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Abstract Pathological tau fibrils in progressive supranuclear palsy, frontotemporal dementia, chronic traumatic encephalopathy, and Alzheimer’s disease each have unique conformations, and post-translational modifications that correlate with unique disease characteristics. However, within Alzheimer’s disease (AD), both fibrillar (sarkosyl insoluble (AD SARK tau)), and nonfibrillar (aqueous extractable high molecular weight (AD HMW tau)) preparations have been suggested to be seed-competent. We now explore if these preparations are similar or distinct in their in vivo seeding characteristics. Using an in vivo amplification and time-course paradigm we demonstrate that, for AD HMW and AD SARK tau species, the amplified material is biochemically similar to the original sample. The HMW and SARK materials also show different clearance, propagation kinetics, and propagation patterns. These data indicate the surprising co-occurrence of multiple distinct tau species within the same AD brain, supporting the idea that multiple tau conformers – both fibrillar and nonfibrillar- can impact phenotype in AD.

Disease‐specific oligomers Tau assay system is anticipated in Alzheimer disease (AD) to elucidate their etiological roles. We developed a highly sensitive and selective ELISA for high‐molecular‐weight oligomer tau (HMWoTau) with LLOQ of 0.3 pg/well for the first time, using a novel mouse monoclonal antibody APNmAb005. The target molecule was identified as HMWoTau with circa 2000 kD as a minimum size and the more oligomerized species (>5000 kD), in combination analysis with Size‐Exclusion‐Chromatography and Sucrose‐Density‐Gradient‐Centrifugation for both recombinant human (rh) Tau‐derived aggregates and AD brain‐lysates in PBS(−). HMWoTau was labeled by Thioflavin S and visualized as a homogeneous globular particle (about 30 nm in diameter) by two different technologies of atomic force microscopy and dSTORM‐Nanoimager. Specific quantitation was also confirmed by immune‐absorption, rhHMWoTau‐spiked, and cross‐reactivity studies. APNmAb005 failed to detect the HMWoTau signal by treatment with DTT/SDS under no influence on the pan‐tau antibody, indicating its conformation‐specific recognition. APNmAb005‐ELISA showed AD‐specific and statistically significant ELISA signals from 1 ng brain lysate protein/well. Analysis of the frontal neocortex (N = 40, Braak stage I–VI) by ELISA revealed the detection‐limit levels of HMWoTau species at stage I–III, and drastic and statistically significant increases at stage V/VI (AD). By contrast, total Tau and p181 Tau showed 1/4–1/5 levels of AD even at Stage I, while both tau species also showed a statistically significant increase in AD. In sum, our novel APNmAb005‐ELISA clarified the disease‐specific increase in HMWoTau species and will be useful for not only further etiological elucidation but also the potential diagnostics in AD and relevant tauopathy. [ABSTRACT FROM AUTHOR]

Background: Second-generation tau tracers for positron emission tomography (PET) show high affinity for paired helical filaments tau deposits characteristic of Alzheimer´s disease and low off-target binding. Differences in their chemical structure though may lead to variations in their regional tau uptake and off-target signal. In this work, we aimed to compare the in-vivo uptake of tau tracers [18F]PI-2620 and [18F]RO948 in the early stages of the AD continuum. Methods: Data from the TAU-PET FACEHBI clinical trial (EUDRA-CT 2021–000473-83) were analyzed. All participants were non-demented and underwent tau imaging with [18F]PI-2620 and [18F]RO948 PET within 3 months, amyloid imaging with [18F]Florbetaben and brain magnetic resonance imaging. Tau PET standardized uptake values ratios (SUVR) were calculated in Braak and typical off-target regions using the inferior cerebellar cortex as a reference region. Results: The cohort consisted of 18 individuals with subjective cognitive decline (n = 13) and mild cognitive impairment (n = 5), with centiloid values ranging from 17 to 159. Both tau tracers showed similar tau pathology distribution but presented a distinct off-target signal pattern on visual read. SUVR measurements for [18F]PI-2620 and [18F]RO948 were highly correlated in all Braak regions (R2 range [0.65–0.80]). Regarding off-target signal, [18F]PI-2620 had higher SUVRs in vascular structures, and [18F]RO948 had higher SUVRs in the skull/meninges. Conclusions: In a cohort of individuals at early stages of the AD continuum, tau PET tracers [18F]PI-2620 and [18F]RO948 showed similar in-vivo uptake in all Braak regions and distinct off-target signal. These preliminary results support the development of standardized quantification scales for tau deposition that are tracer-independent. Trial registration: AEMPS EudraCT 2021–000473-83. Registered 30 December 2021. [ABSTRACT FROM AUTHOR]

Background: DNA methylation forms 5-methylcytosine and its regulation in the hippocampus is critical for learning and memory. Indeed, dysregulation of DNA methylation is associated with neurological diseases. Alzheimer's disease (AD) is the predominant of dementia and a neurodegenerative disorder. Methods: We examined the learning and memory function in 3- and 9-month-old wild-type and 5xfamiliar Alzheimer's disease (5xFAD) transgenic mice by performing the object recognition memory and Y-maze tests, and identified the hippocampal amyloid beta burden. To investigate the epigenetically regulated genes involved in the development or neuropathology of AD, we performed genome-wide DNA methylation sequencing and RNA sequencing analyses in the hippocampus of 9-month-old wild-type and 5xFAD tg mice. To validate the genes inversely regulated by epigenetics, we confirmed their methylation status and mRNA levels. Results: At 9 months of age, 5xFAD tg mice showed significant cognitive impairment and amyloid-beta plaques in the hippocampus. DNA methylation sequencing identified a total of 13,777 differentially methylated regions, including 4484 of hyper- and 9293 of hypomethylated regions, that are associated with several gene ontology (GO) terms including 'nervous system development' and 'axon guidance'. In RNA sequencing analysis, we confirmed a total of 101 differentially expressed genes, including 52 up- and 49 downregulated genes, associated with GO functions such as 'positive regulation of synaptic transmission, glutamatergic' and 'actin filament organization'. Through further integrated analysis of DNA methylation and RNA sequencing, three epigenetically regulated genes were selected: thymus cell antigen 1, theta (Thy1), myosin VI (Myo6), and filamin A-interacting protein 1-like (Filip1l). The methylation level of Thy1 decreased and its mRNA levels increased, whereas that of Myo6 and Filip1l increased and their mRNA levels decreased. The common functions of these three genes may be associated with the neural cytoskeleton and synaptic plasticity. Conclusions: We suggest that the candidate genes epigenetically play a role in AD-associated neuropathology (i.e., amyloid-beta plaques) and memory deficit by influencing neural structure and synaptic plasticity. Furthermore, counteracting dysregulated epigenetic changes may delay or ameliorate AD onset or symptoms. [ABSTRACT FROM AUTHOR]

Background and purpose Methods Results Conclusion The Food and Drug Administration approved two disease‐modifying treatments (DMTs) for Alzheimer's disease (AD), aducanumab and lecanemab, with limited clinical impact but significant biomarker changes. Identifying suitable candidates for these DMTs outside randomized clinical trials (RCTs) remains uncertain.This cross‐sectional study, conducted in an Italian tertiary centre for cognitive disorders, aimed to evaluate how the RCT eligibility criteria for DMT treatments applies to participants with early AD. The broader Cummings et al. (Journal of Prevention of Alzheimer's Disease, 2021, 2023) criteria and the clinical differences between DMT candidates were also assessed.The study involved 408 participants (mean age 71.1 ± 8.5 years, 48% male) with a clinical diagnosis of mild cognitive impairment (161/408, 39.5%) or mild dementia (247/408, 60.5%). Amongst them, 169 individuals (41%) showed positive AD pathology biomarkers. Eligibility RCT assessment revealed 14 patients eligible for aducanumab (3.43% of 408) and 28 for lecanemab (6.86% of 408). Following Cummings' real‐world criteria, aducanumab eligibility increased to 9.56%, whereas lecanemab eligibility rose to 8.33%. Applying selection criteria to only the amyloid positive (169 out of 408), the selection for DMTs was 8.3% for aducanumab and 16.5% for lecanemab.Amongst subjects diagnosed with mild AD and mild cognitive impairment in a tertiary centre for cognitive disorders, only a small percentage of patients using RCT diagnostic criteria are eligible for DMT. The application of Cummings criteria strongly increased the DMT candidates. Nevertheless, the majority of patients with cognitive disorders have been excluded from DMTs approved so far. [ABSTRACT FROM AUTHOR]

