Age-related Neurological Disorders Research Articles

Neurology of Aging : adapting neurology provision for an aging population.

Background Over the past few decades, advances in neurology of aging have been considerable and have led to a better understanding of the science of age-related neurological disorders. Likewise, it changed the perception of classical neurology practice, research and the way of looking at age-related conditions. Neurological disorders are the most frequent cause of major disability in the elderly and account for almost half of the incapacitation occurring beyond age 65 and more than 90% of serious dependency. However, a number of neurological changes occur also in the absence of a specific disease, making the assessment and management of neurological complaints and findings a specific expertise. Summary Maximizing success in clinical care of the elderly requires expertise in geriatric neurology, which includes an understanding of current research regarding aging and age-related neurological dysfunctions, and the ability to work with other geriatric health care providers. Although current therapies for neurodegenerative diseases mainly offer symptomatic relief without slowing progression, the landscape is evolving. Biomarkers of pathology and neuroimaging have continued to develop, with a significant impact on diagnosis and treatment. These advances have helped to improve our knowledge of disease pathophysiology but also disease stages, guiding symptomatic monitoring, and possible therapeutic options at a pre-symptomatic stage. Key Messages Neurological disorders are a leading cause of major disability and dependency in the elderly, underscoring the need for expertise in geriatric neurology for effective clinical care of this population. Although current therapies for neurodegenerative diseases primarily provide symptomatic relief without slowing disease progression, advancements in biomarkers and neuroimaging are significantly evolving. These advancements enhance our understanding of disease pathophysiology and stages, guiding symptomatic monitoring and potential therapeutic options at a pre-symptomatic stage. As knowledge about age-associated conditions is steadily rising and geriatric medicine gains further recognition, this article argues for a new focus on the role of neurologists in geriatric medicine, emphasizing the importance of integrating current research and collaborative care approaches in the management of elderly patients.

Transcriptomic changes in oligodendrocyte lineage cells during the juvenile to adult transition in the mouse corpus callosum.

The corpus callosum, a major white matter tract in the brain, undergoes age-related functional changes. To extend our investigation of age-related gene expression dynamics in the mouse corpus callosum, we compared RNA-seq data from 2week-old and 12week-old wild-type C57BL/6J mice and identified the differentially expressed genes (e.g., Marcksl1, Chst3, C4b, Neat1, Ndrg1, Emid1, etc.) between these ages. Interestingly, we found that genes highly expressed in myelinating oligodendrocytes were upregulated in 12week-old mice compared to 2week-old mice, while genes highly expressed in oligodendrocyte precursor cells (OPCs) and newly formed oligodendrocytes were downregulated. Furthermore, by comparing these genes with the datasets from 20week-old and 96week-old mice, we identified novel sets of genes with age-dependent variations in the corpus callosum. These gene expression changes potentially affect key biological pathways and may be closely linked to age-related neurological disorders, including dementia and stroke. Therefore, our results provide an additional dataset to explore age-dependent gene expression dynamics of oligodendrocyte lineage cells in the corpus callosum.

