Disease Pathology Research Articles

Neuronal Vulnerability to Degeneration in Parkinson's Disease and Therapeutic Approaches.

Parkinson's disease is the second most common neurodegenerative disease affecting millions of people worldwide. Despite the crucial threat it poses, currently, no specific therapy exists that can completely reverse or halt the progression of the disease. Parkinson's disease pathology is driven by neurodegeneration caused by the intraneuronal accumulation of alpha-synuclein (α-syn) aggregates in Lewy bodies in the substantia nigra region of the brain. Parkinson's disease is a multiorgan disease affecting the central nervous system (CNS) as well as the autonomic nervous system. A bidirectional route of spreading α-syn from the gut to CNS through the vagus nerve and vice versa has also been reported. Despite our understanding of the molecular and pathophysiological aspects of Parkinson's disease, many questions remain unanswered regarding the selective vulnerability of neuronal populations, the neuromodulatory role of the locus coeruleus, and alpha-synuclein aggregation. This review article aims to describe the probable factors that contribute to selective neuronal vulnerability in Parkinson's disease, such as genetic predisposition, bioenergetics, and the physiology of neurons, as well as the interplay of environmental and exogenous modulators. This review also highlights various therapeutic strategies with cell transplants, through viral gene delivery, by targeting α -synuclein and aquaporin protein or epidermal growth factor receptors for the treatment of Parkinson's disease. The application of regenerative medicine and patient-specific personalized approaches have also been explored as promising strategies in the treatment of Parkinson's disease.

Clinical Predictors of Postmortem Amyloid and Nonamyloid Cerebral Small Vessel Disease in Middle-Aged to Older Adults.

Sporadic cerebral small vessel disease (CSVD) is a class of important pathologic processes known to affect the aging brain and to contribute to cognitive impairment. We aimed to identify clinical risk factors associated with postmortem CSVD in middle-aged to older adults. We developed and tested risk models for their predictive accuracy of a pathologic diagnosis of nonamyloid CSVD and cerebral amyloid angiopathy (CAA) in a retrospective sample of 160 autopsied cases from the Edinburgh Brain Bank. Individuals aged 40 years and older covering the spectrum of healthy aging and common forms of dementia (i.e., highly-prevalent etiologies such as Alzheimer disease (AD), vascular cognitive impairment (VCI), and mixed dementia) were included. We performed binomial logistic regression models using sample splitting and cross-validation methods. Demographics, lifestyle habits, traditional vascular risk factors, chronic medical conditions, APOE4, and cognitive status were assessed as potential predictors. Forty percent of our sample had a clinical diagnosis of dementia (AD = 33, VCI = 26 and mixed = 5) while others were cognitively healthy (n = 96). The mean age at death was 73.8 (SD 14.1) years, and 40% were female. The presence of none-to-mild vs moderate-to-severe nonamyloid CSVD was predicted by our model with good accuracy (area under the curve [AUC] = 0.84, sensitivity [SEN] = 72%, specificity [SPE] = 95%), with the most significant clinical predictors being age, history of cerebrovascular events, and cognitive impairment. The presence of CAA pathology was also predicted with high accuracy (AUC = 0.86, SEN = 93%, SPE = 79%). Significant predictors included alcohol intake, history of cerebrovascular events, and cognitive impairment. In a subset of atypical dementias (n = 24), our models provided poor predictive performance for both nonamyloid CSVD (AUC = 0.50) and CAA (AUC = 0.43). CSVD pathology can be predicted with high accuracy based on clinical factors in patients within the spectrum of AD, VCI, and normal aging. Whether this prediction can be enhanced by the addition of fluid and neuroimaging biomarkers warrants additional study. Improving our understanding of clinical determinants of vascular brain health may lead to novel strategies in the prevention and treatment of vascular etiologies contributing to cognitive decline. This study provides Class II evidence that selected clinical factors accurately distinguish between middle-aged to older adults with and without cerebrovascular small vessel disease (amyloid and nonamyloid) pathology.

A cross-sectional study of α-synuclein seed amplification assay in Alzheimer's disease neuroimaging initiative: Prevalence and associations with Alzheimer's disease biomarkers and cognitive function.

