Chemical exchange saturation transfer magnetic resonance imaging is an advanced imaging technique that enables the detection of compounds at low concentrations with high sensitivity and spatial resolution and has been...Chemical exchange saturation transfer magnetic resonance imaging is an advanced imaging technique that enables the detection of compounds at low concentrations with high sensitivity and spatial resolution and has been extensively studied for diagnosing malignancy and stroke.In recent years,the emerging exploration of chemical exchange saturation transfer magnetic resonance imaging for detecting pathological changes in neurodegenerative diseases has opened up new possibilities for early detection and repetitive scans without ionizing radiation.This review serves as an overview of chemical exchange saturation transfer magnetic resonance imaging with detailed information on contrast mechanisms and processing methods and summarizes recent developments in both clinical and preclinical studies of chemical exchange saturation transfer magnetic resonance imaging for Alzheimer’s disease,Parkinson’s disease,multiple sclerosis,and Huntington’s disease.A comprehensive literature search was conducted using databases such as PubMed and Google Scholar,focusing on peer-reviewed articles from the past 15 years relevant to clinical and preclinical applications.The findings suggest that chemical exchange saturation transfer magnetic resonance imaging has the potential to detect molecular changes and altered metabolism,which may aid in early diagnosis and assessment of the severity of neurodegenerative diseases.Although promising results have been observed in selected clinical and preclinical trials,further validations are needed to evaluate their clinical value.When combined with other imaging modalities and advanced analytical methods,chemical exchange saturation transfer magnetic resonance imaging shows potential as an in vivo biomarker,enhancing the understanding of neuropathological mechanisms in neurodegenerative diseases.展开更多
Neural tissue engineering,nanotechnology and neuroregeneration are diverse biomedical disciplines that have been working together in recent decades to solve the complex problems linked to central nervous system(CNS)re...Neural tissue engineering,nanotechnology and neuroregeneration are diverse biomedical disciplines that have been working together in recent decades to solve the complex problems linked to central nervous system(CNS)repair.It is known that the CNS demonstrates a very limited regenerative capacity because of a microenvironment that impedes effective regenerative processes,making development of CNS therapeutics challenging.Given the high prevalence of CNS conditions such as stroke that damage the brain and place a severe burden on afflicted individuals and on society,it is of utmost significance to explore the optimum methodologies for finding treatments that could be applied to humans for restoration of function to pre-injury levels.Extracellular vesicles(EVs),also known as exosomes,when derived from mesenchymal stem cells,are one of the most promising approaches that have been attempted thus far,as EVs deliver factors that stimulate recovery by acting at the nanoscale level on intercellular communication while avoiding the risks linked to stem cell transplantation.At the same time,advances in tissue engineering and regenerative medicine have offered the potential of using hydrogels as bio-scaffolds in order to provide the stroma required for neural repair to occur,as well as the release of biomolecules facilitating or inducing the reparative processes.This review introduces a novel experimental hypothesis regarding the benefits that could be offered if EVs were to be combined with biocompatible injectable hydrogels.The rationale behind this hypothesis is presented,analyzing how a hydrogel might prolong the retention of EVs and maximize the localized benefit to the brain.This sustained delivery of EVs would be coupled with essential guidance cues and structural support from the hydrogel until neural tissue remodeling and regeneration occur.Finally,the importance of including nonhuman primate models in the clinical translation pipeline,as well as the added benefit of multi-modal neuroimaging analysis to establish non-invasive,in vivo,quantifiable imagingbased biomarkers for CNS repair are discussed,aiming for more effective and safe clinical translation of such regenerative therapies to humans.展开更多
To the editor:A wide range of affective disorders affects people of all ages globally and contributes significantly to the global disease burden.1 In China,a nationwide survey found a 3.21% prevalence of affective dis...To the editor:A wide range of affective disorders affects people of all ages globally and contributes significantly to the global disease burden.1 In China,a nationwide survey found a 3.21% prevalence of affective disorders in children and adolescents,with major depressive disorder(MDD)at 2.00%and bipolar disorder at 0.86%.展开更多
