The aim of this study was to investigate the correlation between dopamine transporter (DAT) positron emission tomography (PET)/computed tomography (CT) and the clinical characteristics and rating scales of Parkinson’s disease (PD) patients. Additionally, we sought to assess the scientific validity and feasibility of integrating 3D-dopaminergic binding parameters into the clinical scoring system for PD.
A total of 75 patients with PD who underwent 11C-methyl-N-2β-methyl ester-3β-(4-fluorophenyl) tropane (11C-CFT) PET/CT from April, 2019 to June, 2021 were retrospectively analyzed. Clinical characteristics, including age, sex, and disease duration, as well as the modified Hoehn-Yahr (H-Y) scale, Unified Parkinson’s Disease Rating Scale (UPDRS) parts II and III (II-III), and Mini-Mental State Examination (MMSE) scores of PD patients during the corresponding time periods were collected. DAT binding parameters and their derived parameters based on plane and 3D images in the neostriatum were analyzed for consistency with plane and 3D parameters, and the correlation between DAT parameters and the clinical features of patients were assessed using SPSS software.
The DAT binding parameters derived from 3D images demonstrated good consistency with the plane parameters (p < 0.05). The asymmetry index (ai) of DAT binding parameters based on 3D and plane images showed good consistency in the anterior putamen (p < 0.05). The plane parameters of the anterior and posterior putamen were statistically correlated with the UPDRS II-III score and H-Y score of PD patients (p < 0.05), whereas those of the caudate nucleus were correlated with UPDRS II and MMSE scores. The 3D parameters in the neostriatum showed good statistical correlation with disease duration, UPDRS II-III score, H-Y score, and H-Y stage of PD patients (p < 0.05), and the ai was significantly correlated with MMSE score (p < 0.05). The 3D parameters in the putamen and posterior putamen exhibited significant statistical correlation with the UPDRS II-III score, H-Y score, and H-Y stage in PD patients (p < 0.05). The ai in the putamen showed statistical correlation with UPDRS III and MMSE scores, and the ai in the posterior putamen showed statistical correlation with UPDRS II score (p < 0.05).
Quantitative parameters based on plane and 3D images of 11C-CFT PET/CT showed good consistency. Moreover, 3D parameters in the neostriatum had a stronger correlation with activities of daily living, UPDRS motor scores, disease severity and duration, and cognition compared with plane parameters in PD patients.
Chronic fatigue syndrome is primarily caused by myalgic encephalomyelitis (ME)-associated dysfunction of the central nervous system. Postural instability or disequilibrium is a typical neural sign and is classified as static or kinetic.
A total of 160 ME patients (53 males and 107 females) with a mean age of 37 ± 12 years were enrolled in this study. They underwent both the Romberg test for static disequilibrium and the tandem gait test with turn and return for kinetic disequilibrium.
Static disequilibrium was found in 40 (25%) patients who showed instability when standing with both feet together and eyes either open (n = 7, 4%) or closed (n = 33, 21%). Kinetic disequilibrium was found in 71 (44%) patients, with 57 (36%) being positive for the straight tandem gait test. Fourteen (9%) patients were negative for the straight tandem gait test, but showed a positive result after turning and returning. Almost all patients with static disequilibrium also had kinetic disequilibrium (39/40, 98%). Patients with static and/or kinetic disequilibrium had a significantly higher prevalence of orthostatic intolerance, diagnosed as failure to complete the 10-min standing test, compared with patients without disequilibrium. They also had a significantly higher median performance status score (0–9) for restricted activities of daily living. Both types of disequilibria were recovered in 11 (85%) of 13 patients treated with repetitive transcranial magnetic stimulation (rTMS) of the left dorsolateral prefrontal cortex and primary motor area in the brain, suggesting a central vestibular origin.
Static disequilibrium related to orthostatic intolerance, and kinetic disequilibrium related to gait disturbance are both prevalent in patients with ME and are important central neural signs that restrict activities of daily living. rTMS treatment effectively alleviated these disequilibria.
The study has been registered on https://jrct.mhlw.go.jp/ (registration number: jRCT1042240065; registration date: July 30, 2024).