Alzheimer's disease (AD) pathology is defined by β-amyloid (Aβ) plaques and neurofibrillary tau, but Lewy bodies (LBs; 𝛼-synuclein aggregates) are a common co-pathology for which effective biomarkers are needed. A validated α-synuclein Seed Amplification Assay (SAA) was used on recent cerebrospinal fluid (CSF) samples from 1638 Alzheimer's Disease Neuroimaging Initiative (ADNI) participants, 78 with LB-pathology confirmation at autopsy. We compared SAA outcomes with neuropathology, Aβ and tau biomarkers, risk-factors, genetics, and cognitive trajectories. SAA showed 79% sensitivity and 97% specificity for LB pathology, with superior performance in identifying neocortical (100%) compared to limbic (57%) and amygdala-predominant (60%) LB-pathology. SAA+ rate was 22%, increasing with disease stage and age. Higher Aβ burden but lower CSF p-tau181 associated with higher SAA+ rates, especially in dementia. SAA+ affected cognitive impairment in MCI and Early-AD who were already AD biomarker positive. SAA is a sensitive, specific marker for LB-pathology. Its increase in prevalence with age and AD stages, and its association with AD biomarkers, highlights the clinical importance of α-synuclein co-pathology in understanding AD's nature and progression. SAA shows 79% sensitivity, 97% specificity for LB-pathology detection in AD. SAA positivity prevalence increases with disease stage and age. Higher Aβ burden, lower CSF p-tau181 linked with higher SAA+ rates in dementia. SAA+ impacts cognitive impairment in early disease stages. Study underpins need for wider LB-pathology screening in AD treatment.

Single molecule characterisation of salivary protein aggregates from Parkinson's disease patients – a pilot study

Abstract Saliva is a convenient and accessible biofluid that has potential as a future diagnostic tool for Parkinson’s disease. Candidate diagnostic tests for Parkinson’s disease to date have predominantly focused on measurements of alpha-synuclein in cerebrospinal fluid, but there is a need for accurate tests utilising more easily accessible sample types. Prior studies utilising saliva have used bulk measurements of salivary α-synuclein to provide diagnostic insight. Aggregate structure may influence the contribution of α-synuclein to disease pathology. Single molecule approaches can characterise the structure of individual aggregates present in the biofluid and may therefore provide greater insight than bulk measurements. We have employed an antibody-based single-molecule pulldown assay to quantify salivary α-synuclein and amyloid-β peptide aggregate number and subsequently super-resolved captured aggregates using direct Stochastic Optical Reconstruction Microscopy to describe their morphological features. We show that the salivary α-synuclein aggregate/amyloid-β aggregate ratio is increased almost two-fold in Parkinson’s disease patients (n = 20) compared to controls (n = 20, p <0.05). Morphological information also provides insight with saliva from Parkinson’s disease patients containing a greater proportion of larger and more fibrillar amyloid-β aggregates than control saliva (p <0.05). Furthermore, the combination of count and morphology data provides greater diagnostic value than either measure alone distinguishing between the people with Parkinson’s disease (n = 17) and controls (n = 18) with a high degree of accuracy (AUC = 0.87, p <0.001) and a larger dynamic range. We therefore demonstrate for the first time the application of highly sensitive single molecule imaging techniques to saliva. In addition, we show that aggregates present within saliva retain relevant structural information further expanding the potential utility of saliva-based diagnostic methods.

The chronic cerebral hypoperfusion model induces proinflammatory cascades in Alzheimer's disease

Cerebral neuroinflammation has emerged as a significant pathway contributing to the progression of Alzheimer's disease (AD) pathology. Research implicates the NOD-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome complex, initiating caspase 1-mediated maturation of interleukin-1 β (IL-1β) and interleukin-18 (IL-18). This study investigates whether chronic cerebral hypoperfusion (CCH), induced via permanent bilateral occlusion of the common carotid arteries (PBOCCA), leads to cognitive dysfunction and NLRP3 inflammasome activation. Twenty male Sprague Dawley (SD) rats underwent PBOCCA to induce CCH. Two weeks post-surgery, locomotor and Morris water maze (MWM) tests were conducted to examine motor functions, spatial learning, and memory, respectively. The gene expression levels of cathepsin B, NLRP3, an apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC), and caspase-1 were analysed using real-time PCR, while the expression levels of the inflammatory cytokines were estimated using the ELISA method. Structural damage to the hippocampus was assessed using hematoxylin and eosin (HE) staining. Escape latencies and time spent in specific quadrants in PBOCCA significantly increased compared to sham-operated animals. There was no notable difference in locomotor activity between the PBOCCA and sham-operated groups. The number of pyknotic neurons with cytoplasmic shrinkage increased in the hippocampus. Gene expression of cathepsin B, NLRP3, ASC, and caspase-1 was upregulated in the PBOCCA group. The expression levels of IL-1β, IL-18, interleukin-6 (IL-6), and amyloid-β 1-42 (Aβ 1-42) were elevated in the PBOCCA group relative to sham. The findings confirm NLRP3 inflammasome induction, cognitive dysfunction, and inflammatory cytokines associated with AD and cerebral ischemia. The PBOCCA model provides a valuable tool for studying neurodegenerative including AD.

