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Role of the gut microbiota in the development of various neurological diseases.

In recent years, the scientific evidence supporting a relationship between the microbiota and various diseases has increased significantly this trend has also been observed for neurological diseases. This has given rise to the concept of the gut-brain axis and the idea of a relationship between the gut microbiota and several neurological diseases whose aetiopathogenesis is yet to be clearly defined. We review the role of the gut microbiota in the gut-brain axis and analyse those neurological diseases in which alterations in the gut microbiota have been described as a result of human studies specifically, Parkinsons disease, Alzheimer disease, amyotrophic lateral sclerosis, neuromyelitis optica, and multiple sclerosis. The body of evidence linking the gut microbiota to various neurological diseases has grown considerably. Several interesting studies show a relationship between the gut microbiota and Parkinsons disease, Alzheimer disease, neuromyelitis optica, and multiple sclerosis, whereas other controversial studies implicate it in amyotrophic lateral sclerosis. Many of these studies place considerable emphasis on modulation of inflammation, particularly by bacteria capable of producing short-chain fatty acids. Despite these encouraging results, many questions remain, and there is a need to demonstrate causality, determine the role of fungi or viruses, and research possible treatment through diet, probiotics, or faecal microbiota transplantation.

Design, synthesis and evaluation of 2-(2-oxoethyl)pyrimidine-5-carboxamide derivatives as acetylcholinesterase inhibitors.

A novel series of 2-(2- oxoethyl)pyrimidine-5-carboxamide derivatives were designed, synthesized and evaluated as acetylcholinesterase inhibitors (AChEIs) for the treatment of Alzheimers disease (AD). Biological activity results demonstrated that compound 10q showed the best inhibitory activity against AChE (IC

Glucose enrichment impair neurotransmission and induce Aβ oligomerization that cannot be reversed by manipulating O-β-GlcNAcylation in the C. elegans model of Alzheimers disease.

Amyloid beta (Aβ) plaques formation and impaired neurotransmission and neuronal behaviors are primary hallmarks of Alzheimers disease (AD) that are further associated with impaired glucose metabolism in elderly ADs patients. However, the exact role of glucose metabolism on disease progression has not been elucidated yet. In this study, the effect of glucose on Aβ-mediated toxicity, neurotransmission and neuronal behaviors has been investigated using a C. elegans model system expressing human Aβ. In addition to regular diet, worms expressing Aβ were supplemented with different concentrations of glucose and glycerol and 5 mM 2-deoxyglucose to draw any conclusions. Addition of glucose to the growth medium delayed Aβ-associated paralysis, promoted abnormal body shapes and movement, unable to restore impaired acetylcholine neurotransmission, inhibited egg laying and hatching in pre-existing Aβ-mediated pathology. The harmful effects of glucose may associate with an increase in toxic Aβ oligomers and impaired neurotransmission. O-β-GlcNAcylation (O-GlcNAc), a well-known post-translational modification is directly associated with glucose metabolism and has been found to ameliorates the Aβ- toxicity. We reasoned that glucose addition might induce O-GlcNAc, thereby protect against Aβ. Contrary to our expectations, induced glucose levels were not protective. Increasing O-GlcNAc, either with Thiamet-G (TMG) or by suppressing the O-GlcNAcase (oga-1) gene does interfere with and, therefore, reduce Aβ- toxicity but not in the presence of high glucose. The effects of glucose cannot be effectively managed by manipulating O-GlcNAc in AD models of C. elegans. Our observations suggest that glucose enrichment is unlikely to be an appropriate therapy to minimize AD progression.

(R)-ketamine as prophylactic and therapeutic drug for neurological disorders Beyond depression.

Neurological disorders are the leading cause of disability and the second leading cause of death worldwide. The increasing social and economic burdens of neurological disorders are driven by global population growth and aging. Depression is a common psychiatric symptom in numerous neurological disorders. It is also a risk factor for Alzheimers disease (AD) and other dementias, Parkinsons disease (PD), and stroke. The rapid-acting and sustained antidepressant actions of (R,S)-ketamine for severe depression was accidentally discovered. Interestingly, (R)-ketamine has greater potency and longer-lasting antidepressant-like effects than (S)-ketamine in rodents. Importantly, its side effects in rodents and humans are lower than those of (R,S)-ketamine and (S)-ketamine. Furthermore, (R)-ketamine could elicit beneficial actions in various rodent models of neurological disorders, including PD, multiple sclerosis (MS), and stroke. In this article, we review the potential of (R)-ketamine as a prophylactic or therapeutic drug for neurological disorders including AD and other dementias, PD, MS, and stroke.

Chlorpyrifos oxon crosslinking of amyloid beta 42 peptides is a new route for generation of self-aggregating amyloidogenic oligomers that promote Alzheimers disease.

Epidemiological evidence suggests that people chronically exposed to organophosphorus pesticides are at increased risk of neurodegenerative disease. Covalently linked amyloid beta dimers have been isolated from the brains of Alzheimers patients. The toxic forms of amyloid beta are amyloid dimers that spontaneously oligomerize. In the present report we treated recombinant and synthetic amyloid beta (1-42) with 1 mM chlorpyrifos oxon or 1 mM paraoxon. The trypsin-digested samples were analyzed by liquid chromatography tandem mass spectrometry on an Orbitrap Fusion Lumos mass spectrometer. Data were searched with Protein Prospector software. We found two new types of crosslinks in amyloid dimers. An isopeptide Asp-Asp link occurred between the N-terminal amine of Asp 1 in one peptide and the beta carboxyl group of Asp 1 in another peptide. An Asp-Arg link occurred between the guanidino group of Arg 5 in one peptide and the beta carboxyl group of Asp 1 in another peptide. These results show that the active metabolites of the pesticides chlorpyrifos and parathion catalyze the crosslinking of amyloid beta (1-42) into toxic dimers. It was concluded that the increased risk of neurodegenerative disease in people exposed to organophosphorus pesticides could be explained by the crosslinking activity of these chemicals. Data are available via ProteomeXchange with identifier PXD034163.

The dual effect of acetate on microglial TNF-α production.

Short-Chain Fatty Acids (SCFA) are products of intestinal microbial metabolism that can reach the brain and alter microglia in health and disease contexts. However, data are conflicting on the effect of acetate, the most abundant SCFA in the blood, in these cells. The authors aimed to investigate acetate as a modulator of the inflammatory response in microglia stimulated with LPS. The authors used an immortalized cell line, C8-B4, and primary cells for in vitro treatments with acetate and LPS. Cell viability was analyzed by MTT, cytokine by RT-PCR, ELISA, and flow cytometry. The authors also performed in vivo and in silico analyses to study the role of acetate and the TNF-α contribution to the development of Experimental Autoimmune Encephalomyelitis (EAE). Acetate co-administered with LPS was able to exacerbate the production of pro-inflammatory cytokines at gene and protein levels in cell lines and primary culture of microglia. However, the same effects were not observed when acetate was administered alone or as pretreatment, prior to the LPS stimulus. Additionally, pharmacological inhibition of histone deacetylase concomitantly with acetate and LPS led to decreased TNF-α production. In silico analysis showed a crucial role of the TNF-α pathway in EAE development. Moreover, acetate administration in vivo during the initial phase of EAE led to a better disease outcome and reduced TNF-α production. Treatment with acetate was able to promote the production of TNF-α in a concomitant LPS stimulus of microglia. However, the immune modulation of microglia by acetate pretreatment may be a component in the generation of future therapies for neurodegenerative diseases.

Carbohydrate-derived bicyclic selenazolines as new dual inhibitors (cholinesterasesOGA) against Alzheimers disease.

Concerned by the urgent need to explore new approaches for the treatment of Alzheimers disease, we herein describe the synthesis and evaluation of new multitarget molecules. In particular, we have focused our attention on modulating the activity of cholinesterases (AChE, BuChE) in order to restore the levels of the neurotransmitter acetylcholine, and of O-GlcNAcase (OGA), which is associated with hyperphosphorylation of tau protein, in turn related to the formation of neurofibrillary tangles in the brain. Specifically, we considered the possibility of using carbohydrate-fused 1,3-selenazolines, decorated with a 2-alkylamino or 2-alkoxy moieties. On the one hand, the presence of a selenium atom might be useful in modulating the intrinsic oxidative stress in AD. On the other hand, such bicyclic structure might behave as a transition state analogue of OGA hydrolysis. Moreover, upon protonation, it could mimic the ammonium cation of acetylcholine. The lead compound, bearing a propylamino moiety on C-2 position of the selenazoline motif, proved to be a good candidate against AD it turned out to be a strong inhibitor of BuChE (IC

UHPLC-HRMS study of pharmacokinetics of a novel hybrid cholinesterase inhibitor K1234 A comparison between in silico, in vitro and in vivo data.

Alzheimers disease (AD) is one of the most common forms of dementia. Current anti-AD therapeutics exploit the cholinergic hypothesis of its pathophysiology they aim to inhibit cerebral cholinesterases. K1234 is a novel hybrid molecule derived from Huperzine A and 7-MEOTA-huperzine which shows increased potency in acetylcholinesterase inhibition in vitro compared to the compounds themselves. The study focused on description of the pharmacokinetic behaviour of K1234, blood-brain barrier penetration, identification of the main in vitro and in vivo metabolites. K1234 is relatively non-toxic compound, that is rapidly absorbed after i.p. administration reaching C

Safety, Tolerability, Pharmacokinetics and Initial Pharmacodynamics of a Subcommissural Organ-Spondin-Derived Peptide A Randomized, Placebo-Controlled, Double-Blind, Single Ascending Dose First-in-Human Study.

This randomized, double-blind, placebo-controlled study in healthy volunteers assessed the safety, tolerability, and pharmacokinetics of single ascending doses of intravenously administered NX210-a linear peptide derived from subcommissural organ-spondin-and explored the effects on bloodurine biomarkers and cerebral activity. Participants in five cohorts (n 8 each) were randomized to receive a single intravenous dose of NX210 (n 6 each) (0.4, 1.25, 2.5, 5, and 10 mgkg) or placebo (n 2 each) in total, 10 and 29 participants received placebo and NX210, respectively. Blood samples were collected for pharmacokinetics within 180 min post dosing. Plasma and urine were collected from participants (cohorts 2.5, 5, and 10 mgkg) for biomarker analysis and electroencephalography (EEG) recordings within 48 h post dosing. Safetytolerability and pharmacokinetic data were assessed before ascending to the next dose. The study included 39 participants. All dosages were safe and well tolerated. All treatment-emergent adverse events (n 17) were of mild severity and resolved spontaneously (except one with unknown outcome). Twelve treatment-emergent adverse events (70.6%) were deemed drug related seven of those (58.3%) concerned nervous system disorders (dizziness, headache, and somnolence). The pharmacokinetic analysis indicated a short half-life in plasma (6-20 min), high apparent volume of distribution (1870-4120 L), and rapid clearance (7440-16,400 Lh). In plasma, tryptophan and homocysteine showed dose-related increase and decrease, respectively. No drug dose effect was found for the glutamate or glutamine plasma biomarkers. Nevertheless, decreased blood glutamate and increased glutamine were observed in participants treated with NX210 versus placebo. EEG showed a statistically significant decrease in beta and gamma bands and a dose-dependent increasing trend in alpha bands. Pharmacodynamics effects were sustained for several hours (plasma) or 48 h (urine and EEG). NX210 is safe and well tolerated and may exert beneficial effects on the central nervous system, particularly in terms of cognitive processing.

Blood extracellular vesicles carrying synaptic function- and brain-related proteins as potential biomarkers for Alzheimers disease.

Objective and accessible markers for Alzheimers disease (AD) and other dementias are critically needed. We identified NMDAR2A, a protein related to synaptic function, as a novel marker of central nervous system (CNS)-derived plasma extracellular vesicles (EVs) and developed a flow cytometry-based technology for detecting such plasma EVs readily. The assay was initially tested in our local cross-sectional study to distinguish AD patients from healthy controls (HCs) or from Parkinsons disease (PD) patients, followed by a validation study using an independent cohort collected from multiple medical centers (the Alzheimers Disease Neuroimaging Initiative). Cerebrospinal fluid AD molecular signature was used to confirm diagnoses of all AD participants. Likely CNS-derived EVs in plasma were significantly reduced in AD compared to HCs in both cohorts. Integrative models including CNS-derived EV markers and AD markers present on EVs reached area under the curve of 0.915 in discovery cohort and 0.810 in validation cohort. This study demonstrated that robust and rapid analysis of individual neuron-derived synaptic function-related EVs in peripheral blood may serve as a helpful marker of synaptic dysfunction in AD and dementia.

Apolipoprotein E ε4 Mediates Myelin Breakdown by Targeting Oligodendrocytes in Sporadic Alzheimer Disease.

White matter degradation in the frontal lobe is one of the earliest detectable changes in aging and Alzheimer disease. The ε4 allele of apolipoprotein E (APOE4) is strongly associated with such myelin pathology but the underlying cellular mechanisms remain obscure. We hypothesized that, as a lipid transporter, APOE4 directly triggers pathology in the cholesterol-rich myelin sheath independent of AD pathology. To test this, we performed immunohistochemistry on brain tissues from healthy controls, sporadic, and familial Alzheimer disease subjects. While myelin basic protein expression was largely unchanged, in frontal cortex the number of oligodendrocytes (OLs) was significantly reduced in APOE4 brains independent of their Braak stage or NIA-RI criteria. This high vulnerability of OLs was confirmed in humanized APOE3 or APOE4 transgenic mice. A gradual decline of OL numbers was found in the aging brain without associated neuronal loss. Importantly, the application of lipidated human APOE4, but not APOE3, proteins significantly reduced the formation of myelinating OL in primary cell culture derived from Apoe-knockout mice, especially in cholesterol-depleted conditions. Our findings suggest that the disruption of myelination in APOE4 carriers may represent a direct OL pathology, rather than an indirect consequence of amyloid plaque formation or neuronal loss.

Conformational entropy limits the transition from nucleation to elongation in amyloid aggregation.

The formation of β-sheet-rich amyloid fibrils in Alzheimers disease and other neurodegenerative disorders is limited by a slow nucleation event. To understand the initial formation of β-sheets from disordered peptides, we used all-atom simulations to parameterize a lattice model that treats each amino acid as a binary variable with β- and non-β-sheet states. We show that translational and conformational entropy give the nascent β-sheet an anisotropic surface tension that can be used to describe the nucleus with 2D classical nucleation theory. Since translational entropy depends on concentration, the aspect ratio of the critical β-sheet changes with protein concentration. Our model explains the transition from the nucleation phase to elongation as the point where the β-sheet core becomes large enough to overcome the conformational entropy cost to straighten the terminal molecule. At this point the β-strands in the nucleus spontaneously elongate, which results in a larger binding surface to capture new molecules. These results suggest that nucleation is relatively insensitive to sequence differences in coaggregation experiments because the nucleus only involves a small portion of the peptide.

Role of animal models in biomedical research a review.

The animal model deals with the species other than the human, as it can imitate the disease progression, its diagnosis as well as a treatment similar to human. Discovery of a drug andor component, equipment, their toxicological studies, dose, side effects are in vivo studied for future use in humans considering its ethical issues. Here lies the importance of the animal model for its enormous use in biomedical research. Animal models have many facets that mimic various disease conditions in humans like systemic autoimmune diseases, rheumatoid arthritis, epilepsy, Alzheimers disease, cardiovascular diseases, Atherosclerosis, diabetes, etc., and many more. Besides, the model has tremendous importance in drug development, development of medical devices, tissue engineering, wound healing, and bone and cartilage regeneration studies, as a model in vascular surgeries as well as the model for vertebral disc regeneration surgery. Though, all the models have some advantages as well as challenges, but, present review has emphasized the importance of various small and large animal models in pharmaceutical drug development, transgenic animal models, models for medical device developments, studies for various human diseases, bone and cartilage regeneration model, diabetic and burn wound model as well as surgical models like vascular surgeries and surgeries for intervertebral disc degeneration considering all the ethical issues of that specific animal model. Despite, the process of using the animal model has facilitated researchers to carry out the researches that would have been impossible to accomplish in human considering the ethical prohibitions.

Proteomics-based investigation of cerebrovascular molecular mechanisms in cerebral amyloid angiopathy by the FFPE-LMD-PCT-SWATH method.