The central nervous system is known to have limited regenerative capacity.Not only does this halt the human body’s reparative processes after central nervous system lesions,but it also impedes the establishment of ef...The central nervous system is known to have limited regenerative capacity.Not only does this halt the human body’s reparative processes after central nervous system lesions,but it also impedes the establishment of effective and safe therapeutic options for such patients.Despite the high prevalence of stroke and spinal cord injury in the general population,these conditions remain incurable and place a heavy burden on patients’families and on society more broadly.Neuroregeneration and neural engineering are diverse biomedical fields that attempt reparative treatments,utilizing stem cells-based strategies,biologically active molecules,nanotechnology,exosomes and highly tunable biodegradable systems(e.g.,certain hydrogels).Although there are studies demonstrating promising preclinical results,safe clinical translation has not yet been accomplished.A key gap in clinical translation is the absence of an ideal animal or ex vivo model that can perfectly simulate the human microenvironment,and also correspond to all the complex pathophysiological and neuroanatomical factors that affect functional outcomes in humans after central nervous system injury.Such an ideal model does not currently exist,but it seems that the nonhuman primate model is uniquely qualified for this role,given its close resemblance to humans.This review considers some regenerative therapies for central nervous system repair that hold promise for future clinical translation.In addition,it attempts to uncover some of the main reasons why clinical translation might fail without the implementation of nonhuman primate models in the research pipeline.展开更多
The concept of reserve appears in the neurological literature in the 1940s arising from the observation that there is no linear relationship between neurological damage and severity of the clinical symptoms.Basically,...The concept of reserve appears in the neurological literature in the 1940s arising from the observation that there is no linear relationship between neurological damage and severity of the clinical symptoms.Basically,this concept sustains that the experiences pursued during life-span enrich the brain by making it more resilient to neuronal damage.However,in the last three decades the reserve concept has become very popular in the scientific field,mainly associated with the pathophysiological mechanisms underlying the Alzheimer’s Disease(AD)(Serra et al.,2018;Stern et al.,2018).展开更多
We refute the controversial statement that addiction is not a brain disorder. Extensive peer-reviewed studies support the underlying neurobiological and neurogenetic basis of addiction’s “disease model”. In the 70s...We refute the controversial statement that addiction is not a brain disorder. Extensive peer-reviewed studies support the underlying neurobiological and neurogenetic basis of addiction’s “disease model”. In the 70s and 80s, a few clinical scientists suggested that it is possible to use behavioral training to teach controlled drinking. However, this controversial model failed drastically and increased labeling and stigmatization. Additionally, it was unhelpful in the search for treatment. Instead, we assert that addiction is a neuropsychiatric disorder characterized by a recurring desire to continue taking substances despite harmful physical and mental consequences. Work from our laboratory in 1995 supported the Reward Deficiency Syndrome (RDS) concept based on a common neurogenetic mechanism (hypodopaminergia) that underlies all substance and non-substance addictions. Non-substance addictions include behaviors like pathological gambling, internet addiction, and mobile phone addiction. Certain impulsive and compulsive behaviors or the acute intake of psychoactive substances result in heightened dopaminergic activity, while the opposite, hypodopaminergia, occurs following chronic abuse. Patients with Substance Use Disorder (SUD) can have a genetic predisposition compounded by stress or other epigenetic insults that can impact recovery. Relapse will occur post-short-term recovery if dopaminergic dysfunction remains untreated. Addiction, a brain disorder, requires treatment with DNA-directed pro-dopamine regulation and rehabilitation.展开更多
Pediatric autoimmune neuropsychiatric disorders associated with group A streptococcal infections (PANDAS) is a concept that is used to characterize a subset of children with neuropsychiatric symptoms, tic disorders, o...Pediatric autoimmune neuropsychiatric disorders associated with group A streptococcal infections (PANDAS) is a concept that is used to characterize a subset of children with neuropsychiatric symptoms, tic disorders, or obsessive-compulsive disorder (OCD), whose symptoms are exacerbated by group A streptococcal (GAS) infection. PANDAS has been known to cause a sudden onset of reward deficiency syndrome (RDS). RDS includes multiple disorders that are characterized by dopaminergic signaling dysfunction in the brain reward cascade (BRC), which may result in addiction, depression, avoidant behaviors, anxiety, tic disorders, and/or OCD. According to research by Blum et al., the dopamine receptor D2 (DRD2) gene polymorphisms are important prevalent genetic determinants of RDS. The literature demonstrates that infections like Borrelia and Lyme, as well as other infections like group A beta-hemolytic streptococcal (GABHS), can cause an autoimmune reaction and associated antibodies target dopaminergic loci in the mesolimbic region of the brain, which interferes with brain function and potentially causes RDS-like symptoms/behaviors. The treatment of PANDAS remains controversial, especially since there have been limited efficacy studies to date. We propose an innovative potential treatment for PANDAS based on previous clinical trials using a pro-dopamine regulator known as KB220 variants. Our ongoing research suggests that achieving “dopamine homeostasis” by precision-guided DNA testing and pro-dopamine modulation could result in improved therapeutic outcomes.展开更多