The neutrophil to lymphocyte ratio associates with markers of Alzheimer's disease pathology in cognitively unimpaired elderly people.

An elevated neutrophil-lymphocyte ratio (NLR) in blood has been associated with Alzheimer's disease (AD). However, an elevated NLR has also been implicated in many other conditions that are risk factors for AD, prompting investigation into whether the NLR is directly linked with AD pathology or a result of underlying comorbidities. Herein, we explored the relationship between the NLR and AD biomarkers in the cerebrospinal fluid (CSF) of cognitively unimpaired (CU) subjects. Adjusting for sociodemographics, APOE4, and common comorbidities, we investigated these associations in two cohorts: the Alzheimer's Disease Neuroimaging Initiative (ADNI) and the M.J. de Leon CSF repository at NYU. Specifically, we examined associations between the NLR and cross-sectional measures of amyloid-β42 (Aβ42), total tau (t-tau), and phosphorylated tau181 (p-tau), as well as the trajectories of these CSF measures obtained longitudinally. A total of 111 ADNI and 190 NYU participants classified as CU with available NLR, CSF, and covariate data were included. Compared to NYU, ADNI participants were older (73.79 vs. 61.53, p < 0.001), had a higher proportion of males (49.5% vs. 36.8%, p = 0.042), higher BMIs (27.94 vs. 25.79, p < 0.001), higher prevalence of hypertensive history (47.7% vs. 16.3%, p < 0.001), and a greater percentage of Aβ-positivity (34.2% vs. 20.0%, p = 0.009). In the ADNI cohort, we found cross-sectional associations between the NLR and CSF Aβ42 (β = -12.193, p = 0.021), but not t-tau or p-tau. In the NYU cohort, we found cross-sectional associations between the NLR and CSF t-tau (β = 26.812, p = 0.019) and p-tau (β = 3.441, p = 0.015), but not Aβ42. In the NYU cohort alone, subjects classified as Aβ + (n = 38) displayed a stronger association between the NLR and t-tau (β = 100.476, p = 0.037) compared to Aβ- subjects or the non-stratified cohort. In both cohorts, the same associations observed in the cross-sectional analyses were observed after incorporating longitudinal CSF data. We report associations between the NLR and Aβ42 in the older ADNI cohort, and between the NLR and t-tau and p-tau in the younger NYU cohort. Associations persisted after adjusting for comorbidities, suggesting a direct link between the NLR and AD. However, changes in associations between the NLR and specific AD biomarkers may occur as part of immunosenescence.

Neutrophil-Derived Proteases in Lung Inflammation: Old Players and New Prospects

Neutrophil-derived proteases are critical to the pathology of many inflammatory lung diseases, both chronic and acute. These abundant enzymes play roles in key neutrophil functions, such as neutrophil extracellular trap formation and reactive oxygen species release. They may also be released, inducing tissue damage and loss of tissue function. Historically, the neutrophil serine proteases (NSPs) have been the main subject of neutrophil protease research. Despite highly promising cell-based and animal model work, clinical trials involving the inhibition of NSPs have shown mixed results in lung disease patients. As such, the cutting edge of neutrophil-derived protease research has shifted to proteases that have had little-to-no research in neutrophils to date. These include the cysteine and serine cathepsins, the metzincins and the calpains, among others. This review aims to outline the previous work carried out on NSPs, including the shortcomings of some of the inhibitor-orientated clinical trials. Our growing understanding of other proteases involved in neutrophil function and neutrophilic lung inflammation will then be discussed. Additionally, the potential of targeting these more obscure neutrophil proteases will be highlighted, as they may represent new targets for inhibitor-based treatments of neutrophil-mediated lung inflammation.