Cerebral amyloid angiopathy (CAA) occurs in 80% of patients with Alzheimers disease (AD) and is mainly caused by the abnormal deposition of Aβ in the walls of cerebral blood vessels. Cerebrovascular molecular mechanisms in CAA were investigated by using comprehensive and accurate quantitative proteomics. Concerning the molecular mechanisms specific to CAA, formalin-fixed paraffin-embedded (FFPE) sections were prepared from patients having AD neuropathologic change (ADNC) with severe cortical Aβ vascular deposition (ADNC CAA ), and from patients having ADNC without vascular deposition of Aβ (ADNC CAA - so called, AD). Cerebral cortical vessels were isolated from FFPE sections using laser microdissection (LMD), processed by pressure cycling technology (PCT), and applied to SWATH (sequential window acquisition of all theoretical fragment ion spectra) proteomics. The protein expression levels of 17 proteins in ADNC CAA H donors (ADNC CAA donors with highly abundant Aβ in capillaries) were significantly different from those in ADNC CAA - and ADNC -CAA - donors. Furthermore, we identified 56 proteins showing more than a 1.5-fold difference in average expression levels between ADNC CAA and ADNC -CAA - donors, and were significantly correlated with the levels of Aβ or Collagen alpha-2(VI) chain (COL6A2) (CAA markers) in 11 donors (6 ADNC CAA and 5 ADNC -CAA -). Over 70% of the 56 proteins showed ADNC CAA specific changes in protein expression. The comparative analysis with brain parenchyma showed that more than 90% of the 56 proteins were vascular-specific pathological changes. A literature-based pathway analysis showed that 42 proteins are associated with fibrosis, oxidative stress and apoptosis. This included the increased expression of Heat shock protein HSP 90-alpha, CD44 antigen and Carbonic anhydrase 1 which are inhibited by potential drugs against CAA. The combination of LMD-based isolation of vessels from FFPE sections, PCT-assisted sample processing and SWATH analysis (FFPE-LMD-PCT-SWATH method) revealed for the first time the changes in the expression of many proteins that are involved in fibrosis, ROS production and cell death in ADNC CAA (CAA patients) vessels. The findings reported herein would be useful for developing a better understanding of the pathology of CAA and for promoting the discovery and development of drugs and biomarkers for CAA.

Association between ultra-processed food consumption and cognitive performance in US older adults a cross-sectional analysis of the NHANES 2011-2014.

This study evaluated the association between ultra-processed food (UPF) consumption and cognitive performance among older US adults. This cross-sectional study assessed 3632 participants aged 60 years from the National Health and Nutrition Examination Survey (NHANES) 2011-14. Cognitive performance was assessed using the Consortium to Establish a Registry for Alzheimers Disease (CERAD), Word Learning test, Animal Fluency test, and the Digit Symbol Substitution test (DSST). Dietary intake was assessed using two 24-h diet recalls. Food items were classified according to the NOVA system, a classification based on the nature, extent, and purpose of industrial food processing. Linear regression models were used to evaluate the association of dietary share of UPF (% of daily energy intake) (categorized as tertiles) and cognitive test scores, adjusting for socio-demographic variables, physical activity, smoking status, and chronic diseases (cardiovascular diseases, diabetes, and depression). Models excluding participants with pre-existing diseases were carried out to address potential reverse causality. On average, UPF accounted for 53% of total energy intake, ranging from 33 to 70% across extreme tertiles. Inverted U-shape association between UPF consumption and Animal fluency and DSST was observed. No significant associations were observed between the UPF intake tertiles and the cognitive test results. Nonetheless, UPF consumption was significantly associated with worse performance in Animal Fluency in older adults without pre-existing diseases (P < 0.05). UPF consumption was associated with worse performance in Animal Fluency among older people without pre-existing diseases. Decreasing UPF consumption may be a way to improve impaired cognition among older adults.

Clinical Staging of Alzheimers Disease Concordance of Subjective and Objective Assessments in the Veterans Affairs Healthcare System.

Uncertainty surrounding the accurate assessment of the early-stage Alzheimers disease (AD) may cause delayed care and inappropriate patient access to new AD therapies. To analyze clinical assessments of patients with AD in the Veterans Affairs (VA) Healthcare System and evaluate concordance between subjective and objective assessments, we processed clinical notes extracted by text integration utilities between April 1, 2008 and October 14, 2021. Veterans who had mild, moderate, or severe AD with clinical notes documenting both clinicians judgement of AD severity and objective test scores from the Mini-Mental State Examination or the Montreal Cognitive Assessment were included. Using clinician-defined severity cohorts, we determined concordance between the clinicians (subjective) assessments and the test-derived (objective) assessments of AD severity. Concordance was assessed over time and by selected symptoms and comorbidities, as well as healthcare system factors. A total of 8888 notes were initially extracted the final analysis sample included 7514 notes corresponding to 4469 unique patients (mean standard deviation age of 78 9 years 96.5% male 77.8% White). Subjective and objective assessments were concordant in approximately half (53%) of overall notes. In the mild Alzheimers cohort, patients were assessed to have more severe disease by objective test scores in 40% of notes. Concordance varied about 21-73%, 47-58%, and 40-64% across symptomscomorbidities, clinician types, and Veterans Integrated Service Networks, respectively. The proportion of concordant notes was higher in visits to dementia (61%) instead of non-dementia clinics (53%). We found higher concordance between clinicians assessment and test-based assessment of Alzheimers disease severity in dementia specialty clinics. Discordance is especially high for the subjectively assessed mild AD cohort where objective assessments showed a higher severity level in 40% of notes. These data indicate a critical need for improved understanding of clinical assessments and decision-making to identify appropriate patients for anti-amyloid therapy.

Prediabetes and the incidence of dementia in general population a systematic review and meta-analysis of prospective studies.

Continuous hyperglycaemia has been related with dementia. However, it remains unclear whether prediabetes poses a higher risk of dementia. A meta-analysis was therefore conducted to comprehensively investigate the possible role of prediabetes as a risk factor of dementia. Prospective cohort studies reporting the association of prediabetes and dementia were identified from PubMed, Web of Science, and Embase databases. A random-effects model was applied to combine the results by incorporating the influence of heterogeneity. Subgroup analyses were also conducted to explore the influences of study features on the relationship. Sensitivity analysis re-estimated the combined effect size after excluding single studies separately to explore the robustness of the results. Nine studies involving 29 986 adults from the general population, 6265 (20.9%) of whom had prediabetes, were included. It was shown that prediabetes was not independently associated with a higher incidence of dementia compared with normoglycaemia (adjusted risk ratio (RR) 1.01, 95% confidence interval (CI) 0.85-1.21, P 0.89, I Prediabetes may not be an independent risk factor of all-cause dementia or vascular dementia in the general adult population. However, changing the definition of prediabetes may have an impact on the outcome for Alzheimers disease.

Amyloid-β aggregates induced by β-cholesteryl glucose-embedded liposomes.

Senile plaques that is characterized as an amyloid deposition found in Alzheimers disease are composed primarily of fibrils of an aggregated peptide, amyloid β (Aβ). The ability to monitor senile plaque formation on a neuronal membrane under physiological conditions provides an attractive model. In this study, the growth behavior of amyloid Aβ fibrils in the presence of liposomes incorporating β-cholesteryl-D-glucose (β-CG) was examined using total internal reflection fluorescence microscopy, transmittance electron microscopy, and other spectroscopic methods. We found that β-CG on the liposome membrane induced the spontaneous formation of spherulitic Aβ fibrillar aggregates. The β-CG cluster formed on liposome membranes appeared to induce the accumulation of Aβ, followed by the growth of the spherulitic Aβ aggregates. In contrast, DMPC and DMPC incorporated cholesterol-induced fibrils that are laterally associated with each other. A comparison study using three types of liposomes implied that the induction of glucose contributed to the agglomeration of Aβ fibrils and liposomes. This agglomeration required the spontaneous formation of spherulitic Aβ fibrillary aggregates. This action can be regarded as a counterbalance to the growth of fibrils and their toxicity, which has great potential in the study of amyloidopathies.

Study on the pharmacodynamic effect of Rhizoma Dioscoreae polysaccharides on cerebral ischemia-reperfusion injury in rats and the possible mechanism.

Rhizoma Dioscoreae (RD) is the rhizome of Dioscorea opposita Thunb., a traditional Chinese medicine, which can treat hypertension, diabetes, cerebral vasospasm headache and Alzheimers disease. Meanwhile, RD is the main component of Liuwei Dihuang pill, a Chinese patent medicine. Rhizoma Dioscoreae polysaccharides (RDPS) are the primary active ingredient of RD. Modern medical research confirmed RDPS has multiple pharmacological effects, including neuroprotection, immunoregulation, antioxidant effect in many organs. The primary ischemiahypoxia injury and secondary reperfusion injury are mainly caused by oxidative stress, which caused by hypoxia, such as free radical generation, energy metabolism disorder, intracellular calcium overload, excitatory amino acid release and inflammatory reaction. We have investigated the pharmacodynamic effect of RDPS on cerebral ischemia-reperfusion (IR) injury in rats and the possible mechanism in vitro. The pharmacodynamic effect of RDPS on IR injury in rats was studied by the construction of the occlusion of middle cerebral artery (MCAO) model, measuring the volume of cerebral infarct area, the content of oxidation index, inflammatory cytokines, and the expression of CaMMKβ in brain tissue. The in vitro study was explored by oxygen-glucose deprivationglycogen reoxygenation (OGDR) model, construction of the CaMMKβ interference sequence, measuring the expression of CaMMKβ in BV2 cells before and after inhibition of CaMMKβ, and the influence of RDPS on Nrf2HO-1 signal pathway, in order to investigate the possible mechanism. Compared with the model group, the present study showed that RDPS with high-dose and low-dose groups could significantly reduce the volume of cerebral infarction. The content of MDA decreased and the activities of GSH and SOD increased in the two dose groups of RDPS. We confirmed that after RDPS treatment, the levels of IL-6, IL-1 β and TNF-α in brain tissue were lower than those in model group, and the expression of CaMMKβ in brain tissue of rats decreased in the model group, but increased in the groups of RDPS. In the in vitro study, compared with the control group, RDPS could regulate the OGDR-induced apoptosis of BV2 cells and increase the level of CaMMKβ, Nrf2 and HO-1 induced by OGDR. To our surprise, these therapeutic effects are no longer present after the inhibition of CaMMKβ protein. The activity of BV2 induced by OGDR could not be enhanced by RDPS after the inhibition of CaMMKβ protein. RDPS has the pharmacodynamic effect in IR injury, which reduce the area of cerebral infarction, up-regulate the activity of anti-oxidant kinase, and down-regulate the inflammatory cytokine. Additionally, RDPS could affect the activation of Nrf2HO-1 signaling pathway by regulating the expression of CaMMKβ. Our observations justify the RDPS could be a new strategy for IR injury therapy, and the mechanism may be related to the improvement of antioxidant enzyme activity and inhibition of inflammatory reaction.

Androgens Regulate Tau Phosphorylation Through Phosphatidylinositol 3-Kinase-Protein Kinase B-Glycogen Synthase Kinase 3β Signaling.

Age-related testosterone depletion in men is a risk factor for Alzheimers disease (AD). How testosterone modulates AD risk remains to be fully elucidated, although regulation of tau phosphorylation has been suggested as a contributing protective action. To investigate the relationship between testosterone and tau phosphorylation, we first evaluated the effect of androgen status on tau phosphorylation in 3xTg-AD mice. Depletion of endogenous androgens via gonadectomy resulted in increased tau phosphorylation that was prevented by acute testosterone treatment. Parallel alterations in the phosphorylation of both glycogen synthase kinase 3β (GSK3β) and protein kinase B (Akt) suggest possible components of the underlying signaling pathway. To further explore mechanism, primary cultured neurons were treated with a physiological concentration of testosterone or its active metabolite dihydrotestosterone (DHT). Results showed that testosterone and DHT induced significant decreases in phosphorylated tau and significant increases in phosphorylation of Akt and GSK3β. Pharmacological inhibition of phosphatidylinositol 3-kinase (PI3K) effectively inhibited androgen-induced increases in Akt and GSK3β phosphorylation, and decreases in tau phosphorylation. In addition, androgen receptor (AR) knock-down by small interfering RNA prevented androgen-induced changes in the phosphorylation of Akt, GSK3β and tau, suggesting an AR-dependent mechanism. Additional experiments demonstrated androgen-induced changes in Akt, GSK3β and tau phosphorylation in AR-expressing PC12 cells but not in AR-negative PC12 cells. Together, these results suggest an AR-dependent pathway involving PI3K-Akt-GSK3β signaling through which androgens can reduce tau phosphorylation. These findings identify an additional protective mechanism of androgens that can improve neural health and inhibit development of AD.

Stress level of glucocorticoid exacerbates neuronal damage and Aβ production through activating NLRP1 inflammasome in primary cultured hippocampal neurons of APP-PS1 mice.

Glucocorticoid (GC), secreted by adrenal cortex, plays important roles in regulating many physiological functions, while chronic stress level of GC exposure has many adverse effects on the structure and function of hippocampal neurons, and is closely implicated to the deterioration of Alzheimers disease (AD). Oxidative stress and neuroinflammation play an important role in the occurrence and development of AD. However, it is still unclear whether chronic GC exposure promotes beta-amyloid (Aβ) accumulation and neuronal injury by increasing oxidative stress and neuroinflammation. In this study, we investigated the effects of chronic GC exposure on NOX2-NLRP1 inflammasome activation and the protective effects of NLRP1-siRNA against GC-induced neuronal injury in primary hippocampal neurons of APPPS1 mice. The results showed that chronic dexamethasone (DEX, 1 µM) exposure 72 h had no significant effect on the primary hippocampal neurons of WT mice, but significantly increased Aβ

Neuroprotective Effects of Hesperidin and Naringin in SK-N-AS Cell as an

Hesperidin and naringin are flavonoids that are found in citrus fruits. Our aim was to create an

Autopsy Human Brain Dissection Protocol for Common Age-Related Neurodegenerative Disorders.

Age-related neurodegenerative disorders are common causes of dementia-associated morbidity and mortality in populations throughout the world. Standardized, protocol-based methods for the examination and diagnosis of these disorders allow direct comparison between human cohorts and play a key role in understanding how these disorders impact our population. Further understanding of these protocols and harmonization with animal and in vitro investigative techniques is imperative to demonstrate relevance to human disease. The following is a concise protocol for the examination of human whole brain autopsy samples, with and without spinal cord, for the examination of neurodegenerative disorders. The following protocol is designed to provide samples appropriate for most neurodegenerative diseases. The collection of both fresh-frozen and formalin-fixed tissues is described.This guide presumes general knowledge of neuroanatomy of the human central nervous system. Tissue processing, detailed histological techniques and complete diagnostic examination of the brain is beyond the scope of this chapter however, a limited evaluation appropriate for the evaluation of neurodegenerative disease is described here. Diagnostic protocols for the most common causes of dementia-associated, age-related neurodegenerative disorders are also summarized.

Three-Dimensional Atlas of the Human Amygdala Subnuclei Constructed Using Immunohistochemical and Ultrahigh-Field Magnetic Resonance Imaging Data.

The amygdala is central for social and emotional processing and has been implicated in various disorders including autism spectrum disorder (ASD) and Alzheimers disease (AD). Animal research and some limited research with humans has indicated that widespread alterations in neuronal development or neuronal loss in the basolateral and other amygdala subnuclei may be a contributing factor to variations in social behaviours. Yet, the basolateral amygdala is comprised of three subnuclei, each with a specialized role related to the coordination of emotional regulation. Due to their small size, the nuclei which comprise the basolateral amygdala remain understudied in humans in vivo. In this work, we describe methodology to examine the basolateral amygdala and other subnuclei in human ex vivo medial temporal lobe prosections using ultrahigh-field magnetic resonance imaging (MRI) at 9.4 T. Manual segmentations of the amygdala subnuclei on MR images, verified with immunohistochemical data, provide a robust three-dimensional atlas of the human amygdala. The goal is to apply the atlas to in vivo MRI scans to examine basolateral amygdala macrostructural development attributed to social cognitive dysfunction in ASD and other neurodevelopmental disorders. Furthermore, the atlas can be used to examine MRI-based correlates of neuronal loss commonly seen in neurodegenerative disorders.

Assessment of Dopaminergic Neurodegeneration in Mice.