Background: Recent US proposals suggest defining Alzheimer's disease (AD) based on β‐amyloidosis alone. This sparked debates that echoed historical ones about the significance of brain lesions and clinical phenotype. Methods: This review covers debates on AD nosology through three key periods: AD's discovery in German‐speaking countries in the early 20th century, its redefinition in Anglo‐Saxon countries in the 1960s–1980s, and current debates on the biological or clinicobiological definitions of AD. Key players' opinions are focused on. Results: At the beginning of the 20th century, AD was defined as a clinicopathological entity. Debates arose around the pathological anchor, which included extended neurofibrillary tangles versus neuritic plaques (Alzheimer vs. Fischer) and its association with senile dementia (Kraepelin). In the 1960s–1980s, the debate shifted towards whether AD could be diagnosed using qualitative or quantitative neuropathological features and whether it was a unique process (Terry and Katzman) or had subtypes (Roth). The current definition proposed by the US Alzheimer's Association is based purely on biological β‐amyloid abnormalities and represents a double break: from the historical clinicopathological definition of AD and from the historical emphasis on tau or combined tau and β‐amyloid high levels of pathology. Conversely, the clinicobiological proposal of the International Working Group remains aligned with historical concepts of AD. Conclusions: This historical perspective illustrates the unresolved questions surrounding AD pathogenesis, role of lesions, and the clinical phenotype, especially for sporadic cases. The intense nosological debates throughout the history of AD also illustrate the diversity of theoretical frameworks for defining disease in medicine. [ABSTRACT FROM AUTHOR]

Aluminum (Al) is a known neurotoxic trace element linked to Alzheimer's disease (AD). Naltrexone, an opioid antagonist, has shown promising effects in reducing neuroinflammation at lower doses than those prescribed for addiction. This study aimed to determine the neuroprotective effects of naltrexone on Al-induced neurotoxicity in an in vitro AD model. The SH-SY5Y cells were first cultivated in a standard growth medium. Subsequently, the cells were induced to differentiate by decreasing the concentration of fetal bovine serum and introducing retinoic acid (RA) into the culture media. Subsequently, the inclusion of brain-derived neurotrophic factor (BDNF) was implemented in conjunction with RA. The process of differentiation was concluded on the seventh day. Study groups (n = 3) were designed as the control group, naltrexone group, Al group, Al-Nal group, Alzheimer' model (AD) group, Alzheimer model + Al-exposed group (AD-Al), Alzheimer model + Nal applied group (AD-Nal) and Alzheimer model + Al-exposed + Nal applied group (AD-Al-Nal). Hyperphosphorylated Tau protein as the specific marker of AD was measured in all groups. Glycogen synthase kinase-3 (GSK-3)β, Protein phosphatase 2A (PP2A), Akt and Wnt signaling pathways were analyzed comparatively. In addition, oxidative stress parameters (total antioxidant capacity, lipid peroxidase, protein carbonyl and reactive oxygen species) were measured comparatively in the study groups. The results showed that naltrexone reduced hyperphosphorylated tau protein levels by regulating GSK-3β, PP2A, Akt and Wnt signaling. Also, exposure to naltrexone decreased oxidative stress parameters. Based on these results, naltrexone shows promise as a potential therapy for AD, subject to additional clinical assessments. [ABSTRACT FROM AUTHOR]

Background: The ubiquitination process plays a crucial role in neuronal differentiation and function. Numerous studies have focused on the expression and functions of E3 ligases during these different stages, far fewer on E2 conjugating enzymes. In mice, as in humans, these E2s belong to 17 conjugating enzyme families. Objectives: We analyzed by real-time PCR the expression dynamics of all known E2 genes during an in vitro differentiation of mouse hippocampal neuronal cultures, and after, we analyzed their stimulation with N-methyl-D-aspartate (NMDA). Results: We found that 36 of the 38 E2 genes were expressed in hippocampal neurons. Many were up-regulated during neuritogenesis and/or synaptogenesis stages, such as Ube2h, Ube2b, and Aktip. Rapid and delayed responses to NMDA stimulation were associated with the increased expression of several E2 genes, such as Ube2i, the SUMO-conjugating E2 enzyme. We also observed similar expression profiles within the same E2 gene family, consistent with the presence of similar transcription factor binding sites in their respective promoter sequences. Conclusions: Our study indicates that specific expression profiles of E2 genes are correlated with changes in neuronal differentiation and activity. A better understanding of the regulation and function of E2s is needed to better understand the role played by the ubiquitination process in physiological mechanisms and pathophysiological alterations involved in neurodevelopmental or neurodegenerative diseases. [ABSTRACT FROM AUTHOR]

Pomegranate (Punica granatum L.) has a rich historical background in traditional medicine and is currently the subject of scientific exploration due to its potential health benefits. In this review, the biological characteristics of pomegranate, with a specific focus on the diverse phytochemicals found in its various parts were investigated. Additionally, the medicinal and therapeutic properties associated with these phytochemicals were explored. Pomegranates are abundant in bioactive compounds, including flavonoids, flavones, flavonols, anthocyanidins, ellagic acid, anthocyanins, ellagitannins, and punicic acid. These compounds are associated with various potential health benefits based on the laboratory data. Chromatography and mass spectrometry are used to identify these phytochemicals. Traditional medicinal uses of pomegranate span a broad spectrum, from treating ailments like diarrhoea to combating parasites, underscoring its historical significance. Furthermore, modern scientific research sheds light on the therapeutic properties of pomegranate, including its roles as an antioxidant, an anticancer agent, an anti-inflammatory substance, and a supporter of cardiovascular health. Notably, pomegranate's potential in mitigating conditions, such as Alzheimer's disease is also attractive. In summary, exploring phytochemicals in pomegranate underscores its value as a natural source of diverse therapeutic compounds with applications in medicine and health. However, future clinical trials are necessary to validate these potential benefits. [ABSTRACT FROM AUTHOR]

Background: Alzheimer's and other neurodegenerative forms of dementia affect 8 million Europeans. Assistive technologies are suggested to reduce the burden of care and improve the quality of life of person living with dementia. Nonetheless, the acceptance and attitudes toward technological interventions pose challenges not only for people living with dementia and caregivers but also for healthcare workers. This review specifically aims to investigate how these key groups perceive and accept technology in European dementia care settings. Methods: This systematic review was conducted to identify studies, published between 2013 and 2023, that examined the acceptance and attitude of assistive technologies in Alzheimer's and other dementia European settings, following the PRISMA guidelines. Rayyan AI was used for data extraction, and bias was assessed using the Mixed Methods Appraisal Tool. Results: Among the 1,202 identified articles, 13 met the inclusion criteria, revealing a prevailing positivity toward technological interventions in dementia care. Nonetheless, several barriers to adoption, including technological unfamiliarity, and specific dementia-related symptoms that complicate usage were identified. They also unveiled varying attitudes, influenced by factors such as familiarity with technologies, perceived usefulness, and the broader context of the COVID-19 pandemic which accelerated telemedicine and digital solution acceptance during restricted mobility and social distancing. Conclusion: Understanding attitudes toward technology in dementia care is crucial as it influences the adoption and utilization of tech-based interventions, impacting symptom management and quality of life. Addressing these attitudes through tailored interventions and education can enhance well-being and quality of life for people living with dementia, caregivers, and healthcare professionals. [ABSTRACT FROM AUTHOR]

Our study analyzes the effects of the permanent presence of cats on the health and social network of residents with pathologies in nursing home. Fifty-three residents, thirty-six caregivers, and four cats in three Alzheimer's Disease units ("ADU") and one Disability unit ("DISU") were observed for 180 hours. Social networks were created via instantaneous sampling of physical proximities and social exchanges between residents, caregivers, and the cats. Our results showed that: (1) the four units behave similarly in the presence or absence of a cat (2) cats are placed at the periphery of the network and interact with residents showing a keen interest in them, and (3) caregivers who are in strong contact with the cat show a greater number of social interactions in their unit. This study, using for the first time a social network approach, opens up a new field of understanding of human-animal relationships in a care dimension. [ABSTRACT FROM AUTHOR]

