimetabolomic phenomenon. These assemblies, termed metabolite amyloids, were shown to be pathologically related to several inherited metabolic disorders. The diverse set of capabilities presented by these small molecules potentially suggests their multiple functional roles in a certain disease including those related to abnormal proteostasis conditions19. In light of this, when trying to decipher the connection between the differential metabolites and their mechanism of action in a given pathology, their link to other pathologies with similar symptoms, physical localization in the body based on high-resolution microscopy, propensity to aggregate and form a variety of assemblies and their chemical structure derived from crystallographic analyses should all be considered. The ability to integrate data regarding a specific metabolite in terms of its chemical structure as well as its native and pathological function may lead to a better understanding of its mechanism of action in an unexplored system, thereby facilitating a more focused and specifically-targeted functional metabolomics research14.Metabolomics research aims to measure and identify both endogenous and exogenous small molecules in a given sample. The metabolomics analysis of cells, tissues, and body fluids reflects the biochemical status of the sample and may serve as a direct readout of the current phenotype, either normal or pathological, of the organism. While different molecular techniques can identify changes at the genetic level, it remains unclear how mutations, single nucleotide polymorphisms or other changes in the DNA or in gene expression are manifested in the cell phenotype. Metabolism and biochemical reactions, on the other hand, receive inputs from every level of cellular regulation and thus better represent the actual cellular output. For example, in the case of identical twins who have the same genomic background, metabolomics might predict the tendency of one to develop a certain disease, thus providing valuable information. In this regard, metabolomics has been successfully used to provide insights into the course of diverse diseases, discover novel biomarkers, and shed light on the impact of drug metabolism and drug effects in vivo. While obtaining the list of metabolites of each analyzed sample is one challenge, understanding the basis for their change in a specific situation and exploring their functional role in the pathological mechanism might be an even greater one. As mentioned above, metabolites participate in various biological and chemical activities in the body including catabolic and anabolic pathways, small molecule regulators, and active biomolecules that regulate important cellular and physiological processes, designated as epimetabolites3. For decades, phenylalanine was known to accumulate in PKU, one of the most common IEM disorders. While phenylalanine was utilized as a hallmark biomarker for the diagnosis of PKU, for example in newborn metabolomics screening, its pathological mode of action was not fully understood21. Interestingly, previous work that examined the amyloid aggregation propensity of all 20 coded amino acids revealed that phenylalanine, as an isolated amino acid, has one of the highest aggregative propensities22. Moreover, the diphenylalanine dipeptide, the core recognition motif within the β‐amyloid polypeptide, was found to form well-ordered amyloid assemblies, showing optical and functional properties characteristic of protein and poly-peptide amyloids23. Together with the aromatic nature of phenylalanine, which is known to play a significant role in amyloid aggregation24, this line of evidence proposed a possible functionality of the amino acid as an amyloidogenic building block. Indeed, as initially discovered by us3 and followed by others26, phenylalanine possesses the ability to self-assemble and form supramolecular nano-fibrils, which exhibit typical ultrastructural, biophysical and biochemical properties. Moreover, we have shown these phenylalanine assemblies to confer a cytotoxic effect via an apoptotic cell death mechanism, which could be rescued using specific antibodies raised against these fibrillar species. The presence of anti-phenylalanine fibrils antibodies in a PKU mouse model, as well as the presence of these fibrils in post-mortem brain samples of individuals affected with the disease, potentially suggest a role for the phenylalanine assemblies in the etiology of PKU3. To study whether these observations represent a general amyloid-like mechanism prevalent in other IEM disorders, we tested additional metabolites that accumulate in IEM disorders. We revealed that several other metabolites could self-assemble to form ordered amyloid-like ultrastructures in solution with an array of characteristics that resemble canonical proteinaceous amyloids. We established a new terminology, designated metabolite amyloid, describing the formation of amyloid-like assemblies by metabolites, which implies a general phenomenon of amyloid formation, not limited to proteins and peptides31. Interestingly, specific IEM disorders present a neuropathology and a series of neurological symptoms similar to those observed in neurodegenerative disorders33, in which the formation of amyloids and their pathological role are well established. These symptoms might therefore be triggered by the presence of metabolite amyloid assemblies. On top of the excess amount of a certain metabolite in a specific pathology, this example highlights the importance of thoroughly investigating the functionality of metabolites by taking into account their chemical composition, which dictates possible intrinsic properties, as well as their appearance in other known diseases.One example that reflects the metabolite medicine concept is the discovery of the mechanistic role of phenylalanine amyloid assemblies in phenylketonuria (PKU) pathology34. However, as presented here, we view metaboloinformatics as a much broader approach. Establishing a database of metabolites linked to their related pathologies as well as their possible known functions as druggable small molecules might aid to provide a significantly more comprehensive tool . Similarly, the field of metabolomics is on the verge of shifting from the collection of enormous amounts of data regarding the levels of metabolites under various conditions to deciphering the function of each metabolite in a given experimental system. Nevertheless, while the genomic information is predetermined, the amount of the metabolic data is practically infinite and thus requires advanced and creative metaboloinformatics analysis. By combining experimental and bioinformatical tools, the metabolite medicine model described here suggests a methodological framework for advancing such studies, thereby allowing to gain further insights into the unexplored roles of metabolites.


