Decoding molecular mechanisms:brain aging and Alzheimer's disease

The complex morphological,anatomical,physiological,and chemical mechanisms within the aging brain have been the hot topic of research for centuries.The aging process alters the brain structure that affects functions and cognitions,but the worsening of such processes contributes to the pathogenesis of neurodegenerative disorders,such as Alzheimer's disease.Beyond these observable,mild morphological shifts,significant functional modifications in neurotransmission and neuronal activity critically influence the aging brain.Understanding these changes is important for maintaining cognitive health,especially given the increasing prevalence of age-related conditions that affect cognition.This review aims to explore the age-induced changes in brain plasticity and molecular processes,differentiating normal aging from the pathogenesis of Alzheimer's disease,thereby providing insights into predicting the risk of dementia,particularly Alzheimer's disease.

Unraveling brain aging through the lens of oral microbiota

The oral cavity is a complex physiological community encompassing a wide range of microorganisms.Dysbiosis of oral microbiota can lead to various oral infectious diseases,such as periodontitis and tooth decay,and even affect systemic health,including brain aging and neurodegenerative diseases.Recent studies have highlighted how oral microbes might be involved in brain aging and neurodegeneration,indicating potential avenues for intervention strategies.In this review,we summarize clinical evidence demonstrating a link between oral microbes/oral infectious diseases and brain aging/neurodegenerative diseases,and dissect potential mechanisms by which oral microbes contribute to brain aging and neurodegeneration.We also highlight advances in therapeutic development grounded in the realm of oral microbes,with the goal of advancing brain health and promoting healthy aging.

Imaging characteristics of brain microstructure and cerebral perfusion in Crohn’s disease patients with anxiety: A prospective comparative study

BACKGROUND Anxiety is a common comorbidity in patients with Crohn’s disease(CD).Data on the imaging characteristics of brain microstructure and cerebral perfusion in CD with anxiety are limited.AIM To compare the imaging characteristics of brain microstructure and cerebral perfusion among CD patients with or without anxiety and healthy individuals.METHODS This prospective comparative study enrolled consecutive patients with active CD and healthy individuals who visited the study hospital between January 2022 and January 2023.Anxiety was measured using the Hospital Anxiety and Depression Scale-Anxiety.The imaging characteristics of brain microstructure and cerebral perfusion were measured by diffusion kurtosis imaging and intravoxel incoherent motion.RESULTSA total of 57 participants were enrolled. Among the patients with active CD, 16 had anxiety. Compared withhealthy individuals, patients with active CD demonstrated significantly lower radial kurtosis values in the rightcerebellar region 6, lower axial kurtosis (AK) values in the right insula, left superior temporal gyrus, and rightthalamus, and higher slow and fast apparent diffusion coefficients (ADCslow and ADCfast) in the bilateral frontal lobe,bilateral temporal lobe, and bilateral insular lobe (all P < 0.05). Compared with patients with CD without anxiety,patients with CD and anxiety exhibited significantly higher ADCslow values in the left insular lobe and lower AKvalues in the right insula and right anterior cuneus (all P < 0.05).CONCLUSIONThere are variations in brain microstructure and perfusion among CD patients with/without anxiety and healthyindividuals, suggesting potential use in assessing anxiety-related changes in active CD.

Epileptic brain network mechanisms and neuroimaging techniques for the brain network

Epilepsy can be defined as a dysfunction of the brain network,and each type of epilepsy involves different brain-network changes that are implicated diffe rently in the control and propagation of interictal or ictal discharges.Gaining more detailed information on brain network alterations can help us to further understand the mechanisms of epilepsy and pave the way for brain network-based precise therapeutic approaches in clinical practice.An increasing number of advanced neuroimaging techniques and electrophysiological techniques such as diffusion tensor imaging-based fiber tra ctography,diffusion kurtosis imaging-based fiber tractography,fiber ball imagingbased tra ctography,electroencephalography,functional magnetic resonance imaging,magnetoencephalography,positron emission tomography,molecular imaging,and functional ultrasound imaging have been extensively used to delineate epileptic networks.In this review,we summarize the relevant neuroimaging and neuroelectrophysiological techniques for assessing structural and functional brain networks in patients with epilepsy,and extensively analyze the imaging mechanisms,advantages,limitations,and clinical application ranges of each technique.A greater focus on emerging advanced technologies,new data analysis software,a combination of multiple techniques,and the construction of personalized virtual epilepsy models can provide a theoretical basis to better understand the brain network mechanisms of epilepsy and make surgical decisions.