Pediatric autoimmune neuropsychiatric disorders associated with or without streptococcal and other bacterial infections (PANDAS/CANS) are emerging as a featured pediatric disorder. Although there is some controversy r...Pediatric autoimmune neuropsychiatric disorders associated with or without streptococcal and other bacterial infections (PANDAS/CANS) are emerging as a featured pediatric disorder. Although there is some controversy regarding treatment approaches, especially related to the behavioral sequelae, we have hypothesized in other published work that it is characterized by the rapid onset of Reward Deficiency Syndrome (RDS) in children. We propose utilizing a multi-systems biological approach involving the coupling of genetic addiction risk testing and pro-dopamine regulation (KB220/POLYGEN®) to help induce “dopamine homeostasis” in patients with PANDAS, especially those with known DNA-induced hypodopaminergia. This case study examines a 12-year-old Caucasian male with no prior psychiatric issues who presented with a sudden onset of severe anxiety, depression, emotional liability, and suicidal ideation. The patient underwent genotyping and the genetic addiction risk score (GARS) testing, which revealed risk polymorphisms in the dopamine D2 (-DRD2/ANKK (Taq1A), OPRM1 (A/G), DRD3 (C/T), and MAOA (4R) genes. These polymorphisms have been linked to hypodopaminergia. The patient was subsequently placed on research ID-KB220ZPBMPOLY (POLYGEN®), and albeit the possibility of bias, based upon self and parental assessment, a marked rapid improvement in psychiatric symptoms was observed. In the second phase of treatment (102 days utilizing KB220), the patient received standard antibody testing, which was positive for Lyme. Antibacterial therapy started immediately, and KB220z was discontinued to provide a wash-out period. A monotonic trend analysis was performed on each outcome measure, and a consistently decreasing trend was observed utilizing antibacterial therapy. Our recommendation, albeit only one case, is to utilize and further research a combined therapeutic approach, involving precision-guided DNA testing and pro-dopamine regulation along with antibacterial therapy, as well as glutathione to address offensive enhanced cytokines, in patients with suspected PANDAS/CANS.展开更多
Background:Auditory verbal hallucinations(AVHs)of schizophrenia have been associated with structural and functional alterations of some brain regions.However,the brain regional homogeneity(ReHo)alterations specific to...Background:Auditory verbal hallucinations(AVHs)of schizophrenia have been associated with structural and functional alterations of some brain regions.However,the brain regional homogeneity(ReHo)alterations specific to AVHs of schizophrenia remain unclear.In the current study,we aimed to investigate ReHo alterations specific to schizophrenic AVHs.Methods:Thirty-five schizophrenic patients with AVH,41 schizophrenic patients without AVHs,and fifty healthy subjects underwent resting-state functional magnetic resonance imaging.ReHo differences across the three groups were tested using a voxel-wise analysis.Results:Compared with the healthy control group,the two schizophrenia groups showed significantly increased ReHo in the right caudate and inferior temporal gyrus and decreased ReHo in the bilateral postcentral gyrus and thalamus and the right inferior occipital gyrus(false discovery rate corrected,P〈0.05).More importantly,the AVH group exhibited significantly increased ReHo in the left precuneus compared with the non-AVH group.However,using correlation analysis,we did not find any correlation between the auditory hallucination rating scale score and the ReHo of brain regions.Conclusions:Our results suggest that increased ReHo in the left precuneus may be a pathological feature exclusive to schizophrenic AVHs.展开更多
Numerous studies have identified many specific structural alterations in the brains of patients with schizophrenia and depression. Schizophrenia is associated with gray matter volume (GMV) impairment in certain key br...Numerous studies have identified many specific structural alterations in the brains of patients with schizophrenia and depression. Schizophrenia is associated with gray matter volume (GMV) impairment in certain key brain regions, which progresses in the first 2-3 years after the first episode of schizophrenic symptoms,m Schizophrenia has also been shown to be associated with concurrent white matter (WM) alterations. The fasciculus uncinatus and arcuate fasciculus have been proposed to be a part of the quality index for schizophrenia.12j Similar to schizophrenia, major depressive disorder (MDD) is associated with a GMV reduction and aberrant WM. GMV reductions in the bilateral middle temporal gyrus left ventral medial prefrontal gyrus, left lingual gyms, and dorsal medial prefrontal gyrus have been correlated with the severity of the depressive symptoms. Schizophrenic and depressive symptoms usually coexist in schizophrenia and MDD. In this pilot study, we compared the GMV and WM differences in the brains of chronic schizophrenia patients with depressive symptoms with those of chronic depression patients with psychotic symptoms.展开更多
Main text Synaptic degeneration is a prominent feature of vari-ous neurodegenerative diseases and represents an early pathogenic event in Alzheimer’s disease(AD)[1,2].Multiple synapse-specific proteins involved in di...Main text Synaptic degeneration is a prominent feature of vari-ous neurodegenerative diseases and represents an early pathogenic event in Alzheimer’s disease(AD)[1,2].Multiple synapse-specific proteins involved in distinct synaptic pathways can be measured in the cerebrospi-nal fluid(CSF)and have been implicated as promising biomarkers of synaptic degeneration.Among them,the most extensively studied ones include the presynaptic proteins synaptosomal-associated protein-25(SNAP25),growth-associated protein-43(GAP43)and synaptotag-min-1(SYT1)and postsynaptic protein neurogranin(NRGN)[3,4].展开更多