Traditional Chinese medicine (TCM) injection is the combination of modern pharmaceutical technology and traditional Chinese prescription, which was born in 1941 and played a great role in the backward medical conditions at that time. However, the debate over TCM injections has never stopped due to adverse drug reactions (ADRs). The regulation on TCM injections has been further strengthened since 2017, which has prompted many TCM injections to carry out re-evaluations on quality, safety, efficiency as well as pharmacoeconomics, which made significant changes and progress. This review presented an up-to-date analysis of the types, amounts, and ADRs of TCM injections based on the published data and literature. This review also summarized the potential reasons for the ADRs and re-evaluation strategies. This review will provide some useful clues for TCM injections and their clinical use. Traditional Chinese medicine (TCM) injection is defined as a sterile preparation  intended for injecting into the human body, which is extracted from traditional Chinese herbs . TCM injUnlike other TCM dosage forms that have evolved over thousands of years, TCM injection has been developed for about 80 years Table . Traces For a long time, the adverse drug reaction (ADR) reports caused by TCM injections have resulted in hot debates on TCM injections, and also raised safety concerns among people. In recent years, especially after 2017, the strengthening supervision of TCM injections has brought changes to TCM injections. This review aims to give a summary of the changes in TCM injections from the current situation, ADRs, and re-evaluation, hoping to provide the basis for re-evaluating TCM injections and their clinical use.Drug Lists of National Essential Medicine (version 2018) [Medicines List for National Basic Medical Insurance (version 2021), 47 TCM injection items with 44 unique serial numbers are contained and almost all of them are restricted to be used by second-class or above hospitals [Diagnosis and Treatment Protocol for COVID-19, four kinds of TCM injections have been recommended to treat pneumonia in China for the first time, and up to eight kinds in the latest 9th version to treat severe or critically ill patients [TCM injections are special preparations with the approval number “Z”, which means that their raw materials are Chinese herbs. On the other hand, those with the approval number “H” belong to the category of chemical drugs. Up to July 6, 2022, the data from the National Medical Products Administration (NMPA) showed that China had approved 128 TCM injections, involving 872 approval numbers and 196 manufacturing enterprises [on 2018) . In the ospitals . TCM injpatients .Fig. 1NuTCM is rooted in the clinical practice experience for thousands of years. It is usually taken through oral administration, thus some unwanted harmful substances can be eliminated by the physiological barriers and the liver first-pass effect. However, the parenteral injection of herb extractions will bypass these barriers and enter the human body directly, which although takes effect rapidly but greatly increases the risk of side effects . With thFigure Different from chemical injections with well-defined ingredients, TCM injections are made from herbal extracts with complex compositions, which are very difficult to carry out research with total active components. Moreover, due to the low-level scientific research in the early period, most TCM injections only did ambiguous research on their active ingredients and harmful impurities. Thus, the safety and effectiveness of TCM injections can’t be guaranteed .The pharmacokinetic study is an important method to reveal the effect and the in vivo process of active ingredients. The pharmacokinetic studies of TCM injections mainly involve the interaction within the components and the interaction studies in combination with chemical drugs. Considering the complex composition of most TCM injections and their unknown pharmacodynamic material basis, the pharmacokinetic research of TCM injections is much more difficult than that of chemical drugs. At present, the pharmacokinetic studies of TCM injections are not insufficient, especially in the human body, which leads to uncontrollable risks in clinical use .Fritillaria growing in Zhejiang has different therapeutic outcomes from those growing in Sichuan, although they belong to the same genus [The occurrence of ADR is mainly related to the lack of rigorous management of raw materials. TCMs are extracted from herbs, which are influenced by environmental factors, origin, agriculture, collecting, harvesting, and primary processing of raw materials . The difme genus . Besidesme genus .The quality control system plays a pivotal role in drug quality. The preparation processes of TCM injections determine the safety and effectiveness of the products. Compared with chemical injections, the preparation processes of TCM injections are more complicated, including extraction, filtration, precipitation, purification, sterilization, etc., which greatly increases the difficulties of quality control . FurtherBesides the manufacturing and quality problems of TCM injections, another issue is the irrational use of TCM injections in clinical practice. Firstly, improper use may attribute to non-standard drug instructions. As the important basis for rational drug use, the drug instruction approved by the drug administration department should contain detailed information such as drug ingredients, clinical usage and precautions . HoweverOpinions on Deepening the Reform of the Review and Approval System and Encouraging the Innovation of Drugs and Medical Devices released in 2017, for the purpose of evaluating both chemical and TCM injections in safety, efficacy, and quality controllability, enterprises must conduct the comprehensive research at approval, and the post-marketing researches, including the active ingredients, mechanism of action, and clinical efficacy [The early approval threshold for TCM injections was low, and most TCM injections had no thorough research on safety and efficacy . In receRecently the re-evaluation of TCM injections has achieved certain positive results. For example, the ADR proportion caused by TCM injections has decreased continually since the rigorous requirements for the injections in approval and re-valuation were proposed in 2017  and meta-analysis were published every year –41. DanhAs one of the dosage forms with the highest quality requirements, TCM injection is required higher standards of consistency and controllability than other traditional Chinese medicine products. As the important raw materials for TCM injection production, the quality of medicinal plant raw materials should be controlled first.Quality Management Standards of Chinese Herbal Medicine was released to control the quality of herb medicine by using Good Agricultural Practice (GAP) [In 2002, the first ce (GAP) . GAP is ce (GAP) . But thice (GAP) . CompareMost enterprises still adopt outdated methods and low-standard quality control. To ensure high-standard and controllable production processes, enterprises should speed up their transformation to more advanced and scientific production processes. In 2016, the NMPA clarified the requirements for enterprises to achieve drug traceability . The quaNational Basic Medical Insurance should be investigated to compare with other alternative dosage forms. On the other hand, the cost of ADR treatment from TCM injections should be monitored too.The purpose of the pharmacoeconomic evaluation is to rationally select and use drugs to achieve efficient, safe, and economical use of limited medical and health resources to get the optimal treatment effect and the minimal economic burden. TCM injections occupy a huge share of the TCM market compared with other dosage forms of TCMs, accounting for one-third of the total TCM sales in hospitals . while tCurrent paper summarized and discussed the brief history, current situation, ADRs, and re-evaluation and progress of TCM injections. Due to the limited research on TCM injections at the early stage, there was insufficient evidence in nearly all aspects of clinical efficiency, safety, quality control, manufacturing process, and pharmacoeconomics to support the clinical usage of most TCM injections. TCM injections are currently at a critical moment to do the post-marketing evaluation. Although the qualities of some TCM injections have been improved in recent years, re-evaluation of TCM injections needs to be further promoted to obtain more acceptance and recognition. For instance, the quality management of raw herbs should be strengthened; convincible studies of material basis and pharmacokinetics should be finished; the modernization of preparation processes should be accelerated; the necessity for using TCM injections should be assessed through pharmacoeconomic evaluation. In general, the post-market evaluation has played a positive role in the quality control of TCM injections. Under the increasingly strict requirement of the government and market, the quality control and clinic use of TCM injections will be more standardized.