Future perspective and clinical applicability of the combined use of plasma phosphorylated tau 181 and neurofilament light chain in Subjective Cognitive Decline and Mild Cognitive Impairment

We aimed to assess diagnostic accuracy of plasma p-tau181 and NfL separately and in combination in discriminating Subjective Cognitive Decline (SCD) and Mild Cognitive Impairment (MCI) patients carrying Alzheimer’s Disease (AD) pathology from non-carriers; to propose a flowchart for the interpretation of the results of plasma p-tau181 and NfL. We included 43 SCD, 41 MCI and 21 AD-demented (AD-d) patients, who underwent plasma p-tau181 and NfL analysis. Twenty-eight SCD, 41 MCI and 21 AD-d patients underwent CSF biomarkers analysis (Aβ1-42, Aβ1-42/1–40, p-tau, t-tau) and were classified as carriers of AD pathology (AP+) it they were A+/T+ , or non-carriers (AP−) when they were A−, A+/T−/N−, or A+/T−/N+ according to the A/T(N) system. Plasma p-tau181 and NfL separately showed a good accuracy (AUC = 0.88), while the combined model (NfL + p-tau181) showed an excellent accuracy (AUC = 0.92) in discriminating AP+ from AP− patients. Plasma p-tau181 and NfL results were moderately concordant (Coehn’s k = 0.50, p < 0.001). Based on a logistic regression model, we estimated the risk of AD pathology considering the two biomarkers: 10.91% if both p-tau181 and NfL were negative; 41.10 and 76.49% if only one biomarker was positive (respectively p-tau18 and NfL); 94.88% if both p-tau181 and NfL were positive. Considering the moderate concordance and the risk of presenting an underlying AD pathology according to the positivity of plasma p-tau181 and NfL, we proposed a flow chart to guide the combined use of plasma p-tau181 and NfL and the interpretation of biomarker results to detect AD pathology.

Pro-resolving lipid mediator reduces amyloid-β42– induced gene expression in human monocyte-derived microglia

Abstract Specialized pro-resolving lipid mediators including maresin 1 mediate resolution but the levels of these are reduced in Alzheimer's disease brain, suggesting that they constitute a novel target for the treatment of Alzheimer's disease to prevent/stop inflammation and combat disease pathology. Therefore, it is important to clarify whether they counteract the expression of genes and proteins induced by amyloid-β. With this objective, we analyzed the relevance of human monocyte-derived microglia for in vitro modeling of neuroinflammation and its resolution in the context of Alzheimer's disease and investigated the pro-resolving bioactivity of maresin 1 on amyloid-β42-induced Alzheimer's disease-like inflammation. Analysis of RNA-sequencing data and secreted proteins in supernatants from the monocyte-derived microglia showed that the monocyte-derived microglia resembled Alzheimer's disease-like neuroinflammation in human brain microglia after incubation with amyloid-β42. Maresin 1 restored homeostasis by down-regulating inflammatory pathway related gene expression induced by amyloid-β42 in monocyte-derived microglia, protection of maresin 1 against the effects of amyloid-β42 is mediated by a re-balancing of inflammatory transcriptional networks in which modulation of gene transcription in the nuclear factor-kappa B pathway plays a major part. We pinpointed molecular targets that are associated with both neuroinflammation in Alzheimer's disease and therapeutic targets by maresin 1. In conclusion, monocyte-derived microglia represent a relevant in vitro microglial model for studies on Alzheimer's disease-like inflammation and drug response for individual patients. Maresin 1 ameliorates amyloid-β42–induced changes in several genes of importance in Alzheimer's disease, highlighting its potential as a therapeutic target for Alzheimer's disease.