Synergy of exercise and hypoxia for brain health and aging – A narrative review

Regular exercise is a well-established means to improve brain health and prevent age-related neurological diseases, including dementia (Marques-Aleixo et al., 2020). The precise mechanisms how direct exercise effects are transmitted to the brain remain incompletely understood. However, the increased oxygen demand and associated metabolic stress in the primarily affected tissues – the working skeletal muscle, the cardiovascular and the respiratory system – likely play crucial roles in exercise-signalling to the brain (Severinsen & Pedersen, 2020). Besides the mobilization of beneficial circulating factors, the modulation of blood properties and blood-flow, the immune system and the autonomous system are involved. Intriguingly, physiological stress induced by low environmental oxygen availability (hypoxia) can induce the activation of similar processes like exercise. The aim of this contribution is to evaluate the role of hypoxia in the benefits of exercise on the brain. Accumulating evidence demonstrates the potential of direct modulation of inspired oxygen levels to improve neurological diseases (Burtscher et al., 2021). Reduced all-cause mortality in people living at moderate altitudes (and therefore in chronic, mild hypobaric hypoxia) may also be associated with reduced risk of neurological diseases, including of stroke (Faeh et al., 2009). This is surprising, because the hypoxic stress at moderate altitudes (usually defined as altitudes between 1,500 and 2,500 m) is generally considered too low to induce substantial hypoxia adaptations. It is thus possible that the combination of moderate environmental hypoxia at moderate altitude with the increased oxygen demand during exercise is required to promote protective adaptations, such as of the brain. Considering this possibility, synergistic and complementary molecular and systemic responses and adaptations to exercise and hypoxia may benefit the brain. Among the involved molecular processes are mitochondrial changes following cellular stress that are also linked to the regulation of adaptations by the transcription factor hypoxia inducible factor, which is activated by both hypoxia and exercise. Mitochondria are the main molecular oxygen consumers, respond sensitively to stress and dispose of a wide array of intra- and intercellular communication modes (Memme et al., 2021). Moreover, exerkines, blood-borne factors released in response to exercise, have emerged as important mediators of inter-organ exercise-signalling (Severinsen & Pedersen, 2020) and modulate the autonomic and immune system in response to hypoxic and metabolic stress. In conclusion, the activation of endogenous responses to hypoxic and metabolic stress are powerful means to improve brain health and healthy aging. Based on the overlapping and distinct physiological responses to hypoxia and exercise, brain benefits of exercising at higher altitudes and advances in the development of customized strategies to improve brain resilience are promising approaches to target neurological diseases. While the safe performance of exercise in moderate altitudes is already considered an impactful way to improve brain health, the optimization of combined exercise and (artificially induced) hypoxia for specific target groups requires further in-depth investigation. References Burtscher, J., Mallet, R. T., Burtscher, M., & Millet, G. P. (2021). Hypoxia and brain aging: Neurodegeneration or neuroprotection? Ageing Research Reviews, 68, Article 101343. https://doi.org/10.1016/j.arr.2021.101343 Faeh, D., Gutzwiller, F., Bopp, M., & Group, S. N. C. S. (2009). Lower mortality from coronary heart disease and stroke at higher altitudes in Switzerland. Circulation, 120(6), 495-501. https://doi.org/10.1161/CIRCULATIONAHA.108.819250 Marques-Aleixo, I., Beleza, J., Sampaio, A., Stevanović, J., Coxito, P., Gonçalves, I., Ascensão, A., & Magalhães, J. (2020). Preventive and therapeutic potential of physical exercise in neurodegenerative diseases. Antioxidants & Redox Signaling, 34(8), 674–693. https://doi.org/10.1089/ars.2020.8075 Memme, J. M., Erlich, A. T., Phukan, G., & Hood, D. A. (2021). Exercise and mitochondrial health. The Journal of Physiology, 599(3), 803-817. https://doi.org/10.1113/jp278853 Severinsen, M. C. K., & Pedersen, B. K. (2020). Muscle-organ crosstalk: The emerging roles of myokines. Endocrine Reviews, 41(4), 594-609. https://doi.org/10.1210/endrev/bnaa016

Hallmarks of aging in age-related macular degeneration and age-related neurological disorders: novel insights into common mechanisms and clinical relevance.

Age-related macular degeneration (AMD) and age-related neurological diseases (ANDs), such as Alzheimer's and Parkinson's Diseases, are increasingly prevalent conditions that significantly contribute to global morbidity, disability, and mortality. The retina, as an accessible part of the central nervous system (CNS), provides a unique window to study brain aging and neurodegeneration. By examining the associations between AMD and ANDs, this review aims to highlight novel insights into fundamental mechanisms of aging and their role in neurodegenerative disease progression. This review integrates knowledge from the emerging field of aging research, which identifies common denominators of biological aging, specifically loss of proteostasis, impaired macroautophagy, mitochondrial dysfunction, and inflammation. Finally, we emphasize the clinical relevance of these pathways and the potential for cross-disease therapies that target common aging hallmarks. Identifying these shared pathways could open avenues to develop therapeutic strategies targeting mechanisms common to multiple degenerative diseases, potentially attenuating disease progression and promoting the healthspan.