Previous studies have reported that auditory verbal hallucinations （AVHs） may be caused by resting-state neuronal hyperactivity in the default mode network （DMN）. Abnormally increased functional connectivity （FC...Previous studies have reported that auditory verbal hallucinations （AVHs） may be caused by resting-state neuronal hyperactivity in the default mode network （DMN）. Abnormally increased functional connectivity （FC） between the DMN and other cortical regions may cause disturbances in neuronal network architecture and interactions. Subsequently, disturbed neuronal network architecture and interactions may induce increased activation in auditory and speech perception areas in the absence of external auditory stimuli as well as reduced activation in the same areas in the presence of external auditory stimuli.展开更多
Hyperphosphorylation of the tau protein leading to the formation of neurofibrillary tangles(NFTs)is a common feature in a wide range of neurodegenerative diseases known as tauopathies,which include Alzheimer’s diseas...Hyperphosphorylation of the tau protein leading to the formation of neurofibrillary tangles(NFTs)is a common feature in a wide range of neurodegenerative diseases known as tauopathies,which include Alzheimer’s disease(AD)and the frontotemporal dementias(FTDs).Although heavily investigated,the mechanisms underlying the pathogenesis and progression of tauopathies have yet to be fully understood.In this context,several rodent models have been developed that successfully recapitulate the behavioral and neurochemical features of tau pathology,aiming to achieve a better understanding of the link between tau and neurodegeneration.To date,behavioral and biochemical parameters assessed using these models have been conducted using a combination of memory tasks and invasive methods such as cerebrospinal fluid(CSF)sampling or post-mortem analysis.Recently,several novel positron emission tomography(PET)radiopharmaceuticals targeting tau tangles have been developed,allowing for non-invasive in vivo quantification of tau pathology.Combined with tau transgenic models and micro-PET,these tracers hold the promise of advancing the development of theoretical models and advancing our understanding of the natural history of AD and non-AD tauopathies.In this review,we briefly describe some of the most important insights for understanding the biological basis of tau pathology,and shed light on the opportunity for improved modeling of tau pathology using a combination of tau-radiopharmaceuticals and animal models.展开更多
Background:Neuropsychiatric symptoms(NPS)are increasingly recognized as early non-cognitive manifestations in the Alzheimer's disease(AD)continuum.However,the role of NPS as an early marker of pathophysiological p...Background:Neuropsychiatric symptoms(NPS)are increasingly recognized as early non-cognitive manifestations in the Alzheimer's disease(AD)continuum.However,the role of NPS as an early marker of pathophysiological progression in AD remains unclear.Dominantly inherited AD(DIAD)mutation carriers are young individuals who are destined to develop AD in future due to the full penetrance of the genetic mutation.Hence,the study of DIAD mutation carriers enables the evaluation of the associations between pure AD pathophysiology and metabolic correlates of NPS without the confounding effects of co-existing pathologies.In this longitudinal study,we aimed to identify regional brain metabolic dysfunctions associated with NPS in cognitively intact DIAD mutation carriers.Methods:We stratified 221 cognitively intact participants from the Dominantly Inherited Alzheimer's Network according to their mutation carrier status.The interactions of NPS measured by the Neuropsychiatric Inventory-Questionnaire(NPI-Q),age,and estimated years to symptom onset(EYO)as a function of metabolism measured by[^(18)F]flurodeoxyglucose([^(18)F]FDG)positron emission tomography,were evaluated by the mixed-effects regression model with family-level random effects in DIAD mutation carriers and non-carriers.Exploratory factor analysis was performed to identify the neuropsychiatric subsyndromes in DIAD mutation carriers using the NPI-Q subcomponents.Then the effects of interactions between specific neuropsychiatric subsyndromes and EYO on metabolism were evaluated with the mixed-effects regression model.Results:A total of 119 mutation carriers and 102 non-carriers were studied.The interaction of higher NPI-Q and shorter EYO was associated with more rapid declines of global and regional[18F]FDG uptake in the posterior cingulate and ventromedial prefrontal cortices,the bilateral parietal lobes and the right insula in DIAD mutation carriers.The neuropsychiatric subsyndromes of agitation,disinhibition,irritability and depression interacted with the EYO to drive the[^(18)F]FDG uptake decline in the DIAD mutation carriers.The interaction of NPI and EYO was not associated with[^(18)F]FDG uptake in DIAD mutation non-carriers.Conclusions:The NPS in cognitively intact DIAD mutation carriers may be a clinical indicator of subsequent metabolic decline in brain networks vulnerable to AD,which supports the emerging conceptual framework that NPS represent early manifestations of neuronal injury in AD.Further studies using different methodological approaches to identify NPS in predinical AD are needed to validate our findings.展开更多
基金supported by The University of Hong Kong,China(109000487,109001694,204610401,and 204610519)National Natural Science Foundation of China(82402225)(to JH).