Resting-state brain network remodeling after different nerve reconstruction surgeries:a functional magnetic resonance imaging study in brachial plexus injury rats

Distinct brain remodeling has been found after different nerve reconstruction strategies,including motor representation of the affected limb.However,differences among reconstruction strategies at the brain network level have not been elucidated.This study aimed to explore intranetwork changes related to altered peripheral neural pathways after different nerve reconstruction surgeries,including nerve repair,endto-end nerve transfer,and end-to-side nerve transfer.Sprague–Dawley rats underwent complete left brachial plexus transection and were divided into four equal groups of eight:no nerve repair,grafted nerve repair,phrenic nerve end-to-end transfer,and end-to-side transfer with a graft sutured to the anterior upper trunk.Resting-state brain functional magnetic resonance imaging was obtained 7 months after surgery.The independent component analysis algorithm was utilized to identify group-level network components of interest and extract resting-state functional connectivity values of each voxel within the component.Alterations in intra-network resting-state functional connectivity were compared among the groups.Target muscle reinnervation was assessed by behavioral observation(elbow flexion)and electromyography.The results showed that alterations in the sensorimotor and interoception networks were mostly related to changes in the peripheral neural pathway.Nerve repair was related to enhanced connectivity within the sensorimotor network,while end-to-side nerve transfer might be more beneficial for restoring control over the affected limb by the original motor representation.The thalamic-cortical pathway was enhanced within the interoception network after nerve repair and end-to-end nerve transfer.Brain areas related to cognition and emotion were enhanced after end-to-side nerve transfer.Our study revealed important brain networks related to different nerve reconstructions.These networks may be potential targets for enhancing motor recovery.

Dietary Lipid Intervention in the Prevention of Brain Aging

As people live longer,the burden of aging-related brain diseases,especially dementia,is increasing.Brain aging increases the risk of cognitive impairment,which manifests as a progressive loss of neuron function caused by the impairment of synaptic plasticity via disrupting lipid homeostasis.Therefore,supplemental dietary lipids have the potential to prevent brain aging.This review summarizes the important roles of dietary lipids in brain function from both structure and mechanism perspectives.Epidemiological and animal studies have provided evidence of the functions of polyunsaturated fatty acids(PUFAs)in brain health.The results of interventions indicate that phospholipids—including phosphatidylcholine,phosphatidylserine,and plasmalogen—are efficient in alleviating cognitive impairment during aging,with plasmalogen exhibiting higher efficacy than phosphatidylserine.Plasmalogen is a recognized nutrient used in clinical trials due to its special vinyl ether bonds and abundance in the postsynaptic membrane of neurons.Future research should determine the dose-dependent effects of plasmalogen in alleviating brain-aging diseases and should develop extraction and storage procedures for its clinical application.

Microglia in brain aging:An overview of recent basic science and clinical research developments

Aging is characterized by progressive degeneration of tissues and organs,and it is positively associated with an increased mortality rate.The brain,as one of the most significantly affected organs,experiences age-related changes,including abnormal neuronal activity,dysfunctional calcium homeostasis,dysregulated mitochondrial function,and increased levels of reactive oxygen species.These changes collectively contribute to cognitive deterioration.Aging is also a key risk factor for neurodegenerative diseases,such as Alzheimer's disease and Parkinson's disease.For many years,neurodegenerative disease investigations have primarily focused on neurons,with less attention given to microglial cells.However,recently,microglial homeostasis has emerged as an important mediator in neurological disease pathogenesis.Here,we provide an overview of brain aging from the perspective of the microglia.In doing so,we present the current knowledge on the correlation between brain aging and the microglia,summarize recent progress of investigations about the microglia in normal aging,Alzheimer's disease,Parkinson's disease,Huntington's disease,and amyotrophic lateral sclerosis,and then discuss the correlation between the senescent microglia and the brain,which will culminate with a presentation of the molecular complexity involved in the microglia in brain aging with suggestions for healthy aging.

