Age-related Neurological Disorders Research Articles

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.

Development of early prediction and discriminating techniques for Lewy body diseases

The advent of a super-aged society poses urgent challenges in overcoming age-related neurological disorders and extending a healthy lifespan. Neurodegenerative diseases such as Alzheimer's disease, dementia with Lewy bodies, and Parkinson's disease are characterized by the accumulation of pathogenic proteins in the brain, leading to the formation of intracellular aggregates known as pathological hallmarks. In the early stages of protein accumulation, before the onset of clinical symptoms such as cognitive impairment or motor dysfunction, brain inflammation begins to occur. Subsequently, neuronal death progresses, and clinical symptoms manifest as dementia or Parkinson's disease. Therefore, there is a need for early prediction of neurodegeneration and the development of disease-modifying drugs for pre-symptomatic prevention. To address this issue, we have focused on enhancing the degradation of amyloid-β protein by targeting Ca2+/calmodulin-dependent kinase II (CaMKII)/proteasome system and on suppressing the propagation and uptake mechanisms of α-synuclein by targeting fatty acid-binding proteins (FABPs) coupled with the long isoform of dopamine D2 (D2L) receptor. Additionally, our analysis of FABP knockout mice has revealed an increased expression of FABPs in the neurodegenerative process, suggesting their involvement in mitochondrial dysfunction and neuronal death. Based on these findings, this article highlights the physiological significance of FABP family proteins in neurodegeneration and discusses the analysis of plasma biomarkers for predicting neurodegenerative disorders and the discriminatory methods for distinguishing between Alzheimer's disease, dementia with Lewy bodies, and Parkinson's disease. Furthermore, we explore the potential of ultra-early prediction of neurodegenerative disorders.

CSF Extracellular Vesicle Aβ42 and Tau/Aβ42 Ratio Are Associated with Cognitive Impairment in Older People with HIV.

HIV-associated neurocognitive disorders (HAND) remain prevalent despite viral suppression on antiretroviral therapy (ART). Older people with HIV (PWH) are also at risk for amnestic mild cognitive impairment (aMCI) and Alzheimer's disease (AD). β-amyloid (Aβ) and Tau biomarkers are associated with aMCI/AD, but their relationship to HAND is unclear. Given the role of extracellular vesicles (EVs) in age-related neurological disorders, we investigated soluble and EV-associated Aβ42, total Tau, NFL, GFAP, ICAM-1, VCAM-1, and CRP in relation to cognitive impairment in PWH. Plasma and CSF EVs were isolated from 184 participants (98 PWH on ART and 86 HIV- controls). Biomarkers were measured using Meso Scale Discovery assays. The median age of PWH was 53 years, and 52% were diagnosed with mild forms of HAND. PWH had increased plasma NFL (p = 0.04) and CSF Aβ42 (p = 0.0003) compared with HIV- controls but no significant difference in Tau or EV-associated forms of these markers. CSF EV Aβ42 was decreased (p = 0.0002) and CSF EV Tau/Aβ42 ratio was increased (p = 0.001) in PWH with HAND vs. no HAND, while soluble forms of these markers showed no significant differences. Decreased CSF EV Aβ42 (p < 0.0001) and an increased CSF EV Tau/Aβ42 ratio (p = 0.0003) were associated with lower neurocognitive T scores in age-adjusted models; an optimal model included both CSF EV Aβ42 and plasma NFL. Levels of soluble, but not EV-associated, ICAM-1, VCAM-1, and CRP were increased in PWH with HAND vs. no HAND (p < 0.05). These findings suggest that decreased Aβ42 and an increased Tau/Aβ42 ratio in CSF EVs are associated with cognitive impairment in older PWH, and these EV-associated biomarkers may help to distinguish aMCI/AD from HIV-related cognitive disorders in future studies.

Improving brain age prediction with anatomical feature attention-enhanced 3D-CNN

Currently, significant progress has been made in predicting brain age from structural Magnetic Resonance Imaging (sMRI) data using deep learning techniques. However, despite the valuable structural information they contain, the traditional engineering features known as anatomical features have been largely overlooked in this context. To address this issue, we propose an attention-based network design that integrates anatomical and deep convolutional features, leveraging an anatomical feature attention (AFA) module to effectively capture salient anatomical features. In addition, we introduce a fully convolutional network, which simplifies the extraction of deep convolutional features and overcomes the high computational memory requirements associated with deep learning. Our approach outperforms several widely-used models on eight publicly available datasets (n = 2501), with a mean absolute error (MAE) of 2.20 years in predicting brain age. Comparisons with deep learning models lacking the AFA module demonstrate that our fusion model effectively improves overall performance. These findings provide a promising approach for combining anatomical and deep convolutional features from sMRI data to predict brain age, with potential applications in clinical diagnosis and treatment, particularly for populations with age-related cognitive decline or neurological disorders.