O20 Dissecting junctional epidermolysis bullosa heterogeneity

Abstract Introduction and aims Epidermolysis bullosa (EB) is a family of rare, incurable, inherited disorders that are characterized by extreme skin and mucosal fragility. One of the most severe forms is junctional EB (JEB). JEB is caused by mutations in genes encoding the skin basement membrane proteins laminin 332 (α3, β3, γ2), type XVII collagen or integrin α6β4. Despite similarities between the disease pathology of JEB and other forms of EB there is a dramatic reduction in life expectancy for patients with JEB. Patients with JEB rarely survive beyond the first year of life. To investigate this disparity, we have optimized a previously published conditional tamoxifen induced knockout JEB mouse model (Lama3flx/flxK14CreERT). This mouse model recapitulates all key features of JEB, such as thickening of the epidermis and visible blistering owing to the loss of laminin α3 at the basement membrane. Methods Single-cell (sc)RNA-Seq analysis was conducted on pooled skin samples from a healthy (control) and JEB mouse model (n = 3 per genotype). Immunofluorescent staining was conducted to confirm scRNA-Seq analysis including markers for skin differentiation (K14, transglutaminase 1, loricrin), proliferation (Ki67), basement membrane (laminin α3, laminin β3, laminin γ2, collagen VII) and immune markers (F4/80, Ly6-G/C, CD3, CD79). Results We can see large differences in cellular populations across the two conditions. With increased T- and B-immune-cell subpopulations in the JEB model compared with the healthy control. Utilizing CellChatDB we identified disease-specific signalling pathways that identify activated T- and B-cell populations interacting with JEB macrophage populations via proinflammatory pathways. Conclusions We have utilized an in vivo mouse model to gain insight into the molecular and cellular differences in a JEB diseased phenotype. Identifying changes in cellular pathways could be used as a targeted approach to identify a beneficial therapeutic treatment for JEB.

APOE ε4 carrier status modifies plasma p-tau181 concentrations in cognitively healthy super-seniors.

This study investigates the effect of apolipoprotein E (APOE) genotype on neurology plasma biomarkers in cognitively healthy Super-Seniors. Three hundred seventy plasma specimens from Super-Senior participants ≥ 85 years old, who have never been diagnosed with dementia, cancer, diabetes, cardiovascular, or major pulmonary disease, were analyzed on the Quanterix Simoa HD-X analyzer using commercial Neurology 4-plex E and phosphorylated tau (p-tau)181 assays. Eighty (22%) participants were APOE ε4 carriers and 290 (73%) were non-carriers. No significant differences were found between APOE ε4 carriers and non-carriers regarding age, sex, or Mini-Mental State Examination scores. In APOE ε4 carriers, plasma amyloid beta 42/40 was lower and p-tau181 and glial fibrillary acidic protein were higher compared to non-APOE ε4 carriers. After adjusting for demographic variables, p-tau181 was the only biomarker to remain significantly associated with APOE ε4 carrier status. APOE ε4 genotype modifies plasma p-tau181 concentration in seniors resilient to age-related clinical disease, suggesting that some Super-Seniors may have Alzheimer's disease pathology without progressing to cognitive decline. Healthy seniors enable identification of associations that may be masked by disease. Plasma phosphorylated tau (p-tau)181 concentrations associate with apolipoprotein E (APOE) ε4 carriership in healthy seniors. APOE should be accounted for when interpreting p-tau181, regardless of disease.

Comparison of plasma and neuroimaging biomarkers to predict cognitive decline in non-demented memory clinic patients.

Plasma biomarkers of Alzheimer's disease (AD) pathology, neurodegeneration, and neuroinflammation are ideally suited for secondary prevention programs in self-sufficient persons at-risk of dementia. Plasma biomarkers have been shown to be highly correlated with traditional imaging biomarkers. However, their comparative predictive value versus traditional AD biomarkers is still unclear in cognitively unimpaired (CU) subjects and with mild cognitive impairment (MCI). Plasma (Aβ42/40, p-tau181, p-tau231, NfL, and GFAP) and neuroimaging (hippocampal volume, centiloid of amyloid-PET, and tau-SUVR of tau-PET) biomarkers were assessed at baseline in 218 non-demented subjects (CU = 140; MCI = 78) from the Geneva Memory Center. Global cognition (MMSE) was evaluated at baseline and at follow-ups up to 5.7 years. We used linear mixed-effects models and Cox proportional-hazards regression to assess the association between biomarkers and cognitive decline. Lastly, sample size calculations using the linear mixed-effects models were performed on subjects positive for amyloid-PET combined with tau-PET and plasma biomarker positivity. Cognitive decline was significantly predicted in MCI by baseline plasma NfL (β=-0.55), GFAP (β=-0.36), hippocampal volume (β = 0.44), centiloid (β=-0.38), and tau-SUVR (β=-0.66) (all p < 0.05). Subgroup analysis with amyloid-positive MCI participants also showed that only NfL and GFAP were the only significant predictors of cognitive decline among plasma biomarkers. Overall, NfL and tau-SUVR showed the highest prognostic values (hazard ratios of 7.3 and 5.9). Lastly, we demonstrated that adding NfL to the inclusion criteria could reduce the sample sizes of future AD clinical trials by up to one-fourth in subjects with amyloid-PET positivity or by half in subjects with amyloid-PET and tau-PET positivity. Plasma NfL and GFAP predict cognitive decline in a similar manner to traditional imaging techniques in amyloid-positive MCI patients. Hence, even though they are non-specific biomarkers of AD, both can be implemented in memory clinic workups as important prognostic biomarkers. Likewise, future clinical trials might employ plasma biomarkers as additional inclusion criteria to stratify patients at higher risk of cognitive decline to reduce sample sizes and enhance effectiveness.

