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Background and Purpose: The effect of physical activity and living in enriched environment on some cognitive mechanisms in Alzheimer's disease (AD) is not yet well understood. Therefore, this study aimed to investigate the effect of aerobic training along with enriched environment on spatial memory and brain-derived neurotrophic factor in the Hippocampal tissue of elderly female Wistar rats with Alzheimer's disease.Materials and Methods: In this experimental study, 30 elderly female Wistar rats with twenty-one-month-old and average weight of 260±20 grams were used and divided into 6 groups: control-healthy, Alzheimer's, sham group, Alzheimer's + aerobic exercise (treadmill), Alzheimer's + enriched environment, Alzheimer's + enriched environment + aerobic exercise (treadmill). Rats in the training groups performed two 15-min sessions with 5-minute passive rest at a speed of 10 m/min in the first and second weeks. In the third week, they performed three sessions at a speed of 15 m/min with a 5-min break, and in the fourth week, four sessions per day at a speed of 15 m/min with a 5-min break. In the enriched environment group, the animals were kept in a plexiglass material larger than the standard cage (60×50×70 cm3). In these cages, devices such as ladders, hollow pipes, wooden blocks and plastic toys were placed. In Alzheimer's groups, rats were anesthetized by intraperitoneal injection of ketamine (80 mg/kg) and xylazine (20 mg/kg). Then, Alzheimer's Aβ was induced by intracerebroventricular injections (10μg/rat). Spatial memory was measured by Morris water maze, barin derived neurotrophic factor (BDNF) and Trk-B by western blot. In a pilot study in order to evaluate the spatial memory of rats, one week after beta-amyloid injection, all rats were divided into Alzheimer's and control groups. Rats were trained in the maze for four days and the mean percentage permanence in the platform area was recorded. The results of the independent t-test showed that there is a significant difference between the control group and Alzheimer's group (P=0.0152). Therefore, One-way analysis of variance with Tukey's post-hoc test (P

Context: Alzheimer's disease (AD) is a debilitating neurodegenerative condition primarily afflicting the elderly, causing a progressive decline in cognitive function. It is marked by the presence of beta-amyloid protein plaques that trigger inflammation and neuronal death. Unfortunately, effective treatments for Alzheimer's remain elusive. One promising approach involves targeting the mitochondrial cascade to shield neurons from inflammation-induced cell death, and flavonoids have been identified for their potential neuroprotective properties. Aims: To investigate the most potential bioactive compound that has neuroprotective effects, especially for Alzheimer's, through molecular simulation and in vitro studies. Methods: The study employed molecular simulations to identify apigenin as a potential neuroprotective compound. Quercetin and donepezil were selected as control compounds. The MTT assay was conducted to evaluate the neuroprotective activity of apigenin, quercetin, and donepezil on the SHSY5Y cell line induced by beta-amyloid protein. Results: The MTT assay demonstrated the neuroprotective activity of apigenin and reference compounds quercetin and donepezil against beta-amyloid-induced damage in the SHSY5Y cell line. Conclusions: These findings suggest that apigenin could hold promise as a neuroprotective treatment for AD. However, further research is essential to elucidate its mechanism of action and evaluate its efficacy in more complex organisms. This study underscores the crucial role of bioinformatics tools and experimental validation in the quest for potential neuroprotective compounds for the treatment of AD.

Abstract Background Research into the neurobiological underpinnings of learning and memory has demonstrated the cognitive-enhancing effects associated with diverse classes of phosphodiesterase (PDE) inhibitors. Specific PDE inhibitors have been identified to improve neuronal communication through selective inhibition of PDE activity. Roflumilast, a PDE4 inhibitor, has demonstrated efficacy in enhancing episodic memory in healthy adults and elderly participants with pronounced memory impairment, indicative of amnestic mild cognitive impairment (aMCI). In alignment with these findings, the present protocol aims to provide a proof of concept phase II of the potential of roflumilast to aid patients diagnosed with (a)MCI or mild Alzheimer’s disease (AD) dementia. Methods The study will be conducted according to a double-blind, randomized placebo-controlled, between-subjects design. Participants with (a)MCI and mild AD dementia will be recruited through the Memory Clinic at the Maastricht University Medical Centre + (MUMC +) in Maastricht, the Netherlands, alongside outreach through regional hospitals, and social media. The study will have three arms: placebo, 50 μg roflumilast, and 100 μg roflumilast, with a treatment duration of 24 weeks. The primary outcome measure will focus on the assessment of episodic memory, as evaluated through participants’ performance on the 15-word Verbal Learning Task (VLT). Our secondary objectives are multifaceted, including an exploration of various cognitive domains. In addition, insights into the well-being and daily functioning of participants will be investigated through interviews with both the participants and their (informal) caregivers, we are interested in the well-being and daily functioning of the participants. Discussion The outcomes of the present study aim to elucidate the significance of the PDE4 inhibition mechanism as a prospective therapeutic target for enhancing cognitive function in individuals with (a)MCI and mild AD dementia. Identifying positive effects within these patient cohorts could extend the relevance of this treatment to encompass a broader spectrum of neurological disorders. Trial registration The Medical Ethics Committee of MUMC + granted ethics approval for the 4th version of the protocol on September 10th, 2020. The trial was registered at the European Drug Regulatory Affairs Clinical Trials (EudraCT) registered on the 19th of December 2019 ( https://www.clinicaltrialsregister.eu/ctr-search/trial/2019-004959-36/NL ) and ClinicalTrial.gov (NCT04658654, https://clinicaltrials.gov/study/NCT04658654?intr=roflumilast&cond=mci&rank=1 ) on the 8th of December 2020. The Central Committee on Research Involving Human Subjects (CCMO) granted approval on the 30th of September 2020.