Nerve injury is a significant cause of postherpetic neuralgia (PHN). It is marked by upregulated expression of cytokines secreted by immune cells such as tumor necrosis factor alpha, interleukin 1 beta (IL-1β), IL-6, IL-18, and IL-10. In neuropathic pain (NP) due to nerve injury, cytokines are important for the induction of neuroinflammation, activation of glial cells, and expression of cation channels. The release of chemokines due to nerve injury promotes immune cell infiltration, recruiting inflammatory cytokines and further amplifying the inflammatory response. The resulting disequilibrium in neuroimmune response and neuroinflammation leads to a reduction of nerve fibers, altered nerve excitability, and neuralgia. PHN is a typical NP and cytokines may induce PHN by promoting central and peripheral sensitization. Currently, treating PHN is challenging and research on the role of cytokine signaling pathways in PHN is lacking. This review summarizes the potential mechanisms of cytokine-mediated PHN and discusses the cytokine signaling pathways associated with the central and peripheral sensitization of PHN. By elucidating the mechanisms of cytokines, the cells and molecules that regulate cytokines, and their signaling systems in PHN, this review reveals important research developments regarding cytokines and their signaling pathways mediating PHN, highlighting new targets of action for the development of analgesic drugs.
Alzheimer’s disease (AD) is a neurodegenerative disease characterized by the formation of amyloid plaques, neurofibrillary tangles and progressive cognitive decline. Amyloid-beta peptide (Aβ) monoclonal antibody therapeutic clinical trials have nearly failed, raising significant concerns about other etiological hypotheses about AD. Recent evidence suggests that AD patients also exhibit persistent neuronal loss and neuronal death accompanied by brain iron deposition or overload-related oxidative stress. Ferroptosis is a type of cell death that depends on iron, unlike autophagy and apoptosis. Inhibiting neuronal ferroptosis function is effective in improving cognitive impairment in AD. Notably, new research shows that ferroptosis in AD is crucially dependent on glial cell activation. This review examines the relationship between the imbalance of iron metabolism, the regulation of iron homeostasis in glial cells and neuronal death in AD pathology. Finally, the review summarizes some current drug research in AD targeting iron homeostasis, many novel iron-chelating compounds and natural compounds showing potential AD-modifying properties that may provide therapeutic targets for treating AD.
Stroke is a major health problem with high mortality and morbidity rates, partly due to limited treatment options. Inflammation has a critical role in the secondary damage that occurs following a stroke event. Neutrophil extracellular traps (NETs) are released by neutrophils and contribute to the progression of neuroinflammation that further worsens brain damage. The prevention of NET formation at sites of brain damage has been reported to prevent neuroinflammation and improve neurological deficits. The aim of this article was to assess the importance of NETs as a treatment target for hemorrhagic stroke in light of the available evidence. NETs are network structures that consist of decondensed DNA strands coated with granule proteins such as citrullinated histones, neutrophile esterase (NE), myeloperoxidase (MPO), and high mobility group protein B1 (HMGB1). Peptidyl arginine deiminase type-IV (PAD4) plays a key role in the formation of NETs. Inhibitors of NET formation, such as the PAD4-specific inhibitor GSK484, are effective at preventing inflammation and thus ultimately reducing brain damage after stroke. In conclusion, inhibition of NETs offers a potential therapeutic strategy for hemorrhagic stroke, although further research is needed to clarify the role of NETs in this condition.
The prevalence and rising use of alcohol, opioids, and stimulants have led to substance use disorders (SUDs) that are a significant public health challenge. Traditional treatments offer some benefit; however, they often limited by efficacy, side effects, and accessibility, highlighting the urgent need for novel therapeutics. This review explores the current literature surrounding three different classes of novel treatments: glucagon-like peptide-1 (GLP-1) receptor agonists, dopamine D3 receptor (D3R) antagonists, and corticotropin-releasing factor (CRF) antagonists. These therapeutics collectively target different aspects of the addiction process, such as stress and relapse prevention, reward modulation, and the reduction of drug-seeking behavior, leading to a combined multifaceted approach to treating SUDs. This review includes preclinical and clinical evidence supporting the use of these therapies, highlighting their potential to reduce substance use and prevent relapse to alcohol, opioid, and stimulant use. Despite the potentially promising findings of these treatments, further research is necessary to fully understand their mechanisms, optimize their application, and confirm their efficacy in clinical settings.