文摘Chemical exchange saturation transfer magnetic resonance imaging is an advanced imaging technique that enables the detection of compounds at low concentrations with high sensitivity and spatial resolution and has been extensively studied for diagnosing malignancy and stroke.In recent years,the emerging exploration of chemical exchange saturation transfer magnetic resonance imaging for detecting pathological changes in neurodegenerative diseases has opened up new possibilities for early detection and repetitive scans without ionizing radiation.This review serves as an overview of chemical exchange saturation transfer magnetic resonance imaging with detailed information on contrast mechanisms and processing methods and summarizes recent developments in both clinical and preclinical studies of chemical exchange saturation transfer magnetic resonance imaging for Alzheimer’s disease,Parkinson’s disease,multiple sclerosis,and Huntington’s disease.A comprehensive literature search was conducted using databases such as PubMed and Google Scholar,focusing on peer-reviewed articles from the past 15 years relevant to clinical and preclinical applications.The findings suggest that chemical exchange saturation transfer magnetic resonance imaging has the potential to detect molecular changes and altered metabolism,which may aid in early diagnosis and assessment of the severity of neurodegenerative diseases.Although promising results have been observed in selected clinical and preclinical trials,further validations are needed to evaluate their clinical value.When combined with other imaging modalities and advanced analytical methods,chemical exchange saturation transfer magnetic resonance imaging shows potential as an in vivo biomarker,enhancing the understanding of neuropathological mechanisms in neurodegenerative diseases.
基金This work was supported by the National Center for Complementary and Integrative Health(NCCIH),No.R21AT008865(to NM)the National Institute of Aging(NIA)/National Institute of Mental Health(NIMH),No.R01AG042512(to NM).
文摘Neural tissue engineering,nanotechnology and neuroregeneration are diverse biomedical disciplines that have been working together in recent decades to solve the complex problems linked to central nervous system(CNS)repair.It is known that the CNS demonstrates a very limited regenerative capacity because of a microenvironment that impedes effective regenerative processes,making development of CNS therapeutics challenging.Given the high prevalence of CNS conditions such as stroke that damage the brain and place a severe burden on afflicted individuals and on society,it is of utmost significance to explore the optimum methodologies for finding treatments that could be applied to humans for restoration of function to pre-injury levels.Extracellular vesicles(EVs),also known as exosomes,when derived from mesenchymal stem cells,are one of the most promising approaches that have been attempted thus far,as EVs deliver factors that stimulate recovery by acting at the nanoscale level on intercellular communication while avoiding the risks linked to stem cell transplantation.At the same time,advances in tissue engineering and regenerative medicine have offered the potential of using hydrogels as bio-scaffolds in order to provide the stroma required for neural repair to occur,as well as the release of biomolecules facilitating or inducing the reparative processes.This review introduces a novel experimental hypothesis regarding the benefits that could be offered if EVs were to be combined with biocompatible injectable hydrogels.The rationale behind this hypothesis is presented,analyzing how a hydrogel might prolong the retention of EVs and maximize the localized benefit to the brain.This sustained delivery of EVs would be coupled with essential guidance cues and structural support from the hydrogel until neural tissue remodeling and regeneration occur.Finally,the importance of including nonhuman primate models in the clinical translation pipeline,as well as the added benefit of multi-modal neuroimaging analysis to establish non-invasive,in vivo,quantifiable imagingbased biomarkers for CNS repair are discussed,aiming for more effective and safe clinical translation of such regenerative therapies to humans.
基金the Tianjin Health Research Project(Grant No.TJWJ2023MS038)Tianjin Education Commission Research Project(Grant No.2023KJ044)S&T Program of Hebei(SG2021189)。
文摘To the editor:A wide range of affective disorders affects people of all ages globally and contributes significantly to the global disease burden.1 In China,a nationwide survey found a 3.21% prevalence of affective disorders in children and adolescents,with major depressive disorder(MDD)at 2.00%and bipolar disorder at 0.86%.