Abstract Extensive research into dementia has more recently honed in on several key areas. These areas include the advancement of techniques such as the accumulation of amyloid-β and tau proteins, the monitoring of cerebral hypometabolism rates etc. The primary objective of this study is to explore the intricate interplay between Alzheimer's disease (AD)—other dementias (D) and various chronic illnesses in terms of time, intensity, and connectivity. In this context, we retrospectively examined data of 149,786 individuals aged 65 and above who received diagnoses of AD and D in the year 2020. At first, logistic regression (LR) analysis has been made with “sex”, “age” and “foreigner” (citizenship status) independent variables for AD and D. The LR models shows that while “sex” and “age” variables have a small rate on the risk of developing AD/D, it is detected that being a foreigner increase the risk of AD and D as 69.8% and 88.5% respectively. Besides, the LR models have middle-level success prediction rate for both of the two dependent variables. Additionally, we used the parallel coordinates graphs method within the R Studio to visualize their relationships and connections. The findings of this investigation strongly suggest that AD/D don’t stand as isolated conditions, but rather stem from intricate interactions and progressive processes involving diverse chronic diseases over time. Notably, ailments including hypertension, coronary artery disease, diabetes, hyperlipidemia, and psychological disorders, contribute substantially to the emergence of both AD and D. This study highlights that the fight against AD/D can only be possible with next-generation prophylactic interventions that can predict and manage risks. Such an approach holds the potential to potentially lower AD and dementia to levels that are amenable to treatment.

Abstract Alzheimer’s disease (AD) is the most common type of dementia with millions of affected patients worldwide. Currently, there is still no cure and AD is often diagnosed long time after onset because there is no clear diagnosis. Thus, it is essential to study the physiology and pathogenesis of AD, investigating the risk factors that could be strongly connected to the disease onset. Despite AD, like other complex diseases, is the result of the combination of several factors, there is emerging agreement that environmental pollution should play a pivotal role in the causes of disease. In this work, we implemented an Artificial Intelligence model to predict AD mortality, expressed as Standardized Mortality Ratio, at Italian provincial level over 5 years. We employed a set of publicly available variables concerning pollution, health, society and economy to feed a Random Forest algorithm. Using methods based on eXplainable Artificial Intelligence (XAI) we found that air pollution (mainly $$O_3$$ O 3 and $$NO_2$$ N O 2 ) contribute the most to AD mortality prediction. These results could help to shed light on the etiology of Alzheimer’s disease and to confirm the urgent need to further investigate the relationship between the environment and the disease.

In recent years, there has been an increase in suicide rates in Brazil. From 2015 to 2019, a 34% increase in self-inflicted deaths was observed. The aim of this study was to analyse population data to determine whether some subgroups of the population, specifically the elderly population with Alzheimer's disease, are at a greater risk of suicide. An analysis of population data was carried out. Population data from the state of São Paulo, Brazil, were obtained from two platforms: the Brazilian Institute of Geography and Statistics (IBGE); and the Brazilian Ministry of Health (DataSUS). Data were measured and compared in 2010 and 2022 using the two most recent censuses. Between 2010 and 2022, the number of registered deaths of patients with Alzheimer's increased by 21.93%. In addition, there was a 100.37% increase in suicides among the elderly population compared to a 37.78% increase in the general population. In recent years, there has been a notable increase in both suicides among the elderly and mortality rates attributed to Alzheimer's disease within São Paulo state, Brazil. However, it is not possible to conclude that the increase in suicide among the elderly is directly linked to Alzheimer's disease. To determine a correlation between suicide and Alzheimer's disease, further studies are required. [ABSTRACT FROM AUTHOR]

Associations between age-related neuropathological lesions and adult-onset lifetime major depressive disorder (a-MDD), late-life MDD (LLD), or depressive symptoms close to death (DS) were examined in a large community sample of non-demented older adults. Seven hundred forty-one individuals (age at death = 72.2 ± 11.7 years) from the Biobank for Aging Studies were analyzed. a-MDD was present in 54 (7.3%) participants, LLD in 80 (10.8%), and DS in 168 (22.7%). After adjustment for covariates and compared to controls, a-MDD, LDD and DS were associated with small vessel disease (p = 0.039, p = 0.003, and p = 0.003 respectively); LLD, and DS were associated with brain infarcts (p = 0.012, p = 0.018, respectively) and Lewy body disease (p = 0.043, p = 0.002, respectively). DS was associated with beta-amyloid plaque burden (p = 0.027) and cerebral amyloid angiopathy (p = 0.035) in cognitively normal individuals (Clinical Dementia Rating scale = 0). Vascular brain pathology was the strongest correlate of clinical depictions of depression in the absence of dementia, corroborating the vascular hypothesis of depression. Lewy body pathology underlay DS. An older adult with DS or LLD should be monitored for possible cognitive decline or neurodegenerative disorders.