The term inflammatory arthritis defines a family of diseases, including rheumatoid arthritis (RA), caused by an overactive immune system, and influenced by host aspects including sex, reproductive state, and stress. Prolactin (PRL) is a sexually dimorphic, reproductive, stress-related hormone long-linked to RA under the general assumption that it aggravates the disease. However, this conclusion remains controversial since PRL has both negative and positive outcomes in RA that may depend on the hormone circulating levels, synthesis by joint tissues, and complex interactions at the inflammatory milieu. The inflamed joint is rich in matrix metalloproteases that cleave PRL to vasoinhibin, a PRL fragment with proinflammatory effects and the ability to inhibit the hyperpermeability and growth of blood vessels. This review addresses this field with the idea that explanatory mechanisms lie within the PRL/vasoinhibin axis, an integrative framework influencing not only the levels of systemic and local PRL, but also the proteolytic conversion of PRL to vasoinhibin, as vasoinhibin itself has dual actions on joint inflammation. In this review, we discuss recent findings from mouse models suggesting the upregulation of endogenous vasoinhibin by the pro-inflammatory environment and showing dichotomous actions and signaling mechanisms of PRL and vasoinhibin on joint inflammation that are cell-specific and context-dependent. We hypothesize that these opposing actions work together to balance the inflammatory response and provide new insights for understanding the pathophysiology of RA and the development of new treatments. Inflammatory arthritis is a collective name for a group of acute and chronic diseases driven by an overactive immune system that causes painful inflammation and stiffness of one or more articular joints. These diseases, broadly classified as non-autoimmune (sepsis arthritis and gout) and autoimmune  are progressively debilitating if untreated. Rheumatoid arthritis (RA) is the most common chronic inflammatory arthritis affecting around 1% of the global population with a female to male ratio 3 to 1  to disease progression . HoweverThe fact that RA is more frequent in women and disparity is greater at younger ages  encouragOpposite effects of PRL on the immune response have been known for more than three decades and are essentially associated to PRL concentration , with loThe PRL/vasoinhibin axis is a newly described endocrine axis where the proteolytic cleavage of PRL to vasoinhibin is regulated at the hypothalamus, the pituitary, and the target tissue levels . DisruptThe influence of the PRL/vasoinhibin axis in arthritis is suggested by the presence of PRL in the synovial fluid and of PRL, vasoinhibin, and PRL-cleaving MMPs in joint tissues including chondrocytes, vascular endothelial cells, synoviocytes, fibroblasts, and immune cells  and antigen-induced arthritis (AIA) are models of inflammatory arthritis, including RA, where disease is mediated by antigen-specific immune responses by T and B lymphocytes . The AA Prlr-/-) exhibited a more severe AA  reduced pannus vasopermeability and angiogenesis, joint inflammation, and bone loss in mice under severe AIA  by a direct action on synovial fibroblasts  activation required for pannus vasopermeability and angiogenesis  function as anti-inflammatory mediators and classical anti-inflammatory factors  exhibit proinflammatory effects depending on cytokine concentration, the stage of the disease, and the combination with other cytokines , 55. Majre stage . We hypovia the PRL conversion to antiangiogenic vasoinhibin  on RA is reinforced by experimental studies showing that sustained PRL administration or genetic deletion of the PRL receptor ameliorates or worsens the severity of inflammatory arthritis, respectively. PRL signals on arthritic joint tissues  to inhibit cartilage degradation, synovial inflammation, and osteoclastogenesis. Hyperprolactinemia promotes the conversion of PRL to vasoinhibin, a PRL fragment that directly stimulates and indirectly inhibits (via an antiangiogenic mechanism) joint inflammation in a context- and cell type-dependent manner. Understanding the mechanisms governing the regulation and action of the PRL/vasoinhibin axis in inflammatory arthritis should help clarify the role of PRL in RA to ultimately develop novel therapeutic interventions that can be tested in patients.CC wrote the manuscript. GO, JG-R, ML-C, FM-D, NA, and GME edited, and revised the manuscript. All authors contributed to the article and approved the submitted version.This work was supported by grants from UNAM DGAPA-PAPIIT IN202321 and L’Oréal-UNESCO-AMC-CONALMEX to CC.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Enzyme replacement therapy (ERT) has paved the way for treating the somatic symptoms of lysosomal storage diseases (LSDs), but the inability of intravenously administered enzymes to cross the blood–brain barrier (BBB) has left the central nervous system (CNS)-related symptoms of LSDs largely impervious to the therapeutic benefits of ERT, although ERT via intrathecal and intracerebroventricular routes can be used for some neuronopathic LSDs . However, the considerable practical issues involved make these routes unsuitable for long-term treatment. Efforts have been made to modify enzymes  so that they can cross the BBB via receptor-mediated transcytosis (RMT) and address neuronopathy in the CNS. This review summarizes the various scientific and technological challenges of applying RMT to the development of safe and effective enzyme therapeutics for neuronopathic mucopolysaccharidoses; it then discusses the translational and methodological issues surrounding preclinical and clinical evaluation to establish RMT-applied ERT. Delivery of therapeutics to the brain has always been hampered by the blood–brain barrier (BBB), which protects the brain from external macromolecules, such as pathogenic and toxic substances . Indeed,In contrast to the traditional view of the BBB as being made up primarily of restrictive endothelial tight junctions that sequester the systemic/peripheral blood flow and the brain, recent advances in BBB research have revealed that the BBB works more as a dynamic neurovascular unit that regulates the transport of substances . TranscyLysosomal storage diseases (LSDs) are a group of some 70 genetic metabolic disorders in which enzyme deficiencies in lysosomes cause systemic pathological accumulation of uncatabolyzed substrates, resulting in multisystemic progressive damage that manifests in a broad spectrum of debilitating symptoms, including coarse facies, hepatosplenomegaly, upper airway obstruction, cardiac dysfunction, and neurocognitive impairments , some ofFor intra-CSF administration of therapeutic enzymes, the ICV route has proved viable, as exemplified by cerliponase alfa for the treatment of neuronal ceroid lipofuscinosis type 2 ,20 and iConsequently, an enzyme therapeutic designed to address both the peripheral/somatic and CNS manifestations will be the most suitable means of overcoming these difficulties and providing an improved form of ERT for neuronopathic LSDs. Several attempts have been made to realize these objectives by equipping enzyme therapeutics with the capacity to undergo RMT. This review summarizes the hitherto known applications of RMT for drug delivery to treat neuronopathic MPSs, in particular, illustrates the pitfalls and challenges of engineering enzyme therapeutics to harness effective RMT, highlights translational issues in establishing RMT-applied ERT by preclinical and clinical evaluations, and, finally, delineates the remaining issues surrounding drug delivery to the brain in general.Transcytosis