Microglial and neuronal fates following inhibition of CSF-1R in synucleinopathy mouse model

Synucleinopathies are age-related neurological disorders characterized by the abnormal accumulation of α-synuclein (α-syn) in neuronal and non-neuronal cells. It has been proposed that microglial cells play an important role in synucleinopathy neuroinflammation, as well as homeostatically, such as in the clearance of α-syn aggregates in the brain. Here, we examined the effects of microglia on the pathogenesis of synucleinopathies by cell depletion in a mouse model of synucleinopathies. For this purpose, we treated non-transgenic (Non-tg) and α-synuclein transgenic (α-syn-tg) mice with pexidartinib (PLX3397), a tyrosine kinase inhibitor of colony-stimulating factor 1 receptor (CSF-1R). Neuropathological and immunoblot analysis confirmed that Iba-1 immunoreactive microglial cells were decreased by 95% following PLX3397 treatment in Non-tg and α-syn-tg mice. The level of total α-syn in the Triton X-insoluble fraction of brain homogenate was significantly decreased by microglial depletion in the α-syn-tg mice, while the level of Triton X-soluble human α-syn was not affected. Furthermore, the number of p-α-syn immunoreactive inclusions was reduced in α-syn-tg mice treated with PLX3397. Microglial depletion also ameliorated neuronal and synaptic degeneration in α-syn-tg mice, thereby resulted partially improving the motor behavioral deficit in α-syn-tg mice. Moreover, we demonstrated that microglia that survived post-PLX3397 treatment (PLX-resistant microglia) have lower expressions of CSF-1R, and microglial transcriptome analysis further elucidated that PLX-resistant microglia have unique morphology and transcriptomic signatures relative to vehicle-treated microglia of both genotypes; these include differences in definitive microglial functions such as their immune response, cell mobility, cell–cell communications, and regulation of neural homeostasis. Therefore, we suggest that microglia play a critical role in the pathogenesis of synucleinopathies, and that modulation of microglial status might be an effective therapeutic strategy for synucleinopathies.

Sex-steroid hormones relate to cerebellar structure and functional connectivity across adulthood.

Aging involves complex biological changes that affect disease susceptibility and aging trajectories. Although females typically live longer than males, they have a higher susceptibility to diseases like Alzheimer's, speculated to be influenced by menopause, and reduced ovarian hormone production. Understanding sex-specific differences is crucial for personalized medical interventions and gender equality in health. Our study aims to elucidate sex differences in regional cerebellar structure and connectivity during normal aging by investigating both structural and functional connectivity variations, with a focus on investigating these differences in the context of sex-steroid hormones. The study included 138 participants (mean age = 57(13.3) years, age range = 35-86 years, 54% women). The cohort was divided into three groups: 38 early middle-aged individuals (EMA) (mean age = 41(4.7) years), 48 late middle-aged individuals (LMA) (mean age = 58(4) years), and 42 older adults (OA) (mean age = 72(6.3) years). All participants underwent MRI scans, and saliva samples were collected for sex-steroid hormone quantification (17β-estradiol (E), progesterone (P), and testosterone (T)). We found less connectivity in females between Lobule I-IV and the cuneus, and greater connectivity in females between Crus I, Crus II, and the precuneus with increased age. Higher 17β-estradiol levels were linked to greater connectivity in Crus I and Crus II cerebellar subregions. Analyzing all participants together, testosterone was associated with both higher and lower connectivity in Lobule I-IV and Crus I, respectively, while higher progesterone levels were linked to lower connectivity in females. Structural differences were observed, with EMA males having larger volumes compared to LMA and OA groups, particularly in the right I-IV, right Crus I, right V, and right VI. EMA females showed higher volumes in the right lobules V and VI. These results highlight the significant role of sex hormones in modulating cerebellar connectivity and structure across adulthood, emphasizing the need to consider sex and hormonal status in neuroimaging studies to better understand age-related cognitive decline and neurological disorders.