Understanding Role of Pesticides in Development of Parkinson's Disease: Insights from Drosophila and Rodent Models.

Parkinson's disease is a neurodegenerative illness linked to ageing, marked by the gradual decline of dopaminergic neurons in the midbrain. The exact aetiology of Parkinson's disease (PD) remains uncertain, with genetic predisposition and environmental variables playing significant roles in the disease's frequency. Epidemiological data indicates a possible connection between pesticide exposure and brain degeneration. Specific pesticides have been associated with important characteristics of Parkinson's disease, such as mitochondrial dysfunction, oxidative stress, and α-synuclein aggregation, which are crucial for the advancement of the disease. Recently, many animal models have been developed for Parkinson's disease study. Although these models do not perfectly replicate the disease's pathology, they provide valuable insights that improve our understanding of the condition and the limitations of current treatment methods. Drosophila, in particular, has been useful in studying Parkinson's disease induced by toxins or genetic factors. The review thoroughly analyses many animal models utilised in Parkinson's research, with an emphasis on issues including pesticides, genetic and epigenetic changes, proteasome failure, oxidative damage, α-synuclein inoculation, and mitochondrial dysfunction. The text highlights the important impact of pesticides on the onset of Parkinson's disease (PD) and stresses the need for more research on genetic and mechanistic alterations linked to the condition.

The vascular contribution of apolipoprotein E to Alzheimer's disease.

Alzheimer's disease, the most prevalent form of dementia, imposes a substantial societal burden. The persistent inadequacy of disease-modifying drugs targeting amyloid plaques and neurofibrillary tangles suggests the contribution of alternative pathogenic mechanisms. A frequently overlooked aspect is cerebrovascular dysfunction, which may manifest early in the progression of Alzheimer's disease pathology. Mounting evidence underscores the pivotal role of the apolipoprotein E gene, particularly the apolipoprotein ε4 allele as the strongest genetic risk factor for late-onset AD, in the cerebrovascular pathology associated with Alzheimer's disease. In this review, we examine the evidence elucidating the cerebrovascular impact of both central and peripheral apolipoprotein E on the pathogenesis of Alzheimer's disease. We present a novel three-hit hypothesis, outlining potential mechanisms that shed light on the intricate relationship among different pathogenic events. Finally, we discuss prospective therapeutics targeting the cerebrovascular pathology associated with apolipoprotein E and explore their implications for future research endeavors.

Exploring Neuroprotective Botanical Remedies in Neurodegenerative Conditions: A Review

Neuroprotection refers to the mechanisms and strategies used to protect the Central Nervous System (CNS) from neuronal injuries caused by neurodegenerative disorders. Neurodegenerative disorders are a type of chronic condition in which parts of the nervous system deteriorate over time, most notably the brain. These disorders have a slow and gradual effect on an individual. Neurodegeneration is a neuropathological condition and brain aging process. The brain pathology of neurodegenerative and cerebrovascular disease is a leading cause of death worldwide, with a death rate of approximately 8% and an incidence rate of approximately 2/1000. It is a major health issue in the twenty-first century. According to researchers, this disease affects over 50 million people worldwide. These disorders primarily affect people over the age of 65, and the World Health Organization predicts that this number will more than double in the next 30 years. Confusion, difficulty thinking, pain, muscle spasms, behavioral changes, paralysis, tremors, balance problems, coordination issues, hunched posture, and fatigue are symptoms of these disorders. These disorders are caused by age, genetics, medical history, habits, routine, and environment. This review article is focused on herbs such as Crocus sativus and Curcuma longa which are very helpful in Neurodegenerative diseases and serve as a resource for future research. Keywords: Neurodegeneration, Medicinal Herbs, Neuroprotection, Neuroprotective plants, Parkinson, Alzheimer.