is a mechanism of transcellular transport of molecules via vesicles ,24 and cThe main receptors studied for RMT so far are insulin ,32,33 anSuccessful application of RMT for ERT can be realized, first, when attachment of the enzyme to the ‘Trojan horse’  is achieved through high-standard genetic engineering , and, seIn order to design and generate ideal antibodies for specific RMT, several serious limitations that have long compromised biotherapeutic engineering need to be overcome; these include poor pharmacokinetic parameters, non-optimal distribution, inhibition of their binding with Fc receptors, toxicity , and untGoulatis  pointed Most of the enzymes that are deficient in LSDs incorporate modified mannose-6-phosphatase (M6P) and undergo hepatic and other clearance dependent on M6P receptors (M6PRs), which accounts for their limited plasma retention time. This negatively affects their binding to the TfRs on cerebrovascular endothelial cells. In order to ensure sufficient binding to the TfRs, enzyme therapeutics need to have binding affinity higher than is generally seen in biologics with good plasma retention. However, when enzymes are released from endothelial cells into the brain parenchyma, high binding affinity invariably leads to reduced dissociation of the enzymes from the TfRs, thereby diminishing the number of molecules that reach the brain. Taken together, it seems sensible to strike a balance between the binding efficiency of enzyme therapeutics to the apical side of endothelial cells and their efficient dissociation on the vasolateral side at the same time to achieve the most suitable avidity for drug delivery across the BBB. Furthermore, accumulated clinical data from mid- to long-term ERT are needed to determine the optimal dosage and actual clinical efficacy of the therapeutics for neuronopathic LSDs, because such matters cannot be resolved by preclinical and theoretical discussions alone.After appropriate bioengineering methods for creating a biotherapeutic for RMT-applied ERT are duly established, sufficient quantities have to be manufactured for the drug to be tested in preclinical and clinical studies. This invariably involves timely scaling-up of drug production, with an eye to further augmentation to supply a wider patient population after the drug is approved. Unlike the preclinical and clinical studies of the therapeutic, the ingenious and painstaking efforts devoted to the bioengineering and manufacturing of the drug usually remain unpublished, because these endeavors involve essential information pertaining to intellectual property. Thus, discussion of these critical processes is inevitably restricted to mere general descriptions of the major issues without any quantitative or qualitative details. It would actually be very helpful if detailed descriptions of the caveats and other issues were published to avoid unnecessary repetition of mistakes, underestimation of critical points, and unguided guesswork in this unchartered field. Numerous factors are known to affect the transcytosis mechanism , with ph®). It received regulatory approval in Japan in 2021, spearheading other RMT-applied enzyme therapeutics in development worldwide.A PubMed literature search using enzyme replacement therapy and transcytosis as keywords produced only 10 hits for the past 10 years up to April 2022. Given this limited number of references, this section looks mainly at the preclinical and clinical studies of pabinafusp alfa (JR-141), a recently developed drug for RMT-applied ERT. Pabinafusp alfa is a genetically engineered fusion protein developed by JCR Pharmaceuticals for intravenous ERT for neuronopathic MPS II. It consists of an anti-human TfR (hTfR) antibody and human iduronate-2-sulfatase (IDS) fused to the C terminus of the immunoglobulin G (IgG) heavy chain. Robust preclinical ,59,60,61Preclinical proof of concept of pabinafusp alfa in terms of its dual efficacy was examined stepwise . First, Measurement of intracerebral GAG accumulations is the most direct indicator of enzyme activity in the brain, but because such measurement is inimical to clinical drug evaluation in patients, a surrogate efficacy endpoint had to be sought instead that could be used in both the preclinical and clinical investigations . GAG conTo further validate the efficacy of pabinafusp alfa against neurodegeneration, Morimoto et al.  demonstrArguello et al.  have alsThese preclinical evaluations have revealed a number of challenges that may be informative for similar future endeavors to establish RMT-applied ERT for neuronopathic LSDs at large. First, in contrast to the ostensibly straightforward pathophysiology common in LSDs , the exact neuropathogenesis is complex and remains to be elucidated . MoreoveKey pathognomonic signs and symptoms to be selected and focused on;Clinical efficacy endpoints that correlate well with these signs and symptoms and are considered most likely to respond to treatment;Surrogate endpoints that can represent and correlate with these clinical endpoints, and that are also measurable in animal models of the disease;Quantitative and qualitative methods to evaluate these endpoints: these methods also need to be conducive to both preclinical and clinical studies.Antibody-based drugs generally have high target specificity , as seenA four-week repeat-dose toxicity study of pabinafusp alfa at dosages of up to 30 mg/kg/week was conducted in sexually mature and juvenile monkeys, along with a 26-week repeat-dose study in 2- to 4-year-old monkeys . CDC , α-L-iduronidase fused with anti-insulin receptor antibody, found drug-related transient hypoglycemia in 6.4% of the patients with MPS I . HoweverIn contrast, preclinical studies of pabinafusp alfa show no interference with the binding of transferrin to its receptors . We consOverall, the likelihood of potential interactions between the antibody in the RMT-applied therapeutic and the targeted receptor seems to differ from one therapeutic to another, and is, perhaps, not dependent on the kind of receptor that mediates transcytosis. Furthermore, preclinically identified interactions may not directly translate into relevant or clinically significant adverse events, while preclinically undetected interactions may very well lead to receptor-associated adverse events. Translating preclinical toxicological findings into clinically meaningful safety endpoints is never easy, but given the debilitating nature of progressive neurodegeneration in neuronopathic LSDs, for which no ERT is available, the potential risks of these events are almost certainly outweighed by the clinical benefits of RMT-applied ERT, provided that adverse events related to RMT, if any, are clinically manageable and do not offset the overall benefits of the treatment.As detailed in The antibodies utilized for enzyme therapeutics in RMT-applied ERT are designed to bind to the innate human receptors on the cerebrovascular endothelial cells. However, preclinical efficacy and safety evaluations of the therapeutics have to be conducted in animal models . Although inter-species differences in the amino acid sequence of the TfR may be relatively small, subtle differences in the epitope of the TfR can have a significant influence on the antibody affinity of the biotherapeutic. Therefore, hTfR-knockin/Ids-knockout mice were required, as they enable comparable and extrapolatable efficacy evaluation. However, as genetic induction in rats and monkeys is prohibitively difficult, the extrapolability of the preclinical data on these animals depends on the extent to which the antibody affinity of the biotherapeutics to their respective TfRs is reasonably comparable to that in humans. This general