Transcriptomic Profile of Mouse Brain Ageing in Early Developmental Stages.

Ageing is a continuous process that can cause neurodevelopmental changes in the body. Several studies have examined its effects, but few have focused on how time affects biological processes in the early stages of brain development. As studying the changes that occur in the early stages of life is important to prevent age-related neurological and psychiatric disorders, we aim to focus on these changes. The transcriptomic markers of ageing that are common to the analysed brain regions of C57Bl/6J mice were identified after conducting two-way ANOVA tests and effect size analysis on the time courses of gene expression profiles in various mouse brain regions. A total of 16,374 genes (59.9%) significantly changed their expression level, among which 7600 (27.8%) demonstrated tissue-dependent differences only, and 1823 (6.7%) displayed time-dependent and tissue-independent responses. Focusing on genes with at least a large effect size gives the list of potential biomarkers 12,332 (45.1%) and 1670 (6.1%) genes, respectively. There were 305 genes that exhibited similar significant time response trends (independently of the brain region). Samples from an 11-day-old mouse embryo validated the identified early-stage brain ageing markers. The overall functional analysis revealed tRNA and rRNA processing in the mitochondrion and contact activation system (CAS), as well as the kallikrein/kinin system (KKS), together with clotting cascade and defective factor F9 activation being affected by ageing. Most ageing-related pathways were significantly enriched, especially those that are strongly connected to development processes and neurodegenerative diseases.

Pharmacotherapeutic potential of Vitis vinifera (grape) in age-related neurological diseases

Age-related neurological disorders (ANDs), including neurodegenerative diseases, are complex illnesses with an increasing risk with advancing years. The central nervous system's neuropathological conditions, including oxidative stress, neuroinflammation, and protein misfolding, are what define ANDs. Due to the rise in age-dependent prevalence, efforts have been made to combat ANDs. Vitis vinifera has a long history of usage to treat a variety of illness symptoms. Because multiple ligand sites may be targeted, Vitis vinifera components can be employed to treat ANDs. This is demonstrated by the link between the structure and action of these compounds. This review demonstrates that Vitis vinifera and its constituents, including flavonoids, phenolic compounds, stilbenoids and aromatic acids, are effective at reducing the neurological symptoms and pathological conditions of ANDs. This is done by acting as an antioxidant and anti-inflammatory. The active Vitis vinifera ingredients have therapeutic effects on ANDs, as this review explains.

Therapeutic potential of berries in age-related neurological disorders.

Aging significantly impacts several age-related neurological problems, such as stroke, brain tumors, oxidative stress, neurodegenerative diseases (Alzheimer's, Parkinson's, and dementia), neuroinflammation, and neurotoxicity. Current treatments for these conditions often come with side effects like hallucinations, dyskinesia, nausea, diarrhea, and gastrointestinal distress. Given the widespread availability and cultural acceptance of natural remedies, research is exploring the potential effectiveness of plants in common medicines. The ancient medical system used many botanical drugs and medicinal plants to treat a wide range of diseases, including age-related neurological problems. According to current clinical investigations, berries improve motor and cognitive functions and protect against age-related neurodegenerative diseases. Additionally, berries may influence signaling pathways critical to neurotransmission, cell survival, inflammation regulation, and neuroplasticity. The abundance of phytochemicals in berries is believed to contribute to these potentially neuroprotective effects. This review aimed to explore the potential benefits of berries as a source of natural neuroprotective agents for age-related neurological disorders.

Modeling of age-related neurological disease: utility of zebrafish.