基金supported by Onassis Foundation(to MT)the National Center for Complementary and Integrative Health(NCCIH),No.R21AT008865(to NM)National Institute of Aging(NIA)/National Institute of Mental Health(NIMH),No.R01AG042512(to NM)
文摘The central nervous system is known to have limited regenerative capacity.Not only does this halt the human body’s reparative processes after central nervous system lesions,but it also impedes the establishment of effective and safe therapeutic options for such patients.Despite the high prevalence of stroke and spinal cord injury in the general population,these conditions remain incurable and place a heavy burden on patients’families and on society more broadly.Neuroregeneration and neural engineering are diverse biomedical fields that attempt reparative treatments,utilizing stem cells-based strategies,biologically active molecules,nanotechnology,exosomes and highly tunable biodegradable systems(e.g.,certain hydrogels).Although there are studies demonstrating promising preclinical results,safe clinical translation has not yet been accomplished.A key gap in clinical translation is the absence of an ideal animal or ex vivo model that can perfectly simulate the human microenvironment,and also correspond to all the complex pathophysiological and neuroanatomical factors that affect functional outcomes in humans after central nervous system injury.Such an ideal model does not currently exist,but it seems that the nonhuman primate model is uniquely qualified for this role,given its close resemblance to humans.This review considers some regenerative therapies for central nervous system repair that hold promise for future clinical translation.In addition,it attempts to uncover some of the main reasons why clinical translation might fail without the implementation of nonhuman primate models in the research pipeline.
文摘The concept of reserve appears in the neurological literature in the 1940s arising from the observation that there is no linear relationship between neurological damage and severity of the clinical symptoms.Basically,this concept sustains that the experiences pursued during life-span enrich the brain by making it more resilient to neuronal damage.However,in the last three decades the reserve concept has become very popular in the scientific field,mainly associated with the pathophysiological mechanisms underlying the Alzheimer’s Disease(AD)(Serra et al.,2018;Stern et al.,2018).
文摘We refute the controversial statement that addiction is not a brain disorder. Extensive peer-reviewed studies support the underlying neurobiological and neurogenetic basis of addiction’s “disease model”. In the 70s and 80s, a few clinical scientists suggested that it is possible to use behavioral training to teach controlled drinking. However, this controversial model failed drastically and increased labeling and stigmatization. Additionally, it was unhelpful in the search for treatment. Instead, we assert that addiction is a neuropsychiatric disorder characterized by a recurring desire to continue taking substances despite harmful physical and mental consequences. Work from our laboratory in 1995 supported the Reward Deficiency Syndrome (RDS) concept based on a common neurogenetic mechanism (hypodopaminergia) that underlies all substance and non-substance addictions. Non-substance addictions include behaviors like pathological gambling, internet addiction, and mobile phone addiction. Certain impulsive and compulsive behaviors or the acute intake of psychoactive substances result in heightened dopaminergic activity, while the opposite, hypodopaminergia, occurs following chronic abuse. Patients with Substance Use Disorder (SUD) can have a genetic predisposition compounded by stress or other epigenetic insults that can impact recovery. Relapse will occur post-short-term recovery if dopaminergic dysfunction remains untreated. Addiction, a brain disorder, requires treatment with DNA-directed pro-dopamine regulation and rehabilitation.
文摘Pediatric autoimmune neuropsychiatric disorders associated with group A streptococcal infections (PANDAS) is a concept that is used to characterize a subset of children with neuropsychiatric symptoms, tic disorders, or obsessive-compulsive disorder (OCD), whose symptoms are exacerbated by group A streptococcal (GAS) infection. PANDAS has been known to cause a sudden onset of reward deficiency syndrome (RDS). RDS includes multiple disorders that are characterized by dopaminergic signaling dysfunction in the brain reward cascade (BRC), which may result in addiction, depression, avoidant behaviors, anxiety, tic disorders, and/or OCD. According to research by Blum et al., the dopamine receptor D2 (DRD2) gene polymorphisms are important prevalent genetic determinants of RDS. The literature demonstrates that infections like Borrelia and Lyme, as well as other infections like group A beta-hemolytic streptococcal (GABHS), can cause an autoimmune reaction and associated antibodies target dopaminergic loci in the mesolimbic region of the brain, which interferes with brain function and potentially causes RDS-like symptoms/behaviors. The treatment of PANDAS remains controversial, especially since there have been limited efficacy studies to date. We propose an innovative potential treatment for PANDAS based on previous clinical trials using a pro-dopamine regulator known as KB220 variants. Our ongoing research suggests that achieving “dopamine homeostasis” by precision-guided DNA testing and pro-dopamine modulation could result in improved therapeutic outcomes.