issue of scientific appropriateness and regulatory acceptability of extrapolated preclinical data is of particular importance for RMT-applied ERT in terms of pharmacokinetics and pharmacodynamics, as detailed below.Higher brain functions  and their disorders are notoriously difficult to evaluate in animal experiments and, even if it is possible, further difficulties arise in extrapolating the preclinical data to humans, hence the low clinical success rate for drugs that show tremendous promise in animal experiments intended to model psychiatric pathophysiology ,75. As iIn our preclinical studies with mouse disease models, we have often observed markedly aggressive behavior  in caged animals (unpublished). Such behavioral findings may be of translational importance, because they may correspond to neurocognitive impairments and associated behavioral features that have been well documented in MPS II patients. Indeed, throughout our clinical trials in Japan and Brazil, many patients exhibited anxiety, excitability, and hyperactivity that often rendered even sitting at a table for meals difficult and family outings impossible. As the trials continued, narrative reports from physicians, caregivers, and family members described markedly improved mood, emotional stability, comprehension, and responsiveness in the patients, some of whom then even managed to stay calm during mealtimes in and outside their homes ,64,65,76In intrathecal and intracerebroventricular administration of enzyme therapeutics for delivery to the brain, the CSF in the subarachnoid space and the ventricles assumes an essential pharmacokinetic role as a medium for drug administration, distribution, and elimination. In allowing the substrate concentrations therein to serve as a critical surrogate efficacy endpoint, as described above, the CSF is also of pharmacodynamic importance. However, RMT-applied ERT differs from ERT via intra-CSF drug administration in terms of the role of the CSF. In the former, the drug is distributed through the systemic blood circulation; RMT then occurs, followed by drug diffusion towards the brain parenchyma. In this process, the CSF works more or less as a reservoir into which a very limited portion of the drug is excreted after being consumed, making the intra-CSF drug concentrations negligibly small. In contrast, drug concentrations in the CSF are naturally very high after intra-CSF drug administration, although smaller quantities of the drugs actually reach the brain parenchyma than in RMT-applied ERT. This is because drugs administered via the CSF must be distributed in retrograde  diffusion against the normal CSF flow to reach the brain parenchyma, so drug penetration from the CSF can be minimal ,78. ThusThe general challenges for clinical trials involving rare diseases include paucity of patients available for trials, limited enrollment capacity/efficiency at investigational sites, limited numbers of investigators/specialists globally, and operational hurdles to conducting multinational multi-site trials. It follows that the oft-employed strategy of increasing the number of participating sites to compensate for the limited number of patients at each one is not as helpful when it comes to clinical trials involving rare diseases as it is in other therapeutic areas. Neuronopathic LSDs present further problems related mostly to their complex and progressive pathology, which renders efficacy evaluation and subsequent determination of therapeutic effects difficult and time-consuming. One counterintuitive challenge is that even though neuronopathic LSDs are rare, they exhibit enormous phenotypic heterogeneity, which partly accounts for their frequently delayed diagnosis and treatment initiation. These factors only further complicate the constraints involved in designing and conducting clinical trials, making the gold standard of clinical trials—a sufficiently powered comparative randomized controlled trial—enormously challenging to conduct in a timely and operationally realistic fashion. Furthermore, when there is no established standard treatment at all for the disease, an untreated comparator arm is not ethically acceptable. In such cases, one sensible option for making informative efficacy comparisons is to compare the treatment group with what is known as a historical control, which means using clinical data on previous patients with the same disease. It is necessary to ensure, of course, that both datasets are collected using the same, or at least comparable, assessment methods to allow meaningful efficacy analysis .Treatment for neuronopathic LSDs must address both the peripheral/somatic and CNS manifestations, so both of these efficacy endpoints need to be captured quantitatively and qualitatively.Peripheral efficacy endpoints focus on major somatic signs and symptoms , while central efficacy evaluation needs to examine some major aspects of the neuronopathy that affect the manifold functions and structures of the CNS. The trials described above (completed or ongoing) have commonly examined substrate levels in the CSF, along with various neuropsychological functions via such established test batteries as the Bayley Scales of Infant and Toddler Development, the Kaufman Assessment Battery for Children, and the Vineland Adaptive Behavior Scales ,64,65. NOne fundamental difficulty inherent in neurodevelopmental assessment is that while normal development always takes years, in patients with neuronopathic LSDs, it can proceed without marked disturbance from birth, reach a plateau in early childhood, and then deteriorate afterwards, albeit with marked variability . TherefoFor RMT-applied ERT, two groups of safety endpoints require particular attention: adverse events related to the infusion of biotherapeutics  , and advThe potential adverse events related to the specific receptors utilized for RMT-applied ERT are discussed in diagnosis ex juvantibus (attempting to diagnose a disease by treating it) [Regulatory approval of RMT-applied ERT for neuronopathic LSDs on the basis of relatively limited efficacy data is necessary to meet the urgent medical needs of affected patients, but this means that long-term efficacy data are of particular importance to consolidate the effects of the drug on the CNS and ensure that the regulatory conditions for its approval are fully met. Furthermore, because neuronopathic LSDs are rare yet heterogenous as a nosological entity, much about them remains to be elucidated. It is very likely, therefore, that clinical data and observations from both pre- and post-approval studies will shed new light on the pathogenesis, clinical course, and prognosis of the disease by, for instance, differentiating patients with the same diagnosis according to their treatment response, thereby revealing hitherto unknown characteristics of the disease. Information thus obtained will facilitate accurate and timely diagnosis of the disease, which will, in turn, enable early initiation of the most appropriate treatment. The intertwined yet reciprocal relationship between diagnosis and treatment seen in LSDs, whereby a novel treatment helps refine diagnosis and vice versa, is reminiscent of the ancient clinical approach known as ting it) .This review summarizes some of the trailblazing efforts made to apply RMT to ERT for the treatment of neuronopathic MPSs. After more than 25 years and umpteen attempts to develop biotherapeutics for brain diseases, the possibility of using transcytotic mechanisms to reengineer biologics has been greeted with great excitement . HoweverNevertheless, the efficacy of RMT-applied ERT against CNS symptoms requires long-term evaluation. Furthermore, in addition to its inability to treat neuronopathy, conventional ERT suffers from other notable limitations, such as lack of effect on the cardiac valves, trachea and bronchi, ears, and eyes, due to its limited ability to penetrate these tissues . Notably