It is becoming increasingly evident that Artificial intelligence (AI) development draws inspiration from the architecture and functions of the human brain. This manuscript examines the alignment between key brain regions—such as the brainstem, sensory cortices, basal ganglia, thalamus, limbic system, and prefrontal cortex—and AI paradigms, including generic AI, machine learning, deep learning, and artificial general intelligence (AGI). By mapping these neural and computational architectures, I herein highlight how AI models progressively mimic the brain’s complexity, from basic pattern recognition and association to advanced reasoning. Current challenges, such as overcoming learning limitations and achieving comparable neuroplasticity, are addressed alongside emerging innovations like neuromorphic computing. Given the rapid pace of AI advancements in recent years, this work underscores the importance of continuously reassessing our understanding as technology evolves exponentially.
The conversion of pyruvate to lactate is primarily catalyzed by lactate-dehydrogenase-5 (LDH-5), which comprises four lactate-dehydrogenase-A (LDHA) subunits. However, the mechanism of LDH-5 in tuberculous meningitis (TBM) remains elusive.
Thirty-two samples of cerebrospinal fluid (CSF) were collected, including 15 from individuals without central nervous system (CNS) infectious diseases (control group) and 17 from individuals with TBM (TBM group). Based on the results of brain imaging, nine patients with TBM with meningeal enhancement were included in the meninges group. Eight patients with TBM with lesions in the brain parenchyma were included in the brain parenchyma group. The levels of adenosine triphosphatase (ATP), lactate, LDH-1, pyruvate and LDH-5 in the CSF were assessed. Subsequently, the levels of ATP, pyruvate and lactate, as well as the amplitude and frequency of action potentials (APs) in neurons overexpressing LDHA, were investigated.
Reduced levels of pyruvate and ATP and elevated levels of lactate and LDH-5 were observed in the CSF of individuals with TBM. The ATP level was decreased in the brain parenchyma group. In neurons with LDHA overexpression, the lactate level increased, while ATP and pyruvate levels, as well as the amplitude and frequency of APs, decreased.
Elevated levels of LDH-5 in the CNS of individuals with TBM may lead to a disturbance in brain energy and negatively affect neuronal activity.
Chemotherapy-induced cognitive impairments are a significant adverse sequela of cancer treatment. The potential mechanism of chemotherapy-induced cognitive impairments remains elusive. The present study evaluated the impact of a commonly utilized chemotherapy agent, 5-fluorouracil (5-FU), on acetylcholine (ACh) levels in the hippocampus.
5-FU was injected into mice once a day for 10 days to create a mouse model of chemotherapy-induced cognitive impairment. Microdialysis and HPLC-MS/MS were used to determine hippocampal ACh levels. Biocytin injection and patch-clamp recordings were performed on cholinergic (ChAT) neurons in the medial septum (MS) to observe their morphological and electrophysiological changes. Chemogenetic tools were used to activate ChAT neurons in the MS. The acetylcholinesterase inhibitor donepezil was injected i.p. into mice to elevate ACh levels in the brain.
Cognitive performance in mice was impaired after 5-FU treatment, accompanied by reduced ACh release in the hippocampus. The administration of 5-FU led to compromised structural integrity and diminished activity of ChAT neurons in the MS. Chemogenetic stimulation of MS ChAT neurons ameliorated the cognitive impairments. The administration of donepezil also reduced the cognitive impairments caused by 5-FU.
5-FU therapy caused cognitive impairments in mice by affecting the neuronal structure and activity of ChAT neurons in the MS. Inducing the increase of ACh levels could be a promising therapeutic approach for addressing 5-FU treatment-induced cognitive impairments.
Neuromyelitis optica spectrum disorder (NMOSD) is a recurrent demyelinating neuroinflammatory disorder of the central nervous system. This study aimed to evaluate the neural conduction and sound information processing in individuals with NMOSD, through the analysis of auditory brainstem responses (ABRs) and cortical auditory evoked potentials (CAEPs).