Many age-related neurological diseases still lack effective treatments, making their understanding a critical and urgent issue in the globally aging society. To overcome this challenge, an animal model that accurately mimics these diseases is essential. To date, many mouse models have been developed to induce age-related neurological diseases through genetic manipulation or drug administration. These models help in understanding disease mechanisms and finding potential therapeutic targets. However, some age-related neurological diseases cannot be fully replicated in human pathology due to the different aspects between humans and mice. Although zebrafish has recently come into focus as a promising model for studying aging, there are few genetic zebrafish models of the age-related neurological disease. This review compares the aging phenotypes of humans, mice, and zebrafish, and provides an overview of age-related neurological diseases that can be mimicked in mouse models and those that cannot. We presented the possibility that reproducing human cerebral small vessel diseases during aging might be difficult in mice, and zebrafish has potential to be another animal model of such diseases due to their similarity of aging phenotype to humans.

Compounding Effects of Aging and Sex on Cerebrovascular Endothelial Mitochondria

Despite the increasing burden of age-related neurological diseases such as vascular cognitive impairment and dementia or Alzheimer’s disease, the underlying mechanisms of these pathologies are not clear. Nonetheless, structural and functional changes in the microvasculature represent probable pathological aspects of these age-associated diseases. The silent and cumulative changes in endothelial mitochondria with subsequently compromised cerebral vascular function are thought to play a central role in neurological disease development. We tested the hypothesis that mitochondrial morphological changes in endothelial cells facilitate the distinct aging- and sex-related differences in the cerebral microvascular proteome and energetics. Mito-dendra2 (mt-D2) labeled endothelial mitochondria were imaged in vivo via a cranial window using two-photon microscopy at 875 nm in young and old, male and female, mito-Dendra2 mice (YM, YF, OM, and OF, respectively). Mt-D2 associated signal was analyzed in 3D stacks using the Huygens Pro CE 23.04.0p3 object analyzer (160 images, originated from 4-5 mt-D2 mice/groups). We also measured mRNA copy numbers of mitochondrial fission and fusion genes in isolated, cortical microvessels (<70 μm) from YM, YF, OM, and OF C57Bl/6J mice (n=7-11/age/sex) using ddPCR. Kruskal-Wallis test with Dwass-Steel-Critchlow-Fligner post-hoc comparisons were used to compare mt-D2 signal among YM, YF, OM, and OF, whereas Mann-Whitney U test determined changes across age and sex strata. p<0.05 was considered statistically significant. mRNA copy numbers were normalized to housekeeping genes (GAPDH, β-actin, and HPRT-1) and compared with one-way ANOVA based on data distribution. Analysis of four object parameters revealed that object surface was smaller in old vs. young that was significant in YM vs. OM. We found significantly greater corrected lateral width in OM vs. YM, OF vs. YF, and in YF vs. YM. The lateral aspect ratio was significantly greater in YM vs. OM, in YF vs. OF, as well as in YM vs. YF. Accordingly, the axial sphericity of the principal box was significantly greater in OM vs. YM, in OF vs. YF, and in YF vs. YM. Normalized mRNA copy numbers of mitochondrial fission and fusion genes were not statistically different in our samples for DRP-1, Fis-1 or Mfn-1/2, Opa-1, respectively. These results suggest that aging driven morphological differences, such as the shortening of endothelial mt-D2 signal are, at least in part, facilitated by altered fission/fusion protein abundances and/or activity rather than transcriptional changes in our samples. Although we are still analyzing other morphological parameters, by assessing the effect sizes and their physiological relevance, we postulate that these morphological differences contribute to the vulnerability of the aged cerebral microvasculature to injury. AG083567, 3P30GM145498-01, U54GM104940, HL148836. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Unrevealing abducens palsy vs. divergence insufficiency: A comprehensive review