The Brazilian continental margin (BCM) extends from the Tropical to the Subtropical Atlantic Ocean, with much of its seafloor within deep waters, supporting rich geomorphological features and under wide productivity gradients. Deep-sea biogeographic boundaries on the BCM have been limited to studies that used water mass and salinity properties of deep-water masses, partly as a result of historical under sampling and a lack of consolidation of available biological and ecological datasets. The aim of this study was to consolidate benthic assemblage datasets and test current oceanographic biogeographical deep-sea boundaries  using available faunal distributions. We retrieved over 4,000 benthic data records from open-access databases and used cluster analysis to examine assemblage distributions against the deep-sea biogeographical classification scheme from Watling et al. (2013). Starting from the assumption that vertical and horizontal distribution patterns can vary regionally, we test other schemes incorporating latitudinal and water masses stratification within the Brazilian margin. As expected, the classification scheme based on benthic biodiversity is in overall agreement with the general boundaries proposed by Watling et al. (2013). However, our analysis allowed much refinement in the former boundaries, and here we propose the use of two biogeographic realms, two provinces and seven bathyal ecoregions , and three abyssal provinces  along the BCM. The main driver for these units seems to be latitudinal gradients as well as water mass characteristics such as temperature. Our study provides a significant improvement of benthic biogeographic ranges along the Brazilian continental margin allowing a more detailed recognition of its biodiversity and ecological value, and also supports the needed spatial management for industrial activities occurring in its deep waters. The deep ocean is the largest ecosystem on Earth, comprising approximately 70% of the global sea-floor area and hence more than half of the planet’s surface . This en2, ranking 11th in terms of size worldwide  extends along the Tropical and Subtropical Atlantic Ocean , and belorldwide . It contorldwide . Much oforldwide .There has been a limited assessment of deep-sea biogeographic ranges along the BCM, which prevents a detailed recognition of its ecological value, its conservation status and threats. For one part, these assessments have lagged ones made over terrestrial ecosystems and coastal waters due to a much-limited sampling , and forWith evidence that deep-sea species were commonly associated to deep water masses, the early analyses of zoogeographical distributions carried out in deep waters focused mainly on abyssal  and hadaCurrent knowledge suggests that along deep-sea margins geographical boundaries are commonly structured by water masses, temperature and productivity, which are then used to classify species ranges to potential habitat distributions and extension. One of the most relevant biogeographical classifications works is the Marine Ecoregions of the World (MEOW) by The limited sampling and integration of deep-sea faunal datasets in the South Atlantic has limited the delineation of its biogeographic realms by oceanographic and water mass parameters. As such, although it is likely that large deep-water provinces in the South Atlantic may be well defined by these parameters, the biological ecoregions or small biogeographical units within these provinces are not defined to date. The delimitation of regional biogeographic areas in the deep South Atlantic could improve species distribution modeling and aid the detection of changes in long-term environmental conditions, as well as the threats to which these assemblages may be exposed due to climate change and anthropogenic activities. These steps are critical for an improved management of Brazil’s deep-sea biodiversity and the definition of ecologically or biologically significant areas (EBSAs). Therefore, our purpose in this study was not only to present the biogeographic patterns of the deep benthic fauna along the BCM, but also, to test two existing biogeographical schemes  for the 2, which extends through the tropical and subtropical Southwestern Atlantic Ocean. It contains an extensive deep-sea territory with a wide variety of seafloor features distributed along latitudinal and productivity gradients. One of the largest and most notorious geomorphological features is the Vitoria-Trindade Ridge , a seamount chain adjacent to the BCM that naturally delimits the tropical and subtropical portions of the BCM and the contiguous abyssal plains 2, which The vertical distribution of water masses in the Southwestern Atlantic Ocean exhibits variations along the South American continental border. There are six primary water masses composing the water column in the Southwestern Atlantic, and five of them correspond to deep waters: South Atlantic Central Water (SACW), Antarctic Intermediate Water (AAIW), Upper Circumpolar Water (UCPW), North Atlantic Deep Water (NADW), and the Antarctic Bottom Water (AABW)  Fig. 2)Fig. 2). These water masses are transported by three principal western boundary current systems. The subtropical Brazil Current (BC) and the tropical North Brazil Current (NBC) correspond to main upper-ocean current systems occurring along the BCM. As the upper-ocean contains the mixed layer, the seasonal pycnocline, and the permanent pycnocline, these currents are responsible for transporting surface (TW), central (SACW), and intermediate (AAIW and UCPW) water masses . Below tExisting and openly published databases of deep-sea benthos were obtained in order to synthesize the deep-sea benthic diversity from the Brazilian EEZ. These databases are available online in OBIS (Ocean Biodiversity Information System) and from some relevant natural marine history museums and studies carried out in Brazilian deep basins. The final database was curated and standardized in order to avoid discrepancies and errors. Records outside the EEZ were removed from the database, as well as those that were not identified to species level. The taxonomic status of all records was revised and updated following the World Register of Marine Species site .Species occurrence mapping was carried out in ArcGIS 10.5 software , creatinWith the database in hand, we tested three schemes of biogeographic realms for the Brazilian deep-sea EEZ. In the first one, the definition and delimitation of the deep-sea provinces for the BCM was based on the deep-sea biogeography proposed by Considering that our area of interest is the Brazilian EEZ, and that the In a third biogeographic scheme, we tested the distribution of the deep-sea benthic fauna along depth by comparing the limits of the deep-water masses present on the deep Brazilian margin. In this case, we divided the bathyal zone of the BCM into three regions  based on the currents and water masses distribution and their latitudinal range. The Deep-sea benthic occurrence records were assigned to the biogeographical units they were within and were plotted over the biogeographical units for each scheme using ArcGIS 10.5 software . The bioWe used the Simpson’ dissimilarity index to construct dissimilarity matrices based on the occurrence data for each biogeographic scheme . Simpsoni.e., many spatial units may have identical values of Simpson dissimilarity index, particularly when equal zero, which denotes that there is no species replacement between