In the rapidly evolving healthcare sector, using advanced technologies to improve medical classification systems has become crucial for enhancing patient care, diagnosis, and treatment planning. There are two main challenges faced in this domain (i) imbalanced distribution of medical data, leading to biased model performance and (ii) the need to preserve patient privacy and comply with data protection regulations. The primary goal of this project is to develop a medical classification model for Alzheimer's disease detection that can effectively learn from decentralized and imbalanced datasets without compromising on data privacy. The proposed system aims to address these challenges by employing an approach that combines split federated learning (SFL) with conditional generative adversarial networks (cGANs) to enhance medical classification models. SFL enables efficient set of distributed agents that collaboratively train learning models without sharing their data, thus improving data privacy and the integration of conditional GANs aims to improve the model's ability to generalize across imbalanced classes by generating realistic synthetic samples for minority classes. The proposed system provided an accuracy of approximately 83.54 percentage for the Alzheimer's disease classification dataset. [ABSTRACT FROM AUTHOR]

Alzheimer is a destructive neurodegenerative disease related to elderly age of people and it is described by memory decline, loss of cognitive and psychiatric characters. The Ocimum species has been used for anti-ulcerogenic, antiinflammatory and neuroprotective activities. Therefore, this study was conducted to assess the possible role of basil (Dino cultivar) in rats against Alzheimer disease (AD). Dino cultivar was selected among the 16 basil genotypes and 4 cultivars growing under field condition in 2019 vegetation period. Some quality properties such as essential oil and its compositons and extract yield of the Dino cultivar were determined. Also, biochemical parameters and immunohistochemical findings and behavioral test were obtained in rats against AD. Dino had high essential oil content (1.28%), five major essential oil compositions (p-Allyl-anisole, linalool, transcaryophyllene, methyl eugenol and beta bergamontene) and extract yield. The extract of the Dino cultivar was used for the biochemical parameters of the Alzheimers as total antioxidant status (TAS: 0.21-0.82 mmol/L), total oxidant status (TOS: 5.7-15.23 µmol/L), catalase (CAT: 2.17-177.31 U/L), oxidative stress index (OSI: 1.056-3.818), malondialdehyde (MDA: 0.365-2.022 mmol/L), superoxide dismutase (SOD: 194-207 U/mL) and Glutathione peroxidase1 (GPX1: 10.82-18.22 ng/mL) in experimental rats. Also, the effect of the extract was used to determine immunohistochemical findings and behavirol test results. As a result of the study, the extract of the Dino cultivar had positive effect on AD depending on the examined properties. It can be suggested that basil extract can be used for the treatment of AD. [ABSTRACT FROM AUTHOR]

The prevalence of Alzheimer's disease and other forms of dementia is increasing worldwide, and finding effective treatments for these conditions is a major public health challenge. Natural bioactive drugs have been identified as a promising source of potential treatments, due to their ability to target multiple pathways and their low toxicity. This paper reviews the current state of research on natural bioactive drugs used in the treatment of Alzheimer's disease and other dementias. The paper summarizes the findings of studies on various natural compounds, including curcumin, resveratrol, caffeine, genistein, quercetin, GinkoBiloba, Withaniasomnifera, Ginseng Brahmi, Giloy, and huperzine, and their effects on cognitive function, neuroinflammation, and amyloid-beta accumulation. In this review, we discuss the mechanism of action involved in the treatment of Alzheimer's disease. The paper also discusses the challenges associated with developing natural bioactive drugs for dementia treatment, including issues related to bioavailability and standardization. Finally, the paper suggests directions for future research in this area, including the need for more rigorous clinical trials and the development of novel delivery systems to improve the efficacy of natural bioactive drugs. Overall, this review highlights the potential of natural bioactive drugs as a promising avenue for the development of safe and effective treatments for Alzheimer's disease and other dementias. [ABSTRACT FROM AUTHOR]

Objective: The aims of this study were to provide population-based estimates of prevalence and incidence of any dementia and Alzheimer's dementia (AD) in the Campania region (South Italy) and to validate towards a clinical registry. Methods: This was a population-based study, using routinely collected healthcare data of individuals living in the Campania region (South Italy) from 2015 to 2020. We included individuals aged ≥65 years alive at the prevalence day (January 1, 2021) who had at least one administrative record for dementia and/or AD from 2015 to 2020. Age-and sex-standardised prevalence rates were calculated using direct standardisation method (European population in 2020 as the reference population). To estimate the incidence, we tested three possible algorithms, which differed for the duration of the time interval between study baseline (January 1, 2015) and index date (first record for dementia and/or AD in administrative databases). We employed a clinical database for the validation of our algorithms towards neuropsychological test results. Results: Among individuals aged over 65 years, 80,392 had dementia, of which 35,748 had AD. The age- and sex-standardised prevalence rates per 1,000 individuals for any dementia and AD were 77.64 (95% confidence interval [CI] = 77.57; 77.68) and 34.05 (95% CI = 34.01; 34.09), respectively. There were 82.10 incident cases of any dementia per 100,000 per year (0.79 sensitivity and 0.62 specificity) and 59.89 incident cases of AD per 100,000 per year (0.80 sensitivity and 0.59 specificity). The capture-recapture method showed a very low number of undetected cases (1.7% for any dementia and 3.0% for AD). Our algorithms showed acceptable performance with the area under the curve ranging from 0.59 to 0.72 and a double likelihood ratio of correctly identifying individuals above and below mini-mental status examination (MMSE) standard cut-offs (24 and 26). Conclusions: Prevalence and incidence of any dementia and AD in the Campania region (South Italy) from 2015 to 2020 are in line with previous estimates from other countries. Our algorithm, integrating administrative and clinical data, holds potential for assessing dementia's epidemiological burden, identifying risk factors, planning healthcare access, and developing prevention strategies. Plain Language Summary: Dementia is a loss of memory and other functions related to thinking and to the ability to do everyday chores, usually occurring in the elderly and getting worse over time. The most common kind is Alzheimer's dementia. Here, we estimated the number of people who are sick with dementia (prevalence) and how many new cases of dementia there are (incidence) in the Campania region (South Italy) from 2015 to 2020. We included individuals aged 65 years and above who have used dementia medications, were admitted to hospitals due to dementia, and/or had payment exemptions for dementia. Among 1,118,545 individuals older than 65 years living in the Campania region of Italy (among 5,624,260 inhabitants), we identified 80,392 people older than 65 years with dementia (62.4% females; age about 80 years), among which 35,748 people had Alzheimer's dementia (63.0% females; age about 79 years). Based on these numbers, we estimated 77 people living with dementia per 1,000 people (85 for females and 67 for males) and 34 with Alzheimer's dementia per 1,000 people (37 for females and 29 for males). The number of new cases per year was 82 per 100,000 for any dementia and 59 for Alzheimer's dementia. We showed that our data were accurate by comparing results of tests measuring memory and other functions and found that only 1.7–3.0% of cases remained undetected. These measures will be important to identify risk factors, guide prevention strategies, and improve care and support for affected individuals and their families. [ABSTRACT FROM AUTHOR]

Ambroxol hydrochloride is a pharmaceutical compound that is primarily used to treat respiratory disorders characterized by excessive mucus production. It is a mucolytic agent used in treating various respiratory conditions, including bronchitis, asthma, COPD (Chronic Obstructive Pulmonary Disease), and cystic fibrosis. The standard industrial‐scale synthesis involves Schiff's base formation followed by reduction; this method is widely adopted due to its efficiency and cost‐effectiveness. Apart from this, various patented methodologies have emerged recently, along with novel therapeutic applications, where it is used for treating Parkinson's and Alzheimer's diseases, including anti‐inflammatory and antioxidant properties. These findings open new avenues for its use in various medical treatments. The current review aims to assess the industrial scale processes in the current market, examine its pharmacological action, and explore recently evaluated therapeutic applications, offering a comprehensive overview of its potential in modern medicine. [ABSTRACT FROM AUTHOR]

The onset and progression of a neurological disease can often be explained in terms of brain-network alteration. They can be formalized as the action of an operator representing the disease, the so-called /C-operator, acting on the network. The healing process can thus be seen as the inverse of the disease mechanism. However, perfect healing is often impossible to achieve. Here, we formalize the ideal healing in terms of perturbative variation of the possible partial healing. The modeling and analytical strategy is based on techniques from theoretical physics, with the language of matrix operators. In addition, using the language of category theory, we also formalize the progressive abstraction from the reality of diseased patients to the definition of a disease and the comparison between different diseases as a natural transformation between colimits. This theoretical presentation can provide a new, interdisciplinary perspective on neurological investigation and possibly foster new theoretical-experimental developments. [ABSTRACT FROM AUTHOR]