Background: The article "Unraveling Abducens Palsy vs. Divergence Insufficiency" provides a comprehensive review of two common ophthalmological conditions, namely Abducens Palsy and Divergence Insufficiency. Aim: In this review article, we aim to unravel the key differences between these conditions, providing healthcare professionals with valuable insights for accurate diagnosis. It provides a comprehensive analysis of the clinical features, diagnostic criteria, etiology, and management strategies for each condition. Methods: A systematic literature search was conducted in electronic databases, including PubMed, MEDLINE, and Google Scholar. Case reports, clinical trials, observational studies, and review articles were considered. The extracted data included information on the clinical presentation, diagnostic tests, etiology, and treatment options for these conditions. Results: The authors emphasize the importance of a thorough ophthalmological examination, including the Hirschberg test and forced duction test, in diagnosing Abducens Palsy accurately. The article also explores the potential causes of Divergence Insufficiency, such as age-related changes and neurologic disorders. The management strategies for both conditions are thoroughly discussed, encompassing both conservative and surgical approaches. Conclusion: The authors present a comprehensive analysis of the clinical features, diagnostic criteria, and management strategies for these two conditions.It serves as a valuable resource for healthcare professionals, providing them with the necessary knowledge to accurately diagnose and manage Abducens Palsy and Divergence Insufficiency. Further research in this field is warranted to enhance our understanding of the underlying mechanisms and optimize treatment outcomes.

Pharmacotherapeutic Potential of Bitter Gourd (Momordica charantia) in Age-related Neurological Diseases.

Due to the growth of the elderly population, age-related neurological disorders are an increasing problem. Aging begins very gradually and later leads to several neurological issues such as lower neurotransmitter levels, oxidative stress, neuronal inflammation, and continual neuronal loss. These changes might contribute to brain disorders such as Alzheimer's disease (AD), dementia or mild cognitive impairment, and epilepsy and glioma, and can also aggravate these disorders if they were previously present. Momordica charantia (bitter gourd), a member of the Cucurbitaceae family, is a good source of carbohydrates, proteins, vitamins, and minerals. It is used for diabetes and known for its hypoglycemic and antioxidant effects. In this review, we discuss the pharmaceutical effects of M. charantia on age-related neurological disorders. We searched several databases, including PubMed and Google Scholar, using MeSH terms. We searched articles published up until 2022 regardless of publication language. M. charantia is rich in luteolin, which increases acetylcholine in neurons by binding to enzymes in acetylcholine metabolism pathways, including butyrylcholinesterase and acetylcholinesterase. This binding inhibits the hyperphosphorylation of tau protein by restraining its kinase enzyme. Furthermore, this substance can lower serum cholesterol and has multi-target activity in AD and memory loss. M. charantia can also improve memory by decreasing tau protein and it also has potent antioxidant activity and anti-inflammatory effects. This review highlights that M. charantia has effects on many age-related neurological disorders, and can be a cost-effective supplement with minimal side effects.

Low-grade systemic inflammation stimulates microglial turnover and accelerates the onset of Alzheimer's-like pathology.

Several in vivo studies have shown that systemic inflammation, mimicked by LPS, triggers an inflammatory response in the CNS, driven by microglia, characterized by an increase in inflammatory cytokines and associated sickness behavior. However, most studies induce relatively high systemic inflammation, not directly compared with the more common low-grade inflammatory events experienced in humans during the life course. Using mice, we investigated the effects of low-grade systemic inflammation during an otherwise healthy early life, and how this may precondition the onset and severity of Alzheimer's disease (AD)-like pathology. Our results indicate that low-grade systemic inflammation induces sub-threshold brain inflammation and promotes microglial proliferation driven by the CSF1R pathway, contrary to the effects caused by high systemic inflammation. In addition, repeated systemic challenges with low-grade LPS induce disease-associated microglia. Finally, using an inducible model of AD-like pathology (Line 102 mice), we observed that preconditioning with repeated doses of low-grade systemic inflammation, prior to APP induction, promotes a detrimental effect later in life, leading to an increase in Aβ accumulation and disease-associated microglia. These results support the notion that episodic low-grade systemic inflammation has the potential to influence the onset and severity of age-related neurological disorders, such as AD.