two areas)  . This geo areas) . Followio areas) . Next, tTo give each species the opportunity to be included in the bootstrap matrices, and strengthen the support for nodes , we perfWe obtained 14 datasets from the OBIS database in addition to records from the Smithsonian National Museum of Natural History (NMNH) and Universidade Federal do Espírito Santo (UFES). After data curation and standardization, we obtained a total of 4,167 benthic Metazoan occurrence records within the deep Brazilian EEZ . MappingEnallopsammia rostrata, Lophelia pertusa (=Desmophyllum pertusum), Madrepora oculata, and Solenosmilia variabilis in bathyal depths of both subtropical and tropical regions. The polychaeta genera Kinbergonuphis was among the most reported in the Subtropical region, as well as the sponge genera Aplysina and the ophiuroid Ophiomisidium tommasii.We retrieved a total of 1,022 species grouped into 10 phyla, with Mollusca and Annelida showing the highest species richness with 326 and 191 species respectively. However, Cnidaria has the highest number of records  belonging to 142 species . The troAcanella, Deltocyathus, and Trochocyathus (in addition to the four CWCs mentioned above), and mollusks of the genera Acteon, Benthonella, and Brookula appear as shared species between the upper and lower bathyal provinces. In the North region, UBNA and LBNA appear as individual biogeographical units, with only Lophelia pertusa (=Desmophyllum pertusum) as a shared species. The Abyssal provinces appear also as individual units with no resemblance to any other province or to each other , Madrepora oculata, and Solenosmilia variabilis), some echinoderms such as Amphiura flexuosa, Ophiacantha cosmica, Ophiomastus satelitae, and the genus Ophiomisidium, and also, polychaetes such as Micronereides capensis, Kinbergonuphis sp., Magelona sp., and Nothria sp. On the other hand, the Northeastern ecoregion (UB_Northeastern) appears clustered with the South Atlantic Lower Bathyal province , Madrepora oculata, and Solenosmilia variabilis. The North Atlantic Lower Bathyal and the abyssal provinces of To test this scheme, benthic records were clustered according to the MEOW ecoregions  for the upper bathyal depth, and according to province , sharingActeon, Benthonella, Drilliola, Odostomia, and Omalogyra , and Solenosmilia variabilis, followed by other cnidarians such as Deltocyathus eccentricus, Cirrhipathes sp., and Flabellum sp., and also by sponges of the genera Aplysina sp. and Cinachyrella sp. The NADW_E seems to be related with the last cluster, however, exhibiting a weak bootstrap node support. In the South region, the North Atlantic Deep Water (NADW_S) and the South Atlantic Central Water (SACW_S) form a distinct biogeographic group which in turn is related to the Antarctic Intermediate Water (AAIW_S) , suggesting that abyssal realms have a distinct faunal composition from bathyal depths and across latitudinal gradients on the BCM  . In this the BCM .Here we tested the current biogeographic schemes for the deep-sea Brazilian margin and proposed new regional divisions based on benthic assemblages from bathyal and abyssal realms. We found that assemblage datasets improved the spatial delineation of previously proposed provinces or biogeographical realms, and generally support the delimitation of deep-sea boundaries based on physical-chemical characteristics of the water masses. Therefore, our hybrid scheme as well as water masses not only shows that the composition of bathyal benthic fauna actually differs between the Northern and Southern of the BCM, but also that there is a new and previously unrecognized biogeographic unit on the transition between the tropical and subtropical realms with a distinct set of species, the “Eastern”.In general, the distribution of deep-sea bottom fauna follows the dynamics of water masses, productivity at the surface of the ocean, and climatic zonation . However−2 yr−1 and 5.24 ml l−1, respectively  and the North (Amazonia and Northeastern) provinces are contrasting with the shallow-water MEOW boundaries, in better accordance with the limits of the Atlantic provinces proposed by A significant part of the Brazilian EEZ corresponds to the lower bathyal, characterized by a narrow continental slope and rapid changes in bathymetry, making it difficult to define the precise limits between upper bathyal biogeographical units. The third scheme allowed us to test the assumption of a vertical species distribution linked to depth limits in deep-sea, where the SACW of North and East regions exhibited a marked difference in benthic composition compared to the deeper water masses of each region . This caIn addition, the Eastern region can be considered a transition zone between the tropical and subtropical portions of the BCM, given the presence of the Vitória Trindade Ridge , and theIn the South, the UPCW water mass showed a clear separation of the other water masses in the region . Even thEguchipsammia cornucopia and Polycyathus senegalensis. Although the records of the abyssal fauna for the Brazilian margin are still scarce, especially for benthic fauna, our data supports the Atlantic abyssal provinces of Despite having few data on the abyssal provinces, they behaved as expected. Taxonomic isolation of deep-sea fauna in different regions has been shown to increase with depth . Both thEven though the Deep South Atlantic Ocean has seen an increment in sampling effort in recent decades due to an increased interest on economic resources , open biAlthough it is believed that each benthic taxonomic group may differ in its vertical and horizontal distribution patterns given its own features towards topographical barriers or environmental conditions, our attempt to compare the biogeographical results using all available benthic data for the BCM with the result using Cnidaria or Mollusca only, did not show significant differences. Furthermore, the species-level approach was expected to allow a better construction of our dendrograms, given the importance of endemic species to delimit regions, but agreeing with other biogeographical studies , our resAt greater depths, the differences between the physical characteristics of water masses are much lower, and food supply constitutes an important factor related to the distribution of benthic animals, especially macro and meiofauna . Our resOur biogeographic analyses support the bathyal South Atlantic deep-sea provinces proposed by In this study we updated existing biogeographic classifications for the deep South Atlantic along the Brazilian continental margin. Our study revealed new latitudinal limits along the bathyal depths of the BCM with a new and formerly unrecognized biogeographical unit on the transition between the tropical and subtropical realms. Our study supports that the broad-scale distribution of benthic fauna in the Brazilian deep sea has a strong relationship with water masses characteristics. Specifically, there is a strong division between the upper bathyal , lower bathyal  and abyssal  depths, which constitute three different environments, each one with their particular faunal composition, but sharing some species between them. In addition, in some areas of the BCM, benthic distribution patterns appear to be more related to horizontal than vertical boundaries. Some of these latitudinal boundaries remain directly related to changes in water column composition that may be influenced by changes in seafloor geomorphology. Furthermore, our work highlights the need for more species distribution studies in the deep-sea, for future comparisons between distribution patterns that allow adequate planning of conservation and protection areas for deep benthos.