Imaging brain plasticity after trauma

The brain is highly plastic after stroke or epilepsy; however, there is a paucity of brain plasticity investigation after traumatic brain injury （TBI）. This mini review summarizes the most recent evidence of brain plasticity in human TBI patients from the perspective of advanced magnetic resonance imaging. Similar to other forms of acquired brain injury, TBI patients also demonstrat- ed both structural reorganization as well as functional compensation by the recruitment of other brain regions. However, the large scale brain network alterations after TBI are still unknown, and the field is still short of proper means on how to guide the choice of TBI rehabilitation or treat- ment plan to promote brain plasticity. The authors also point out the new direction of brain plas- ticity investigation.

Using AI and Precision Nutrition to Support Brain Health during Aging

Artificial intelligence, often referred to as AI, is a branch of computer science focused on developing systems that exhibit intelligent behavior. Broadly speaking, AI researchers aim to develop technologies that can think and act in a way that mimics human cognition and decision-making [1]. The foundations of AI can be traced back to early philosophical inquiries into the nature of intelligence and thinking. However, AI is generally considered to have emerged as a formal field of study in the 1940s and 1950s. Pioneering computer scientists at the time theorized that it might be possible to extend basic computer programming concepts using logic and reasoning to develop machines capable of “thinking” like humans. Over time, the definition and goals of AI have evolved. Some theorists argued for a narrower focus on developing computing systems able to efficiently solve problems, while others aimed for a closer replication of human intelligence. Today, AI encompasses a diverse set of techniques used to enable intelligent behavior in machines. Core disciplines that contribute to modern AI research include computer science, mathematics, statistics, linguistics, psychology and cognitive science, and neuroscience. Significant AI approaches used today involve statistical classification models, machine learning, and natural language processing. Classification methods are widely applicable to problems in various domains like healthcare, such as informing diagnostic or treatment decisions based on patterns in data. Dean and Goldreich, 1998, define ML as an approach through which a computer has to learn a model by itself from the data provided but no specification on the sort of model is provided to the computer. They can then predict values for things that are different from the values used in training the models. NLP looks at two interrelated concerns, the task of training computers to understand human languages and the fact that since natural languages are so complex, they lend themselves very well to serving a number of very useful goals when used by computers.

Contrast Normalization Strategies in Brain Tumor Imaging:From Preprocessing to Classification

Cancer-related to the nervous system and brain tumors is a leading cause of mortality in various countries.Magnetic resonance imaging(MRI)and computed tomography(CT)are utilized to capture brain images.MRI plays a crucial role in the diagnosis of brain tumors and the examination of other brain disorders.Typically,manual assessment of MRI images by radiologists or experts is performed to identify brain tumors and abnormalities in the early stages for timely intervention.However,early diagnosis of brain tumors is intricate,necessitating the use of computerized methods.This research introduces an innovative approach for the automated segmentation of brain tumors and a framework for classifying different regions of brain tumors.The proposed methods consist of a pipeline with several stages:preprocessing of brain images with noise removal based on Wiener Filtering,enhancing the brain using Principal Component Analysis(PCA)to obtain well-enhanced images,and then segmenting the region of interest using the Fuzzy C-Means(FCM)clustering technique in the third step.The final step involves classification using the Support Vector Machine(SVM)classifier.The classifier is applied to various types of brain tumors,such as meningioma and pituitary tumors,utilizing the Contrast-Enhanced Magnetic Resonance Imaging(CE-MRI)database.The proposed method demonstrates significantly improved contrast and validates the effectiveness of the classification framework,achieving an average sensitivity of 0.974,specificity of 0.976,accuracy of 0.979,and a Dice Score(DSC)of 0.957.Additionally,this method exhibits a shorter processing time of 0.44 s compared to existing approaches.The performance of this method emphasizes its significance when compared to state-of-the-art methods in terms of sensitivity,specificity,accuracy,and DSC.To enhance the method further in the future,it is feasible to standardize the approach by incorporating a set of classifiers to increase the robustness of the brain classification method.