Background: Alzheimer's disease (AD) is regarded as one of the most common neurodegenerative diseases. It is a chronic, slowly progressing neurological illness that inhibits memory, cognition, and behavior. This research aimed to evaluate the protective effect of angiotensin II type I receptor (AT1R) blockers versus vitamin B12 (VB12) on the AD rat model. Methods: Thirty adult local strain male albino rats were randomly subdivided into 5 equal groups: Group I (control): vehicle only. Group II (AlCl3 induced AD group): AlCl3 175 mg/kg orally. Group III: telmisartan + AlCl3, Group IV: vitamin B12 + AlCl3, and Group V: vitamin B12 + telmisartan + AlCl3. Modified T maze test was used to evaluate the animal behavior. Rotarod test was employed to assess the animal muscle strength. In addition, serum and hippocampal level of brain derived neurotropic factor (BDNF) were assessed. Also, serum level of MDA and SOD were measured. Additionally, histopathological examination of hippocampus and brain tissue was performed. Results: AlCl3 administration resulted in changes similar to AD as proved by deterioration in behavioral tests, significant reduction in serum and hippocampal BDNF, serum SOD and significant increase in serum MDA level along with corresponding histopathological changes in hippocampus. Furthermore, vitamin B12 and telmisartan ameliorated the previously measured chemical biomarkers and behavioral parameters. Also, the antioxidant power was enhanced with combination prophylaxis therapy of both vitamin B12 and telmisartan. Conclusion: Angiotens in type 1 receptor blockade by telmisartan and vitamin B12 administration each one alone or both in combination could have a potential prophylactic and/or therapeutic effect in AD. [ABSTRACT FROM AUTHOR]

Aims: Alzheimer's disease and related diseases (ADRD) is a progressive and inexorable disease. In France, acetylcholinesterase inhibitors and memantine were reimbursed for subjects with ADRD, until 2 modifications of their reimbursement rate (2012, 2018). We aimed to study the consequences of these measures on ADRD subjects' healthcare use. Methods: We analysed data from the FRA‐DEM cohort, including subjects with presumed incident ADRD identified since 2011 in the French health insurance system. We studied the healthcare use of subjects identified with incident ADRD in 2011, 2013, 2015, 2017 and 2019, notably the annual number of defined daily doses of various psychotropic groups. We performed 2 multivariate multinomial logistic regressions with the subcohort year as the dependent variable. Results: In total, 165 120 subjects were included. A progressive decrease in exposure to antidementia drugs was observed between 2011 and 2019. Consultations with private neurologists or psychiatrists, and exposure to risperidone, antidepressants and benzodiazepines increased in the 2019 subcohort, following the 2018 reimbursement withdrawal. Meanwhile, the use of nursing/allied healthcare and emergency care increased over the subcohort years, whereas we observed a decrease in general practitioner consultations. Conclusion: These results suggest increases in private neurologist or psychiatrist consultations and exposure to recommended drugs after the reimbursement withdrawal, contrary to the fears expressed. However, antidementia drug exposure decreased long before the reimbursement modifications, probably due to the growing evidence of the modest effect of these drugs, and exposure to benzodiazepines increased after the reimbursement withdrawal. [ABSTRACT FROM AUTHOR]

Introduction: Persons with young‐onset dementia (YOD) are confronted with specific challenges. Due to the neurodegenerative nature of the disease, people diagnosed with YOD face many changes with different consequences, for example, regarding their life perspective. These changes can give rise to transition processes and strategies for coping, hopefully stimulating well‐being and acceptance. However, this might not always be the case, and support may be warranted. Our aim was to describe the experiences of those living with YOD due to Alzheimer's disease (AD) and identify signs of transitions during the first year after diagnosis. Method: In this qualitative interview study, we explore the experiences of younger persons living with AD. Thirteen participants under the age of 65 years (nine female and four male; mean age: 57) were included 1 year after being diagnosed with AD. The interviews were transcribed verbatim and analyzed using qualitative content analysis with a deductive approach. To gain a deeper understanding of the data, Meleis's transitions theory was used as a theoretical framework. Results: Two categories were identified: 'Life has changed' and 'Mastering a changed life situation'. One year after diagnosis, participants described how they experienced a changed life situation, changing symptoms, a loss of meaningful activities and an increased risk of social isolation. Furthermore, living with uncertainty about the future caused feelings of being disconnected. Awareness was described as an important aspect of coping with YOD and progressing in the transition process. Participants also highlighted the importance of support from others. Conclusion: The results suggest that preventing social isolation is important in facilitating healthy transitions. Therefore, professionals need to identify signs of transitions and be aware of the complexity of coping with YOD, thereby helping to prevent unwanted responses to change and facilitate a healthy transition process. Patient or Public Contribution: The findings are based on interviews with 13 persons with YOD and provide insight into experiences of living with YOD. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is a progressive and irreversible neurological condition that occurs with age and poses a significant global public health concern, is distinguished by the degeneration of neurons and synapses in various regions of the brain. While the exact processes behind the neurodegeneration in AD are not completely known, it is now acknowledged that inflammation may have a significant impact on the beginning and advancement of AD neurodegeneration. The severity of many neurological illnesses can be influenced by the equilibrium between pro-inflammatory and anti-inflammatory mediators. The IL-1 family of cytokines is linked to innate immune responses, which are present in both acute inflammation and chronic inflammatory diseases. Research on the role of the IL-1 family in chronic neurological disease has been concentrated on AD. In this context, there is indirect evidence suggesting its involvement in the development of the disease. This review aims to provide a summary of the contribution of every IL-1 family member in AD pathogenesis, current immunotherapies in AD disease, and present treatment possibilities for either targeting or boosting these cytokines. [ABSTRACT FROM AUTHOR]

We present our results on the synthesis and preliminary in silico and in vitro studies of the toxicology and antioxidant properties of selenylated analogs of Tacrine. Initially, we synthesized 2‐aminobenzonitriles containing an organic selenium moiety, resulting in sixteen compounds with various substituents linked to the portion derived from diorganyl diselenide. These compounds were then used as substrates in reactions with cyclic ketones, in the presence of 1.4 equivalents of trifluoroboroetherate as a Lewis acid, to synthesize selenylated analogs of Tacrine with yields ranging from 20 % to 87 %. In silico studies explored computational parameters related to antioxidant activity and hepatotoxicity. In vitro studies elucidated the antioxidant effects of Tacrine and its selenium hybrid (TSe) in neutralizing ABTS radicals, scavenging DPPH radicals, and reducing iron ions. Additionally, the acute oral toxicity of one synthesized compound was evaluated. [ABSTRACT FROM AUTHOR]

Background: Alzheimer's disease (AD) heritability is estimated to be around 70–80%. Yet, much of it remains to be explained. Studying transmission patterns may help in understanding other factors contributing to the development of AD. Objective: In this study, we aimed to search for evidence of autosomal recessive or X- and Y-linked inheritance of risk factors in a large cohort of Portuguese AD patients. Methods: We collected family history from patients with AD and cognitively healthy controls over 75 years of age. We compared the proportions of maternal and paternal history in male and female patients and controls (to search for evidence of X-linked and Y-linked inherited risk factors). We compared the risk of developing AD depending on parents' birthplace (same vs. different), as a proxy of remote consanguinity. We performed linear regressions to study the association of these variables with different endophenotypes. Results: We included 3090 participants, 2183 cognitively healthy controls and 907 patients with AD. Men whose mother had dementia have increased odds of developing AD comparing to women whose mother had dementia. In female patients with a CSF biomarker-supported diagnosis of AD, paternal history of dementia is associated with increased CSF phosphorylated Tau levels. People whose parents are from the same town have higher risk of dementia. In multivariate analysis, this proxy is associated with a lower age of onset and higher CSF phosphorylated tau. Conclusions: Our study gives evidence supporting an increased risk of developing AD associated with an X-linked inheritance pattern and remote consanguinity. [ABSTRACT FROM AUTHOR]