Voltage-gated ion channels are essential for membrane potential maintenance, homeostasis, electrical signal production and controlling the Ca2+ flow through the membrane. Among all ion channels, the key regulators of neuronal excitability are the voltage-gated potassium channels (KV), the largest family of K+ channels. Due to the ROS high levels in the aging brain, K+ channels might be affected by oxidative agents and be key in aging and neurodegeneration processes. This review provides new insight about channelopathies in the most studied neurodegenerative disorders, such as Alzheimer Disease, Parkinson's Disease, Huntington Disease or Spinocerebellar Ataxia. The main affected KV channels in these neurodegenerative diseases are the KV1, KV2.1, KV3, KV4 and KV7. Moreover, in order to prevent or repair the development of these neurodegenerative diseases, previous KV channel modulators have been proposed as therapeutic targets. [ABSTRACT FROM AUTHOR]

APOEε4 is the major genetic risk factor for sporadic Alzheimer's disease (AD). Although APOEε4 is known to promote Aβ pathology, recent data also support an effect of APOE polymorphism on phosphorylated Tau (pTau) pathology. To elucidate these potential effects, the pTau interactome was analyzed across APOE genotypes in the frontal cortex of 10 advanced AD cases (n = 5 APOEε3/ε3 and n = 5 APOEε4/ε4), using a combination of anti-pTau pS396/pS404 (PHF1) immunoprecipitation (IP) and mass spectrometry (MS). This proteomic approach was complemented by an analysis of anti-pTau PHF1 and anti-Aβ 4G8 immunohistochemistry, performed in the frontal cortex of 21 advanced AD cases (n = 11 APOEε3/ε3 and n = 10 APOEε4/ε4). Our dataset includes 1130 and 1330 proteins enriched in IPPHF1 samples from APOEε3/ε3 and APOEε4/ε4 groups (fold change ≥ 1.50, IPPHF1vs IPIgG ctrl). We identified 80 and 68 proteins as probable pTau interactors in APOEε3/ε3 and APOEε4/ε4 groups, respectively (SAINT score ≥ 0.80; false discovery rate (FDR) ≤ 5%). A total of 47/80 proteins were identified as more likely to interact with pTau in APOEε3/ε3 vs APOEε4/ε4 cases. Functional enrichment analyses showed that they were significantly associated with the nucleoplasm compartment and involved in RNA processing. In contrast, 35/68 proteins were identified as more likely to interact with pTau in APOEε4/ε4 vs APOEε3/ε3 cases. They were significantly associated with the synaptic compartment and involved in cellular transport. A characterization of Tau pathology in the frontal cortex showed a higher density of plaque-associated neuritic crowns, made of dystrophic axons and synapses, in APOEε4 carriers. Cerebral amyloid angiopathy was more frequent and severe in APOEε4/ε4 cases. Our study supports an influence of APOE genotype on pTau-subcellular location in AD. These results suggest a facilitation of pTau progression to Aβ-affected brain regions in APOEε4 carriers, paving the way to the identification of new therapeutic targets. [ABSTRACT FROM AUTHOR]

Type I interferons (IFN-I) represent a group of pleiotropic cytokines renowned for their antiviral activity and immune regulatory functions. A multitude of studies have unveiled a critical role of IFN-I in the brain, influencing various neurological processes and diseases. In this mini-review, I highlight recent findings on IFNI's effects on brain aging, Alzheimer's disease (AD) progression, and central nervous system (CNS) homeostasis. The multifaceted influence of IFN-I on brain health and disease sheds light on the complex interplay between immune responses and neurological processes. Of particular interest is the cGAS-STINGIFN- I axis, which extensively participates in brain aging and various forms of neurodegeneration. Understanding the intricate role of IFN-I and its associated pathways in the CNS not only advances our comprehension of brain health and disease but also presents opportunities for developing interventions to modify the process of neurodegeneration and prevent age-related cognitive decline. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) remains a significant health challenge, with an increasing prevalence globally. Recent research has aimed to deepen the understanding of the disease pathophysiology and to find potential therapeutic interventions. In this regard, G protein-coupled receptors (GPCRs) have emerged as novel potential therapeutic targets to palliate the progression of neurodegenerative diseases such as AD. Orexin and cannabinoid receptors are GPCRs capable of forming heteromeric complexes with a relevant role in the development of this disease. On the one hand, the hyperactivation of the orexins system has been associated with sleep–wake cycle disruption and Aβ peptide accumulation. On the other hand, cannabinoid receptor overexpression takes place in a neuroinflammatory environment, favoring neuroprotective effects. Considering the high number of interactions between cannabinoid and orexin systems that have been described, regulation of this interplay emerges as a new focus of research. In fact, in microglial primary cultures of APPSw/Ind mice model of AD there is an important increase in CB2R–OX1R complex expression, while OX1R antagonism potentiates the neuroprotective effects of CB2R. Specifically, pretreatment with the OX1R antagonist has been shown to strongly potentiate CB2R signaling in the cAMP pathway. Furthermore, the blockade of OX1R can also abolish the detrimental effects of OX1R overactivation in AD. In this sense, CB2R–OX1R becomes a new potential therapeutic target to combat AD. [ABSTRACT FROM AUTHOR]