Altered spontaneous brain activity patterns in hypertensive retinopathy using fractional amplitude of low-frequency fluctuations:a functional magnetic resonance imaging study

AIM:To study functional brain abnormalities in patients with hypertensive retinopathy(HR)and to discuss the pathophysiological mechanisms of HR by fractional amplitude of low-frequency fluctuations(fALFFs)method.METHODS:Twenty HR patients and 20 healthy controls(HCs)were respectively recruited.The age,gender,and educational background characteristics of the two groups were similar.After functional magnetic resonance imaging(fMRI)scanning,the subjects’spontaneous brain activity was evaluated with the fALFF method.Receiver operating characteristic(ROC)curve analysis was used to classify the data.Further,we used Pearson’s correlation analysis to explore the relationship between fALFF values in specific brain regions and clinical behaviors in patients with HR.RESULTS:The brain areas of the HR group with lower fALFF values than HCs were the right orbital part of the middle frontal gyrus(RO-MFG)and right lingual gyrus.In contrast,the values of fALFFs in the left middle temporal gyrus(MTG),left superior temporal pole(STP),left middle frontal gyrus(MFG),left superior marginal gyrus(SMG),left superior parietal lobule(SPL),and right supplementary motor area(SMA)were higher in the HR group.The results of a t-test showed that the average values of fALFFs were statistically significantly different in the HR group and HC group(P<0.001).The fALFF values of the left middle frontal gyrus in HR patients were positively correlated with anxiety scores(r=0.9232;P<0.0001)and depression scores(r=0.9682;P<0.0001).CONCLUSION:fALFF values in multiple brain regions of HR patients are abnormal,suggesting that these brain regions in HR patients may be dysfunctional,which may help to reveal the pathophysiological mechanisms of HR.

Is it a normal phenomenon for pediatric patients to have brain leptomeningeal contrast enhancement on 3-tesla magnetic resonance imaging?

Determining whether sevoflurane sedation in children leads to“pseudo”prominent leptomeningeal contrast enhancement(pLMCE)on 3 Tesla magnetic resonance imaging will help reduce overdiagnosis by radiologists and clarify the pathophysiological changes of pLMCE.

Homocysteinemia and Depression in Community-Dwelling Older Adults: The Cohort Longitudinal Study “InveCeAb” (Brain Aging in Abbiategrasso)

Depression is a major health problem, especially for elderly people. According to the “homocysteine hypothesis of depression”, high homocysteine levels may cause depression of mood via cerebrovascular diseases. Whilst biologically plausible, such hypothesis needs yet confirmation. We aimed at: 1) studying the relationships between homocysteinemia (HCY) and depression in a community-dwelling cohort of people aged 70 to 75 years at baseline;2) investigating plasma levels of HCY and 3) comparing these levels between males and females, in the same population. We exploited the data from four waves (2010, 2012, 2014 and 2018) of the longitudinal study “InveCeAb”, with specific regard towards mood assessment, by Geriatric Depression Scale (GDS) scoring, and diagnosis of clinically relevant or subthreshold depression. HCY plasma levels were measured in the waves 2012, 2014 and 2018. Sample attrition was due mainly to death or overall worsening. No statistically significant differences were found in plasma homocysteine levels in each wave, according to depressive symptoms. No correlations were found between plasma HCY levels in each wave with their corresponding GDS scores, even after adjustment for folate and cobalamin blood concentrations. Dichotomized levels of HCY (≤15 vs >15 μM/l) were not associated with dichotomized GDS scores (≤4 vs higher), clinically relevant and subthreshold depression diagnosis and any antidepressive use, in any wave. First (2012) HCY levels increased with participants’ increasing age, cross-sectionally. Listwise HCY concentrations decreased along the 3 waves. HCY levels were always higher in males than in females. Our results may challenge the “homocysteine hypothesis” of depression, whilst supporting the role of high homocysteinemia as a marker of overall bad health.

Preventing brain aging by the artificial enforcement of the unfolded protein response:future directions

As the life expectancy of the world’s population increases,age-related diseases are emerging as one of the greatest problems facing modern society.The onset of dementia and neurodegenerative diseases is strictly dependent on aging as a major risk factor and has a profound impact on various aspects of the lives of individuals and their families.