The cholinesterase group, including acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), is responsible for inhibiting the actions of choline esters. Benzimidazole derivatives, renowned for their aromatic organic heterocyclic structure, exhibit diverse biological activities, including enzyme inhibitory effects. Imine compounds, easily synthesized, demonstrate notable biological efficacy against various pathogens and enzymes. Synthesize, purify, and characterize novel benzimidazole scaffolds, and evaluate their anti-Alzheimer's activity by measuring AChE and BChE activities. A new series of benzimidazole phenylmethanimine derivatives (3a–3d) was synthesized through refluxing amine with various benzaldehydes. Products underwent purification by solvent washing and characterization using spectroscopic methods. In vitro anti-Alzheimer's activity was assessed by measuring inhibitory activity (half-maximal inhibitory concentration [IC50]) against cholinesterase enzymes. the newly synthesized Schiff bases, purified solely by solvent washing, yielded high percentages (81%–91%). These derivatives showed significant inhibitory activity, with low IC50 values observed for compounds 3a and 3d against both enzymes. Molecular docking studies estimated binding energies and identified interacting amino acids in active pockets. Four new derivatives were synthesized with high yields using the classical reflux method. Purification involved solvent washing only, followed by direct spectroscopic analysis. In vitro inhibitory activities against AChE and BChE enzymes were observed, with compounds 3a and 3d showing promising results. Docking studies revealed higher inhibitory activity and lower IC50 values for two derivatives, indicating their potential as potent inhibitors. [ABSTRACT FROM AUTHOR]

Successful clinical development of new therapeutic interventions is notoriously difficult, especially in neurodegenerative diseases, where predictive biomarkers are scarce and functional improvement is often based on patient's perception, captured by structured interviews. As a consequence, mechanistic modeling of the processes relevant to therapeutic interventions in CNS disorders has been lagging behind other disease indications, probably because of the perceived complexity of the brain. However in this report, we develop the argument that a combination of Computational Neurosciences and Quantitative Systems Pharmacology (QSP) modeling of molecular pathways is a powerful simulation tool to enhance the probability of successful drug development for neurodegenerative diseases. Computational Neurosciences aims to predict action potential dynamics and neuronal circuit activation that are ultimately linked to behavioral changes and clinically relevant functional outcomes. These processes can not only be affected by the disease state, but also by common genotype variants on neurotransmitter-related proteins and the psycho-active medications often prescribed in these patient populations. Quantitative Systems Pharmacology (QSP) modeling of molecular pathways allows to simulate key pathological drivers of dementia, such as protein aggregation and neuroinflammatory responses. They often impact neurotransmitter homeostasis and voltage-gated ion-channels or lead to mitochondrial dysfunction, ultimately leading to changes in action potential dynamics and clinical readouts. Combining these two modeling approaches can lead to better actionable understanding of the many non-linear pharmacodynamic processes active in the human diseased brain. Practical applications include a rational selection of the optimal doses in combination therapies, identification of subjects more likely to respond to treatment, a more balanced stratification of treatment arms in terms of comedications, disease status and common genotype variants and re-analysis of small clinical trials to uncover a possible clinical signal. Ultimately this will lead to a higher success rate of bringing new therapeutics to the right patient populations. [ABSTRACT FROM AUTHOR]

Objectives: This study aimed to analyze the different factors that intervene in the task of caring for relatives of people with Alzheimer's and other dementias. A first objective focused on assessing the relation between burden and anticipatory grief, considering the possibility of social support and the risk of psychopathology. A second objective aimed to examine whether caregiver burden modulates the relationships between anticipatory grief and psychopathology. A cross-sectional design was employed. Methods: The sample consists of 129 participants who care for a family member with Alzheimer's and other dementias. A protocol based on a battery of tests has been applied and a mediation analysis was carried out. Results: The results show a positive relationship between burden and anticipatory grief. Social support could have an indirect relationship with anticipatory grief, based on its effect on the level of psychopathology and caregiver burden. Finally, a modulation model reflects that the relationship between anticipatory grief and psychopathology is strong, the latter having a greater effect as a result variable than as a risk variable. However, it seems that the relationship between grief and psychopathology is better explained directly than not through the modulating effect of the caregiver burden. Significance of results: The results obtained encourage us to think that an approach focused on intervening in the anticipatory grief may be an opportunity to reduce or buffer other caregiving outcomes, especially those related to the perception of caregiver burden and psychopathology. [ABSTRACT FROM AUTHOR]

Introduction: Previous validation studies demonstrated that BrainCheck Assess (BC-Assess), a computerized cognitive test battery, can reliably and sensitively distinguish individuals with different levels of cognitive impairment (i.e., normal cognition (NC), mild cognitive impairment (MCI), and dementia). Compared with other traditional paper-based cognitive screening instruments commonly used in clinical practice, the Montreal Cognitive Assessment (MoCA) is generally accepted to be among the most comprehensive and robust screening tools, with high sensitivity/specificity in distinguishing MCI from NC and dementia. In this study, we examined: (1) the linear relationship between BC-Assess and MoCA and their equivalent cut-off scores, and (2) the extent to which they agree on their impressions of an individual's cognitive status. Methods: A subset of participants (N = 55; age range 54-94, mean/SD = 80/9.5) from two previous studies who took both the MoCA and BC-Assess were included in this analysis. Linear regression was used to calculate equivalent cut-off scores for BC-Assess based on those originally recommended for the MoCA to differentiate MCI from NC (cut-off = 26), and dementia from MCI (cutoff = 19). Impression agreement between the two instruments were measured through overall agreement (OA), positive percent agreement (PPA), and negative percent agreement (NPA). Results: A high Pearson correlation coefficient of 0.77 (CI = 0.63-0.86) was observed between the two scores. According to this relationship, MoCA cutoffs of 26 and 19 correspond to BC-Assess scores of 89.6 and 68.5, respectively. These scores are highly consistent with the currently recommended BCAssess cutoffs (i.e., 85 and 70). The two instruments also show a high degree of agreement in their impressions based on their recommended cut-offs: (i) OA = 70.9%, PPA = 70.4%, NPA = 71.4% for differentiating dementia from MCI/NC; (ii) OA = 83.6%, PPA = 84.1%, NPA = 81.8% for differentiating dementia/MCI from NC. Discussion: This study provides further validation of BC-Assess in a sample of older adults by showing its high correlation and agreement in impression with the widely used MoCA. [ABSTRACT FROM AUTHOR]

The amyloid-cascade-hypothesis of the pathogenesis of Alzheimer's disease (AD) was introduced 32 years ago, in 1992. From early on, this clear and straight forward hypothesis received a lot of attention, but also a lot of substantial criticism. Foremost, there have always been massive doubts that a complex age-associated disorder of the most intricate organ of the human body, the brain, can be explained by a linear, one-dimensional cause-and-effect model. The amyloid-cascade defines the generation, aggregation, and deposition of the amyloid beta peptide as the central pathogenic mechanism in AD, as the ultimate trigger of the disease, and, consequently, as the key pharmacological target. Certainly, the original 1992 version of this hypothesis has been refined by various means, and the 'formulating fathers' followed up with a few reappraisals and partly very open reflections in 2002, 2006, 2009, and 2016. However, up until today, for the supporters of this hypothesis, the central and initial steps of the cascade are believed to be driven by amyloid beta--even if now displayed somewhat more elaborate. In light of the recently published clinical results achieved with anti-amyloid antibodies, the controversy in the field about (1) the clinical meaningfulness of this approach, (2) the significance of clearance of the amyloid beta peptide, and last but not least (3) the relevance of the amyloid-cascade-hypothesis is gaining momentum. This review addresses the interesting manifestation of the amyloid-cascade-hypothesis as well as its ups and downs over the decades. [ABSTRACT FROM AUTHOR]

Pathological tau fibrils in progressive supranuclear palsy, frontotemporal dementia, chronic traumatic encephalopathy, and Alzheimer's disease each have unique conformations, and post-translational modifications that correlate with unique disease characteristics. However, within Alzheimer's disease (AD), both fibrillar (sarkosyl insoluble (AD SARK tau)), and nonfibrillar (aqueous extractable high molecular weight (AD HMW tau)) preparations have been suggested to be seed-competent. We now explore if these preparations are similar or distinct in their in vivo seeding characteristics. Using an in vivo amplification and time-course paradigm we demonstrate that, for AD HMW and AD SARK tau species, the amplified material is biochemically similar to the original sample. The HMW and SARK materials also show different clearance, propagation kinetics, and propagation patterns. These data indicate the surprising co-occurrence of multiple distinct tau species within the same AD brain, supporting the idea that multiple tau conformers – both fibrillar and nonfibrillar- can impact phenotype in AD. [ABSTRACT FROM AUTHOR]