Alzheimer disease (AD) is a heterogeneous and complex disease in which different pathophysiological mechanisms are involved. This heterogenicity can be reflected in different atrophy patterns or clinical manifestations. Regarding biochemical pathways involved in early AD, lipid metabolism plays an important role; therefore, lipid levels have been evaluated as potential AD diagnosis biomarkers, and their levels could be related to different AD clinical manifestations. Therefore, the aim of this work is to study AD lipid profiles from early AD patients and evaluate their clinical significance. For this purpose, untargeted plasma lipidomic analysis was carried out in early AD patients (n = 31) diagnosed with cerebrospinal fluid (CSF) biomarkers. Cluster analysis was carried out to define early AD subgroups according to the lipid levels. Then, the clinical significance of each lipid profile subgroup was studied, analyzing differences for other variables (cognitive status, CSF biomarkers, medication, comorbidities, age, and gender). The cluster analysis revealed two different groups of AD patients. Cluster 1 showed higher levels of plasma lipids and better cognitive status than Cluster 2. However, no differences were found for the other variables (age, gender, medication, comorbidities, cholesterol, and triglycerides levels) between both groups. Plasma lipid levels could differentiate two early AD subgroups, which showed different cognitive statuses. However, further research with a large cohort and longitudinal study evaluating the clinical evolution of these patients is required. In general, it would involve a relevant advance in the knowledge of AD pathological mechanisms, potential treatments, and precision medicine. [ABSTRACT FROM AUTHOR]

In this study, donepezil hydrochloride (DZ HCl), a crucial medication for the treatment of Alzheimer's disease, is detected using a new sensor built on CuO-TiO 2 hybrid nanostructures. The sensor showed improved performance characteristics with a computed limit of quantitation of 0.211 and a limit of detection of 0.063. These qualities included improved stability, selectivity, and sensitivity. The fabrication process demonstrated repeatability, with a 4.27% relative standard deviation. After 10 successive readings, the sensor maintained 95% of its initial response, demonstrating its long-term stability. By quantifying DZ HCl in urine samples, the practical applicability of the sensor was confirmed. Remarkably, the sensor achieved a remarkable recovery rate of 97.00–99.41% and a suitable relative standard deviation range of 3.29–4.71%. The results of this work contribute to the development of trustworthy electrochemical sensors for medicinal chemicals and have prospective uses in pharmacological, biological, and therapeutic fields. [ABSTRACT FROM AUTHOR]

Background: The locus coeruleus (LC) and the nucleus basalis of Meynert (NBM) are altered in early stages of Alzheimer's disease (AD). Little is known about LC and NBM alteration in limbic-predominant age-related TDP-43 encephalopathy (LATE) and frontotemporal dementia (FTD). The aim of the present study is to investigate in vivo LC and NBM integrity in patients with suspected-LATE, early-amnestic AD and FTD in comparison with controls. Methods: Seventy-two participants (23 early amnestic-AD patients, 17 suspected-LATE, 17 FTD patients, defined by a clinical-biological diagnosis reinforced by amyloid and tau PET imaging, and 15 controls) underwent neuropsychological assessment and 3T brain MRI. We analyzed the locus coeruleus signal intensity (LC-I) and the NBM volume as well as their relation with cognition and with medial temporal/cortical atrophy. Results: We found significantly lower LC-I and NBM volume in amnestic-AD and suspected-LATE in comparison with controls. In FTD, we also observed lower NBM volume but a slightly less marked alteration of the LC-I, independently of the temporal or frontal phenotype. NBM volume was correlated with the global cognitive efficiency in AD patients. Strong correlations were found between NBM volume and that of medial temporal structures, particularly the amygdala in both AD and FTD patients. Conclusions: The alteration of LC and NBM in amnestic-AD, presumed-LATE and FTD suggests a common vulnerability of these structures to different proteinopathies. Targeting the noradrenergic and cholinergic systems could be effective therapeutic strategies in LATE and FTD. [ABSTRACT FROM AUTHOR]

Recent advances in neurology and biochemistry offer new hope for the prevention and treatment of mild cognitive impairment (MCI) and Alzheimer's disease (AD), through the use of antioxidants such as glutathione and plant polyphenols such as oleuropein. A recent study at the San Giovanni di Dio Institute in Rome highlighted these benefits, highlighting the key role of glutathione, a powerful intracellular antioxidant, whose concentration decreases with age and in brain areas affected by AD. Oleuropein, the main polyphenol in olive tree (Olea europaea), shows neuroprotective abilities, interfering with the accumulation of the toxic proteins amyloid and tau, which are associated with neurodegeneration. The study involved 40 patients with mild AD, divided into two groups: one received treatment with S-acetyl-glutathione, oleuropein, and vitamins for six months, while the other started treatment after six months without treatment. The results demonstrated significant improvements in the cognitive, behavioral, and executive skills of the treated patients, confirming the efficacy of this nutraceutical combination. These findings pave the way for new therapeutic protocols for neurodegenerations related to oxidative stress and protein misfolding, highlighting the importance of a preventive approach that integrates antioxidants and polyphenols into the diet, along with a healthy lifestyle, to counteract the advancement of MCI and AD. Research continues with a larger cohort of patients to confirm and expand these promising findings. [ABSTRACT FROM AUTHOR]

Summary: Microglia, the major population of brain‐resident macrophages, are now recognized as a heterogeneous population comprising several cell subtypes with different (so far mostly supposed) functions in health and disease. A number of studies have performed molecular characterization of these different microglial activation states over the last years making use of "omics" technologies, that is transcriptomics, proteomics and, less frequently, epigenomics profiling. These approaches offer the possibility to identify disease mechanisms, discover novel diagnostic biomarkers, and develop new therapeutic strategies. Here, we focus on epigenetic profiling as a means to understand microglial immune responses beyond what other omics methods can offer, that is, revealing past and present molecular responses, gene regulatory networks and potential future response trajectories, and defining cell subtype‐specific disease relevance through mapping non‐coding genetic variants. We review the current knowledge in the field regarding epigenetic regulation of microglial identity and function, provide an exemplary analysis that demonstrates the advantages of performing joint transcriptomic and epigenomic profiling of single microglial cells and discuss how comprehensive epigenetic analyses may enhance our understanding of microglial pathophysiology. [ABSTRACT FROM AUTHOR]