A mathematical model on the propagation of tau pathology in neurodegenerative diseases.

A system of partial differential equations is developed to study the spreading of tau pathology in the brain for Alzheimer's and other neurodegenerative diseases. Two cases are considered with one assuming intracellular diffusion through synaptic activities or the nanotubes that connect the adjacent cells. The other, in addition to intracellular spreading, takes into account of the secretion of the tau species which are able to diffuse, move with the interstitial fluid flow and subsequently taken up by the surrounding cells providing an alternative pathway for disease spreading. Cross membrane transport of the tau species are considered enabling us to examine the role of extracellular clearance of tau protein on the disease status. Bifurcation analysis is carried out for the steady states of the spatially homogeneous system yielding the results that fast cross-membrane transport combined with effective extracellular clearance is key to maintain the brain's healthy status. Numerical simulations of the first case exhibit solutions of travelling wave form describing the gradual outward spreading of the pathology; whereas the second case shows faster spreading with the buildup of neurofibrillary tangles quickly elevated throughout. Our investigation thus indicates that the gradual progression of the intracellular spreading case is more consistent with the clinical observations of the development of Alzheimer's disease.

Medial temporal lobe gray matter microstructure in preclinical Alzheimer's disease.

Typical MRI measures of neurodegeneration have limited sensitivity in early disease stages. Diffusion MRI (dMRI) microstructural measures may allow for detection in preclinical stages. Participants had dMRI and either beta-amyloid PET or plasma biomarkers of Alzheimer's pathology within 18 months of MRI. Microstructure was measured in portions of the medial temporal lobe (MTL) with high neurofibrillary tangle (NFT) burden based on a previously developed post mortem 3D-map. Regressions examined relationships between microstructure and markers of Alzheimer's pathology in preclinical disease and then across disease stages. There was higher isometric volume fraction in amyloid-positive compared to amyloid-negative cognitively unimpaired individuals in high tangle MTL regions. Similarly, plasma biomarkers and 18F-flortaucipir were associated with microstructural changes in preclinical disease. Additional microstructural effects were seen across disease stages. Combining a post mortem atlas of NFT pathology with microstructural measures allows for detection of neurodegeneration in preclinical Alzheimer's disease. Highlights Typical markers of neurodegeneration are not sensitive in preclinical Alzheimer's. dMRI measured microstructure in regions with high NFT. Microstructural changes occur in medial temporal regions in preclinical disease. Microstructural changes occur in other typical Alzheimer's regions in later stages. Combining post mortem pathology atlases with in vivo MRI is a powerful framework.

AGE, DISEASE DURATION AND MULTIMORBIDITY AS PREDICTORS OF HYPOGLYCEMIA IN ELDERLY AND SENILE WOMEN WITH TYPE 2 DIABETES MELLITUS

AbstractAim – to study the relationship between age, duration of the disease and concomitant chronic non-infectious pathology with the risk of developing hypoglycemia in patients with type 2 diabetes mellitus (T2DM).Material and methods. The study involved 90 elderly and senile women (mean age 70.5 ± 6.2 years) with T2DM. A detailed history of the disease was collected from all study participants, and medical documentation was studied. The indicators of clinical blood test and biochemical blood test were studied, and the Charlson comorbidity index was calculated.Results. The prevalence of hypoglycemia among patients with T2DM was: 47% in the elderly and 75% in senile patients. The correlation index between the indicators “Patient’s age” and “Presence of hypoglycemia” was r = 0.2489 (p = 0.018), which indicates a statistical dependence of these values. When calculating χ2 (chi-square), the value obtained was χ2 = 5.513 (p = 0.018). One-way analysis of variance on these values shows a result of F-ratio = 5.811 at the significance level (p = 0.018), which confirms a significant relationship between the two variables. The correlation index was calculated for the indicators “Presence of cases of hypoglycemia” and “Existence of diabetes mellitus” (r = 0.3512 with a significance level of p = 0.0007). The data allows us to draw a conclusion about the statistical dependence of these values. The result of the χ2 test for trend was the value χ2 (trend) = 10.982, (p = 0.0009). The data presented indicate the relationship between these variables. The correlation between the indicators “Presence of cases of hypoglycemia” and “Charlson Comorbidity Index (scores)” is confirmed by the value r = 0.4020 (p = 0.0001). The relationship between these variables was revealed by calculating χ2 = 16.336, (p = 0.0059). Based on the χ2 test for trend, the value χ2 (trend) = 14.544, (p = 0.0001) was obtained. One-way analysis of variance for these indicators shows the result of F-ratio = 3.734 (p = 0.004).Conclusion. The patient's age, duration of T2DM and multimorbidity are significantly associated with the risk of hypoglycemia in patients with T2DM.