Oxidative Stress in Health and Disease.

Oxidative stress, resulting from the excessive intracellular accumulation of reactive oxygen species (ROS), reactive nitrogen species (RNS), and other free radical species, contributes to the onset and progression of various diseases, including diabetes, obesity, diabetic nephropathy, diabetic neuropathy, and neurological diseases, such as Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), and Parkinson's disease (PD). Oxidative stress is also implicated in cardiovascular disease and cancer. Exacerbated oxidative stress leads to the accelerated formation of advanced glycation end products (AGEs), a complex mixture of crosslinked proteins and protein modifications. Relatively high levels of AGEs are generated in diabetes, obesity, AD, and other I neurological diseases. AGEs such as Ne-carboxymethyllysine (CML) serve as markers for disease progression. AGEs, through interaction with receptors for advanced glycation end products (RAGE), initiate a cascade of deleterious signaling events to form inflammatory cytokines, and thereby further exacerbate oxidative stress in a vicious cycle. AGE inhibitors, AGE breakers, and RAGE inhibitors are therefore potential therapeutic agents for multiple diseases, including diabetes and AD. The complexity of the AGEs and the lack of well-established mechanisms for AGE formation are largely responsible for the lack of effective therapeutics targeting oxidative stress and AGE-related diseases. This review addresses the role of oxidative stress in the pathogenesis of AGE-related chronic diseases, including diabetes and neurological disorders, and recent progress in the development of therapeutics based on antioxidants, AGE breakers and RAGE inhibitors. Furthermore, this review outlines therapeutic strategies based on single-atom nanozymes that attenuate oxidative stress through the sequestering of reactive oxygen species (ROS) and reactive nitrogen species (RNS).

Protective Role Of Natural Dietary Antioxidants-A Mini Review

The objective of this review is to study the ameliorative effects of natural dietary antioxidants in the maintenance of health and the prevention and treatment of various pathophysiological disorders, with a focus on data pertaining to L-Ascorbic acid or vitamin C and α- Tocopherol or vitamin E. The current study discusses natural and synthetic antioxidants, its mechanism of action as free radical scavengers, protective role in prevention of some major diseases including lifestyle exposure diseases. There appear to be significant health benefits from dietary antioxidants, have important roles in preventing pathogenic processes related to Diabetic neuropathy, major depressive disorder, inflammation, cataract, age-related muscular degeneration, liver disorders, cardiovascular and neurological disorders, asthma and may enhance immune function. The combined supplementation of vitamins were found to be more beneficial in protection against oxidative stress due to their synergistic effects particularly vitamin C and vitamin E. Thus the findings in the present review will throw considerable light on the use of natural dietary antioxidants against various diseases thus adding more information on therapeutic approaches.

Aberrant spontaneous static and dynamic amplitude of low-frequency fluctuations in cerebral small vessel disease with or without mild cognitive impairment.

Cerebral small vessel disease (CSVD) is considered an age-related degenerative neurological disorder and the most common risk factor for vascular cognitive impairment (VCI). The amplitude of fluctuation of low frequency (ALFF) can detect altered intrinsic brain activity in CSVD. This study explored the static and dynamic ALFFs in the early stage of CSVD with (CSVD-M) or without (CSVD-W) mild cognitive impairment (MCI) in these patients and how these changes contribute to cognitive deterioration. Thirty consecutive CSVD cases and 18 healthy controls (HC) were included in this study. All the participants underwent a 3D magnetization-prepared rapid gradient-echo (MPRAGE) sequence to obtain structural T1-weighted images. Simultaneous multislice imaging 5(SMS5) was used for resting-state functional MRI (rs-fMRI), and Data Processing and Analysis of Brain Imaging software helped determine static ALFF (sALFF). The dynamic ALFF (dALFF) was calculated using the sliding window method of DynamicBC software. Analysis of Covariance (ANCOVA) and two-sample t-test were used to evaluate the sALFF and temporal variability of dALFF among the three groups. The subjects were rated on a broad standard neuropsychological scale. Partial correlation analysis was used to evaluate the correlation between sALFF and dALFF variability and cognition (Bonferroni correction, statistical threshold set at p<.05). Compared with HCs, the CSVD-M group indicated decreased sALFF values in the bilateral cerebellum posterior lobe (CPL) and the left inferior Parietal Lobule (IPL), with increased sALFF values in the right SFG. For dALFF analysis, the CSVD-W group had significant dALFF variability in the right fusiform gyrus compared with HC. Moreover, the postcentral gyrus (PoCG) was significantly high in the CSVD-W group. While in the CSVD-M group, the bilateral paracentral lobules (PL) revealed significantly elevated dALFF variability and low dALFF variability in the left CPL and right IPL compared with HCs. The CSVD-M group had high dALFF variability in the bilateral PL but low dALFF variability in the left middle temporal gyrus (MTG) and right PoCG compared with the CSVD-W group. The partial correlation analysis indicated that dALFF variability in the left MTG was positively associated with EM (r=0.713, p=.002) in CSVD-W and CSVD-M groups. In the groups with CSVD-M and HC, altered dALFF variability in the bilateral PL was negatively correlated with EM (r=-0.560, p=.002). There were significant changes in sALFF and dALFF variability in CSVD patients. Abnormal spontaneous static and dynamic ALFFs may provide new insights into cognitive dysfunction in CSVD with MCI and may be valuable biomarkers for early diagnosis.