Objectives: The definition and assessment methods for subjective cognitive decline (SCD) vary among studies. We aimed to investigate which features or assessment methods of SCD best predict Alzheimer's disease (AD)‐related structural atrophy patterns. Methods: We assessed 104 individuals aged 55+ with memory complaints but normal cognitive screening. Our research questions were as follows: To improve the prediction of AD related morphological changes, (1) Would the use of a standardized cognitive screening scale be beneficial? (2) Is conducting a thorough neuropsychological evaluation necessary instead of relying solely on cognitive screening tests? (3) Should we apply SCD‐plus research criteria, and if so, which criterion would be the most effective? (4) Is it necessary to consider medical and psychiatric comorbidities, vitamin deficiencies, vascular burden on MRI, and family history? We utilized Freesurfer to analyze cortical thickness and regional brain volume meta‐scores linked to AD or predicting its development. We employed multiple linear regression models for each variable, with morphology as the dependent variable. Results: AD‐like morphology was associated with subjective complaints in males, individuals with advanced age, and higher education. Later age of onset for complaints, complaints specifically related to memory, excessive deep white matter vascular lesions, and using medications that have negative implications for cognitive health (according to the Beers criteria) were predictive of AD‐related morphology. The subjective cognitive memory questionnaire scores were found to be a better predictor of reduced volumes than a single‐question assessment. It is important to note that not all SCD‐plus criteria were evaluated in this study, particularly the APOE genotype, amyloid, and tau status, due to resource limitations. Conclusions: The detection of AD‐related structural changes is impacted by demographics and assessment methods. Standardizing SCD assessment methods can enhance predictive accuracy. [ABSTRACT FROM AUTHOR]

Familial Alzheimer's disease (FAD) is a complex and multifactorial neurodegenerative disorder for which no curative therapies are yet available. Indeed, no single medication or intervention has proven fully effective thus far. Therefore, the combination of multitarget agents has been appealing as a potential therapeutic approach against FAD. Here, we investigated the potential of combining tramiprosate (TM), curcumin (CU), and the JNK inhibitor SP600125 (SP) as a treatment for FAD. The study analyzed the individual and combined effects of these two natural agents and this pharmacological inhibitor on the accumulation of intracellular amyloid beta iAβ; hyperphosphorylated protein TAU at Ser202/Thr205; mitochondrial membrane potential (ΔΨm); generation of reactive oxygen species (ROS); oxidized protein DJ-1; proapoptosis proteins p-c-JUN at Ser63/Ser73, TP53, and cleaved caspase 3 (CC3); and deficiency in acetylcholine (ACh)-induced transient Ca2+ influx response in cholinergic-like neurons (ChLNs) bearing the mutation I416T in presenilin 1 (PSEN1 I416T). We found that single doses of TM (50 μM), CU (10 μM), or SP (1 μM) were efficient at reducing some, but not all, pathological markers in PSEN 1 I416T ChLNs, whereas a combination of TM, CU, and SP at a high (50, 10, 1 μM) concentration was efficient in diminishing the iAβ, p-TAU Ser202/Thr205, DJ-1Cys106-SO3, and CC3 markers by −50%, −75%, −86%, and −100%, respectively, in PSEN1 I417T ChLNs. Although combinations at middle (10, 2, 0.2) and low (5, 1, 0.1) concentrations significantly diminished p-TAU Ser202/Thr205, DJ-1Cys106-SO3, and CC3 by −69% and −38%, −100% and −62%, −100% and −62%, respectively, these combinations did not alter the iAβ compared to untreated mutant ChLNs. Moreover, a combination of reagents at H concentration was able to restore the dysfunctional ACh-induced Ca2+ influx response in PSEN 1 I416T. Our data suggest that the use of multitarget agents in combination with anti-amyloid (TM, CU), antioxidant (e.g., CU), and antiapoptotic (TM, CU, SP) actions might be beneficial for reducing iAβ-induced ChLN damage in FAD. [ABSTRACT FROM AUTHOR]

Background: Antidementia medication can provide symptomatic improvements in patients with Alzheimer's disease, but there is a lack of consensus guidance on when to start and stop treatment in the nursing home setting. Methods: We describe utilization patterns of cholinesterase inhibitors (ChEI) and memantine for 3,50,197 newly admitted NH residents with dementia between 2011 and 2018. Results: Overall, pre-admission use of antidementia medications declined from 2011 to 2018 (ChEIs: 44.5% to 36.9%; memantine: 27.4% to 23.2%). Older age, use of a feeding tube, and greater functional dependency were associated with lower odds of ChEI initiation. Coronary artery disease, parenteral nutrition, severe aggressive behaviors, severe cognitive impairment, and high functional dependency were associated with discontinuation of ChEIs. Comparison of clinical factors related to anti-dementia drug treatment changes from pre to post NH admission in 2011 and 2018 revealed a change toward lower likelihood of initiation of treatment among residents with more functional dependency and those with indicators of more complex illness as well as a change toward higher likelihood of discontinuation in residents having 2 or more hospital stays. Conclusions: These prescribing trends highlight the need for additional research on the effects of initiating and discontinuing antidementia medications in the NH to provide clear guidance for clinicians when making treatment decisions for individual residents. [ABSTRACT FROM AUTHOR]