Neuron death is a key feature of neurological disorders like Alzheimers or Parkinsons disease (PD). As a result, analysis of neurodegeneration is often considered a central experiment in the postmortem characterization of preclinical PD animal models. Stereology provides a precise estimate of particles, like neurons, in three-dimensional objects, like the brain, and is the gold standard quantification approach for the assessment of neuron survival in neurodegenerative disease research. Here, we provide a detailed step-by-step guide for the quantification of dopaminergic neurons in the substantia nigra pars compacta, a brain area prone to neuron loss in PD. In addition, we outline the protocol for the analysis of the dopaminergic terminals in the striatum, the projection area of midbrain dopaminergic neurons, as a readout for the integrity of the nigrostriatal projections.

Analysis of mRNA Dynamics Using RNA Sequencing Data.

The RNA abundance of each gene is determined by its rates of transcription and RNA decay. Biochemical experiments that measure these rates, including transcription inhibition and metabolic labelling, are challenging to perform and are largely limited to in vitro settings. Most transcriptomic studies have focused on analyzing changes in RNA abundances without attributing those changes to transcriptional or posttranscriptional regulation. Estimating differential transcription and decay rates of RNA molecules would enable the identification of regulatory factors, such as transcription factors, RNA binding proteins, and microRNAs, that govern large-scale shifts in RNA expression. Here, we describe a protocol for estimating differential stability of RNA molecules between conditions using standard RNA-sequencing data, without the need for transcription inhibition or metabolic labeling. We apply this protocol to in vivo RNA-seq data from individuals with Alzheimers disease and demonstrate how estimates of differential stability can be leveraged to infer the regulatory factors underlying them.

Investigating Microglial Ultrastructural Alterations and Intimate Relationships with Neuronal Stress, Dystrophy, and Degeneration in Mouse Models of Alzheimers Disease.

In recent decades, microglia have taken the field of neuroscience by storm, with numerous studies identifying key roles for these cells in the pathophysiology of neurodegenerative conditions, such as Alzheimers disease (AD). The heterogeneity of these cells (e.g., the presence of various subtypes like the disease-associated microglia, microglia associated with neurodegeneration, dark microglia, lipid droplet-accumulating microglia), and their ultrastructural alterations arising from environmental challenges have become a central focus of recent studies. Dark microglia are electron-dense cells defined by their ultrastructural markers of cellular stress using electron microscopy (EM). In this protocol, we first describe the steps required for proper brain tissue preparation for EM experiments. Ultrastructural analysis of microglia and neuronssynapses in AD mouse models is also detailed, using transmission or scanning EM. We next explain how to characterize several ultrastructural markers of cellular stress, dystrophy or degeneration, in microglia and neuronssynapses, with relation to amyloid beta plaques.

Examining Mitochondrial Morphology in Mouse Brains.

Mitochondria are dynamic organelles that rely on a balance of opposing fission and fusion events to sustain mitochondrial function and efficiently meet the energy demands of a cell. As high-energy demanding cells, neurons rely heavily on optimally functional mitochondria with balanced mitochondrial dynamics, to ensure a sufficient energy supply required to maintain cell survival, establish membrane excitability and partake in processes of neurotransmission and plasticity. As such, many neurodegenerative diseases (e.g., Alzheimers disease, Parkinsons disease) and stress conditions (e.g., stroke) leading to neuronal dysfunction or death are often associated with impaired mitochondrial function and dynamics, characterized by excessive mitochondrial fragmentation. For this reason, the assessment of mitochondrial morphology in neurons and within the brain can provide valuable information. The dynamic nature of mitochondria is not only observed in shape changes, but also changes in mitochondrial network connectivity and in cristae architecture. In this chapter, we will describe how mitochondrial morphology can be examined in vitro using hippocampal neuronal cultures and in vivo using mouse brain sections by immunocytochemistry, immunohistochemistry, and electron microscopy techniques.

Phosphoproteomic analysis reveals the effects of sleep deprivation on the hippocampus in mice.

Sleep is essential for brain physiology, including nerve repair, neuronal activity, and metabolite clearance. The hippocampus is responsible for short-term memory, long-term memory, and spatial positioning. Herein, we investigated the effects of sleep deprivation on protein phosphorylation and related signaling pathways in the mouse hippocampus. The treatment group was sleep deprived for nine hours a day, and at the end of sleep deprivation, we removed the hippocampus for phosphoproteomic analysis. Through this analysis, we identified 65 sites and 27 proteins whose phosphorylation was significantly different between sleep-deprived animals and control animals. Differentially phosphorylated proteins (DPPs) were mainly distributed in the postsynaptic density, cytoplasm, and synapse. They participated in metabolic pathways, endocytosis, oxidative phosphorylation and other processes, and they were associated with Huntingtons disease, Parkinsons disease, Alzheimers disease,

COVID-19 and neurodegenerative diseases.

The pandemic of Coronavirus Disease 2019 (COVID-19) caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) continues, and SARS-CoV-2 variants continue to emerge. In addition to typical fever and respiratory symptoms, many patients with COVID-19 experience a variety of neurological complications. In this review, we analyzed and reviewed the current status and possible mechanisms between COVID-19 and several typical neurodegenerative diseases, particularly Alzheimers disease, Parkinsons disease, and amyotrophic lateral sclerosis, hoping to propose the potential direction of further research and concern. Electronic literature search of the databases (MedlinePubMed, Web of Science, and Google Scholar). The keywords used were COVID-19, SARS-CoV-2, neurodegenerative disease, Alzheimers disease, Parkinsons disease, and amyotrophic lateral sclerosis. The retrieved relevant articles were reviewed and critically analyzed. SARS-CoV-2 is a highly neuroinvasive neurotropic virus that invades cells through angiotensin-converting enzyme 2 (ACE2) receptor-driven pathway. SARS-CoV-2 neuroinvasion, neuroinflammation, and blood-brain barrier (BBB) dysfunction may contribute to the pathogenesis of neurodegenerative diseases. Some patients with neurodegenerative diseases have already shown more susceptibility to SARS-CoV-2 infection and significantly higher mortality due to the elderly population with underlying diseases. Moreover, SARS-CoV-2 could cause damage to the central nervous system (CNS) that may substantially increase the incidence of neurodegenerative diseases and accelerate the progression of them.

Development of informant-reported or self-reported MCI-J questionnaire.

Several studies have reported a high prevalence of missed and delayed mild cognitive impairment (MCI) or mild dementia diagnosis, which could lead to delayed treatment and increased patient and caregiver burden. This study aimed to develop a new questionnaire for nonprofessionals to help detect early signs of MCI and dementia. Respondents included patients, family caregivers, or health professionals. Scores are calculated based on the respondent type and age of subject. This study consisted of four steps and included 461 respondents. Steps 1-3 were conducted by a working group, and step 4, by 67 specialist members of the Japanese Society of Geriatric Psychiatry. A scoring algorithm was created and predictive diagnostic probability was analyzed using misdiscrimination rate and cross-validation after item selection to establish a cut-off value for MCI or dementia symptoms. Alzheimers disease, Lewy body dementia, and frontotemporal dementia were diagnosed. The prediction error rate for patient or informant respondents was confirmed from the evaluation results of 13 items. Sensitivity and specificity were 90.6% and 56.6%, respectively, with a cut-off score of 2. Overall, 82% (61 pairs) of respondents received a definitive diagnosis following a diagnosis from the questionnaire. This questionnaire could promote earlier presentation to clinical settings for treatment. The high sensitivity indicates the utility of this instrument, but it is not meant as a definitive diagnostic tool and should be followed with a professional assessment.

Multivariate morphometry statistics reveal the morphological change pattern of hippocampus during normal aging.

There have been numerous studies focusing on normal aging in previous decades which is accompanied by the structural and functional decline in the hippocampus, while the pattern of hippocampal alteration with age remains unclear. Figuring out the mechanism of hippocampal changes precisely is beneficial for a better understanding of the aging process. In this study, we included a total of 451 T1 MRI scans of subjects of age 50-90 who were labeled as normal in the Alzheimers Disease Neuroimaging Initiative. Taking 10 years of age as an age band, we divided the subjects into four groups (denoted as HC1, HC2, HC3, and HC4, respectively), with the youngest being 50-60 and the oldest 81-90. Then the Multivariate Morphometry Statistics (MMS) of the hippocampus segmented from the four groups were extracted by surface reconstruction, mesh generation, and surface registration. Finally, the significant differences between the youngest group and the other three were statistically analyzed. Results showed that the earliest deformation region of the left hippocampus located in the frontal subiculum and the dorsal CA1 of the tail part and gradually expanded with aging, while the right hippocampal deformation mainly concentrated in the dorsal CA1 and spread to the posterior CA2-3, which occurred later than that of the left. All the results illustrated that the hippocampus is truly a vulnerable structure in the course of aging, and the MMS are sensitive metrics for detecting the changes in the subcortical convex structure.

Higher susceptibility to 6 Hz corneal kindling and lower responsiveness to antiseizure drugs in mouse models of Alzheimers disease.

Epileptic spikes and seizures seem present early in the disease process of Alzheimers disease (AD). However, it is unclear how soluble and insoluble amyloid beta (Aβ) and tau proteins affect seizure development in vivo. We aim to contribute to this field by assessing the vulnerability to 6 Hz corneal kindling of young female mice from two well-characterized transgenic AD models and by testing their responsiveness to selected antiseizure drugs (ASDs). We used 7-week-old triple transgenic (3xTg) mice that have both amyloid and tau mutations, and amyloid precursor protein Swedishpresenillin 1 dE9 (APPPS1) mice, bearing only amyloid-related mutations. We assessed the absence of plaques via immunohistochemistry and analyzed the concentrations of both soluble and insoluble forms of Aβ No Aβ plaques were present in either genotype. Soluble Aβ Mutations increasing Aβ only or both Aβ and tau in the brain enhance susceptibility for seizures and kindling in mice. The effect of ASDs on seizures measured by the Racine scale is less pronounced in both investigated AD models and suggests that seizures of young AD mice are more difficult to treat.

Caregiver appraisals of lucid episodes in people with late-stage Alzheimers disease or related dementias.

Little is known about how family caregivers who witness unexpected and spontaneous communication among people in late stages of Alzheimers disease and related dementias (ADRD) appraise these episodes of lucidity (EL). In an electronic, cross-sectional survey for former and current caregivers who participate in UsAgainstAlzheimers A-LIST Caregivers reported 72% of ELs to be quite a bit or very positive, 17% to be stressful, and 10% to be both stressful and positive. Twelve percent of caregivers changed care plans because of ELs and 13% sought out information about ELs. These exploratory data suggest caregiver reactions to EL vary. Caregivers may change or postpone care decisions due to EL, and few resources exist to address caregiver queries about EL.

Evaluation of a Selective Chemical Probe Validates That CK2 Mediates Neuroinflammation in a Human Induced Pluripotent Stem Cell-Derived Mircroglial Model.

Novel treatments for neurodegenerative disorders are in high demand. It is imperative that new protein targets be identified to address this need. Characterization and validation of nascent targets can be accomplished very effectively using highly specific and potent chemical probes. Human induced pluripotent stem cells (hiPSCs) provide a relevant platform for testing new compounds in disease relevant cell types. However, many recent studies utilizing this platform have focused on neuronal cells. In this study, we used hiPSC-derived microglia-like cells (MGLs) to perform side-by-side testing of a selective chemical probe, SGC-CK2-1, compared with an advanced clinical candidate, CX-4945, both targeting casein kinase 2 (CK2), one of the first kinases shown to be dysregulated in Alzheimers disease (AD). CK2 can mediate neuroinflammation in AD, however, its role in microglia, the innate immune cells of the central nervous system (CNS), has not been defined. We analyzed available RNA-seq data to determine the microglial expression of kinases inhibited by SGC-CK2-1 and CX-4945 with a reported role in mediating inflammation in glial cells. As proof-of-concept for using hiPSC-MGLs as a potential screening platform, we used both wild-type (WT) MGLs and MGLs harboring a mutation in presenilin-1 (PSEN1), which is causative for early-onset, familial AD (FAD). We stimulated these MGLs with pro-inflammatory lipopolysaccharides (LPS) derived from

Cerebral Microvascular Pathology Is a Common Endophenotype Between Traumatic Brain Injury, Cardiovascular Disease, and Dementia A Hypothesis and Review.

Traumatic brain injury (TBI) exposure has been associated with an increased risk of age-related cognitive decline or dementia in multiple epidemiological studies. Current therapeutic interventions in the field of Brain Injury Medicine focus largely on episodic symptom management during the chronic phase of TBI recovery, rather than targeting specific underlying pathological processes. This approach may be especially problematic for secondary age-related cognitive decline or dementia following TBI exposure. Although there are likely multiple pathophysiological mechanisms involved, a growing body of literature demonstrates that cerebral microvascular pathology is a common endophenotype across the spectrum of TBI severity. Similarly, a combination of pre-clinical and clinical research over the past two decades has implicated cerebral microvascular pathology in the initiation and progression of multiple neurodegenerative diseases, including Alzheimers disease and other dementias. We hypothesize that cerebral microvascular pathology is a common endophenotype between TBI, cardiovascular disease (CVD), and dementia, which can be targeted through modifiable cardiovascular risk factor reductions during the chronic phase of TBI recovery. We posit that our hypothesis is supported by the currently available scientific literature, as detailed in our review.

Molecular Pathways and Roles for Vitamin K2-7 as a Health-Beneficial Nutraceutical Challenges and Opportunities.

Vitamin K2-7, also known as menaquinone-7 (MK-7) is a form of vitamin K that has health-beneficial effects in osteoporosis, cardiovascular disease, inflammation, cancer, Alzheimers disease, diabetes and peripheral neuropathy. Compared to vitamin K1 (phylloquinone), K2-7 is absorbed more readily and is more bioavailable. Clinical studies have unequivocally demonstrated the utility of vitamin K2-7 supplementation in ameliorating peripheral neuropathy, reducing bone fracture risk and improving cardiovascular health. We examine how undercarboxylated osteocalcin (ucOC) and matrix Gla protein (ucMGP) are converted to carboxylated forms (cOC and cMGP respectively) by K2-7 acting as a cofactor, thus facilitating the deposition of calcium in bones and preventing vascular calcification. K2-7 is beneficial in managing bone loss because it upregulates osteoprotegerin which is a decoy receptor for RANK ligand (RANKL) thus inhibiting bone resorption. We also review the evidence for the health-beneficial outcomes of K2-7 in diabetes, peripheral neuropathy and Alzheimers disease. In addition, we discuss the K2-7-mediated suppression of growth in cancer cells

Alzheimers Disease-Related Genes Identified by Linking Spatial Patterns of Pathology and Gene Expression.

Alzheimers Disease (AD) is an age-related neurodegenerative disease with a poorly understood etiology, shown to be partly genetic. Glucose hypometabolism, extracellular Amyloid-beta (Aβ) deposition, and intracellular Tau deposition are cardinal features of AD and display characteristic spatial patterns in the brain. We hypothesize that regional differences in underlying gene expression confer either resistance or susceptibility to AD pathogenic processes and are associated with these spatial patterns. Data-driven methods for the identification of genes involved in AD pathogenesis complement hypothesis-driven approaches that reflect current theories about the disease. Here we present a data driven method for the identification of genes involved in AD pathogenesis based on comparing spatial patterns of normal gene expression to Positron Emission Tomography (PET) images of glucose hypometabolism, Aβ deposition, and Tau deposition. We performed correlations between the cerebral cortex microarray samples from the six cognitively normal (CN) post-mortem Allen Human Brain Atlas (AHBA) specimens and PET FDG-18, AV-45, and AV-1451 tracer images from AD and CN participants in the Alzheimers Disease and Neuroimaging Initiative (ADNI) database. Correlation coefficients for each gene by each ADNI subject were then entered into a partial least squares discriminant analysis (PLS-DA) to determine sets that best classified the AD and CN groups. Pathway analysis We identified distinct sets of genes strongly associated with each PET modality. Pathway analyses implicated novel genes involved in mitochondrial function, and Notch signaling, as well as genes previously associated with AD. Using an unbiased approach, we derived sets of genes with expression patterns spatially associated with FDG hypometabolism, Aβ deposition, and Tau deposition in AD. This methodology may complement population-based approaches for identifying the genetic underpinnings of AD.

Ontology Specific Alternative Splicing Changes in Alzheimers Disease.