Training muscles to keep the aging brain fit

1.Aging and exercise Aging is associated with the decline of cellular,tissue,and systemic functions and is characterized by at least 7 highly interdependent molecular pillars of aging1(Fig.1).Besides compromised genetic functions(telomer shortening and epigenetic dysregulation),metabolic efficiency(impaired mitochondrial functions and nutrient sensing),and cellular stress responses deteriorate.Consequential disruption of normal protein regulation(proteostasis)in combination with impaired cellular waste clearance leads to the accumulation of macromolecular damage(and in some cases to specific protein aggregation pathologies,like in Alzheimer’s dementia brains).

Functional aspects of the brain lymphatic drainage system in aging and neurodegenerative diseases

The phenomenon of an aging population is advancing at a precipitous rate.Alzheimer's disease(AD)and Parkinson's disease(PD)are two of the most common age-associated neurodegenerative diseases,both of which are primarily characterized by the accumulation of toxic proteins and the progressive demise of neuronal structures.Recent discoveries about the brain lymphatic drainage system have precipitated a growing body of investigations substantiating its novel roles,including the clearance of macromolecular waste and the trafficking of immune cells.Notably,aquaporin 4-mediated glymphatic transport,crucial for maintaining neural homeostasis,becomes disrupted during the aging process and is further compromised in the pathogenesis of AD and PD.Functional meningeal lymphatic vessels,which facilitate the drainage of cerebrospinal fluid into the deep cervical lymph nodes,are integral in bridging the central nervous system with peripheral immune responses.Dysfunction in these meningeal lymphatic vessels exacerbates pathological trajectory of the age-related neurodegenerative disease.This review explores modulatory influence of the glymphatic system and meningeal lymphatic vessels on the aging brain and its associated neurodegenerative disorders.It also encapsulates the insights of potential mechanisms and prospects of the targeted non-pharmacological interventions.

IN VIVO MAPPING BRAIN MICROCIRCULATION BY LASER SPECKLE CONTRAST IMAGING:A MAGNETIC RESONANCE PERSPECTIVE OF THEORETICAL FRAMEWORK

The fundamental limitations of most vascular-based functional neuroimaging techniques are placed by the fact how fine the brain regulates the blood supply system.In vivo mapping of the cerebral microcirculation with high resolution and sensitivity hence becomes unprecedentedly compelling.This paper reviews the theoretical background of the laser speckle contrast imaging(LSCI)technique and attempts to present a complete framework stemming from a simple biophysical model.Through the sensitivity analysis,more insights into the tool optimization are attained for in vivo applications.Open questions of the technical aspects are discussed within this unified framework.Finally,it concludes with a brief perspective of future research in a way analogous to the magnetic resonance imaging(MRI)technique.Such exploration could catalyze their development and initiate a technological fusion for precise assessment of blood flow across various spatial scales.

Low-frequency transcranial magnetic stimulation is beneficial for enhancing synaptic plasticity in the aging brain

In the aging brain, cognitive function gradually dedines and causes a progressive reduction in the structural and functional plasticity of the hippocampus. Transcranial magnetic stimulation is an emerging and novel neurological and psychiatric tool used to investigate the neurobiology of cognitive function. Recent studies have demonstrated that low-frequency transcranial magnetic stimulation （〈1 Hz） ameliorates synaptic plasticity and spatial cognitive deficits in learning-impaired mice. However, the mechanisms by which this treatment improves these deficits during normal aging are still unknown. Therefore, the current study investigated the effects of transcranial magnetic stimulation on the brain-derived neurotrophic factor signal pathway, synaptic protein markers, and spatial memory behavior in the hippocampus of normal aged mice. The study also investigated the downstream regulator, Fyn kinase, and the downstream effectors, synaptophysin and growth-associated protein 43 （both synaptic markers）, to determine the possible mechanisms by which transcranial magnetic stimulation regulates cognitive capacity. Transcranial magnetic stimulation with low intensity （110% average resting motor threshold intensity, 1 Hz） increased mRNA and protein levels of brain-derived neurotrophic factor, tropomyosin receptor kinase B, and Fyn in the hippocampus of aged mice. The treatment also upregulated the mRNA and protein expression of synaptophysin and growth-associated protein 43 in the hippocampus of these mice. In conclusion, brain-derived neurotrophic factor signaling may play an important role in sustaining and regulating structural synaptic plasticity induced by transcranial magnetic stimulation in the hippocampus of aging mice, and Fyn may be critical during this regulation. These responses may change the structural plasticity of the aging hippocampus, thereby improving cognitive function.