Dementia is a clinical illness that becomes more common as people get older. It is defined by a decline in cognitive abilities across several domains and eventually impacts everyday functioning. Consequently, this leads to a decline in autonomy, impairment, dependence on assistance even criminal tendencies/insecure behaviors and ultimately, the disease frequently results in mortality. Particularly with regard to neurodegenerative disorders, various forms of dementia are correlated with criminal activity. According to research, criminal and socially inappropriate behavior is prevalent among dementia patients and is sometimes the initial symptom of the disease. Alzheimer's Disease (AD) is responsible for 60-80% of all occurrences of dementia, and its occurrence increases double every five years beyond the age of 65. Given the availability of health data and the decrease in data processing costs, it is now feasible to detect Alzheimer's disease at an early stage. The objective of this study is to classify individuals as either Alzheimer's sufferers or healthy individuals by employing various machine learning techniques. The "OASIS-2 dataset", which consists of "longitudinal MRI data" from both nondemented and demented older adults, was utilized for this study. Given its potential for early detection of Alzheimer's dementia, the study is anticipated to enhance clinical decision support systems pertaining to modifiable risk factors. [ABSTRACT FROM AUTHOR]

Alzheimer's disease is the main cause of aging-associated dementia, for which there is no effective treatment. In this work, we reanalyze the information of a previous genome wide association study, using a new pipeline design to identify novel potential drugs. With this approach, ribonucleoside-diphosphate reductase gene (RRM2B) emerged as a candidate target and its inhibitor, 2′, 2′-difluoro 2′deoxycytidine (gemcitabine), as a potential pharmaceutical drug against Alzheimer's disease. We functionally verified the effect of inhibiting the RRM2B homolog, rnr-2 , in an Alzheimer's model of Caenorhabditis elegans, which accumulates human Aβ1-42 peptide to an irreversible paralysis. RNA interference against rnr-2 and also treatment with 200 ng/ml of gemcitabine, showed an improvement of the phenotype. Gemcitabine treatment increased the intracellular ATP level 3.03 times, which may point to its mechanism of action. Gemcitabine has been extensively used in humans for cancer treatment but at higher concentrations. The 200 ng/ml concentration did not exert a significant effect over cell cycle, or affected cell viability when assayed in the microglia N13 cell line. Thus, the inhibitory drug of the RRM2B activity could be of potential use to treat Alzheimer's disease and particularly gemcitabine might be considered as a promising candidate to be repurposed for its treatment. [ABSTRACT FROM AUTHOR]

Cytomegalovirus (CMV) belongs to the Herpesviridae family and is also known as human herpesvirus type 5. It is a common virus that usually doesn't cause any symptoms in healthy individuals. However, once infected, the virus remains in the host's body for life and can reactivate when the host's immune system weakens. This virus has been linked to several neurological disorders, including Alzheimer's disease, Parkinson's disease, Autism spectrum disorder, Huntington's disease (HD), ataxia, Bell's palsy (BP), and brain tumours, which can cause a wide range of symptoms and challenges for those affected. CMV may influence inflammation, contribute to brain tissue damage, and elevate the risk of moderate‐to‐severe dementia. Multiple studies suggest a potential association between CMV and ataxia in various conditions, including Guillain‐Barré syndrome, chronic inflammatory demyelinating polyneuropathy, acute cerebellitis, etc. On the other hand, the evidence regarding CMV involvement in BP is conflicting, and also early indications of a link between CMV and HD were challenged by subsequent research disproving CMV's presence. This systematic review aims to comprehensively investigate any link between the pathogenesis of CMV and its potential role in neurological disorders and follows the preferred reporting items for systematic review and meta‐analysis checklist. Despite significant research into the potential links between CMV infection and various neurological disorders, the direct cause‐effect relationship is not fully understood and several gaps in knowledge persist. Therefore, continued research is necessary to gain a better understanding of the role of CMV in neurological disorders and potential treatment avenues. [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. [ABSTRACT FROM AUTHOR]

Recently, various studies have shown that epigenetic changes are associated with aging and age‐related diseases. Both animal and human models have revealed that epigenetic processes are involved in aging mechanisms. These processes happen at multiple levels and include histone modification, DNA methylation, and changes in noncoding RNA expression. Consequently, changes in the organization of chromatin and DNA accessibility lead to the regulation of gene expression. With increasing awareness of the pivotal function of epigenetics in the aging process, researchers' attention has been drawn to how these epigenetic changes can be modified to prevent, stop, or reverse aging, senescence, and age‐related diseases. Among various agents that can affect epigenetic, polyphenols are well‐known phytochemicals found in fruits, vegetables, and plants. Polyphenols are found to modify epigenetic‐related mechanisms in various diseases and conditions, such as metabolic disorders, obesity, neurodegenerative diseases, cancer, and cardiovascular diseases. Resveratrol (RSV) is a member of the stilbene subgroup of polyphenols which is derived from various plants, such as grapes, apples, and blueberries. Therefore, herein, we aim to summarize how RSV affects different epigenetic processes to change aging‐related mechanisms. Furthermore, we discuss its roles in age‐related diseases, such as Alzheimer's, Parkinson's, osteoporosis, and cardiovascular diseases. [ABSTRACT FROM AUTHOR]