Alternative splicing (AS) is a common phenomenon and correlates with aging and aging-related disorders including Alzheimers disease (AD). We aimed to systematically characterize AS changes in the cerebral cortex of 9-month-old APPPS1 mice. The GSE132177 dataset was downloaded from GEO and ENA databases, aligned to the GRCm39 reference genome from ENSEMBL via STAR. Alternative 3SS (A3SS), alternative 5SS (A5SS), skipped exon (SE), retained intron (RI), and mutually exclusive exons (MXE) AS events were evaluated using rMATS, rmats2sashimiplot, and maser. Differential genes or transcripts were analyzed using the limma R package. Gene ontology analysis was performed with the clusterProfiler R package. A total of 60,705 raw counts of AS were identified, and 113 significant AS events were finally selected in accordance with the selection criteria 1) average coverage >10 and 2) delta percent spliced in (ΔPSI) >0.1. SE was the most abundant AS event (61.95%), and RI was the second most abundant AS type (13.27%), followed by A3SS (12.39%), thereafter A5SS and MXE comprised of 12.39%. Interestingly, genes that experienced SE were enriched in histone acetyltransferase (HAT) complex, while genes spliced by RI were enriched in autophagy and those which experienced A3SS were enriched in methyltransferase activity revealed by GO analysis. In conclusion, we revealed ontology specific AS changes in AD. Our analysis provides novel pathological mechanisms of AD.

The Correlation Between White Matter Hyperintensity Burden and Regional Brain Volumetry in Patients With Alzheimers Disease.

White matter hyperintensities (WMHs) and regional brain lobe atrophy coexist in the brain of patients with Alzheimers disease (AD), but the association between them in patients with AD still lacks comprehensive investigation and solid imaging data support. We explored whether WMHs can promote the pathological process of AD by aggravating atrophy in specific brain regions and tried to explain the regional specificity of these relationships. A sample of 240 adults including 180 normal controls (NCs) and 80 cases with AD were drawn from the ADNI database. T1-weighted magnetic resonance imaging (MRI) and T2-weighted fluid-attenuated MRI of the participants were downloaded and were analyzed using AccuBrain Positive association between WMHr and quantitative medial temporal lobe atrophy (QMTA) ( WMH severity tends to be associated with regional brain atrophy in patients with AD, especially with medial temporal lobe, temporal lobe, and insular lobe atrophy. PVWMHs were devoted to these correlations.

Parallel imaging of coagulation pathway proteases activated protein C, thrombin, and factor Xa in human plasma.

Activated protein C (APC), thrombin, and factor (f) Xa are vitamin K-dependent serine proteases that are key factors in blood coagulation. Moreover, they play important roles in inflammation, apoptosis, fibrosis, angiogenesis, and viral infections. Abnormal activity of these coagulation factors has been related to multiple conditions, such as bleeding and thrombosis, Alzheimers disease, sepsis, multiple sclerosis, and COVID-19. The individual activities of APC, thrombin, and fXa in coagulation and in various diseases are difficult to establish since these proteases are related and have similar substrate preferences. Therefore, the development of selective chemical tools that enable imaging and discrimination between coagulation factors in biological samples may provide better insight into their roles in various conditions and potentially aid in the establishment of novel diagnostic tests. In our study, we used a large collection of unnatural amino acids, and this enabled us to extensively explore the binding pockets of the enzymes active sites. Based on the specificity profiles obtained, we designed highly selective substrates, inhibitors, and fluorescent activity-based probes (ABPs) that were used for fast, direct, and simultaneous detection of APC, thrombin, and fXa in human plasma.

Automated Classification of Mild Cognitive Impairment by Machine Learning With Hippocampus-Related White Matter Network.

Detection of mild cognitive impairment (MCI) is essential to screen high risk of Alzheimers disease (AD). However, subtle changes during MCI make it challenging to classify in machine learning. The previous pathological analysis pointed out that the hippocampus is the critical hub for the white matter (WM) network of MCI. Damage to the white matter pathways around the hippocampus is the main cause of memory decline in MCI. Therefore, it is vital to biologically extract features from the WM network driven by hippocampus-related regions to improve classification performance. Our study proposes a method for feature extraction of the whole-brain WM network. First, 42 MCI and 54 normal control (NC) subjects were recruited using diffusion tensor imaging (DTI), resting-state functional magnetic resonance imaging (rs-fMRI), and T1-weighted (T1w) imaging. Second, mean diffusivity (MD) and fractional anisotropy (FA) were calculated from DTI, and the whole-brain WM networks were obtained. Third, regions of interest (ROIs) with significant functional connectivity to the hippocampus were selected for feature extraction, and the hippocampus (HIP)-related WM networks were obtained. Furthermore, the rank sum test with Bonferroni correction was used to retain significantly different connectivity between MCI and NC, and significant HIP-related WM networks were obtained. Finally, the classification performances of these three WM networks were compared to select the optimal feature and classifier. (1) For the features, the whole-brain WM network, HIP-related WM network, and significant HIP-related WM network are significantly improved in turn. Also, the accuracy of MD networks as features is better than FA. (2) For the classification algorithm, the support vector machine (SVM) classifier with radial basis function, taking the significant HIP-related WM network in MD as a feature, has the optimal classification performance (accuracy 89.4%, AUC 0.954). (3) For the pathologic mechanism, the hippocampus and thalamus are crucial hubs of the WM network for MCI. Feature extraction from the WM network driven by hippocampus-related regions provides an effective method for the early diagnosis of AD.

Four-repeat tauopathies and late-onset psychiatric disorders Etiological relevance or incidental findings

Argyrophilic grain disease (AGD), progressive supranuclear palsy (PSP) and corticobasal degeneration are four-repeat (4R) tauopathies that develop in the presenium or later. Whether these diseases are associated with the occurrence of late-onset psychiatric disorders remains unclear. To facilitate the accumulation of clinicopathological findings regarding this issue, we here present a selected series of 11 cases that clinically developed psychotic disorder (n 7 age at onset 41-75 years), depressive disorder (n 1 49 years), bipolar disorder (n 2 32 and 37 years) and somatoform disorder (n 1 88 years), and had at least one pathological hallmark of these tauopathies. The mean age at death was 74.3 years. No case showed dementia, at least in the early stage of the course. Nine cases had AGD. Granular fuzzy astrocytes in the amygdala were noted in all AGD cases and one non-AGD case. Two AGD cases had tufted astrocytes (TAs) in the amygdala but not in the frontal cortex and striatum. Three AGD and two non-AGD cases had TAs in the frontal cortex andor striatum but not in the amygdala. One AGD case had a small number of astrocytic plaques in the frontal cortex, striatum and globus pallidus. Only one case was diagnosed as atypical PSP according to the NINDS-PSP neuropathological criteria. No case had high-level Alzheimers disease pathology, Lewy body disease or limbic-predominant age-related TDP-43 encephalopathy. Two cases had mild neuronal loss in the hippocampus and substantia nigra, respectively. Clinicopathological studies focusing especially on early changes of 4R tauopathies, as well as the development of surrogate markers of these diseases, may be necessary for better understanding of the pathogenic backgrounds of late-onset psychiatric disorders.

Beyond garden design A review of outdoor occupation in hospital and residential care settings for people with dementia.

Access to outdoor space is widely recommended for people with dementia. However, there is limited information on the occupations of people with dementia within these spaces. We sought to review the research literature to identify the occupations of people with dementia in outdoor spaces in residential aged care andor hospitals and report on features that support occupational participation as well as the benefits of occupational participation in these spaces. Scoping review. We searched electronic databases involving health, design, and horticulture literature. Studies were included if they involved people with dementia and considered occupations within gardens or garden-like spaces of hospitals, subacute rehabilitation facilities, or residential aged care. We identified 19 articles meeting the review criteria. Outdoor spaces for people with dementia varied in design and supported a range of occupations with the most common being social occupations, gardening, and physical activities. Quantitative studies suggested that benefits of outdoor occupations for people with dementia were improvements in activity participation, social connection, mood, agitation, light exposure, and sleep. Qualitative studies supported these findings and identified additional perceived benefits such as engagement, maintaining identity, health, and reduced levels of distress. Benefits were also reported for families and staff. Current literature shows that many occupations can be done outside and that these are beneficial for people with dementia. Despite the wide range of benefits, multiple studies reported that outdoor spaces remain under-utilised. More work is required to design spaces for occupational engagement, support access to outdoor spaces, and promote occupational participation.

Automated Segmentation of Lateral Ventricles in Alzheimers Conditions Using UNET Model.

Accurate diagnosis of Alzheimers disease (AD) in early stage can control the disease progression. Enlargement of Lateral Ventricles (LV) is one of the significant imaging biomarkers for the differentiation of Alzheimers conditions. However, segmentation of accurate LV for analysis is still challenging. In this work, an attempt is made to segment LV regions from brain MR images using the UNet model. For this, axial scans of the MR images are taken from the publicly available Open Access Series of Imaging Studies (OASIS) Brain dataset. LV-based region of interest is segmented using the UNet network. Results show that the proposed approach is able to segment brain regions in Alzheimers conditions. The UNet network model yields the highest dice score of 99.4% and sensitivity of 99.3% in segmenting the LV brain region. Thus, the proposed method could be useful for characterizing Alzheimers condition.

Explainable Optimized LightGBM Based Differentiation of Mild Cognitive Impairment Using MR Radiomic Features.

In this study, an explainable Bayesian Optimized (BO) LightGBM model is employed to differentiate the Corpus Callosal (CC) image features of Healthy Controls (HC) and Mild Cognitive Impairment (MCI). For this, Magnetic Resonance (MR) brain images obtained from a public database are pre-processed and CC is segmented using spatial fuzzy clustering-based level set. Radiomic features are extracted from the segmented CC, which are further fed to BO-LightGBM classifier. SHapley Additive exPlanations (SHAP) technique is used to evaluate the interpretability of the model. The results indicate that radiomics based BO-LightGBM is able to differentiate MCI from HC. An area under curve of 0.83 is achieved by the model. SHAP values suggest that out of 56 radiomic features, texture descriptors possess the highest discriminative power in MCI diagnosis. The performance of adopted approach indicates that radiomics based BO-LightGBM aid in the automated diagnosis of early Alzheimers Disease stages.

Comparing Emotional Valence Scores of Twitter Posts from Manual Coding and Machine Learning Algorithms to Gain Insights to Refine Interventions for Family Caregivers of Persons with Dementia.

We randomly extracted Korean-language Tweets mentioning dementiaAlzheimers disease (n 12,413) from November 28 to December 9, 2020. We independently applied three machine learning algorithms (Afinn, Syuzhet, and Bing) using natural language processing (NLP) techniques and qualitative manual scoring to assign emotional valence scores to Tweets. We then compared the means and distributions of the four emotional valence scores. Visual examination of the graphs produced indicated that each method exhibited unique patterns. The aggregated mean emotional valence scores from the NLP methods were mostly neutral, vs. slightly negative for manual coding (Afinn 0.029, 95% CI -0.019, 0.077 Syuzhet 0.266, 0.236, 0.295 Bing -0.271, -0.289, -0.252 manual coding -1.601, -1.632, -1.569). One-way analysis of variance (ANOVA) showed no statistically significant differences among the four means after normalization. These findings suggest that the application of NLP can be fairly effective in extracting emotional valence scores from Korean-language Twitter content to gain insights regarding family caregiving for a person with dementia.

Comparing Themes Extracted via Topic Modeling and Manual Content Analysis Korean-Language Discussions of Dementia on Twitter.

We randomly examined Korean-language Tweets mentioning dementiaAlzheimers disease (n 12,413) posted from November 28 to December 9, 2020, without limiting geographical locations. We independently applied Latent Dirichlet Allocation (LDA) topic modeling and qualitative content analysis to the texts of the Tweets. We compared the themes extracted by LDA topic modeling to those identified via manual coding methods. A total of 16 themes were detected from manual coding, with inter-rater reliability (Cohens kappa) of 0.842. The proportions of the most prominent themes were burdens of family caregiving (48.50%), reports of wanderingmissing family members with dementia (18.12%), stigma (13.64%), prevention strategies (5.07%), risk factors (4.91%), healthcare policy (3.26%), and elder abusesafety issues (1.75%). Seven themes whose contents were similar to themes derived from manual coding were extracted from the LDA topic modeling results (perplexity -6.39, coherence score 0.45). Our findings suggest that applying LDA topic modeling can be fairly effective at extracting themes from Korean Twitter discussions, in a manner analogous to qualitative coding, to gain insights regarding caregiving for family members with dementia, and our approach can be applied to other languages.

Associations between proton pump inhibitors and Alzheimers disease a nested case-control study using a Korean nationwide health screening cohort.

Safety concerns against the use of proton pump inhibitors (PPIs) based on the risk of dementia, especially Alzheimers disease (AD), remain controversial. Here, we investigated the likelihood of AD depending on previous PPI exposure, use duration, and PPI generation. This nested case-control study comprised 17,225 AD patients who were 14 matched with 68,900 controls for age, sex, income, and region of residence from Korean National Health Insurance Service-Health Screening Cohort data between 2002 and 2015 using propensity-score matching method. Conditional and unconditional logistic regression analyses were used to evaluate the effects of previous PPI use on AD adjusting for multiple covariates. Prior PPI use increased likelihood for AD in current and past PPI users (adjusted odds ratio 1.36 95% confidence interval (CI) 1.26-1.46 and 1.11 95% CI 1.04-1.18, respectively). Participants with either < 30 days, 30-90 days, or > 90 days of PPI prescription showed higher odds for AD (1.13 95% CI 1.07-1.19 1.18 95% CI 1.10-1.27 1.26 95% CI 1.16-1.36, respectively). Participants with either 1st-generation or 2nd-generation PPIs demonstrated higher incidences of AD in those with < 30 days (1.14 95% CI 1.07-1.22 and 1.13 95% CI 1.05-1.22, respectively), 30-90 days (1.19 95% CI 1.09-1.30 and 1.17 95% CI 1.05-1.29, respectively), or > 90 days (1.18 95% CI 1.07-1.30 and 1.27 95% CI 1.14-1.43, respectively) of prescription. Prior PPI use, regardless of current or past exposure, duration of use, or use of 1st- or 2nd-generation PPIs, may increase likelihood of AD, providing supportive evidence of previous pharmacoepidemiologic studies.

Potential association of bone mineral density loss with cognitive impairment and central and peripheral amyloid-β changes a cross-sectional study.

There is some evidence in the literature that older adults with cognitive impairments have a higher risk for falls and osteoporotic hip fractures. Currently, the associations between bone health and cognitive health have not been extensively studied. Thus, the present cross-sectional study aims to investigate the relationship between markers of bone loss and cognitive performance in older adults with and without osteopenia as well as older adults with cognitive impairments (i.e., Alzheimers disease AD). Sixty-two non-osteopenia participants and one hundred three osteopenia participants as the cohort 1 and 33 cognitively normal non-AD participants and 39 AD participants as the cohort 2 were recruited. To assess cognitive and bone health, hip bone mineral density (BMD) and cognitive performance (via Minimal Mental State Examination MMSE andor Auditory Verbal Learning Test-delayed recall AVLT-DR) were assessed. Furthermore, in cohort 1, plasma amyloid-β (Aβ) levels, and in cohort 2, cerebrospinal fluid (CSF) Aβ levels were determined. We observed that (1) compared with non-osteopenia participants, BMD values (t - 22.806 95%CI - 1.801, - 1.484 p < 0.001), MMSE scores (t - 5.392 95%CI - 3.260, - 1.698 p < 0.001), and AVLT-DR scores (t - 4.142 95%CI - 2.181, - 0.804 p < 0.001), plasma Aβ42 levels (t - 2.821 95%CI - 1.737, - 0.305 p 0.01), and Aβ4240 ratio (t - 2.020 95%CI - 0.009, - 0.001 p 0.04) were significantly lower in osteopenia participants (2) plasma Aβ4240 ratio showed a mediate effect for the association between BMD values and the performance of cognitive function in osteopenia participants by mediation analysis, adjusting age, sex, years of education, and body mass index (BMI) (3) BMD values (95%CI - 1.085, 0.478 p < 0.001) were significantly reduced in AD participants as compared with cognitively normal non-AD participants (4) in AD participants, the interactive effects of BMD and CSF Aβ4240 ratio on MMSE scores was found by regression analysis, controlling age, sex, years of education, and BMI (5) BMD can distinguish AD participants from cognitively normal non-AD participants with AUC of 0.816 and distinguish participants with the cognitive impairment from cognitively normal participants with AUC of 0.794. Our findings suggest a relationship between bone health and cognitive health. Given the correlations between BMD and important markers of cognitive health (e.g., central and peripheral pathological change of Aβ), BMD might serve as a promising and easy-accessible biomarker. However, more research is needed to further substantiate our findings.