Human Umbilical Cord Mesenchymal Stem Cell-derived Exosomes Induce Macrophage M2 Polarization by Antagonizing LPS-mediated Stimulation of the NF-κB and STAT3 Pathways.

Many studies have documented the protective effects of regulating macrophage M1/M2 polarization in inflammatory diseases characterized by their imbalance state. In pathological diseases associated with inflammation, mesenchymal stem cells (MSCs) regulate macrophages, thereby having anti-inflammatory and tissue regenerative effects. Exosomes have been suggested as an alternative mechanism that underlies the paracrine function of MSCs. Thus, this study explored the anti-inflammatory impact of human umbilical cord MSCssecreted exosomes (hucMSCs-EX) by influencing macrophage polarization in normal and inflammatory environments in vitro. In this study, hucMSCs-conditioned medium (hucMSCs-CM) and hucMSCs- EX were used to treat RAW264.7 macrophages with or without LPS. The expressions of TNF- α, IL-10, IL-6, IL-1β, and Arg-1 were quantified by qPCR. The expressions of IL-6 and IL-10 were evaluated by ELISAs. Western blots (WB) were performed to observe the expressions of CD206, NF-κB P65, NF-κB p-p65, p-STAT3, STAT3, and NF-κB phosphorylation. The number of cells expressing CD206 and the fluorescence intensity were measured via flow cytometry (FC) and immunofluorescence staining. Cell propagation and migration were examined via MTT and transwell assays, respectively. The inhibition of LPS-induced inflammatory polarization by hucMSCs-EX or hucMSCs- CM led to increases in IL-10 and arginase (Arg) levels and decreases in those of IL-6 and TNF-α. Moreover, hucMSCs-EX enhanced the CD206 expression in RAW264.7 cells and accelerated the propagation and migration of LPS-induced cells. The suppressive impact of hucMSCs-EX on the LPS-induced phenotypic polarization of M1 macrophages was linked with the reduction of NF-κB signaling. They stimulated the transition of M2 macrophages by enhancing the activity of STAT3 in RAW264.7 cells. This study indicated that hucMSCs-EX enhances the macrophage transition into the M2 phenotype by inhibiting the NF-κB p65 axis and stimulating that of STAT3.

Oxidative stress and neurological disorders: Therapeutic strategies and pharmacological intervention

Oxidative stress plays a significant role in cerebral biochemical dysfunction, contributing to the increased sensitivity of the central nervous system to reactive oxygen species (ROS)-mediated injury. It is characterized by an imbalance between the production of ROS and the antioxidant capacity of the cell, which results in a variety of pathological disorders and diseases, including neurological conditions such as Parkinson&amp;rsquo;s disease, Alzheimer&amp;rsquo;s disease, schizophrenia, bipolar disorder, and anxiety. In this review, we delve into the role of oxidative stress in neurodegenerative disorders. We conducted a comprehensive search across various databases, including Google Scholar, ScienceDirect, and PubMed, with a focus on literature published within the past decade. Our search utilized terms such as &amp;ldquo;oxidative stress and neurological disorders,&amp;rdquo; &amp;ldquo;pharmacological interventions for neurological disorders,&amp;rdquo; &amp;ldquo;oxidative stress, free radicals, and neurological disorders,&amp;rdquo; and &amp;ldquo;free radicals and neurological disorders. Our aim was to elucidate the relationship between oxidative stress and neurological disorders, as well as to summarize available therapies and pharmacological interventions for these conditions.