Aging brain: exploring the interplay between bone marrow aging, immunosenescence, and neuroinflammation.

Aging is a complex process characterized by a myriad of physiological changes, including alterations in the immune system termed immunosenescence. It exerts profound effects on both the bone marrow and the central nervous system, with significant implications for immunosenescence in neurological contexts. Our mini-review explores the complex relationship between bone marrow aging and its impact on immunosenescence, specifically within the context of neurological diseases. The bone marrow serves as a crucial hub for hematopoiesis and immune cell production, yet with age, it undergoes significant alterations, including alterations in hematopoietic stem cell function, niche composition, and inflammatory signaling. These age-related shifts in the bone marrow microenvironment contribute to dysregulation of immune cell homeostasis and function, impacting neuroinflammatory processes and neuronal health. In our review, we aim to explore the complex cellular and molecular mechanisms that link bone marrow aging to immunosenescence, inflammaging, and neuroinflammation, with a specific focus on their relevance to the pathophysiology of age-related neurological disorders. By exploring this interplay, we strive to provide a comprehensive understanding of how bone marrow aging impacts immune function and contributes to the progression of neurological diseases in aging individuals. Ultimately, this knowledge can hold substantial promise for the development of innovative therapeutic interventions aimed at preserving immune function and mitigating the progression of neurological disorders in the elderly population.

A novel deep learning-based method for automatic stereology of microglia cells from low magnification images

Microglial cells mediate diverse homeostatic, inflammatory, and immune processes during normal development and in response to cytotoxic challenges. During these functional activities, microglial cells undergo distinct numerical and morphological changes in different tissue volumes in both rodent and human brains. However, it remains unclear how these cytostructural changes in microglia correlate with region-specific neurochemical functions. To better understand these relationships, neuroscientists need accurate, reproducible, and efficient methods for quantifying microglial cell number and morphologies in histological sections. To address this deficit, we developed a novel deep learning (DL)-based classification, stereology approach that links the appearance of Iba1 immunostained microglial cells at low magnification (20×) with the total number of cells in the same brain region based on unbiased stereology counts as ground truth. Once DL models are trained, total microglial cell numbers in specific regions of interest can be estimated and treatment groups predicted in a high-throughput manner (<1 min) using only low-power images from test cases, without the need for time and labor-intensive stereology counts or morphology ratings in test cases. Results for this DL-based automatic stereology approach on two datasets (total 39 mouse brains) showed >90% accuracy, 100% percent repeatability (Test-Retest) and 60× greater efficiency than manual stereology (<1 min vs. ∼ 60 min) using the same tissue sections. Ongoing and future work includes use of this DL-based approach to establish clear neurodegeneration profiles in age-related human neurological diseases and related animal models.

Tremendous Fidelity of Vitamin D3 in Age-related Neurological Disorders.

Vitamin D3 (VD) is a secosteroid hormone and shows a pleiotropic effect in brain-related disorders where it regulates redox imbalance, inflammation, apoptosis, energy production, and growth factor synthesis. Vitamin D3's active metabolic form, 1,25-dihydroxy Vitamin D3 (1,25(OH)2D3 or calcitriol), is a known regulator of several genes involved in neuroplasticity, neuroprotection, neurotropism, and neuroinflammation. Multiple studies suggest that VD deficiency can be proposed as a risk factor for the development of several age-related neurological disorders. The evidence for low serum levels of 25-hydroxy Vitamin D3 (25(OH)D3 or calcidiol), the major circulating form of VD, is associated with an increased risk of Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), dementia, and cognitive impairment. Despite decades of evidence on low VD association with neurological disorders, the precise molecular mechanism behind its beneficial effect remains controversial. Here, we will be delving into the neurobiological importance of VD and discuss its benefits in different neuropsychiatric disorders. The focus will be on AD, PD, and HD as they share some common clinical, pathological, and epidemiological features. The central focus will be on the different attributes of VD in the aspect of its anti-oxidative, anti-inflammatory, anti-apoptotic, anti-cholinesterase activity, and psychotropic effect in different neurodegenerative diseases.