Prevalence of potentially inappropriate medications among old people with major neurocognitive disorder in 2012 and 2017.

The increased risk of adverse drug reactions due to age-related altered pharmacokinetics and pharmacodynamics is a challenge when prescribing medications to older people, and especially among older people with major neurocognitive disorder who are particularly sensitive to drug effects. The aim of this study was to investigate the use of potential inappropriate medications (PIMs) in 2012 and 2017 among old people with major neurocognitive disorder. A secondary aim was to investigate factors associated with PIM use. This register-study was based on the Swedish registry for cognitivedementia disorders and the Swedish prescribed drug register. Criteria from the National Board of Health and Welfare were used to identify PIMs between 1 July-31 December 2012 and 1 July--31 December 2017 among people ≥ 65 years. Drug use was defined as one or more filled prescriptions during each timeframe. The total use of PIMs declined significantly between 2012 (28.7%) and 2017 (21.7%). All PIMs and PIM groups declined between these years, except for antipsychotic drugs, which increased from 11.6% to 12.3%. The results from the multiple regression model found that PIM use was associated with younger age (OR 0.97 CI 0.96-0.97), a lower Mini Mental State Examination score (OR 0.99 CI 0.99-1.00), the use of multi-dispensed drugs (OR 2.05 CI 1.93-2.18), and compared to Alzheimers disease, with the subtypes dementia with Lewy bodies and Parkinsons disease dementia (OR 1.57 CI 1.40-1.75), frontotemporal dementia (OR 1.29 CI 1.08-1.54) and vascular dementia (OR 1.10 CI 1.03-1.16). Overall, the use of PIMs decreased between the years 2012 and 2017. The increase of antipsychotic drugs and the association between PIM use and multi-dispensed drugs warrant concern.

Identification of bioactive peptides from a Brazilian kefir sample, and their anti-Alzheimer potential in Drosophila melanogaster.

Alzheimers disease (AD) is the most common form of dementia in the elderly, affecting cognitive, intellectual, and motor functions. Different hypotheses explain ADs mechanism, such as the amyloidogenic hypothesis. Moreover, this disease is multifactorial, and several studies have shown that gut dysbiosis and oxidative stress influence its pathogenesis. Knowing that kefir is a probiotic used in therapies to restore dysbiosis and that the bioactive peptides present in it have antioxidant properties, we explored its biotechnological potential as a source of molecules capable of modulating the amyloidogenic pathway and reducing oxidative stress, contributing to the treatment of AD. For that, we used Drosophila melanogaster model for AD (AD-like flies). Identification of bioactive peptides in the kefir sample was made by proteomic and peptidomic analyses, followed by in vitro evaluation of antioxidant and acetylcholinesterase inhibition potential. Flies were treated and their motor performance, brain morphology, and oxidative stress evaluated. Finally, we performed molecular docking between the peptides found and the main pathology-related proteins in the flies. The results showed that the fraction with the higher peptide concentration was positive for the parameters evaluated. In conclusion, these results revealed these kefir peptide-rich fractions have therapeutic potential for AD.

LDL cholesterol is associated with higher AD neuropathology burden independent of APOE.

Individuals in the Religious Orders StudyMemory and Ageing Project cohorts with longitudinal measures of blood lipids and detailed autopsies were studied. We modelled the relationship between blood lipids and 12 age-related brain pathologies using a linear mixed model adjusted for potential confounding factors and stratified by 559 participants (69.1% female) had complete data for analysis. They were followed for a median of 7 years and a median of 3 years prior to dementia onset. LDL-C was associated with all measures of AD neuropathology (neurofibrillary tangles, beta-amyloid, Braak stage, modified CERAD score and global AD pathology) and cerebral amyloid angiopathy independent of These findings implicate LDL-C in the pathophysiology of AD independent of

Associating pathways with diseases using single-cell expression profiles and making inferences about potential drugs.

Finding direct dependencies between genetic pathways and diseases has been the target of multiple studies as it has many applications. However, due to cellular heterogeneity and limitations of the number of samples for bulk expression profiles, such studies have faced hurdles in the past. Here, we propose a method to perform single-cell expression-based inference of association between pathway, disease and cell-type (sci-PDC), which can help to understand their cause and effect and guide precision therapy. Our approach highlighted reliable relationships between a few diseases and pathways. Using the example of diabetes, we have demonstrated how sci-PDC helps in tracking variation of association between pathways and diseases with changes in age and species. The variation in pathways-disease associations in mice and humans revealed critical facts about the suitability of the mouse model for a few pathways in the context of diabetes. The coherence between results from our method and previous reports, including information about the drug target pathways, highlights its reliability for multidimensional utility.

Combined association of depressive symptoms and sugar-sweetened beverages consumption with low cognitive performance.

The combined association of depressive symptoms and sugar-sweetened beverages (SSB) consumption with low cognitive performance is poorly understood so far. Data from the National Health and Nutrition Examination Survey 2011-2014 and Food Patterns Equivalents Database was used. Depressive symptoms were identified using the Patient Health Questionnaire-9. The combinations of depressive symptomsSSB were defined as a categorical variable comprising no depressive symptomslow SSB, no depressive symptomshigh SSB, mild-to-severe depressive symptomslow SSB and mild-to-severe depressive symptomshigh SSB. Cognitive function was measured by three tests. People whose score were lower than the gender group stratified lowest quartile were defined as low cognitive performance. Logistic regression model was applied to examine the combined association with low cognitive performance. Interaction analysis was conducted to verify the interaction with gender. The combined associations of depressive symptoms and SSB consumption with low cognitive performance were significant. For the Consortium to Establish a Registry for Alzheimers Disease test, the combinations of mild-to-severe depressive symptomslow SSB (ORs (95 % CI) 1.59 (1.01, 2.52)), no depressive symptomshigh SSB (ORs (95 % CI) 1.48 (0.96, 2.26)) and mild-to-severe depressive symptomshigh SSB (ORs (95 % CI) 1.74 (1.21, 2.53)) had significant or marginally significant associations with low cognitive performance to those with no depressive symptoms and low SSB consumption. This is a cross-sectional study. The combination of depressive symptoms and SSB consumption might be associated with low cognitive performance, which had gender differences. These evidences could help guide interventions that focus on dietary nutrition patterns or mood for low cognitive performance.

Comparing the effects of organic cosolvents on acetylcholinesterase and butyrylcholinesterase activity.

The use of cosolvents to solubilize compounds under investigation while having minimal effects on enzyme activity is an important component in many biochemical studies. Predicting the effects of cosolvents on enzyme activity can be complicated, as enzymes with similar overall structures might exhibit different behaviors in different cosolvents. In this study, the effects of several commonly used cosolvents Methanol, acetonitrile, acetone, and dimethyl sulfoxide (DMSO), on two cholinesterases, acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), were evaluated. Although the overall structures are highly similar, AChE activity was more sensitive to the organic cosolvents tested compared to BChE. Effects of the cosolvents on activity did not vary over time and activity was restored upon dilution of the cosolvent. Michaelis-Menten kinetics experiments showed that V

Nursing Home Characteristics Associated with High and Low Levels of Antipsychotic, Benzodiazepine, and Opioid Prescribing to Residents with Alzheimers Disease and Related Dementias A Cross-Sectional Analysis.

We examined the association between nursing home (NH) characteristics and whether NHs had high or low levels of antipsychotic, benzodiazepine, or opioid prescribing to residents with Alzheimers disease and related dementias (ADRD). We then measured the likelihood that NHs who were high (low) prescribers of antipsychotics were also high (low) prescribers of benzodiazepines or opioids. A retrospective, cross-sectional analysis. The sample included 448,128 Medicare beneficiaries diagnosed with ADRD, who resided in 13,151 NHs in 2017. Using Medicare claims, the Minimum Data Set, and LTCFocus, we measured the share of NH residents with ADRD who filled ≥1 antipsychotic, benzodiazepine, or opioid prescription in 2017. Using linear probability models with state-clustered SEs, we identified which NH characteristics were associated with being in the top (bottom) quartile of the prescribing distribution for each drug class. Finally, we measured whether NHs who were top-quartile (bottom-quartile) antipsychotic prescribers were more likely to be top-quartile (bottom-quartile) benzodiazepine or opioid prescribers. Across NHs, an average of 29.1% of residents with ADRD received an antipsychotic, 30.2% received a benzodiazepine, and 40.9% received an opioid. Smaller NHs and NHs with a larger share of Medicaid-enrolled residents were more likely to be top-quartile prescribers NHs with more registered nursing care were more likely to be bottom-quartile prescribers. Antipsychotic prescribing tracked closely with benzodiazepine prescribing, but not opioid prescribing. The overlap between antipsychotic and benzodiazepine prescribing and our finding that some NH characteristics were consistently associated with prescribing across drug classes may support the idea of an organizational culture of prescribing in NHs, which could inform efforts to improve prescribing quality in NHs. Our results also highlight benzodiazepine and opioid use for ADRD, which were more commonly prescribed than antipsychotics in NHs but have received less regulatory attention.

Stigmasterol attenuates inflammatory response of microglia via NF-κB and NLRP3 signaling by AMPK activation.

Alzheimers disease (AD) is the most common cause of dementia in the elderly. Although its pathogenesis remains unclear, studies have indicated microglia-mediated neuroinflammation playing an important role. Phytosterols are a class of natural compounds presented in food, and have anti-inflammatory abilities. Recent studies suggested that phytosterols can traverse the blood-brain barrier and enter the brain, however, it remains largely unknown that whether phytosterols affect neuroinflammation in the AD pathogenesis. Here, we used APP

Mutations linked to neurological disease enhance self-association of low-complexity protein sequences.

Protein domains of low sequence complexity do not fold into stable, three-dimensional structures. Nevertheless, proteins with these sequences assist in many aspects of cell organization, including assembly of nuclear and cytoplasmic structures not surrounded by membranes. The dynamic nature of these cellular assemblies is caused by the ability of low-complexity domains (LCDs) to transiently self-associate through labile, cross-β structures. Mechanistic studies useful for the study of LCD self-association have evolved over the past decade in the form of simple assays of phase separation. Here, we have used such assays to demonstrate that the interactions responsible for LCD self-association can be dictated by labile protein structures poised close to equilibrium between the folded and unfolded states. Furthermore, missense mutations causing Charcot-Marie-Tooth disease, frontotemporal dementia, and Alzheimers disease manifest their pathophysiology in vitro and in cultured cell systems by enhancing the stability of otherwise labile molecular structures formed upon LCD self-association.

Elucidating the causes of neurodegeneration.

Investigating phase separation in neurodegeneration highlights evidence needed for causation.

Actovegin in the management of patients after ischemic stroke A systematic review.

Actovegin is a hemodialysate of calfs blood and has been used for several decades in the countries of Central Asia, East Asia, Russia and some European countries. It has been used to treat patients with various neurological conditions, vascular disorders, and ischemic stroke. To perform a systematic review to evaluate the effect of Actovegin in patients who have suffered an ischemic stroke. A search of MEDLINE, PubMed, Cochrane and Embase was carried out from inception to October 10, 2021 for clinical trials and observational studies with a control group, published in English or Russian. Of 220 identified unique records, 84 full-text articles were screened, and 5 studies were selected that met the inclusion criteria. This included 4 observational studies with control groups and one randomized, placebo-controlled clinical trial. These studies enrolled a total of 3879 patients of which 720 patients received Actovegin administered intravenously andor orally for a duration ranging from 10 to 180 days. Because of study heterogeneity, meta-analysis was not performed. No consistent evidence on improved survival, quality of life, neurologic symptoms, activities of daily living or disability was identified. One study showed statistically significant improvements in the Alzheimers Disease Assessment Scale, cognitive subscale, extended version (ADAS-cog) for Actovegin compared with placebo at 6 months but the clinical relevance of this change is uncertain. One study reported a higher incidence of recurrent ischemic stroke, transient ischemic attack or intracerebral hemorrhage in patients taking Actovegin compared to placebo. The benefits of Actovegin are uncertain and that there is potential risk of harm in patients with stroke. More evidence is needed from rigorously designed clinical trials to justify the role of Actovegin in patients with ischemic stroke.

Integration of multidimensional splicing data and GWAS summary statistics for risk gene discovery.

A common strategy for the functional interpretation of genome-wide association study (GWAS) findings has been the integrative analysis of GWAS and expression data. Using this strategy, many association methods (e.g., PrediXcan and FUSION) have been successful in identifying trait-associated genes via mediating effects on RNA expression. However, these approaches often ignore the effects of splicing, which can carry as much disease risk as expression. Compared to expression data, one challenge to detect associations using splicing data is the large multiple testing burden due to multidimensional splicing events within genes. Here, we introduce a multidimensional splicing gene (MSG) approach, which consists of two stages 1) we use sparse canonical correlation analysis (sCCA) to construct latent canonical vectors (CVs) by identifying sparse linear combinations of genetic variants and splicing events that are maximally correlated with each other and 2) we test for the association between the genetically regulated splicing CVs and the trait of interest using GWAS summary statistics. Simulations show that MSG has proper type I error control and substantial power gains over existing multidimensional expression analysis methods (i.e., S-MultiXcan, UTMOST, and sCCAACAT) under diverse scenarios. When applied to the Genotype-Tissue Expression Project data and GWAS summary statistics of 14 complex human traits, MSG identified on average 83%, 115%, and 223% more significant genes than sCCAACAT, S-MultiXcan, and UTMOST, respectively. We highlight MSGs applications to Alzheimers disease, low-density lipoprotein cholesterol, and schizophrenia, and found that the majority of MSG-identified genes would have been missed from expression-based analyses. Our results demonstrate that aggregating splicing data through MSG can improve power in identifying gene-trait associations and help better understand the genetic risk of complex traits.

Study protocol for the Alzheimer and music therapy study An RCT to compare the efficacy of music therapy and physical activity on brain plasticity, depressive symptoms, and cognitive decline, in a population with and at risk for Alzheimers disease.

There is anecdotal evidence for beneficial effects of music therapy in patients with Alzheimers Disease (AD). However, there is a lack of rigorous research investigating this issue. The aim of this study is to evaluate the effects of music therapy and physical activity on brain plasticity, mood, and cognition in a population with AD and at risk for AD. One-hundred and thirty-five participants with memory complaints will be recruited for a parallel, three-arm Randomized Controlled Trial (RCT). Inclusion criteria are a diagnosis of mild (early) AD or mild cognitive impairment (MCI), or memory complaints without other neuropsychiatric pathology. Participants are randomised into either a music therapy intervention (singing lessons), an active control group (physical activity) or a passive control group (no intervention) for 12 months. The primary outcomes are the brain age gap, measured via magnetic resonance imaging (MRI), and depressive symptoms. Secondary outcomes include cognitive performance, activities of daily living, brain structure (voxel-based morphometry and diffusion tensor imaging), and brain function (resting-state functional MRI). Screening of participants began in April 2018. A total of 84 participants have been recruited and started intervention, out of which 48 participants have completed 12 months of intervention and post-intervention assessment. Addressing the need for rigorous longitudinal data for the effectiveness of music therapy in people with and at risk for developing AD, this trial aims to enhance knowledge regarding cost-effective interventions with potentially high clinical applicability. ClinicalTrials.gov identifier NCT03444181, registered on February 23, 2018.

The many facets of CD26dipeptidyl peptidase 4 and its inhibitors in disorders of the CNS - a critical overview.

Dipeptidyl peptidase 4 is a serine protease that cleaves X-proline or X-alanine in the penultimate position. Natural substrates of the enzyme are glucagon-like peptide-1, glucagon inhibiting peptide, glucagon, neuropeptide Y, secretin, substance P, pituitary adenylate cyclase-activating polypeptide, endorphins, endomorphins, brain natriuretic peptide, beta-melanocyte stimulating hormone and amyloid peptides as well as some cytokines and chemokines. The enzyme is involved in the maintenance of blood glucose homeostasis and regulation of the immune system. It is expressed in many organs including the brain. DPP4 activity may be effectively depressed by DPP4 inhibitors. Apart from enzyme activity, DPP4 acts as a cell surface (co)receptor, associates with adeosine deaminase, interacts with extracellular matrix, and controls cell migration and differentiation. This review aims at revealing the impact of DPP4 and DPP4 inhibitors for several brain diseases (virus infections affecting the brain, tumours of the CNS, neurological and psychiatric disorders). Special emphasis is given to a possible involvement of DPP4 expressed in the brain.While prominent contributions of extracerebral DPP4 are evident for a majority of diseases discussed herein a possible role of brain DPP4 is restricted to brain cancers and Alzheimer disease. For a number of diseases (Covid-19 infection, type 2 diabetes, Alzheimer disease, vascular dementia, Parkinson disease, Huntington disease, multiple sclerosis, stroke, and epilepsy), use of DPP4 inhibitors has been shown to have a disease-mitigating effect. However, these beneficial effects should mostly be attributed to the depression of peripheral DPP4, since currently used DPP4 inhibitors are not able to pass through the intact blood-brain barrier.