Metropolitan Mexico City (MMC) children and young adults exhibit overlapping Alzheimer and Parkinsons' diseases (AD, PD) and TAR DNA-binding protein 43 pathology with magnetic ultrafine particulate matter (UFPM) and industrial nanoparticles (NPs). We studied magnetophoresis, electron microscopy and energy-dispersive X-ray spectrometry in 203 brain samples from 14 children, 27 adults, and 27 ALS cases/controls. Saturation isothermal remanent magnetization (SIRM), capturing magnetically unstable FeNPs ~ 20nm, was higher in caudate, thalamus, hippocampus, putamen, and motor regions with subcortical vs. cortical higher SIRM in MMC = 40y. Motion behavior was associated with magnetic exposures 25-100 mT and children exhibited IRM saturated curves at 50-300 mT associated to change in NPs position and/or orientation in situ. Targeted magnetic profiles moving under AC/AD magnetic fields could distinguish ALS vs. controls. Motor neuron magnetic NPs accumulation potentially interferes with action potentials, ion channels, nuclear pores and enhances the membrane insertion process when coated with lipopolysaccharides. TEM and EDX showed 7-20 nm NP Fe, Ti, Co, Ni, V, Hg, W, Al, Zn, Ag, Si, S, Br, Ce, La, and Pr in abnormal neural and vascular organelles. Brain accumulation of magnetic unstable particles start in childhood and cytotoxic, hyperthermia, free radical formation, and NPs motion associated to 30-50 μT (DC magnetic fields) are critical given ubiquitous electric and magnetic fields exposures could induce motion behavior and neural damage. Magnetic UFPM/NPs are a fatal brain cargo in children's brains, and a preventable AD, PD, FTLD, ALS environmental threat. Billions of people are at risk. We are clearly poisoning ourselves. [ABSTRACT FROM AUTHOR]

Context: The proportion of the elderly population is on the rise across the globe, and with it the prevalence of age-related neurodegenerative diseases. The gut microbiota, whose composition is highly regulated by dietary intake, has emerged as an exciting research field in neurology due to its pivotal role in modulating brain functions via the gut-brain axis. Objectives: We aimed at conducting a systematic review of preclinical and clinical studies investigating the effects of dietary interventions on cognitive ageing in conjunction with changes in gut microbiota composition and functionality. Methods: PubMed and Scopus were searched using terms related to ageing, cognition, gut microbiota and dietary interventions. Studies were screened, selected based on previously determined inclusion and exclusion criteria, and evaluated for methodological quality using recommended risk of bias assessment tools. Results: A total of 32 studies (18 preclinical and 14 clinical) were selected for inclusion. We found that most of the animal studies showed significant positive intervention effects on cognitive behavior, while outcomes on cognition, microbiome features, and health parameters in humans were less pronounced. The effectiveness of dietary interventions depended markedly on the age, gender, degree of cognitive decline and baseline microbiome composition of participants. Conclusion: To harness the full potential of microbiome-inspired nutrition for cognitive health, one of the main challenges remains to better understand the interplay between host, his microbiome, dietary exposures, whilst also taking into account environmental influences. Future research should aim toward making use of host-specific microbiome data to guide the development of personalized therapies. [ABSTRACT FROM AUTHOR]

Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive brain stimulation method that has been suggested as a possible treatment method for cognitive impairment in patients with Alzheimer's Disease (pwAD), similar to multidomain cognitive training (CT). The effectiveness, however, of combining these techniques for pwAD remains controversial due to the variability in rTMS parameters, differences in CT protocol designs—many of which neglect the language domain—and the inclusion of patients at various stages of Alzheimer's Disease (AD) and with different types of dementia. The current review aims to evaluate the cognitive benefits of combining rTMS with CT, including language training, for individuals with mild to moderate AD. An extensive literature search was conducted in PubMed, Google Scholar, and the Cochrane Library with relevant terms, resulting in nine studies with a total of 290 participants [190 in the Active Group (AG) and 100 in the Control Group (CG)]. The comprehensive review of the articles revealed that the combined treatment improved global cognitive function, as well as neurocognitive, neuropsychiatric, and quality of life in the AG. Nevertheless, these results should be interpreted cautiously, given the relatively small number of existing studies on this specific combination. [ABSTRACT FROM AUTHOR]

In this article, we present a systematic and exhaustive review regarding the trends, datasets employed, as well as findings achieved in the last 11 years in neurological disorder prediction using machine learning models. In this work we present a comparison between the biomarkers used in ML field with the biomarkers that are obtained through other non‐ml‐based research fields. This will help in identifying the potential research gaps for ML domain. As the study of neurological disorders is a far‐reaching task due to the wide variety of diseases, hence the scope of this study is restricted to the three most prevalent neurological diseases, that is, Alzheimer's, Parkinson's, and Autism Spectrum Disorder (ASD). From our analysis, it has been found that over time deep learning techniques especially Convolutional Neural Networks have proved to be beneficial for the disease prediction task. For this reason, Magnetic Resonance Imaging have been a popular modality across all three considered diseases. It is also notable that the employment of a transfer learning approach and maintenance of a global data centre helps in dealing with data scarcity problems for model training. The manuscript also discusses the potential challenges and future scope in this field. To the best of our knowledge, unlike other studies, this work attempts to put forth a conclusion of every article discussed highlighting the salient aspects of the major studies for a particular problem. [ABSTRACT FROM AUTHOR]

Objectives Life events can be stressful and have a detrimental impact on health, but evidence is inconclusive regarding life events and dementia risk. The present study tests whether life events are associated with incident dementia, whether experiencing multiple events has cumulative effects, and whether the associations vary across age, sex, race/ethnicity, socioeconomic status, and genetic vulnerability. Methods UK Biobank participants (N = 493,787) reported on 6 life events that occurred within the past 2 years: serious illness, injury, assault to yourself or close relative, death of a spouse/partner or close relative, marital separation/divorce, and financial problems. Incident all-cause dementia was ascertained through health records from the UK National Health Service over a 16-year follow-up. Results Serious illness, injury, or assault to yourself, marital separation/divorce, and financial difficulties were associated with a higher risk of dementia; serious illness, injury, or assault of a close relative was associated with a lower risk of dementia. When combined, experiencing 3–4 events was associated with a more than 2-fold increase in dementia risk. The association for marital separation/divorce was stronger within the first 5 years of follow-up (consistent with reverse causality). Death of a spouse/partner or close relative was mostly unrelated to dementia risk. With few exceptions, the associations were similar across age, sex, race/ethnicity, socioeconomic status, and apolipoprotein E e4 status groups. Discussion Severe illness, injury, or personal assault, marital separation or divorce, and financial hardships may raise risk of dementia, particularly when these events occur together. [ABSTRACT FROM AUTHOR]

The main purpose of the present study was to evaluate the therapeutic efficacy of Aloe vera-coated curcumin encapsulated nanoparticles in mitigating Alzheimer's disease progression in mice, by examining behavioural changes, biochemical markers, and histopathological alterations, thus elucidating its potential as a treatment strategy. The green synthesis method was used to synthesise this nanoformulation, which was then characterised using a variety of techniques, including percentage encapsulation efficacy, UV-visible spectroscopy, DLS, FT-IR, FESEM, and EDX. Several in-vivo assessments, including behavioural evaluations, dose optimisation studies, oxidative stress marker estimation, and histological studies, were conducted to determine the potential therapeutic impact of nanoformulation on the Alzheimer-induced mice model. The synthesised nanoparticles show a mean diameter of 76.12 nm ±1.23, a PDI of 0.313 ± 0.02, a zeta potential of 6.27 ± 0.65 mV, and the percentage encapsulation efficiency between 90% and 95% indicating good stability of synthesised nanoformulation. With the help of Morris water maze, Y-maze, and novel object recognition assay, the learning capacity and memory were assessed, and the results show that the synthesised nanoformulation significantly decreased the transfer latency to reach baited arm or to the hidden platform within 7 days. The formulation demonstrated significant biochemical benefits and remarkable cognitive advantages, establishing it as a prospective therapeutic intervention option that is both safe and effective. [ABSTRACT FROM AUTHOR]