The increasing proportion of the old aged population worldwide has been followed by the enhanced prevalence of Psychiatric Disorders (PD) in this age group , 2. NeurLate-onset bipolar disorder is more likely to be associated with structural brain changes, depressive symptoms, and cognitive deficits , 11. In Aguera-Ortiz et al. aims to address the heterogeneity of clinical practice in patients with dementia and depressive symptoms. The authors conducted a multicentre, two-round Delphi survey among experts with 53 questions ranging from risk factors, signs and symptoms, and management of depression in dementia. There was an excellent consensus regarding depression being a risk factor for the onset and progression of dementia and presenting as a prodromal symptom of dementia. The authors emphasized the importance of routine cognitive examination using clinical scales and collateral information in the elderly with depression. The panel was skeptical about using the term 'pseudodementia' consistent with other literature on this topic. The panel agreed that the presentation of depression might differ based on the stage of dementia and recommended using specific criteria for depression in dementia rather than commonly used criteria for major depression. Experts recommended a trial of antidepressants in depression with dementia but agreed that antidepressants are less effective than populations with major depressive disorder without cognitive disorder. The panel recommended medications such as duloxetine and venlafaxine while recommending against tricyclic antidepressants. This study has several limitations; first, it was done in one country (Spain) and thus may be biased toward specific clinical practices in that country. Secondly, it relied on expert opinion elicited using closed-ended questions. Nevertheless, this study highlights certain controversies on this topic and the need for more research.The study by Maia da Silva et al. reviewed the common and distinctive clinical, genetic, and neuroimaging features of Bipolar Disorder (BD) and Behavioral variant Frontotemporal Dementia (bvFTD). The paper highlights the remarkably overlapping phenomenological and biological changes shared by the disorders, which include an array of mood and cognitive abnormalities and prominent dysfunctions in frontotemporal circuitry. Also noteworthy, as described by the authors, is the occurrence of cases with typical bvFTD symptomatology that do not follow the expected pattern of functional decline. This condition, referred to as bvFTD Phenocopy Syndrome, could be associated with deteriorating end-stage presentations of BD. Most importantly, further investigation on this clinical entity may hint about a possible link between the pathophysiology of mood and neurodegenerative disorders.Other studies on this issue have explored the intricate connections between psychiatric and neurogenerative affections through different perspectives. Mendonca et al. After adjustment for multiple confounders, individuals with these diagnoses presented poorer performances in verbal memory and executive function tasks than controls. Interestingly, ADHD and MCI did not differ concerning cognitive profiles, suggesting that differential diagnosis between these conditions could be challenging in clinical practice. Mostly, it is intriguing to note that, despite long-term clinical and social outcomes related to ADHD  overlap with many established risk factors for late-life cognitive impairment [see Livingston et al.  and Mild Cognitive Impairment (MCI) have been cross-sectionally assessed by n et al. ], data oFrankenberg et al. investigated the correlates between semantic and episodic autobiographical memory (AM) and brain metabolic rates analyzed by positron emission tomography with 18F-fluorodeoxyglucose (FDG-PET) in MCI, mild AD, and controls. Decreased patterns of cerebral activity were detected in the frontal cortex, mesial temporal substructures, and occipital cortex in MCI and AD relatively to controls. In addition, higher values in the posterior cingulum and left temporal-prefrontal areas were found in MCI compared to AD and controls, suggesting compensatory over activation in early-stage neurodegenerative disorders. Finally, alterations in semantic and episodic AM in MCI and AD correlated with increased and diminished activities in the mesial temporal substructures. Therefore, it could be inferred that AM deficits may manifest both neurodegenerative and compensatory changes within the AD spectrum .Additional themes addressed in this issue concern neuropsychological aspects of Alzheimer's Disease (AD). Kotzé et al. assessed the end-of-life decision-making capacity (DMC) and the capacity to consent to treatment among older patients with serious mental illnesses (SMI), including schizophrenia and other psychotic disorders. Capacity to consent to treatment correlated with all domains of DCM. Using the semi-structured DMC evaluation, 65% of the participants were deemed capable, 31% were not capable, and 4% presented an uncertain degree of DMC. After controlling for age, level of education, and admission status, subjects with bipolar disorder or major depressive disorder were 4.61 times more likely to present DMC than those with psychotic disorders. Odds of having unimpaired DCM were 7.51 times higher among patients admitted voluntarily or assisted compared to involuntary cases. Finally, odds of showing preserved DCM were nearly 3-fold higher among participants with tertiary than in lower educational levels. These findings should increase awareness among healthcare providers about their duty to initiate advance care discussions, optimize decision-making capacity, and protect autonomous decision-making of older patients with SMI.Finally, Mendonca et al.), neuropsychological follow-up and a refined psychopathology exam . Thus, more research is needed to further understand the interplay between specific components of the aging process including neuroplasticity and changes in specific brain networks and compensatory mechanisms, and the trajectory of psychiatric illness including the role of personality traits and genetic endophenotypes, and their impact on the onset and outcome of cognitive disorders in the elderly (There is an emerging consensus in the field that the trajectory of PD affects the likelihood of developing dementia, and the use of advanced tools, including genetic tests, molecular and functional neuroimaging, are becoming more critical as tools in understanding the mechanisms underlying cognitive decline in this population. Despite the advances, most of the neurobiological underpinnings of PD still await further elucidation, and the diagnosis and treatment of PD and cognitive disorders at this time is primarily based on clinical history taking ( elderly , 18.FS and GA: literature review and writing of the manuscript. SK: literature review and compilation and writing of the manuscript. All authors contributed to the article and approved the submitted version.This work was supported in part by an Academic Scholars Award to SK from the Department of Psychiatry, University of Toronto. SK has also received research support from Brain and Behavior Foundation, National Institute on Aging, BrightFocus Foundation, Brain Canada, Canadian Institute of Health Research, Canadian Consortium on Neurodegeneration in Aging, Center for Aging and Brain Health Innovation, Center for Addiction and Mental Health, and equipment support from Soterix Medical.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.