Association of Posttraumatic Stress Disorder With Accelerated Cognitive Decline in Middle-aged Women.

Posttraumatic stress disorder (PTSD) has been hypothesized to lead to impaired cognitive function. However, no large-scale studies have assessed whether PTSD is prospectively associated with cognitive decline in middle-aged adults. To assess the association between PTSD and decline in cognitive function over time. This cohort study included participants from the Nurses Health Study II, an ongoing longitudinal cohort study involving community-dwelling middle-aged female nurses residing in the US who had at least a 2-year nursing degree at the time of enrollment in 1989. The present study included 12 270 trauma-exposed women who were enrolled in the PTSD substudy of the Nurses Health Study II and completed 1 to 5 cognitive assessments. Data were collected from March 1, 2008, to July 30, 2019. Lifetime PTSD symptoms, assessed using a validated questionnaire between March 1, 2008, and February 28, 2010. The main outcome was evaluated using the Cogstate Brief Battery, a self-administered online cognitive battery. Cognitive function was measured by a psychomotor speed and attention composite score and a learning and working memory composite score. Women completed the Cogstate Brief Battery every 6 or 12 months (up to 24 months) from October 3, 2014, to July 30, 2019. Linear mixed-effects models were used to evaluate the association of PTSD symptoms with the rate of change in cognition over follow-up, considering a broad range of relevant covariates, including the presence of depression symptoms and history of clinician-diagnosed depression. The rate of cognitive change was adjusted for potential practice effects (ie, potential changes in test results that occur when a test is taken more than once) by including indicators for the number of previous tests taken. Among 12 270 women, the mean (SD) age at the baseline cognitive assessment was 61.1 (4.6) years 125 women (1.0%) were Asian, 75 (0.6%) were Black, 156 (1.3%) were Hispanic, 11 767 (95.9%) were non-Hispanic White, and 147 (1.2%) were of other race andor ethnicity. A higher number of PTSD symptoms was associated with worse cognitive trajectories. Compared with women with no PTSD symptoms, women with the highest symptom level (6-7 symptoms) had a significantly worse rate of change in both learning and working memory (β -0.08 SDy 95% CI, -0.11 to -0.04 SDy P < .001) and psychomotor speed and attention (β -0.05 SDy 95% CI, -0.09 to -0.01 SDy P .02), adjusted for demographic characteristics. Associations were unchanged when additionally adjusted for behavioral factors (eg, 6-7 symptoms in the analysis of learning and working memory β -0.08 SDy 95% CI, -0.11 to -0.04 SDy P < .001) and health conditions (eg, 6-7 symptoms in the analysis of learning and working memory β -0.08 SDy 95% CI, -0.11 to -0.04 SDy P < .001) and were partially attenuated but still evident when further adjusted for practice effects (eg, 6-7 symptoms in the analysis of learning and working memory β -0.07 SDy 95% CI, -0.10 to -0.03 SDy P < .001) and comorbid depression (eg, 6-7 symptoms in the analysis of learning and working memory β -0.07 SDy 95% CI, -0.11 to -0.03 SDy P < .001). In this large-scale prospective cohort study, PTSD was associated with accelerated cognitive decline in middle-aged women, suggesting that earlier cognitive screening among women with PTSD may be warranted. Given that cognitive decline is strongly associated with subsequent Alzheimer disease and related dementias, better understanding of this association may be important to promote healthy aging.

Assessment of Mitochondrial Complex II and III Activity in Brain Sections A Histoenzymological Technique.

Mitochondrial impairment stands to be a major factor which contributes to the onset and pathogenesis of several neurodegenerative disorders, of which Alzheimers disease (AD), Parkinsons disease (PD), and Huntingtons disease (HD) are among the notable ones. Extensive researches suggest the probable role of mitochondrial complex II and III dysfunction as underlying players in the pathogenesis of AD, PD, and HD. Present scenario of the world in occurrence of neurodegenerative disorders demands more research and development in this field. The development of enzyme histochemistry as an analytical technique has eased the assessment of mitochondrial complex activity at both qualitative and quantitative levels. Based on the principle of redox reactions of chromogenic substrates catalyzed by the enzymes in question, this histochemical analysis has been applied by researchers worldwide and has proved to be reliable. The present chapter hereby discusses the methods followed in performing histoenzymology of mitochondrial complex II and III activity. The chapter also puts light on the precautions which should be followed while performing histoenzymology in order to yield significant results.

StatPearls

Lewy bodies (LB) are protein inclusions containing disaggregated oligomers of many cellular proteins. The German neurologist named Friederich Lewy was the first physician-scientist to describe the abnormal protein deposits in 1912 in people with paralysis agitans and, later on, Parkinson disease. Dystrophic neurites (LNs) are precursors of LB and they can contain deposits of ubiquitin (Ub) and alpha-synuclein (a-Syn), formally becoming LB and accumulating in synaptic terminals and axonal processes. A-Syn, encoded by SNCA, is a protein found in presynaptic terminals and thought to have an important neurotransmission communication between neurons and neurotransmitter vesicle trafficking. Ubiquitin is a protein involved in changing proteins biochemically to target them to degradation and autophagy. The Ub is usually at the core and neurofilaments at the outermost layer. Per recent animal model studies, a mutated form of a-Syn (A30P) leads to disaggregation, transcriptional deregulation, and silencing of DNA it also leads to the disruption of Golgi and endoplasmic reticulum, and finally it may also play a role in collagen gene transcription, a basement membrane protein that maintains the integrity of dopaminergic neurons. These cellular processes go awry in dementia with Lewy bodies (DLB) and Parkinson disease (PD). These aberrant oligomers are also present in many other neurodegenerative disorders including, Alzheimer disease (AD), striatonigral degeneration, olivopontocerebellar atrophy, and pantothenate kinase-associated neurodegeneration (Hallervorden Spatz disease), but it is unknown if they share the same pathogenesis. This article focuses on DLB and PD dementia as they are the most common forms of dementia besides Alzheimer disease. The worldwide incidence of DLB is about 1% to 2% (approximately 3 to 4 per 100,000 person-years) on patients older than 65 years and about 5% of all dementia cases in those over the age of 75. For PD dementia, approximately 10% of a PD population will develop dementia annually with an overall prevalence of 31.1% in patients between 65 to 90 years old. The data concerning age at disease or dementia onset are highly variable in the literature. The disaggregation of alpha-synuclein, Ub, and LN are a pathognomonic neuropathological finding on autopsy in patients with PD, and DLB, found in many regions within the central nervous system including the cerebral cortex, limbic cortex, substantia nigra, hippocampus. Structurally, they are single, multiple, or polymorphic. It characterizes them into two major groups classical or cortical LB. The classifications are based on morphology, cellular components, and location within the brain. Although Lewy Bodies are implicated in many of these disorders, it is debatable whether they are a consequence of cellular damage and dysfunction within the neuro integrity or a cause itself of the clinicopathological symptoms seen in patients. This article briefly covers the different anatomical, clinical and biochemical pathologies involved with Lewy body formation. The goal is not to provide an exhaustive description of LBs, rather a snapshot that can be useful for the everyday clinician interested in the topic.

Relationship between thyroid hormones and central nervous system metabolism in physiological and pathological conditions.

Thyroid hormones (THs) play an important role in the regulation of energy metabolism. They also take part in processes associated with the central nervous system (CNS), including survival and differentiation of neurons and energy expenditure. It has been reported that a correlation exists between the functioning of the thyroid gland and the symptoms of CNS such as cognitive impairment, depression, and dementia. Literature data also indicate the influence of THs on the pathogenesis of CNS diseases, such as Alzheimers disease, epilepsy, depression, and Parkinsons disease. This review describes the relationship between THs and metabolism in the CNS, the effect of THs on the pathological conditions of the CNS, and novel options for treating these conditions with TH derivatives.

Magnetic Resonance Imaging Studies of Neurodegenerative Disease From Methods to Translational Research.

Neurodegenerative diseases (NDs) have become a significant threat to an aging human society. Numerous studies have been conducted in the past decades to clarify their pathologic mechanisms and search for reliable biomarkers. Magnetic resonance imaging (MRI) is a powerful tool for investigating structural and functional brain alterations in NDs. With the advantages of being non-invasive and non-radioactive, it has been frequently used in both animal research and large-scale clinical investigations. MRI may serve as a bridge connecting micro- and macro-level analysis and promoting bench-to-bed translational research. Nevertheless, due to the abundance and complexity of MRI techniques, exploiting their potential is not always straightforward. This review aims to briefly introduce research progress in clinical imaging studies and discuss possible strategies for applying MRI in translational ND research.

Computational Study of the Allosteric Effects of p5 on CDK5-p25 Hyperactivity as Alternative Inhibitory Mechanisms in Neurodegeneration.

The cyclin-dependent kinase (CDK5) forms a stable complex with its activator p25, leading to the hyperphosphorylation of tau proteins and to the formation of plaques and tangles that are considered to be one of the typical causes of Alzheimers disease (AD). Hence, the pathological CDK5-p25 complex is a promising therapeutic target for AD. Small peptides, obtained from the truncation of CDK5 physiological activator p35, have shown promise in inhibiting the pathological complex effectively while also crossing the blood-brain barrier. One such small 24-residue peptide, p5, has shown selective inhibition toward the pathological complex in vivo. Our previous research focused on the characterization of a computationally predicted CDK5-p5 binding mode and of its pharmacophore, which was consistent with competitive inhibition. In continuation of our previous work, herein, we investigate four additional binding modes to explore other possible mechanisms of interaction between CDK5 and p5. The quantitative description of the pharmacophore is consistent with both competitive and allosteric p5-induced inhibition mechanisms of CDK5-p25 pathology. The gained insights can direct further in vivoin vitro tests and help design small peptides, linear or cyclic, or peptidomimetic compounds as adjuvants of orthosteric inhibitors or as part of a cocktail of drugs with enhanced effectiveness and lower side effects.

Intranasal Delivery of BACE1 siRNA and Rapamycin by Dual Targets Modified Nanoparticles for Alzheimers Disease Therapy.

Alzheimers disease (AD), as a progressive and irreversible brain disorder, remains the most universal neurodegenerative disease. No effective therapeutic methods are established yet due to the hindrance of the blood-brain barrier (BBB) and the complex pathological condition of AD. Therefore, a multifunctional nanocarrier (RapaDAKsiRNA) for AD treatment is constructed to achieve small interfering RNA of β-site precursor protein (APP) cleaving enzyme-1 (BACE1 siRNA) and rapamycin co-delivery into the brain, based on Aleuria aurantia lectin (AAL) and β-amyploid (Aβ)-binding peptides (KLVFF) modified PEGylated dendrigraft poly-l-lysines (DGLs) via intranasal administration. Nasal administration provides an effective way to deliver drugs directly into the brain through the nose-to-brain pathway. AAL, specifically binding to L-fucose located in the olfactory epithelium, endows RapaDAKsiRNA with high brain entry efficiency through intranasal administration. KLVFF peptide as an Aβ targeting ligand and aggregation inhibitor enables nanoparticles to bind with Aβ, inhibit Aβ aggregation, and reduce toxicity. Meanwhile, the release of BACE1 siRNA and rapamycin is confirmed to reduce BACE1 expression, promote autophagy, and reduce Aβ deposition. RapaDAKsiRNA is verified to improve the cognition of transgenic AD mice after intranasal administration. Collectively, the multifunctional nanocarrier provides an effective and potential intranasal avenue for combination therapy of AD.

Editome landscape of CCM-derived endothelial cells.

By regulating several phases of gene expression, RNA editing modifications contribute to maintaining physiological RNA expression levels. RNA editing dysregulation can affect RNA molecule half-life, codingnoncoding RNA interaction, alternative splicing, and circular RNA biogenesis. Impaired RNA editing has been observed in several pathological conditions, including cancer and Alzheimers disease. No data has been published yet on the editome profile of endothelial cells (ECs) isolated from human cerebral cavernous malformation (CCM) lesions. Here, we describe a landscape of editome modifications in sporadic CCM-derived ECs (CCM-ECs) by comparing editing events with those observed in human brain microvascular endothelial cells (HBMECs). With a whole transcriptome-based variant calling pipeline, we identified differential edited genes in CCM-ECs that were enriched in pathways related to angiogenesis, apoptosis and cell survival, inflammation and, in particular, to thrombin signalling mediated by protease-activated receptors and non-canonical Wnt signalling. These pathways, not yet associated to CCM development, could be a novel field for further investigations on CCM molecular mechanisms. Moreover, enrichment analysis of differentially edited miRNAs suggested additional small noncoding transcripts to consider for development of targeted therapies.

Genome-wide association and multi-omics studies identify MGMT as a novel risk gene for Alzheimers disease among women.

Variants in the tau gene (MAPT) region are associated with breast cancer in women and Alzheimers disease (AD) among persons lacking apolipoprotein E ε4 (ε4-). To identify novel genes associated with tau-related pathology, we conducted two genome-wide association studies (GWAS) for AD, one among 10,340 ε4- women in the Alzheimers Disease Genetics Consortium (ADGC) and another in 31 members (22 women) of a consanguineous Hutterite kindred. We identified novel associations of AD with MGMT variants in the ADGC (rs12775171, odds ratio OR 1.4, P 4.9 × 10 These findings suggest that epigenetically regulated MGMT expression is involved in AD pathogenesis, especially in women.

Therapeutic Potential of Astrocyte Transplantation.

Cell transplantation is an attractive treatment strategy for a variety of brain disorders, as it promises to replenish lost functions and rejuvenate the brain. In particular, transplantation of astrocytes has come into light recently as a therapy for amyotrophic lateral sclerosis (ALS) moreover, grafting of astrocytes also showed positive results in models of other conditions ranging from neurodegenerative diseases of older age to traumatic injury and stroke. Despite clear differences in etiology, disorders such as ALS, Parkinsons, Alzheimers, and Huntingtons diseases, as well as traumatic injury and stroke, converge on a number of underlying astrocytic abnormalities, which include inflammatory changes, mitochondrial damage, calcium signaling disturbance, hemichannel opening, and loss of glutamate transporters. In this review, we examine these convergent pathways leading to astrocyte dysfunction, and explore the existing evidence for a therapeutic potential of transplantation of healthy astrocytes in various models. Existing literature presents a wide variety of methods to generate astrocytes, or relevant precursor cells, for subsequent transplantation, while described outcomes of this type of treatment also differ between studies. We take technical differences between methodologies into account to understand the variability of therapeutic benefits, or lack thereof, at a deeper level. We conclude by discussing some key requirements of an astrocyte graft that would be most suitable for clinical applications.

Amyloid-β (Aβ)-Related Cerebral Amyloid Angiopathy Causing Lobar Hemorrhage Decades After Childhood Neurosurgery.

Recent reports raise the possibility of cerebral amyloid angiopathy (CAA) leading to intracerebral hemorrhage in young adults following childhood neurosurgery, suggesting transmission of amyloid-β (Aβ) through neurosurgical procedures including dura mater grafting. Parenchymal Aβ deposition, and to a lesser extent tau aggregation, similar to that seen in Alzheimer disease, have also been described. We conducted a database review of 634 consecutive intracerebral hemorrhage patients aged <65 years at a tertiary stroke center over 20 years to identify such patients. We identified 3 patients aged in their thirties who presented with spontaneous lobar intracerebral hemorrhage, with imaging or neuropathology consistent with CAA, and a history of childhood neurosurgery. Two of these patients had undergone a dural repair using cadaveric dura mater (Lyodura). In addition to CAA, both patients had neuropathologically confirmed parenchymal Aβ and tau deposits, characteristic of Alzheimer disease. Our findings support the concept of neurosurgical Aβ transmission but suggest that such cases are rare in standard clinical practice.