Twenty-four individuals (9–21 years old) were distributed into two groups: the study group (SG), diagnosed with NMOSD, and the control group, healthy individuals. Their ABRs and CAEPs were evaluated, and the results were examined alongside data from cranial magnetic resonance imaging (MRI).
Abnormal ABRs were observed in 33% of the SG and increased I–III interpeak was the most prevalent finding. The CAEPs showed abnormalities in 58% of the SG, mainly to P1 latency. SG subjects presented longer P1, N1, and N2 latencies and lower N2–P3 amplitude. MRI showed alterations mostly in the pons, midbrain, and IV ventricle.
Alterations in neural conduction and sound information processing were observed in individuals with NMOSD when compared with their peers. Auditory evoked potentials are important instruments to identify central auditory dysfunction in this population as well as to monitor disease evolution.
Cerebral ischemia-reperfusion injury (CIRI) exacerbates neuronal damage through mechanisms including apoptosis and autophagy dysregulation. Resveratrol (Res), a natural polyphenol with neuroprotective properties, may alleviate CIRI-induced damage by modulating key signaling pathways. This study investigates the therapeutic effects of Res on CIRI, focusing on its role in balancing apoptosis and autophagy via regulation of nuclear receptor subfamily 3 group C member 2 (NR3C2) and tripartite motif containing 28 (TRIM28).
In vivo, cognitive impairment, neurological dysfunction, cerebral infarction, neuronal damage, and inflammatory response were assessed in Sprague Dawley (SD) rats subjected to middle cerebral artery occlusion/reperfusion (MCAO/R) using the morris water maze, Longa and Bederson scores, 2,3,5-tripheny ltetrazolium chloride (TTC) staining, hematoxylin and eosin staining, Nissl staining, and enzyme-linked immunosorbent assay (ELISA). The expression of NR3C2 and TRIM28 were analyzed by real time quantitative polymerase chain reaction (RT-qPCR) and western blot (WB). In vitro, Res effects on oxygen-glucose deprivation/reperfusion (OGD/R)-treated PC12 cells were evaluated using cell counting kit-8 (CCK-8), ELISA, terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end labeling (TUNEL) staining, and WB. The relationship between NR3C2 and TRIM28 was validated using dual luciferase and chromatin immunoprecipitation followed by quantitative polymerase chain reaction (ChIP-qPCR).
Res treatment significantly improved cognitive performance in the morris water maze test, and the infarct area was reduced by 16.736%. It was accompanied by downregulation of NR3C2 and TRIM28 expression. In vitro, Res enhanced cell viability, reduced inflammatory responses and apoptosis (with a 17.70% decrease in cell apoptosis rate), and restored autophagy balance. Mechanistically, NR3C2 was shown to directly regulate TRIM28 transcription, mediating the observed neuroprotective effects.
Res inhibits NR3C2 expression, which in turn directly regulates the transcription of TRIM28 through NR3C2, alleviating apoptosis and autophagy dysregulation induced by CIRI. This mechanism clearly demonstrates the important role of NR3C2 in CIRI and reveals its regulatory relationship with TRIM28. By uncovering the neuroprotective effects of Res, we provide new insights for the treatment of CIRI and lay the foundation for future targeted therapeutic strategies involving NR3C2 and TRIM28.
Stress is a critical determinant of social behavior, with oxytocin playing a key role in buffering stress effects and facilitating social bonding. However, the relationship between stress-induced fear and oxytocin-associated sociability remains unclear, particularly in contexts reminiscent of prior stress. This study investigates whether acute restraint stress (ARS) alters anxiety-related behaviors and prosocial choices, and whether these effects can be modulated by pharmacological intervention targeting the oxytocin and corticotropin-releasing hormone (CRH) systems.
Sprague-Dawley rats were subjected to ARS and assessed for anxiety-like behavior using the elevated T-maze (ETM) and for prosocial behavior using the social choice test (SCT). The effects of the oxytocin receptor antagonist L-368899 and CRH receptor antagonist antalarmin were evaluated in this paradigm. Plasma corticosterone was checked peripherally and the tissue concentrations of serotonin (5-HT), dopamine (DA), and norepinephrine (NE) were measured in the hippocampus, medial prefrontal cortex (mPFC), and amygdala to assess stress-related neurochemical changes in the fear circuit.