To successfully develop disease‐modifying therapies (DMT) against Alzheimer's disease (AD), it is important to target the mild stage of the disease, before the pathological changes progress and dementia symptoms are fully manifested. To this end, the AD Neuroimaging Initiative (ADNI), a large‐scale observational study, was initiated in the U.S. with the goal of development of DMT that are effective in the early stages of mild cognitive impairment (MCI) by utilizing imaging and biomarkers. In Japan, J‐ADNI enrolled and followed up 537 patients, mainly with MCI, and established a platform for evaluation including amyloid PET, and demonstrated a high similarity in the clinical course of amyloid‐positive MCI (prodromal AD) in Japan and the U.S. In 2023, the anti‐Aβ antibody lecanemab successfully completed a Phase III clinical trial for early AD (prodromal AD + mild AD dementia) and was granted regulatory approval and made available both in the US and Japan. Also, phase III trial of donanemab was completed successful. The J‐TRC study was initiated in Japan as a "trial ready cohort (TRC)" consisting of participants who met the eligibility criteria for participation in preclinical and prodromal AD trials. Based on such a platform, the development of DMT for AD will progress more rapidly in the future. [ABSTRACT FROM AUTHOR]

The α-Klotho protein (hereafter Klotho) is an obligate coreceptor for fibroblast growth factor 23 (FGF23). It is produced in the kidneys, brain and other sites. Klotho insufficiency causes hyperphosphatemia and other anomalies. Importantly, it is associated with chronic pathologies (often age-related) that have an inflammatory component. This includes atherosclerosis, diabetes and Alzheimer's disease. Its mode of action in these diseases is not well understood, but it inhibits or regulates multiple major pathways. Klotho has a membrane form and a soluble form (s-Klotho). Cytosolic Klotho is postulated but not well characterized. s-Klotho has endocrine properties that are incompletely elucidated. It binds to the FGF receptor 1c (FGFR1c) that is widely expressed (including endothelial cells). It also attaches to soluble FGF23, and FGF23/Klotho binds to FGFRs. Thus, s-Klotho might be a roaming FGF23 coreceptor, but it has other functions. Notably, Klotho (cell-bound or soluble) counteracts inflammation and appears to mitigate related aging (inflammaging). It inhibits NF-κB and the NLRP3 inflammasome. This inflammasome requires priming by NF-κB and produces active IL-1β, membrane pores and cell death (pyroptosis). In accord, Klotho countered inflammation and cell injury induced by toxins, damage-associated molecular patterns (DAMPs), cytokines, and reactive oxygen species (ROS). s-Klotho also blocks the TGF-β receptor and Wnt ligands, which lessens fibrotic disease. Low Klotho is associated with loss of muscle mass (sarcopenia), as occurs in aging and chronic diseases. s-Klotho counters the inhibitory effects of myostatin and TGF-β on muscle, reduces inflammation, and improves muscle repair following injury. The inhibition of TGF-β and other factors may also be protective in diabetic retinopathy and age-related macular degeneration (AMD). This review examines Klotho functions especially as related to inflammation and potential applications. [ABSTRACT FROM AUTHOR]

Creative augmentation methods in medical imaging, particularly in diagnosing Alzheimer's disease, is a breakthrough approach in the current medical field. Alzheimer's disease, a condition that causes the gradual deterioration of cognitive abilities, presents considerable difficulties in accurately diagnosing and interpreting brain imaging, particularly in the early stages. Neural-enhance Style Transfer (NST), once recognized in the creative field for its capacity to combine the styles of many images, is currently being adapted to improve the clarity and comprehensibility of brain scans used to diagnose Alzheimer's disease. The scalability of this technology is incredibly revolutionary in managing the immense amount of neuroimaging data. In addition, this method also includes the transfer of stylistic characteristics from high-resolution, annotated brain MRIs to broader sets of standard scans, which often need to be clarified and defined. Such enhancement greatly enhances important characteristics, such as brain networks and regions of degeneration, which are essential for the early identification of Alzheimer's disease. An exemplary use of NST in this field has shown a significant enhancement in the discernibility of brain microstructures, vital for early diagnosis of Alzheimer's disease. This improvement has resulted in a considerable rise of over 25% in the accuracy of detecting first pathological alterations. This technological progress not only assists in the prompt and precise identification of medical conditions but also tackles the difficulty of effectively handling the increasing amount of neurological imaging data. [ABSTRACT FROM AUTHOR]

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Objective: This investigation endeavors to elucidate the methodologies through which selfregulation can be imparted to older adults to enhance their acquisition of a foreign language while concurrently enabling them to navigate adverse emotional experiences. In particular, this study scrutinizes the phenomena of obsession and depression. Furthermore, Alzheimer's disease represents a considerable burden for the older population, compounding the inherent difficulties associated with aging and detrimentally influencing their overall quality of life. Consequently, we aim to propose a framework that empowers elderly individuals to reclaim a semblance of control over their obsessive thoughts and depressive states. Methods: The research encompasses 40 Iranian participants who are 65 years of age or older, in alignment with the World Health Organization's classification of elderly individuals. These participants were recruited employing a convenience sampling method. The study utilizes a quasi-experimental design featuring pre-test and post-test assessments alongside a control group. Results: The results indicate that the instruction of the English language exerts a notable effect in mitigating obsessive thoughts and depressive symptoms among adults diagnosed with Alzheimer's disease. Conclusions: This research bears significant implications for elderly individuals in the initial phases of Alzheimer's, their caregiving relatives, psychologists addressing the emotional difficulties faced by older adults, and policymakers involved in the domain of language education. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is a neurocognitive disorder characterized by gradual onset and gradual progression, presenting a wide range of symptoms, with one of its main features being episodic memory impairment, present from the early stages of the disease. Currently, there is no cure for AD, so a multidimensional approach combining pharmacology with other non-pharmacological treatments is recommended to halt or delay cognitive and functional decline in patients. In this regard, music therapy emerges as a promising non-pharmacological treatment for memory in patients with AD, as musical memory appears to be preserved, retaining the ability to recall familiar songs and the memories associated with them. Therefore, the aim of this study is to conduct a systematic review of the current state of scientific research on the effects of music therapy on the memory of patients with AD in mild and moderate stages. A search was conducted in the Google Scholar, ProQuest, Summon, Web of Science, and Scopus databases, finding 15 articles that met the inclusion and exclusion criteria. The results seem to support the use of music-based interventions for memory in patients with AD, especially regarding autobiographical memory. However, given the limitations encountered, we consider that the results pave the way for future research rather than providing solid conclusions about their effectiveness. [ABSTRACT FROM AUTHOR]

Many researchers have studied the role of air pollutants on cognitive function, changes in brain structure, and occurrence of dementia. Due to the wide range of studies and often contradictory results, the present systematic review was conducted to try and clarify the relationship between air pollutants and dementia. To identify studies for this review, a systematic search was conducted in Scopus, PubMed, and Web of Science databases (without historical restrictions) until May 22, 2023. The PECO statement was created to clarify the research question, and articles that did not meet the criteria of this statement were excluded. In this review, animal studies, laboratory studies, books, review articles, conference papers and letters to the editors were avoided. Also, studies focused on the effect of air pollutants on cellular and biochemical changes (without investigating dementia) were also excluded. A quality assessment was done according to the type of design of each article, using the checklist developed by the Joanna Briggs Institute (JBI). Finally, selected studies were reviewed and discussed in terms of Alzheimer's dementia and non-Alzheimer's dementia. We identified 14,924 articles through a systematic search in databases, and after comprehensive reviews, 53 articles were found to be eligible for inclusion in the current systematic review. The results showed that chronic exposure to higher levels of air pollutants was associated with adverse effects on cognitive abilities and the presence of dementia. Studies strongly supported the negative effects of PM2.5 and then NO2 on the brain and the development of neurodegenerative disorders in old age. Because the onset of brain structural changes due to dementia begins decades before the onset of disease symptoms, and that exposure to air pollution is considered a modifiable risk factor, taking preventive measures to reduce air pollution and introducing behavioral interventions to reduce people's exposure to pollutants is advisable. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is the most prevalent form of neurodegeneration. Despite the well-established link between tau aggregation and clinical progression, the major pathways driven by this protein to intrinsically damage neurons are incompletely understood. To model AD-relevant neurodegeneration driven by tau, we overexpressed non-mutated human tau in primary mouse neurons and observed substantial axonal degeneration and cell death, a process accompanied by activated caspase 3. Mechanistically, we detected deformation of the nuclear envelope and increased DNA damage response in tau-expressing neurons. Gene profiling analysis further revealed significant alterations in the mitogen-activated protein kinase (MAPK) pathway; moreover, inhibitors of dual leucine zipper kinase (DLK) and c-Jun N-terminal kinase (JNK) were effective in alleviating wild-type human tau-induced neurodegeneration. In contrast, mutant P301L human tau was less toxic to neurons, despite causing comparable DNA damage. Axonal DLK activation induced by wild-type tau potentiated the impact of DNA damage response, resulting in overt neurotoxicity. In summary, we have established a cellular tauopathy model highly relevant to AD and identified a functional synergy between the DLK-MAPK axis and DNA damage response in the neuronal degenerative process.