文摘Pediatric autoimmune neuropsychiatric disorders associated with or without streptococcal and other bacterial infections (PANDAS/CANS) are emerging as a featured pediatric disorder. Although there is some controversy regarding treatment approaches, especially related to the behavioral sequelae, we have hypothesized in other published work that it is characterized by the rapid onset of Reward Deficiency Syndrome (RDS) in children. We propose utilizing a multi-systems biological approach involving the coupling of genetic addiction risk testing and pro-dopamine regulation (KB220/POLYGEN®) to help induce “dopamine homeostasis” in patients with PANDAS, especially those with known DNA-induced hypodopaminergia. This case study examines a 12-year-old Caucasian male with no prior psychiatric issues who presented with a sudden onset of severe anxiety, depression, emotional liability, and suicidal ideation. The patient underwent genotyping and the genetic addiction risk score (GARS) testing, which revealed risk polymorphisms in the dopamine D2 (-DRD2/ANKK (Taq1A), OPRM1 (A/G), DRD3 (C/T), and MAOA (4R) genes. These polymorphisms have been linked to hypodopaminergia. The patient was subsequently placed on research ID-KB220ZPBMPOLY (POLYGEN®), and albeit the possibility of bias, based upon self and parental assessment, a marked rapid improvement in psychiatric symptoms was observed. In the second phase of treatment (102 days utilizing KB220), the patient received standard antibody testing, which was positive for Lyme. Antibacterial therapy started immediately, and KB220z was discontinued to provide a wash-out period. A monotonic trend analysis was performed on each outcome measure, and a consistently decreasing trend was observed utilizing antibacterial therapy. Our recommendation, albeit only one case, is to utilize and further research a combined therapeutic approach, involving precision-guided DNA testing and pro-dopamine regulation along with antibacterial therapy, as well as glutathione to address offensive enhanced cytokines, in patients with suspected PANDAS/CANS.
基金This work was supported by grants from the Natural Science Foundation of China(No.81425013,No.91332113 and No.81271551)the Tianjin Key Technology R&D Program(No.14ZCZDSY00018)the National Key Clinical Specialty Project and the China Postdoctoral Science Foundation funded project(No.2012M520585).
文摘Background:Auditory verbal hallucinations(AVHs)of schizophrenia have been associated with structural and functional alterations of some brain regions.However,the brain regional homogeneity(ReHo)alterations specific to AVHs of schizophrenia remain unclear.In the current study,we aimed to investigate ReHo alterations specific to schizophrenic AVHs.Methods:Thirty-five schizophrenic patients with AVH,41 schizophrenic patients without AVHs,and fifty healthy subjects underwent resting-state functional magnetic resonance imaging.ReHo differences across the three groups were tested using a voxel-wise analysis.Results:Compared with the healthy control group,the two schizophrenia groups showed significantly increased ReHo in the right caudate and inferior temporal gyrus and decreased ReHo in the bilateral postcentral gyrus and thalamus and the right inferior occipital gyrus(false discovery rate corrected,P〈0.05).More importantly,the AVH group exhibited significantly increased ReHo in the left precuneus compared with the non-AVH group.However,using correlation analysis,we did not find any correlation between the auditory hallucination rating scale score and the ReHo of brain regions.Conclusions:Our results suggest that increased ReHo in the left precuneus may be a pathological feature exclusive to schizophrenic AVHs.
文摘Numerous studies have identified many specific structural alterations in the brains of patients with schizophrenia and depression. Schizophrenia is associated with gray matter volume (GMV) impairment in certain key brain regions, which progresses in the first 2-3 years after the first episode of schizophrenic symptoms,m Schizophrenia has also been shown to be associated with concurrent white matter (WM) alterations. The fasciculus uncinatus and arcuate fasciculus have been proposed to be a part of the quality index for schizophrenia.12j Similar to schizophrenia, major depressive disorder (MDD) is associated with a GMV reduction and aberrant WM. GMV reductions in the bilateral middle temporal gyrus left ventral medial prefrontal gyrus, left lingual gyms, and dorsal medial prefrontal gyrus have been correlated with the severity of the depressive symptoms. Schizophrenic and depressive symptoms usually coexist in schizophrenia and MDD. In this pilot study, we compared the GMV and WM differences in the brains of chronic schizophrenia patients with depressive symptoms with those of chronic depression patients with psychotic symptoms.
基金supported by the Canadian Institutes of Health Research(CIHR)[MOP-11–51-31,RFN 152985,159815,162303]Canadian Consortium of Neurodegeneration and Aging(CCNA+4 种基金MOP-11–51-31-team 1)Weston Brain Institute,the Alzheimer’s Association[NIRG-12–92090,NIRP-12–259245]Brain Canada Foundation(CFI Project 34874,33397)the Fonds de Recherche du Québec–Santé(FRQSChercheur Boursier,2020-VICO-279314)。
文摘Main text Synaptic degeneration is a prominent feature of vari-ous neurodegenerative diseases and represents an early pathogenic event in Alzheimer’s disease(AD)[1,2].Multiple synapse-specific proteins involved in distinct synaptic pathways can be measured in the cerebrospi-nal fluid(CSF)and have been implicated as promising biomarkers of synaptic degeneration.Among them,the most extensively studied ones include the presynaptic proteins synaptosomal-associated protein-25(SNAP25),growth-associated protein-43(GAP43)and synaptotag-min-1(SYT1)and postsynaptic protein neurogranin(NRGN)[3,4].