Mechanistic and Etiological Similarities in Diabetes Mellitus and Alzheimers Disease Antidiabetic Drugs as Optimistic Therapeutics in Alzheimers Disease.

Diabetes mellitus and Alzheimers disease are two common diseases that majorly affect the elderly population. Patients in both cases are increasing day by day. They are considered two independent diseases, but recent evidence suggests that they have a lot in common. In this review we focused on the connection between Alzheimers disease and diabetes and highlighted the importance of antidiabetic drugs against Alzheimers disease. Common pathways such as obesity, vascular diseases, oxidative stress, mitochondrial dysfunction, mutation of ApoE4 gene, and Sirtuin gene were found to manipulate both diseases. Antidiabetic drugs are found to have promising effects on Alzheimers disease, acting by reducing insulin resistance, neuronal protection, and reducing amyloid-beta plaques. Some anti-diabetic drugs have shown promising results in vivo and in vitro studies. No review present focuses on the structural features of the antidiabetic molecules against Alzheimers disease, their crosslinking pathophysiology, the role of natural bioactive molecules, in silico advancements followed by preclinical and clinical studies, and current advancements. Hence, we concentrated on the factors mentioned in the objectives. Alzheimers disease can be considered a form of type-3 diabetes, and repurposing the anti-diabetic drug will open up new paths of research in the field of Alzheimers disease drug discovery.

Music-based interventions for community-dwelling people with dementia A systematic review.

The majority of people with dementia (PwD) live in the community. Compared to institutionalised PwD, their access to formalised music therapy is limited. Initial works suggest that non-therapist-led music-based interventions (MBIs) may be an accessible and effective alternative. The aim of this review was, therefore, to synthesise evidence on MBIs for community-dwelling PwD. We systematically searched electronic databases (PubMed, PsycInfo, Web of Science) for records reporting on controlled studies of MBIs delivered to community-dwelling PwD. Two reviewers independently screened records according to inclusionexclusion criteria. A total of 15 relevant publications reporting on 14 studies were initially identified and assessed using the Cochrane risk-of-bias tool for randomised trials (RoB 2) and the risk of bias. In non-randomised studies of interventions (ROBINS-I) tool. A total of 11 records of 10 studies, with a total of n 327 PwD, were included in the synthesis. MBIs consisted either of singing or music listening interventions and were variable in duration. MBIs had immediate positive effects on cognition. Short-term MBIs (lasting 1-4 months) benefited cognition, anxiety and pain. Evidence on depressive symptoms was conflicting. The benefits of longer term MBIs (lasting 6 months) were less apparent. According to GRADE criteria, the overall quality of evidence was moderate to low. The inconsistency in designs, procedures and measures prevents specific conclusions at this stage. Still, the diversity observed in existing studies suggests that there are multiple interesting avenues for researchers to pursue, including the involvement of informal caregivers in MBI delivery. Future studies need to ensure adequate reporting to facilitate continued development. The protocol of this review was pre-registered with the Prospective Register of Systematic Reviews (PROSPERO, Registration Number CRD42020191606).

Experimental radar data for monitoring brain atrophy progression.

This data set contains complex frequency domain signals obtained from unidirectional antennas mainly fabricated for radar-based head imaging. Data were obtained as part of a project investigating radar-based microwave imaging for monitoring neurodegenerative diseases, especially Alzheimers disease. The wearable device, measurement setup, and phantoms used are described. Multiple experiments were performed to get the data from three lamb brain phantoms that realistically mimic the whole-brain atrophy due to Alzheimers disease. Microwave imaging has shown great potential for breast and brain screening due to its low cost, non-ionizing, portable, and wearable nature. Most of the studies are based on simulations with good results, but further evaluation on experimental data is required before its clinical viability. This work provides an open-source experimental dataset that can be used to evaluate novel signal processing and imaging techniques and validate simulation results. The data provide both the magnitude and phase value at each discrete frequency, making this data set useful for both time-delay and phase-shift based imaging algorithms.

Effects of Transcranial Direct Current Stimulation on Memory of Elderly People with Mild Cognitive Impairment or Alzheimers Disease A Systematic Review.

Transcranial direct current stimulation (tDCS) is one of the most studied non-invasive neuromodulation techniques, presenting itself as a promising technique for several pathologies, such as cognitive decline. The aim of this study was to conduct a systematic review of the effects of tDCS on the memory of elderly people with mild cognitive impairment or Alzheimers disease, in order to describe the main protocols used, and to investigate the therapeutic effectiveness of this technique. 869 studies reporting controlled clinical trials were found in the databases PubMed, Web of Science, Lilacs, PsycArticles and Scielo, from which 13 met the expected requirements and were included in the final analysis. There was a great variability in the stimulation protocols used in the studies and methodological weaknesses were observed, such as absence of sample size calculation, and of information on effect sizes. Positive effects of tDCS were observed only in five studies, and the combination of stimulation and cognitive training did not seem to potentiate the effects of tDCS. Although tDCS can be considered a technique with important therapeutic potential, more studies are needed to understand the acute effects of tDCS on memory of elderly people and the durability of these effects over time. PROSPERO (CRD-42020200573).

Immunity gene

We investigated single-nucleotide polymorphisms (SNPs) in We used data from the Alzheimers Disease Neuroimaging Initiative (ADNI Gene-based association analysis showed that This suggests that rs10751647 in

A proposed theoretical framework for retinal biomarkers.

Propose a theoretical framework for retinal biomarkers of Alzheimers disease (AD). The retina and brain share important biological features that are relevant to AD. Developing retinal biomarkers of AD is a strategic priority but as yet none have been validated for clinical use. Part of the reason may be that fundamental inferential assumptions have been overlooked. Failing to recognize these assumptions will disadvantage biomarker discovery and validation, but incorporating them into analyses could facilitate translation. The biological assumption that a disease causes analogous effects in the brain and retina can be expressed within a Bayesian network. This allows inferences about abstract theory and individual events, and provides an opportunity to falsify the foundational hypothesis of retina-brain analogy. Graphical representation of the relationships between variables simplifies comparison between studies and facilitates judgements about whether key assumptions are valid given the current state of knowledge. The framework provides a visual approach to retinal biomarkers and may help to rationalize analysis of future studies. It suggests possible reasons for inconsistent results in existing literature on AD biomarkers. The framework can be modified to describe alternative theories of retinal biomarker biology, such as retrograde degeneration resulting from brain disease, and can incorporate confounding factors such as co-existent glaucoma or macular degeneration. Parallels with analogue confirmation theory and surrogate marker validation suggest strengths and weaknesses of the framework that can be anticipated when developing analysis plans. Retinal biomarkers hold great promise for Alzheimers disease (AD), but none are currently used clinically.Assumptions about the cause of retinal and brain changes are often overlooked, and this may disadvantage biomarker discovery and validation.We present a new approach to retinal biomarkers that describes cause and effect graphically in a Bayesian network.We show how this allows a more complete assessment of how well a biomarker might reflect the brain, and how data from right and left eyes can be used to rule out poor biomarker candidates.

HSP10 as a Chaperone for Neurodegenerative Amyloid Fibrils.

Neurodegenerative diseases (NDs) are associated with accumulated misfolded proteins (MPs). MPs oligomerize and form multiple forms of amyloid fibril polymorphs that dictate fibril propagation and cellular dysfunction. Protein misfolding processes that impair protein homeostasis are implicated in onset and progression of NDs. A wide variety of molecular chaperones safeguard the cell from MP accumulation. A rather overlooked molecular chaperone is HSP10, known as a co-chaperone for HSP60. Due to the ubiquitous presence in human tissues and protein overabundance compared with HSP60, we studied how HSP10 alone influences fibril formation

The Brilliance of the Zebrafish Model Perception on Behavior and Alzheimers Disease.

Alzheimers disease (AD) has become increasingly prevalent in the elderly population across the world. Its pathophysiological markers such as overproduction along with the accumulation of amyloid beta (Aβ) plaques and neurofibrillary tangles (NFT) are posing a serious challenge to novel drug development processes. A model which simulates the human neurodegenerative mechanism will be beneficial for rapid screening of potential drug candidates. Due to the comparable neurological network with humans, zebrafish has emerged as a promising AD model. This model has been thoroughly validated through research in aspects of neuronal pathways analogous to the human brain. The cholinergic, glutamatergic, and GABAergic pathways, which play a role in the manifested behavior of the zebrafish, are well defined. There are several behavioral models in both adult zebrafish and larvae to establish various aspects of cognitive impairment including spatial memory, associative memory, anxiety, and other such features that are manifested in AD. The zebrafish model eliminates the shortcomings of previously recognized mammalian models, in terms of expense, extensive assessment durations, and the complexity of imaging the brain to test the efficacy of therapeutic interventions. This review highlights the various models that analyze the changes in the normal behavioral patterns of the zebrafish when exposed to AD inducing agents. The mechanistic pathway adopted by drugs and novel therapeutic strategies can be explored

Phosphorylated Tau 181 Serum Levels Predict Alzheimers Disease in the Preclinical Stage.

There is an urgent need for cost-effective, easy-to-measure biomarkers to identify subjects who will develop Alzheimers disease (AD), especially at the pre-symptomatic stage. This stage can be determined in autosomal dominant AD (ADAD) which offers the opportunity to observe the dynamic biomarker changes during the life-course of AD stages. This study aimed to investigate serum biomarkers during different AD stages and potential novel protein biomarkers of presymptomatic AD. In the first stage, 32 individuals 20 mutation carriers including 10 with AD, and 10 with mild cognitive impairment (MCI), and 12 healthy controls from ADAD families were analyzed. All subjects underwent a complete clinical evaluation and a comprehensive neuropsychological battery. Serum samples were collected from all subjects, and antibody arrays were used to analyze 170 proteins in these samples. The most promising biomarkers were identified during this screening and were then measured in serum samples of 12 subjects with pre-MCI and 20 controls. The serum levels of 13 proteins were significantly different in patients with AD or MCI compared to controls. Of the 13 proteins, cathepsin D, immunoglobulin E, epidermal growth factor receptor (EGFR), matrix metalloproteinase-9 (MMP-9), von Willebrand factor (vWF), haptoglobin, and phosphorylated Tau-181 (p-Tau181) correlated with all cognitive measures ( A total of 13 serum proteins showed significant differences between subjects with AD and MCI and healthy controls. The p-Tau181 serum level might be a broadly available and cost-effective biomarker to identify individuals with preclinical AD and assess the severity of AD.

Knowledge Mapping of Necroptosis From 2012 to 2021 A Bibliometric Analysis.

Necroptosis, a recently discovered programmed cell death, has been pathologically linked to various diseases and is thus a promising target for treating diseases. However, a comprehensive and objective report on the current status of entire necroptosis research is lacking. Therefore, this study aims to conduct a bibliometric analysis to quantify and identify the status quo and trending issues of necroptosis research in the last decade. Articles were acquired from the Web of Science Core Collection database. We used two bibliometric tools (CiteSpace and VOSviewer) to quantify and identify the individual impact and cooperation information by analyzing annual publications, journals, co-cited journals, countriesregions, institutions, authors, and co-cited authors. Afterwards, we identified the trending research areas of necroptosis by analyzing the co-occurrence and burst of keywords and co-cited references. From 2012 to 2021, a total of 3,111 research articles on necroptosis were published in 786 academic journals by 19,687 authors in 885 institutions from 82 countriesregions. The majority of publications were from China and the United States, of which the United States maintained the dominant position in necroptosis research meanwhile, the Chinese Academy of Sciences and Ghent University were the most active institutions. Peter Vandenabeele published the most papers, while Alexei Degterev had the most co-citations. Necroptosis research had a stable stepwise growth in the past decade. Current necroptosis studies focused on its cross-talk with other types of cell death, potential applications in disease treatment, and further mechanisms. Among them, the synergy with ferroptosis, further RIPK1RIPK3MLKL studies, its association with inflammation and oxidative stress and translational applications, and the therapeutic potential to treat cancer and neurodegenerative diseases are the trending research area. These might provide ideas for further research in the necroptosis field.

Non-Communicable Neurological Disorders and Neuroinflammation.

Traumatic brain injury, stroke, and neurodegenerative diseases represent a major cause of morbidity and mortality in Africa, as in the rest of the world. Traumatic brain and spinal cord injuries specifically represent a leading cause of disability in the younger population. Stroke and neurodegenerative disorders predominantly target the elderly and are a major concern in Africa, since their rate of increase among the ageing is the fastest in the world. Neuroimmunology is usually not associated with non-communicable neurological disorders, as the role of neuroinflammation is not often considered when evaluating their cause and pathogenesis. However, substantial evidence indicates that neuroinflammation is extremely relevant in determining the consequences of non-communicable neurological disorders, both for its protective abilities as well as for its destructive capacity. We review here current knowledge on the contribution of neuroinflammation and neuroimmunology to the pathogenesis of traumatic injuries, stroke and neurodegenerative diseases, with a particular focus on problems that are already a major issue in Africa, like traumatic brain injury, and on emerging disorders such as dementias.

Metformin, Rapamycin, or Nicotinamide Mononucleotide Pretreatment Attenuate Cognitive Impairment After Cerebral Hypoperfusion by Inhibiting Microglial Phagocytosis.

Vascular cognitive impairment (VCI) is the second leading form of dementia after Alzheimers disease (AD) plaguing the elder population. Despite the enormous prevalence of VCI, the biological basis of this disease has been much less well-studied than that of AD, with no specific therapy currently existing to prevent or treat VCI. As VCI mainly occurs in the elderly, the role of anti-aging drugs including metformin, rapamycin, and nicotinamide mono nucleotide (NMN), and the underlying mechanism remain uncertain. Here, we examined the role of metformin, rapamycin, and NMN in cognitive function, white matter integrity, microglial response, and phagocytosis in a rat model of VCI by bilateral common carotid artery occlusion (BCCAO). BCCAO-induced chronic cerebral hypoperfusion could cause spatial working memory deficits and white matter lesions (WMLs), along with increasing microglial activation and phagocytosis compared to sham-operated rats. We found the cognitive impairment was significantly improved in BCCAO rats pretreated with these three drugs for 14 days before BCCAO compared with the vehicle group by the analysis of the Morris water maze and new object recognition tests. Pretreatment of metformin, rapamycin, or NMN also increased myelin basic protein (MBP, a marker for myelin) expression and reduced SMI32 (a marker for demyelinated axons) intensity and SMI32MBP ratio compared with the vehicle group, suggesting that these drugs could ameliorate BCCAO-induced WMLs. The findings were confirmed by Luxol fast blue (LFB) stain, which is designed for staining myelinmyelinated axons. We further found that pretreatment of metformin, rapamycin, or NMN reduced microglial activation and the number of M1 microglia, but increased the number of M2 microglia compared to the vehicle group. Importantly, the number of MBP

Assessing time processing ability and daily time management in persons with dementia Psychometric properties of three instruments.

Persons with dementia experience time-related problems, but there is a lack of instruments evaluating their time processing ability and daily time management. This study aimed to evaluate the psychometric properties of the instruments KaTid®-Senior measuring time processing ability, and Time-S© Senior and Time-Proxy© measuring daily time management for persons with dementia. Persons with dementia (n 53) and their significant others (n 49) participated in the study. Rasch analyses were used to evaluate the instruments rating scale functioning internal scale validity person-response validity unidimensionality person-separation reliability and internal consistency. Versions excluding items with poor fit to the Rasch model were also evaluated. Overall, the Rasch analyses showed acceptable psychometric properties. All instruments met the criteria for unidimensionality and the reliability was good. More challenging items should be added in KaTid-Senior for better targeting of persons with mild dementia. Person-response validity issues in Time-S Senior need to be addressed. The instruments can validly and reliably be used to assess time processing ability and daily time management in persons with dementia in clinical research and healthcare settings. In turn, this can contribute to the development of methods to compensate for impaired time processing ability and daily time management. The assessments can also increase the possibility of early detection of impaired time processing ability and daily time management, thereby facilitating adequate timing of interventions and enhanced occupational performance.

The Spanish-English bilingual experience and cognitive change in HispanicsLatinos from the Hispanic Community Health StudyStudy of Latinos-Investigation of Neurocognitive Aging.