(i) ARS rats showed a significant increase in prosocial preference compared to control, an effect blocked by L-368899 or antalarmin. (ii) ARS rats exhibited reduced corticosterone levels, together with shorter avoidance latency, and longer escape latency in the ETM. (iii) Neurochemically, ARS rats had decreased DA and increased NE levels in the mPFC, both of which were normalized by L-368899 treatment.
Oxytocin modulates stress-induced alterations in monoaminergic activity within the mPFC, influencing social choice behavior. These findings provide new insights into the neurobiological mechanisms underlying stress-related sociability and the context-dependent role of oxytocin in fear memory and social behavior.
Cognitive dysfunction in cerebral small vessel disease (CSVD) patients is associated with white matter hyperintensity (WMH), which demonstrates frequency-dependent correlations with brain functional activities. However, the neural mechanisms underlying the relationship between these structural and functional abnormalities and cognitive impairment remain unclear.
We recruited 34 CSVD patients (mean age 63.74 ± 4.85 years, 19 males) and 45 age-matched healthy controls (mean age 63.69 ± 6.15 years, 15 males). All participants underwent magnetic resonance imaging (MRI) scanning and comprehensive cognitive assessments, including three behavioral tasks and a cognitive questionnaire battery. Regional brain activity and network topological properties were separately compared between the two groups for each of the three frequency bands (slow-4, slow-5, and typical band) using two-sample t-tests. Simple and multiple mediation analyses were performed to examine the relationships among WMH, functional brain measures, and global cognition.
CSVD patients exhibited frequency-specific alterations in regional activity and reduced global functional organization in the slow-4 band. Frequency-dependent functional measures in the slow-4 band significantly mediated the relationship between deep WMH and cognitive performance.
Our findings demonstrate the frequency-specific mediating role of abnormal brain functions in the pathophysiological pathway linking WMHs to cognitive impairment. This study provides new insight into the pathological mechanisms underlying WMH-related cognitive dysfunction.
ChiCTR2100043346, 02 November 2021, https://www.chictr.org.cn/showproj.html?proj=52285.
Symptomatic chronic internal carotid artery occlusion (CICAO) may lead to stroke and cognitive decline. Although endovascular recanalization has been proven to reduce the risk of future strokes, the effect on cognition remains controversial and requires further exploration. We explored alterations in functional connectivity (FC) and their associations with cognition in patients with symptomatic CICAO before and after carotid revascularization.
Eighteen patients with unilateral CICAO and fifteen healthy controls (HCs) were enrolled. Resting-state functional magnetic resonance imaging (rs-fMRI) and neuropsychological assessment were performed on all participants, before and after 6 months post-recanalization in the patient group. FC alterations in multiple brain networks and their correlations with cognitive scores were analyzed.
The FC of the CICAO group were markedly lower relative to the HC group for the following: the dorsal attention network (DAN) with the ipsilateral (occlusion side, right) middle frontal gyrus and frontal pole; the default mode network (DMN) with the ipsilateral angular gyrus; the visual network (VN) with the ipsilateral fusiform gyrus; and the frontoparietal network (FPN) with middle temporal gyrus on the side contralateral to the occlusion. The decreased FC of the DAN exhibited a positive association with the total score of the Mini-Mental State Examination (MMSE, r = 0.499, p = 0.049), Montreal Cognitive Assessment (MoCA, r = 0.515, p = 0.041), and Backward Digit Span Test (BDST, r = 0.594, p = 0.015), and negatively correlated with the score of Trail Making Test (TMT)-A (r = –0.563, p = 0.023) and TMT-B (r = –0.602, p = 0.014). The CICAO group exhibited significantly increased FC of the DMN seed region with the middle occipital gyrus ipsilateral to the occlusion. Additionally, the VN seed region demonstrated increased FC with the fusiform gyrus ipsilateral to the occlusion following endovascular recanalization. The preoperative FC values of the DMN exhibited a strong positive association with the improvement in TMT-A score (r = 0.629, p = 0.021).