基金This work was＇supported by grants from the Tianjin Health Bureau Foundation （No. 2014KR02） and Key Projects of the Natural Science Foundation of Tianjin, China （No. 17JCZDJC35700）.
文摘Previous studies have reported that auditory verbal hallucinations （AVHs） may be caused by resting-state neuronal hyperactivity in the default mode network （DMN）. Abnormally increased functional connectivity （FC） between the DMN and other cortical regions may cause disturbances in neuronal network architecture and interactions. Subsequently, disturbed neuronal network architecture and interactions may induce increased activation in auditory and speech perception areas in the absence of external auditory stimuli as well as reduced activation in the same areas in the presence of external auditory stimuli.
基金This work was supported by Canadian institutes of Health Research(CIHR)[MOP-11-51-31]Alzheimer's Association[NIRG-08-92090]+1 种基金Nussia&AndreAisenstadt FoundationFonds de la recherche en santedu Québec(chercheur boursier).
文摘Hyperphosphorylation of the tau protein leading to the formation of neurofibrillary tangles(NFTs)is a common feature in a wide range of neurodegenerative diseases known as tauopathies,which include Alzheimer’s disease(AD)and the frontotemporal dementias(FTDs).Although heavily investigated,the mechanisms underlying the pathogenesis and progression of tauopathies have yet to be fully understood.In this context,several rodent models have been developed that successfully recapitulate the behavioral and neurochemical features of tau pathology,aiming to achieve a better understanding of the link between tau and neurodegeneration.To date,behavioral and biochemical parameters assessed using these models have been conducted using a combination of memory tasks and invasive methods such as cerebrospinal fluid(CSF)sampling or post-mortem analysis.Recently,several novel positron emission tomography(PET)radiopharmaceuticals targeting tau tangles have been developed,allowing for non-invasive in vivo quantification of tau pathology.Combined with tau transgenic models and micro-PET,these tracers hold the promise of advancing the development of theoretical models and advancing our understanding of the natural history of AD and non-AD tauopathies.In this review,we briefly describe some of the most important insights for understanding the biological basis of tau pathology,and shed light on the opportunity for improved modeling of tau pathology using a combination of tau-radiopharmaceuticals and animal models.
文摘Background:Neuropsychiatric symptoms(NPS)are increasingly recognized as early non-cognitive manifestations in the Alzheimer's disease(AD)continuum.However,the role of NPS as an early marker of pathophysiological progression in AD remains unclear.Dominantly inherited AD(DIAD)mutation carriers are young individuals who are destined to develop AD in future due to the full penetrance of the genetic mutation.Hence,the study of DIAD mutation carriers enables the evaluation of the associations between pure AD pathophysiology and metabolic correlates of NPS without the confounding effects of co-existing pathologies.In this longitudinal study,we aimed to identify regional brain metabolic dysfunctions associated with NPS in cognitively intact DIAD mutation carriers.Methods:We stratified 221 cognitively intact participants from the Dominantly Inherited Alzheimer's Network according to their mutation carrier status.The interactions of NPS measured by the Neuropsychiatric Inventory-Questionnaire(NPI-Q),age,and estimated years to symptom onset(EYO)as a function of metabolism measured by[^(18)F]flurodeoxyglucose([^(18)F]FDG)positron emission tomography,were evaluated by the mixed-effects regression model with family-level random effects in DIAD mutation carriers and non-carriers.Exploratory factor analysis was performed to identify the neuropsychiatric subsyndromes in DIAD mutation carriers using the NPI-Q subcomponents.Then the effects of interactions between specific neuropsychiatric subsyndromes and EYO on metabolism were evaluated with the mixed-effects regression model.Results:A total of 119 mutation carriers and 102 non-carriers were studied.The interaction of higher NPI-Q and shorter EYO was associated with more rapid declines of global and regional[18F]FDG uptake in the posterior cingulate and ventromedial prefrontal cortices,the bilateral parietal lobes and the right insula in DIAD mutation carriers.The neuropsychiatric subsyndromes of agitation,disinhibition,irritability and depression interacted with the EYO to drive the[^(18)F]FDG uptake decline in the DIAD mutation carriers.The interaction of NPI and EYO was not associated with[^(18)F]FDG uptake in DIAD mutation non-carriers.Conclusions:The NPS in cognitively intact DIAD mutation carriers may be a clinical indicator of subsequent metabolic decline in brain networks vulnerable to AD,which supports the emerging conceptual framework that NPS represent early manifestations of neuronal injury in AD.Further studies using different methodological approaches to identify NPS in predinical AD are needed to validate our findings.