Studies suggest bilingualism may delay behavioral manifestations of adverse cognitive aging including Alzheimers dementia. Three thousand nine hundred sixty-three participants (unweighted mean population age ≈56 years) at Hispanic Community Health StudyStudy of Latinos baseline (2008-2011) self-reported their and their parents birth outside the United States, Spanish as their first language, and used Spanish for baseline and comparable cognitive testing 7 years later (2015-2018). SpanishEnglish language proficiency and patterns of use were self-rated from 1 only Spanish to 4 English > Spanish. Cognitive testing included test-specific and global composite score(s) of verbal learning, memory, word fluency, and Digit Symbol Substitution (DSS). Survey linear regression models examined associations between baseline bilingualism scores and cognition. Higher second-language (English) proficiency and use were associated with higher global cognition, fluency, and DSS at follow-up and better than predicted change in fluency. The bilingual experience was more consistently related to 7-year level versus change in cognition for HispanicsLatinos.

White matter pathology in alzheimers transgenic mice with chronic exposure to low-level ambient fine particulate matter.

Air pollution, especially fine particulate matter (PM), can cause brain damage, cognitive decline, and an increased risk of neurodegenerative disease, especially alzheimers disease (AD). Typical pathological findings of amyloid and tau protein accumulation have been detected in the brain after exposure in animal studies. However, these observations were based on high levels of PM exposure, which were far from the WHO guidelines and those present in our environment. In addition, white matter involvement by air pollution has been less reported. Thus, this experiment was designed to simulate the true human world and to discuss the possible white matter pathology caused by air pollution. 6 month-old female 3xTg-AD mice were divided into exposure and control groups and housed in the Taipei Air Pollutant Exposure System (TAPES) for 5 months. The mice were subjected to the Morris water maze test after exposure and were then sacrificed with brain dissection for further analyses. The mean mass concentration of PM In conclusion, this pilot study showed that even chronic exposure to low PM

White matter hyperintensities are a prominent feature of autosomal dominant Alzheimers disease that emerge prior to dementia.

To promote the development of effective therapies, there is an important need to characterize the full spectrum of neuropathological changes associated with Alzheimers disease. In line with this need, this study examined white matter abnormalities in individuals with early-onset autosomal dominant Alzheimers disease, in relation to age and symptom severity. This is a cross-sectional analysis of data collected in members of a large kindred with a PSEN1 E280A mutation. Participants were recruited between September 2011 and July 2012 from the Colombian Alzheimers Prevention Initiative registry. The studied cohort comprised 50 participants aged between 20 and 55 years, including 20 cognitively unimpaired mutation carriers, 9 cognitively impaired mutation carriers, and 21 non-carriers. Participants completed an MRI, a lumbar puncture for cerebrospinal fluid collection, a florbetapir PET scan, and neurological and neuropsychological examinations. The volume of white matter hyperintensities (WMH) was compared between cognitively unimpaired carriers, cognitively impaired carriers, and non-carriers. Relationships between WMH, age, and cognitive performance were further examined in mutation carriers. The mean (SD) age of participants was 35.8 (9.6) years and 64% were women. Cardiovascular risk factors were uncommon and did not differ across groups. Cognitively impaired carriers median, 6.37 interquartile range (IQR), 9.15 had an increased volume of WMH compared to both cognitively unimpaired carriers median, 0.85 IQR, 0.79 and non-carriers median, 1.07 IQR, 0.71. In mutation carriers, the volume of WMH strongly correlated with cognition and age, with evidence for an accelerated rate of changes after the age of 43 years, 1 year earlier than the estimated median age of symptom onset. In multivariable regression models including cortical amyloid retention, superior parietal lobe cortical thickness, and cerebrospinal fluid phospho-tau, the volume of WMH was the only biomarker independently and significantly contributing to the total explained variance in cognitive performance. The volume of WMH is increased among individuals with symptomatic autosomal-dominant Alzheimers disease, begins to increase prior to clinical symptom onset, and is an independent determinant of cognitive performance in this group. These findings suggest that WMH are a key component of autosomal-dominant Alzheimers disease that is closely related to the progression of clinical symptoms.

Imipramine and olanzapine block apoE4-catalyzed polymerization of Aβ and show evidence of improving Alzheimers disease cognition.

The apolipoprotein E (APOE) ε4 allele confers the strongest risk for late-onset Alzheimers disease (AD) besides age itself, but the mechanisms underlying this risk are debated. One hypothesis supported by evidence from multiple labs is that apoE4 binds to the amyloid-β (Aβ) peptide and catalyzes its polymerization into neurotoxic oligomers and fibrils. Inhibiting this early step in the amyloid cascade may thereby reduce or prevent neurodegeneration and AD. Using a design of experiments (DOE) approach, we developed a high-throughput assay to identify inhibitors of apoE4-catalyzed polymerization of Aβ into oligomers and fibrils. We used it to screen the NIH Clinical Collection of small molecule drugs tested previously in human clinical trials. We then evaluated the efficacy and cytotoxicity of the hit compounds in primary neuron models of apoE4-induced Aβ and phosphorylated tau aggregation. Finally, we performed retrospective analyses of the National Alzheimers Coordinating Center (NACC) clinical dataset, using Cox regression and Cox proportional hazards models to determine if the use of two FDA-approved hit compounds was associated with better cognitive scores (Mini-Mental State Exam), or improved AD clinical diagnosis, when compared with other medications of the same clinical indication. Our high-throughput screen identified eight blood-brain barrier (BBB)-permeable hit compounds that reduced apoE4-catalyzed Aβ oligomer and fibril formation in a dose-dependent manner. Five hit compounds were non-toxic toward cultured neurons and also reduced apoE4-promoted Aβ and tau neuropathology in a dose-dependent manner. Three of the five compounds were determined to be specific inhibitors of apoE4, whereas the other two compounds were Aβ or tau aggregation inhibitors. When prescribed to AD patients for their normal clinical indications, two of the apoE4 inhibitors, imipramine and olanzapine, but not other (non-hit) antipsychotic or antidepressant medications, were associated with improvements in cognition and clinical diagnosis, especially among APOE4 carriers. The critical test of any proposed AD mechanism is whether it leads to effective treatments. Our high-throughput screen identified two promising FDA-approved drugs, imipramine and olanzapine, which have no structural, functional, or clinical similarities other than their shared ability to inhibit apoE4-catalyzed Aβ polymerization, thus identifying this mechanism as an essential contribution of apoE4 to AD.

Recent Updates on the Genetics of Amyotrophic Lateral Sclerosis and Frontotemporal Dementia.

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) primarily affect the motor and frontotemporal areas of the brain, respectively. These disorders share clinical, genetic, and pathological similarities, and approximately 10-15% of ALS-FTD cases are considered to be multisystemic. ALS-FTD overlaps have been linked to families carrying an expansion in the intron of C9orf72 along with inclusions of TDP-43 in the brain. Other overlapping genes (VCP, FUS, SQSTM1, TBK1, CHCHD10) are also involved in similar functions that include RNA processing, autophagy, proteasome response, protein aggregation, and intracellular trafficking. Recent advances in genome sequencing have identified new genes that are involved in these disorders (TBK1, CCNF, GLT8D1, KIF5A, NEK1, C21orf2, TBP, CTSF, MFSD8, DNAJC7). Additional risk factors and modifiers have been also identified in genome-wide association studies and array-based studies. However, the newly identified genes show higher disease frequencies in combination with known genes that are implicated in pathogenesis, thus indicating probable digeneticpolygenic inheritance models, along with epistatic interactions. Studies suggest that these genes play a pleiotropic effect on ALS-FTD and other diseases such as Alzheimers disease, Ataxia, and Parkinsonism. Besides, there have been numerous improvements in the genotype-phenotype correlations as well as clinical trials on stem cell and gene-based therapies. This review discusses the possible genetic models of ALS and FTD, the latest therapeutics, and signaling pathways involved in ALS-FTD.

Sex differences in plasma p-tau181 associations with Alzheimers disease biomarkers, cognitive decline, and clinical progression.

Studies have shown that women on the Alzheimers disease (AD) continuum have more pathological tau in the brain and cerebrospinal fluid (CSF), than men. Some studies have found that higher levels of tau biomarkers are more strongly associated with clinical AD, cognitive decline and neurodegeneration in women than in men. Despite major developments in the use of plasma tau phosphorylated at threonine 181 (p-tau181) as an AD biomarker, it is unknown whether these sex differences apply to plasma p-tau181. In 1060 Alzheimers Disease Neuroimaging Initiative (ADNI) participants (47% women, 73.8 ± 7.6 years old), we examined sex differences in plasma p-tau181 levels and their association with other biomarkers, cognitive decline and incident AD. Linear regressions tested for an effect of sex on plasma p-tau181 levels and for plasma p-tau181 × sex interactions on CSF p-tau181, as well as entorhinal cortex tau, cortical amyloid-β (Aβ) deposition, and brain glucose metabolism, quantified using PET imaging. Linear mixed effects models tested for a sex × baseline plasma p-tau181 interaction on change in cognition over time. Finally, Cox models tested for a sex × plasma p-tau181 interaction on the risk of AD dementia in participants who were free of dementia at baseline. Despite similar plasma p-tau181 levels between sexes, women had lower brain glucose metabolism, greater brain Aβ and entorhinal cortex tau deposition, higher CSF p-tau181 and faster cognitive decline in relation to higher baseline plasma p-tau181 levels compared with men. Among Aβ positive, dementia-free participants, women had higher rates of incident AD dementia associated with increasing baseline plasma p-tau181 levels, relative to men. Our results suggest that sex may impact the clinical interpretation of plasma p-tau181 concentrations. If replicated, these findings could have important implications for the use of plasma p-tau181 as an accessible AD biomarker and screening tool for preventive and therapeutic clinical trials.

Six genetically linked mutations in the CD36 gene significantly delay the onset of Alzheimers disease.

The risk of Alzheimers disease (AD) has a strong genetic component, also in the case of late-onset AD (LOAD). Attempts to sequence whole genome in large populations of subjects have identified only a few mutations common to most of the patients with AD. Targeting smaller well-characterized groups of subjects where specific genetic variations in selected genes could be related to precisely defined psychological traits typical of dementia is needed to better understand the heritability of AD. More than one thousand participants, categorized according to cognitive deficits, were assessed using 14 psychometric tests evaluating performance in five cognitive domains (attentionworking memory, memory, language, executive functions, visuospatial functions). CD36 was selected as a gene previously shown to be implicated in the etiology of AD. A total of 174 polymorphisms were tested for associations with cognition-related traits and other AD-relevant data using the next generation sequencing. Several associations between single nucleotide polymorphisms (SNPs) and the cognitive deficits have been found (rs12667404 with language performance, rs3211827 and rs41272372 with executive functions, rs137984792 with visuospatial performance). The most prominent association was found between a group of genotypes in six genetically linked and the age at which the AD patients presented with, or developed, a full-blown dementia. The identified alleles appear to be associated with a delay in the onset of LOAD. In silico studies suggested that the SNPs alter the expression of CD36 thus potentially affecting CD36-related neuroinflammation and other molecular and cellular mechanisms known to be involved in the neuronal loss leading to AD. The main outcome of the study is an identification of a set of six new mutations apparently conferring a distinct protection against AD and delaying the onset by about 8 years. Additional mutations in CD36 associated with certain traits characteristic of the cognitive decline in AD have also been found.

Traumatic brain injury and post-traumatic stress disorder are not associated with Alzheimers disease pathology measured with biomarkers.

Epidemiological studies report an association between traumatic brain injury (TBI) and post-traumatic stress disorder (PTSD) and clinically diagnosed Alzheimers disease (AD). We examined the association between TBIPTSD and biomarker-defined AD. We identified 289 non-demented veterans with TBI andor PTSD and controls who underwent clinical evaluation, cerebrospinal fluid (CSF) collection, magnetic resonance imaging (MRI), amyloid beta (Aβ) and tau positron emission tomography, and apolipoprotein E testing. Participants were followed for up to 5.2 years. Exposure groups (TBI, PTSD, and TBI PTSD) had higher prevalence of mild cognitive impairment (MCI P < .0001) and worse Mini-Mental State Examination scores (PTSD P .008 TBI PTSD P .009) than controls. There were no significant differences in other cognitive scores, MRI volumes, Aβ or tau accumulation, or in most longitudinal measures. TBI andor PTSD were not associated with elevated AD biomarkers. The poorer cognitive status of exposed veterans may be due to other comorbid pathologies.

Azo-Stilbene and Pyridine-Amine Hybrid Multifunctional Molecules to Target Metal-Mediated Neurotoxicity and Amyloid-β Aggregation in Alzheimers Disease.

Neurodegenerative diseases such as Alzheimers disease (AD) are associated with progressive neuronal cell death, and they are commonly correlated with aberrant protein misfolding and aggregation of Aβ peptides. Transition metal ions (Cu, Fe, and Zn) have been shown to promote aggregation and oxidative stress through formation of Aβ-metal complexes. In this context, integrating molecular scaffolds rationally is used here to generate multifunctional molecules as modulators for metal-induced abnormalities. This work encompasses two azo-stilbene (

Berberine Ameliorates Cognitive Disorder via GSK3βPGC-1α Signaling in APPPS1 Mice.

Previous studies have revealed that Berberine (BBR) had therapeutic effects on Alzheimers disease (AD). However, the underlying mechanism of BBR in the treatment of AD is unclear. The study was to investigate whether berberine ameliorates cognitive disorder in AD by regulating on GSK3βPGC-1α signaling pathway. APPPS1 mice were treated with BBR (50 mgkg and 100 mgkg) for 4 mo, and the cognitive function of mice was tested by Morris water maze. The levels of inflammatory cytokines IL-1β, TNF-α, and IL-6 in hippocampus of mice were detected by ELISA kits. The damage of neuronal in hippocampal CA1 was detected by Nissl staining. The tau and GSK3β protein were detected by western blot. The results showed that BBR treatment obviously improved spatial cognitive function of APPPS1 mice. Meanwhile, the pro-inflammatory cytokines were decreased in hippocampus by the administration of BBR. Additionally, BBR significantly alleviated neuronal damage and reduced the levels of hyperphosphorylated tau at sites of Thr205 and Thr231 in hippocampus. Importantly, BBR inhibited the activity of GSK3β and increased the expression of PGC-1α. Consequently, our results demonstrates that BBR could improve the cognitive function by inhibiting the tau hyperphosphorylation and neuroinflammation. These beneficial effects of BBR may be attributed to the regulation of GSK3βPGC-1α signaling pathway in APPPS1 mice. These findings reveal a vital role for GSK3βPGC-1α signaling pathway in retarding cognitive disorder, indicating that PGC-1α might be a potential target for the treatment of AD.

Pupillometry as an index for cognitive processing in behavioral variant FrontoTemporal Dementia a series of case studies.

We investigated whether pupil size can variate with the intensity of cognitive processing in patients with behavioral-variant-Frontotemporal-Dementia (bvFTD). We invited five bvFTD participants and 21 controls to perform forward spans and backward spans, and, in a control condition, to count aloud. We recorded pupil activity using eye-tracking-glasses during the spans and control condition. Analysis demonstrated larger pupil sizes during backward spans than during forward spans, and larger pupil sizes during forward spans than during counting in both bvFTD and control participants. These findings demonstrate how increased cognitive load triggers increased pupil size and how this connection is maintained in bvFTD.

The effect of long-term exposure to toxic air pollutants on the increased risk of malignant brain tumors.

Toxic air pollutants are one of the most agent that have many acute, chronic and non-communicable diseases (NCDs) on human health under long or short-term exposure has been raised from the past to the present. The aim of this study was investigation effect of long-term exposure to toxic air pollutants on the increased risk of malignant brain tumors. Databases used to for searched were the PubMed, Web of Science, Springer and Science Direct (Scopus) and Google Scholar. 71 papers based on abstract and article text filtered. In the end after sieve we selected 7 papers. Identify all relevant studies published 1970-2022. The literature showed that exposure to toxic air pollutants and their respiration can cause disorders in different parts of the brain by transmission through the circulatory system and other mechanisms. Various unpleasant abnormalities are caused by the inhalation of toxic air pollutants in the human body that some of the most common of them include chronic lung disease, coronary heart disease and heart attacks, strokes and brain diseases (Parkinsons, Alzheimers and multiple Sclerosis), cancers (liver, blood, prostate and brain) and eventually death. According to the finding brain health and proper functioning can be easily disrupted by various genetic or external factors such as air pollution, causing a wide range of abnormalities in the brain and malignant brain tumors. The results of this study showed that reducing the concentration of toxic pollutants in the air, that exposure to them play an increasing role in the development of brain diseases can slow down the process of abnormalities in the brain and will have significant impacts on reducing the number of people affected by them.