α-Synuclein induces deficiency in clathrin-mediated endocytosis through inhibiting synaptojanin1 expression.

Parkinson's disease (PD) is an age-related chronic neurological disorder, mainly characterized by the pathological feature of α-synuclein (α-syn) aggregation, with the exact disease pathogenesis unclear. During the onset and progression of PD, synaptic dysfunction, including dysregulation of axonal transport, impaired exocytosis, and endocytosis are identified as crucial events of PD pathogenesis. It has been reported that over-expression of α-syn impairs clathrin-mediated endocytosis (CME) in the synapses. However, the underlying mechanisms still needs to be explored. In this study, we investigated the molecular events underlying the synaptic dysfunction caused by over-expression of wild-type human α-syn and its mutant form, involving series of proteins participating in CME. We found that excessive human α-syn causes impaired fission and uncoating of clathrin-coated vesicles during synaptic vesicle recycling, leading to reduced clustering of synaptic vesicles near the active zone and increased size of plasma membrane and number of endocytic intermediates. Furthermore, over-expressed human α-syn induced changes of CME-associated proteins, among which synaptojanin1 (SYNJ1) showed significant reduction in various brain regions. Over-expression of SYNJ1 in primary hippocampal neurons from α-syn transgenic mice recovered the synaptic vesicle density, clustering and endocytosis. Using fluorescence-conjugated transferrin, we demonstrated that SYNJ1 re-boosted the CME activity by restoring the phosphatidylinositol-4,5-bisphosphate homeostasis. Our data suggested that over-expression of α-syn disrupts synaptic function through interfering with vesicle recycling, which could be alleviated by re-availing of SYNJ1. Our study unrevealed a molecular mechanism of the synaptic dysfunction in PD pathogenesis and provided a potential therapeutic target for treating PD.

The relation of ApoE and COMT gene-gene interactions to cognitive and motor function in community-dwelling older adults: a pilot study.

Certain genes increase the risk of age-related neurological dysfunction and/or disease. For instance, ApoE is a well-known gene carrying risk for Alzheimer's disease, while COMT has been associated with age-related reductions in motor function. There is growing interest in the interrelationship between age-related changes in cognitive and motor function, and examining gene-gene interactions in this context. In this pilot study we examined the relations of the ApoE and COMT genes and their interaction to both cognitive and motor performance in community-dwelling older adults. We leveraged an archived dataset from a prior study on age-related muscle weakness in community-dwelling older adults. Sample size was between 72 and 82 individuals based on missing data. We examined the relationship of ApoE (Ɛ4 presence/absence), rs4680 SNP on the COMT gene (Val/Met, Val/Val, Met/Met), and sex on (1) overall cognitive functioning and specific cognitive domains known to decline in aging (processing speed, immediate and delayed memory, semantic and phonemic fluency, and executive functioning), and (2) indices of motor function (four square step test, short physical performance battery, grip strength/forearm lean mass, and purdue pegboard test). Homozygous COMT genotypes were associated with worse global cognitive performance, immediate memory, and semantic fluency, but only for older adults with at least one ApoE Ɛ4 allele. There were main effects for COMT for delayed memory and a main effect for both COMT and ApoE for coding and phonemic fluency. Women scored higher than men in overall cognition, immediate and delayed memory, and semantic fluency. There were no main effects or gene interactions for a measure of executive functioning (trial making test part B) or any of the measures of motor function. COMT, ApoE, and their interaction influence cognitive performance, but not motor functioning, in community dwelling older adults. Our work supports prior literature concluding that a heterozygous COMT genotype may be beneficial to sustain healthy cognitive functioning with advancing age for those who have a higher ApoE genetic risk status (at least one Ɛ4 allele). Future research should investigate interactions between COMT and ApoE in larger samples with comprehensive assessment of cognition and motor functioning.