Our exploratory study found that FC disruption may induce cognitive decline in symptomatic CICAO patients. Endovascular recanalization may improve FC within key brain networks, supporting cognitive improvement. The baseline DMN FC was significantly associated with the postoperative improvement in TMT-A scores, suggesting that preoperative DMN FC could serve as a potential predictor of cognitive recovery.
NCT05292729. Registered 1 December 2021, https://clinicaltrials.gov/study/NCT05292729?intr=NCT05292729&rank=1.
This study aimed to explore attention alteration in mild cognitive impairment (MCI) patients and their association with abnormalities of autonomic brain activity within the attention network to reveal the neuroimaging basis behind these changes.
A total of 25 MCI patients and 31 normal controls (NCs) were recruited for the study. The Test of Attention Performance (TAP) version 2.3 was used to evaluate alertness, selective attention, and divided attention in MCI patients and NCs. Subsequently, participants underwent resting-state magnetic resonance imaging (MRI) scans to compare whole-brain autonomic activity characteristics between groups using the amplitude of low-frequency fluctuation (ALFF). Data preprocessing and analysis were conducted using Data Processing & Analysis of Brain Imaging in MATLAB R2018b.
There were significant differences in omissions of intrinsic alertness, total omissions of divided attention, omissions and correct of visual divided attention between the two groups. Meanwhile, independent sample t-tests indicated that the MCI group exhibited higher z-scored ALFF (zALFF) in the left middle occipital gyrus, left superior frontal gyrus (orbital part), and right inferior frontal gyrus (orbital part) when compared with the NC group. The MCI group exhibited reduced zALFF in the left median cingulate and paracingulate gyrus, left precuneus, and right rolandic operculum. Notably, the decreased zALFF in the left precuneus showed a significant negative correlation with divided attention.
Our findings suggest that patients with MCI exhibit relatively normal performance in selective attention and phase alertness tasks, while they demonstrate a decline in capacity for divided attention and intrinsic alertness tasks. Divided attention in MCI patients may be associated with abnormalities in spontaneous neural activity in the left precuneus. This study provides new and complementary insights into the neural basis of divided attention in patients with MCI.
Alzheimer’s disease (AD) is the most common neurodegenerative disease affecting the elderly, with its diagnosis at early stages crucial for effective intervention. Recent evidence increasingly supports the role of epigenetic alterations in AD pathogenesis, highlighting the need for innovative biomarkers that reflect these changes. This study aimed to characterize the genome-wide DNA methylation profiles of cell-free DNA in peripheral blood for potential biomarkers associated with AD.
The Illumina Infinium array was utilized to detect the methylation patterns of circulating cell-free DNA from AD patients and healthy controls. The R Bioconductor Linear Models for Microarray Data (LIMMA) package was employed to identify methylation variable positions (MVPs), and Probe Lasso was used to pinpoint differentially methylated regions (DMRs) linked to AD. Bioinformatics enrichment analysis of the annotated genes was performed using EnrichR. A second cohort was recruited to validate the methylation changes at the C-terminal binding protein1 (CTBP1) promoter cytosine-phosphate-guanine (CpG) sites via pyrosequencing. Additionally, microarray data from the Gene Expression Omnibus (GEO) database were analyzed to further validate gene expression and immune infiltration.
A unique DNA methylation landscape in peripheral blood was characterized for AD patients and 4335 MVPs showed significant differential methylation (p < 0.01). Functional annotation and pathway enrichment analysis underscored processes and pathways inherent in the nervous system. Probe Lasso identified 68 DMRs annotated to 10 genes, with hypermethylation of CpG islands in the CTBP1 TSS1500 promoter showing significant differences when AD and controls were compared (p < 0.01), with an area under the receiver operating characteristic (ROC) curve (AUC) of 0.779. Analysis of immune cell infiltration revealed CTBP1 expression is significantly correlated with altered distribution of immune cells (p < 0.001), underscoring its potential role in modulating immune responses in AD. Moreover, CTBP1 expression levels significantly varied across multiple GEO datasets.
AD displays distinct DNA methylation patterns in peripheral blood and CTBP1 promoter hypermethylation represents a promising potential biomarker for AD diagnosis.