INTRODUCTION: Genetic associations with Alzheimers disease (AD) age at onset (AAO) could reveal genetic variants with therapeutic applications. We present a large Colombian kindred with autosomal dominant AD (ADAD) as a unique opportunity to discover AAO genetic associations. METHODS: A genetic association study was conducted to examine ADAD AAO in 340 individuals with the PSEN1 E280A mutation via TOPMed array imputation. Replication was assessed in two ADAD cohorts, one sporadic early-onset AD study and four late-onset AD studies. RESULTS: 13 variants had p

Alzheimer’s disease (AD) is one of the genetically inherited neurodegenerative disorders that mostly occur when people get old. It can be recognized by severe memory impairment in the late stage, affecting cognitive function and general daily living. Reliable evidence confirms that the enhanced symptoms of AD are linked to the accumulation of amyloid proteins. The dense population of amyloid proteins forms insoluble fibrillar structures, causing significant pathological impacts in various tissues. Understanding amyloid protein’s mechanisms and identifying them at an early stage plays an essential role in treating AD as well as prevalent amyloid-related diseases. Recently, although several machine learning methods proposed for amyloid protein identification have shown promising results, most of them have not yet fully exploited the sequence information of the amyloid proteins. In this study, we develop a computational model for in silico identification of amyloid proteins using bidirectional long short-term memory in combination with an attention mechanism. In the testing phase, our findings showed that the model developed by our proposed method outperformed those developed by state-of-the-art methods with an area under the receiver operating characteristic curve of 0.9126.

IntroductionBehavioral and Psychological Symptoms of Dementia (BPSD) are common neuropsychiatric manifestations that complicate the clinical course of dementia and impact caregiving. Among these, the Hyperactivity–Impulsivity–Irritiability–Disinhibition–Aggression–Agitation (HIDA) and Psychosis (P) domains are particularly challenging to manage. Despite their prevalence, their underlying mechanisms and neuropathological correlates, remain poorly understood. This systematic review aims to elucidate the neuropathological basis of the HIDA and psychosis domains, exploring whether distinct proteinopathies and neural circuit dysfunctions are associated with these symptoms.MethodsThe review follows PRISMA guidelines, with a systematic search conducted across MEDLINE, CENTRAL, and EMBASE databases. Inclusion criteria involved studies exploring the neuropathology of the HIDA and psychosis domains in individuals with dementia. Records were screened using PICO software, and data quality was assessed using the Newcastle-Ottawa Scale (NOS) and CARE guidelines. A narrative synthesis was conducted due to heterogeneity in the data.ResultsFrom 846 records identified, 37 studies met inclusion criteria. Of the 18,823 cases analyzed, the most common diagnoses were Alzheimer's Disease (83.44%), Dementia with Lewy Bodies (5.37%), and Frontotemporal Dementia (13.40%). HIDA-P symptoms were distributed across all clinical diagnoses, with agitation (14.00%), delusions (11.60%), disinhibition (7.61%), and hallucinations (6.83%) being the most frequently reported behaviors. The primary neuropathological diagnosis was Alzheimer's Disease Neuropathologic Change (ADNC), present predominantly in intermediate to severe forms. The neuropathological analysis revealed the co-occurrence of multiple proteinopathies, particularly TAUopathy, TDP-43 pathology, and Lewy-related pathology (LRP), with the latter, in association with ADNC, reported in 15 studies.DiscussionHIDA-P symptoms were linked with overlapping involvement of different neural circuits, particularly the amygdala and the broader limbic system. Evidence suggests that TAUopathy and multiple proteinopathies in key brain regions, such as amygdala, are central to the development of these symptoms. In contrast, the contribution of beta-amyloid and vascular damage appears marginal in the genesis of HIDA and psychotic symptoms. No behavioral symptom is pathognomonic of a specific proteinopathy; rather, the topography and severity of lesions plays a more decisive role than their single molecular composition.Systematic review registrationINPLASY2024100082.

Purpose of the reportAdults with Down Syndrome (DS) have a substantially increased risk for Alzheimer’s disease (AD) due to the triplicated amyloid-precursor-protein gene on chromosome 21, resulting in amyloid and tau accumulation. However, tau PET assessments are not sufficiently implemented in DS-AD research or clinical work-up, and second-generation tau tracers such as [18F]PI-2620 have not been thoroughly characterized in adults with DS. We aim at illustrating feasibility and potential diagnostic value of tau PET imaging with [18F]PI-2620 for the diagnosis of DS-AD.Materials and methodsFive adults with DS (40% female, aged 43–62) and cognitive decline underwent clinical assessments, neuropsychological testing, lumbar puncture and multimodal neuroimaging. All underwent [18F]PI-2620 tau PET. Visual read of tau PET scans was performed by three blinded raters, assessing increased tracer uptake in brain areas corresponding to the six Braak stage regions and basal ganglia.ResultsVisual read of tau burden revealed three tau-positive individuals which corresponded to their clinical decline while two cognitively stable individuals were rated as negative. Rating showed high inter-rater reliability for all Braak stages.ConclusionTau PET imaging is a feasible and important biomarker assessment in the differential diagnosis of cognitive decline in adults with DS at risk of developing AD.

IntroductionNeurodegenerative diseases, including Parkinson’s, Alzheimer’s, and epilepsy, pose significant diagnostic and treatment challenges due to their complexity and the gradual degeneration of central nervous system structures. This study introduces a deep learning framework designed to automate neuro-diagnostics, addressing the limitations of current manual interpretation methods, which are often time-consuming and prone to variability.MethodsWe propose a specialized deep convolutional neural network (DCNN) framework aimed at detecting and classifying neurological anomalies in MRI data. Our approach incorporates key preprocessing techniques, such as reducing noise and normalizing image intensity in MRI scans, alongside an optimized model architecture. The model employs Rectified Linear Unit (ReLU) activation functions, the Adam optimizer, and a random search strategy to fine-tune hyper-parameters like learning rate, batch size, and the number of neurons in fully connected layers. To ensure reliability and broad applicability, cross-fold validation was used.Results and discussionOur DCNN achieved a remarkable classification accuracy of 98.44%, surpassing well-known models such as ResNet-50 and AlexNet when evaluated on a comprehensive MRI dataset. Moreover, performance metrics such as precision, recall, and F1-score were calculated separately, confirming the robustness and efficiency of our model across various evaluation criteria. Statistical analyses, including ANOVA and t-tests, further validated the significance of the performance improvements observed with our proposed method. This model represents an important step toward creating a fully automated system for diagnosing and planning treatment for neurological diseases. The high accuracy of our framework highlights its potential to improve diagnostic workflows by enabling precise detection, tracking disease progression, and supporting personalized treatment strategies. While the results are promising, further research is necessary to assess how the model performs across different clinical scenarios. Future studies could focus on integrating additional data types, such as longitudinal imaging and multimodal techniques, to further enhance diagnostic accuracy and clinical utility. These findings mark a significant advancement in applying deep learning to neuro-diagnostics, with promising implications for improving patient outcomes and clinical practices.

Sleep apnea is regarded as an important risk factor in the pathogenesis of Alzheimer disease (AD). Chronic intermittent hypoxia treatment (IHT) given during the sleep period of the circadian cycle in experimental animals is a well-established sleep apnea model. Here we report that transient IHT for 4 days on AD model mice causes Aβ overproduction 2 months after IHT presumably via upregulation of synaptic BACE1, side-by-side with tau hyperphosphorylation. These results suggest that even transient IHT may be sufficient to cause long-lasting changes in the molecules measured as AD biomarkers in the brain.