Saffron is a spice derived from the flower of Crocus sativus L., which has been used for centuries as a coloring and flavoring agent, as well as a source of medicinal compounds. Saffron contains various bioactive constituents, such as crocin, crocetin, safranal, picrocrocin, and kaempferol, that have shown potential benefits for human health. Among them, crocin is the most abundant and characteristic constituent of saffron, responsible for its bright red color and antioxidant properties. One of the most promising applications of saffron and its constituents is in the prevention and treatment of neurological disorders, such as depression, anxiety, Alzheimer's disease, Parkinson's disease, and other brain disorders. Saffron and its constituents have been reported to exert neuroprotective effects through various mechanisms, such as modulating neurotransmitters, enhancing neurogenesis, reducing neuroinflammation, regulating oxidative stress, activating the Nrf2 signaling pathway, and modulating epigenetic factors. Several clinical and preclinical studies have demonstrated the efficacy and safety of saffron and its constituents in improving cognitive function, mood, and other neurological outcomes. In this review, we summarize the current evidence on the therapeutic potential of saffron and its constituents in neurological disorders, from bench to bedside. We also discuss the challenges and future directions for the development of saffron‐based therapies for brain health. [ABSTRACT FROM AUTHOR]

Various deep learning models have been proposed for the accurate assisted diagnosis of early-stage Alzheimer's disease (AD).Most studies predominantly employ Convolutional Neural Networks (CNNs), which focus solely on local features, thus encountering difficulties in handling global features. In contrast to natural images, Structural Magnetic Resonance Imaging (sMRI) images exhibit a higher number of channel dimensions. However, during the Position Embedding stage ofMulti Head Self Attention (MHSA), the coded information related to the channel dimension is disregarded. To tackle these issues,we propose theRepBoTNet-CESAnetwork, an advancedAD-aided diagnostic model that is capable of learning local and global features simultaneously. It combines the advantages of CNN networks in capturing local information and Transformer networks in integrating global information, reducing computational costs while achieving excellent classification performance. Moreover, it uses the Cubic Embedding Self Attention (CESA) proposed in this paper to incorporate the channel code information, enhancing the classification performance within the Transformer structure. Finally, the RepBoTNet-CESA performs well in various AD-aided diagnosis tasks, with an accuracy of 96.58%, precision of 97.26%, and recall of 96.23% in the AD/NC task; an accuracy of 92.75%, precision of 92.84%, and recall of 93.18% in the EMCI/NC task; and an accuracy of 80.97%, precision of 83.86%, and recall of 80.91% in the AD/EMCI/LMCI/NC task. This demonstrates that RepBoTNet-CESA delivers outstanding outcomes in various AD-aided diagnostic tasks. Furthermore, our study has shown that MHSA exhibits superior performance compared to conventional attention mechanisms in enhancing ResNet performance. Besides, the Deeper RepBoTNet-CESA network fails to make further progress in AD-aided diagnostic tasks. [ABSTRACT FROM AUTHOR]

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

Copyright of Revista CES Derecho is the property of Universidad CES and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Background: Clinical trials in Alzheimer's disease (AD) had high failure rates for several reasons, including the lack of biological endpoints. Fluid-based biomarkers may present a solution to measure biologically relevant endpoints. It is currently unclear to what extent fluid-based biomarkers are applied to support drug development. Methods: We systematically reviewed 272 trials (clinicaltrials.gov) with disease-modifying therapies starting between 01–01-2017 and 01–01-2024 and identified which CSF and/or blood-based biomarker endpoints were used per purpose and trial type. Results: We found that 44% (N = 121) of the trials employed fluid-based biomarker endpoints among which the CSF ATN biomarkers (Aβ (42/40), p/tTau) were used most frequently. In blood, inflammatory cytokines, NFL, and pTau were most frequently employed. Blood- and CSF-based biomarkers were used approximately equally. Target engagement biomarkers were used in 26% (N = 72) of the trials, mainly in drugs targeting inflammation and amyloid. Lack of target engagement markers is most prominent in synaptic plasticity/neuroprotection, neurotransmitter receptor, vasculature, epigenetic regulators, proteostasis and, gut-brain axis targeting drugs. Positive biomarker results did not always translate to cognitive effects, most commonly the small significant reductions in CSF tau isoforms that were seen following anti-Tau treatments. On the other hand, the positive anti-amyloid trials results on cognitive function were supported by clear effect in most fluid markers. Conclusions: As the field moves towards primary prevention, we expect an increase in the use of fluid-based biomarkers to determine disease modification. Use of blood-based biomarkers will rapidly increase, but CSF markers remain important to determine brain-specific treatment effects. With improving techniques, new biomarkers can be found to diversify the possibilities in measuring treatment effects and target engagement. It remains important to interpret biomarker results in the context of the trial and be aware of the performance of the biomarker. Diversifying biomarkers could aid in the development of surrogacy biomarkers for different drug targets. [ABSTRACT FROM AUTHOR]