Elucidating Multimodal Imaging Patterns in Accelerated Brain Aging: Heterogeneity through a Discriminant Analysis Approach Using the UK Biobank Dataset.

Accelerated brain aging (ABA) intricately links with age-associated neurodegenerative and neuropsychiatric diseases, emphasizing the critical need for a nuanced exploration of heterogeneous ABA patterns. This investigation leveraged data from the UK Biobank (UKB) for a comprehensive analysis, utilizing structural magnetic resonance imaging (sMRI), diffusion magnetic resonance imaging (dMRI), and resting-state functional magnetic resonance imaging (rsfMRI) from 31,621 participants. Pre-processing employed tools from the FMRIB Software Library (FSL, version 5.0.10), FreeSurfer, DTIFIT, and MELODIC, seamlessly integrated into the UKB imaging processing pipeline. The Lasso algorithm was employed for brain-age prediction, utilizing derived phenotypes obtained from brain imaging data. Subpopulations of accelerated brain aging (ABA) and resilient brain aging (RBA) were delineated based on the error between actual age and predicted brain age. The ABA subgroup comprised 1949 subjects (experimental group), while the RBA subgroup comprised 3203 subjects (control group). Semi-supervised heterogeneity through discriminant analysis (HYDRA) refined and characterized the ABA subgroups based on distinctive neuroimaging features. HYDRA systematically stratified ABA subjects into three subtypes: SubGroup 2 exhibited extensive gray-matter atrophy, distinctive white-matter patterns, and unique connectivity features, displaying lower cognitive performance; SubGroup 3 demonstrated minimal atrophy, superior cognitive performance, and higher physical activity; and SubGroup 1 occupied an intermediate position. This investigation underscores pronounced structural and functional heterogeneity in ABA, revealing three subtypes and paving the way for personalized neuroprotective treatments for age-related neurological, neuropsychiatric, and neurodegenerative diseases.

Role of Serotonylation and SERT Posttranslational Modifications in Alzheimer's Disease Pathogenesis.

The neurotransmitter serotonin (5-hydroxytryptamine, 5-HT) is implicated mainly in Alzheimer's disease (AD) and reported to be responsible for several processes and roles in the human body, such as regulating sleep, food intake, sexual behavior, anxiety, and drug abuse. It is synthesized from the amino acid tryptophan. Serotonin also functions as a signal between neurons to mature, survive, and differentiate. It plays a crucial role in neuronal plasticity, including cell migration and cell contact formation. Various psychiatric disorders, such as depression, schizophrenia, autism, and Alzheimer's disease, have been linked to an increase in serotonin-dependent signaling during the development of the nervous system. Recent studies have found 5-HT and other monoamines embedded in the nuclei of various cells, including immune cells, the peritoneal mast, and the adrenal medulla. Evidence suggests these monoamines to be involved in widespread intracellular regulation by posttranslational modifications (PTMs) of proteins. Serotonylation is the calcium-dependent process in which 5-HT forms a long-lasting covalent bond to small cytoplasmic G-proteins by endogenous transglutaminase 2 (TGM2). Serotonylation plays a role in various biological processes. The purpose of our article is to summarize historical developments and recent advances in serotonin research and serotonylation in depression, aging, AD, and other age-related neurological diseases. We also discussed several of the latest developments with Serotonin, including biological functions, pathophysiological implications and therapeutic strategies to treat patients with depression, dementia, and other age-related conditions.

Neuroprotective potential of traditional Ayurvedic Kadha: age-related neurological disorders: a comprehensive literature review

Neuroprotective potential of traditional Ayurvedic Kadha: age-related neurological disorders: a comprehensive literature review