Highly Sensitive MoS_2–Indocyanine Green Hybrid for Photoacoustic Imaging of Orthotopic Brain Glioma at Deep Site

Photoacoustic technology in combination with molecular imaging is a highly effective method for accurately diagnosing brain glioma. For glioma detection at a deeper site, contrast agents with higher photoacoustic imaging sensitivity are needed. Herein, we report a MoS_2–ICG hybrid with indocyanine green(ICG) conjugated to the surface of MoS_2 nanosheets. The hybrid significantly enhanced photoacoustic imaging sensitivity compared to MoS_2 nanosheets. This conjugation results in remarkably high optical absorbance across a broad near-infrared spectrum, redshifting of the ICG absorption peak and photothermal/photoacoustic conversion efficiency enhancement of ICG. A tumor mass of 3.5 mm beneath the mouse scalp was clearly visualized by using MoS_2–ICG as a contrast agent for the in vivo photoacoustic imaging of orthotopic glioma, which is nearly twofold deeper than the tumors imaged in our previous report using MoS_2 nanosheet. Thus, combined with its good stability and high biocompatibility, the MoS_2–ICG hybrid developed in this study has a great potential for high-efficiency tumor molecular imaging in translational medicine.

Physical Activity, Mediterranean Diet and Biomarkers-Assessed Risk of Alzheimer’s: A Multi-Modality Brain Imaging Study

Increased physical activity and higher adherence to a Mediterranean-type diet (MeDi) have been independently associated with reduced risk of Alzheimer’s disease (AD). Their association has not been investigated with the use of biomarkers. This study examines whether, among cognitively normal (NL) individuals, those who are less physically active and show lower MeDi adherence have brain biomarker abnormalities consistent with AD. Methods: Forty-five NL individuals (age 54 ± 11, 71% women) with complete leisure time physical activity (LTA), dietary information, and cross-sectional 3D T1-weigthed MRI, 11C-Pittsburgh Compound B (PiB) and 18F-fluorodeoxyglucose (FDG) Positron Emission Tomography (PET) scans were examined. Voxel-wise multivariate partial least square (PLS) regression was used to examine the effects of LTA, MeDi and their interaction on brain biomarkers. Age, gender, ethnicity, education, caloric intake, BMI, family history of AD, Apolipoprotein E (APOE) genotype, presence of hypertension and insulin resistance were examined as confounds. Subjects were dichotomized into more and less physically active (LTA+ vs. LTA-;n = 21 vs. 24), and into higher vs. lower MeDi adherence groups (n = 18 vs. 27) using published scoring methods. Spatial patterns of brain biomarkers that represented the optimal association between the images and the groups were generated for all modalities using voxel-wise multivariate Partial Least Squares (PLS) regression. Results: Groups were comparable for clinical and neuropsychological measures. Independent effects of LTA and MeDi factors were observed in AD-vulnerable brain regions for all modalities (p β load and lower glucose metabolism) were observed in LTA- compared to LTA+ subjects, and in MeDi- as compared to MeDi+ subjects. A gradient effect was observed for all modalities so that LTA+/MeDi+ subjects had the highest and LTA+/MeDi+ subjects had the lowest AD-burden (p < 0.001), although the LTA × MeDi interaction was significant only for FDG measures (p < 0.03). Adjusting for covariates did not attenuate these relationships. Conclusion: Lower physical activity and MeDi adherence were associated with increased brain AD-burden among NL individuals, in-dicating that lifestyle factors may modulate AD risk. Studies with larger samples and longitudinal evaluations are needed to determine the predictive power of the observed associations.