Background: Dementia is one of the major causes of disability and dependency among older people worldwide. The formation of an aging population in Iran can be associated with societal problems, including age-related disorders such as dementia. This study aimed to estimate the prevalence of dementia& Alzheimer disease in adults aged 60 years or older and it's its geographical distribution in Iran. Methods: A systematic review and meta-analysis study included articles published in both English and Persian languages and utilized various databases including: Google Scholar, PubMed, Web of Science, Magiran, and thesis database of medicine universities up to December 2022. The pooled prevalence was calculated using random effects models. The prevalence was reported separately for different geographical locations and types of area sampling, and age adjustment was performed for the selected studies. All statistical analyses were conducted using metaprop package in STATA version 17. The I2 statistic was applied to assess heterogeneity. Results: The meta-analysis considered nine relevant studies that were carried out up to 2023 in Iran. The study found that the prevalence of dementia in central and east counties was estimated to be 0.14 (95% CI; 0.04–0.31), while in western counties, the prevalence was estimated to be 0.1 (95%CI; 0.01–0.27). The estimated overall crude prevalence of dementia was estimated at 0.14 (95% CI; 0.03–0.31). Estimated prevalence-based health centers sampling and hospital-based studies were 0.02 (95% CI; 0.02–0.03), 0.05 (95% CI 0.06–0.11), respectively. One study used nursing home sampling as the sampling method, and the estimated prevalence was 0.43 (95%CI 0.38–0.49). Conclusion: This is the first systematic review and meta-analysis of the prevalence of dementia's disease up to 2023 in Iran. The estimated overall prevalence of dementia is lower than the reported prevalence in European countries and similar to other Asian countries. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is a neurodegenerative disease that affects a wide range of populations and is the primary cause of death in various countries. The treatment of AD is still restricted to oral conventional medicines that act only superficially. Fabrication of intranasal solid lipid nanoparticulate system for the uptake of therapeutic agents will act as a convincing approach with limited off-site toxicity and increased pharmacological activity. The objective of this study was to formulate, optimize, and evaluate the efficiency of rivastigmine tartrate (RT)-loaded intranasal solid lipid nanoparticles (SLNs) employing the solvent-evaporation diffusion method. To optimize the formulation parameters, the central composite design (CCD) was used. Lipid concentration (X1) and surfactant concentration (X2) were considered to be independent variables, while particle size (Y1), percentage entrapment efficiency (Y2), and percentage drug release (Y3) were considered as responses. The solid lipid was glyceryl monostearate, while the surfactant was polysorbate 80. The optimized formulation has a particle size of 110.2 nm, % entrapment efficiency of 82.56%, and % drug release of 94.86%. The incompatibility of drug excipients was established by differential scanning calorimetry (DSC) and Fourier-transform infrared spectroscopy (FTIR). Nasal histopathology tests on sheep mucosa revealed that the developed SLNs were safe to utilize for intranasal delivery with no toxicity. Ex vivo permeation investigations revealed that the flux and diffusion coefficients for RT solid lipid nanoparticles and RT solution were 3.378 g/cm² /h and 0.310-3 cm² /h, respectively. Stability studies demonstrated that the developed SLNs were stable when stored under various storage conditions. The viability and vitality of adopting a lipid particle delivery system for improved bioavailability via the intranasal route were also established in the in vivo pharmacokinetic investigations. According to the histopathological and pharmacokinetic investigations, the developed formulations were safe, non-lethal, efficient, and robust. These results suggest the potentiality provided by rivastigmine tartrate-loaded solid lipid nanoparticles for nasal delivery. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) pathology is characterized by amyloid beta (Aβ) plaques and dysfunctional autophagy. Aβ is generated by sequential proteolytic cleavage of amyloid precursor protein (APP), and the site of intracellular APP processing is highly debated, which may include autophagosomes. Here, we investigated the involvement of autophagy, including the role of ATG9 in APP intracellular trafficking and processing by applying the RUSH system, which allows studying the transport of fluorescently labeled mCherry‐APP‐EGFP in a systematic way, starting from the endoplasmic reticulum. HeLa cells, expressing the RUSH mCherry‐APP‐EGFP system, were investigated by live cell imaging, immunofluorescence, and Western blot. We found that mCherry‐APP‐EGFP passed through the Golgi faster in ATG9 knockout cells. Furthermore, ATG9 deletion shifted mCherry‐APP‐EGFP from early endosomes and lysosomes toward the plasma membrane concomitant with reduced endocytosis. Importantly, this alteration in mCherry‐APP‐EGFP transport resulted in increased secreted mCherry‐soluble APP and C‐terminal fragment‐EGFP. These effects were also phenocopied by pharmacological inhibition of ULK1, indicating that autophagy is regulating the intracellular trafficking and processing of APP. These findings contribute to the understanding of the role of autophagy in APP metabolism and could potentially have implications for new therapeutic approaches for AD. [ABSTRACT FROM AUTHOR]

In Alzheimer's disease, which is characterized by amyloid plaques and neurofibrillary tangles in the brain tissue, many components such as acute phase proteins, cytokines, and proteases contribute to the progression of the disease or are part of the pathological process. The macrophage migration inhibitory factor (MIF) gene encodes a cytokine, which is secreted by lymphocytes, and has a role in the pathogenesis of autoimmune/inflammatory diseases such as rheumatoid arthritis. The purpose of this study to investigate the association between Alzheimer disease and MIF gene promoter polymorphisms. The 205 patients with Alzheimer disease (AD) and 130 age-sex matched healthy individuals were investigated in terms of MIF -173 G/C and MIF −794 CATT polymorphisms. The genotyping of MIF -173 G/C was determined using the RT-PCR method. MIF-794 CATT polymorphism was analyzed using PCR and DNA Sequencing. In terms of binary genotypes and haplotypes, the 5/5-GC (p = 0.004), 6/7-GG (p = 0.02) and, 6/6-GG (p = 0.026) binary genotypes, and 5-C (p = 0.003), 7-G (p = 0.026) and 6-G (p = 0.025) haplotypes were differed significantly between the patients and the controls. This is the first study investigating the relationship between AD and MIF in terms of different genotypes, haplotypes and, alleles. The fact that the binary genotype and allele distributions are significantly different between the patient and control group, suggests that this MIF variants may play a role in the pathogenesis of AD. [ABSTRACT FROM AUTHOR]

One of the common nervous system diseases in older adults is Alzheimer's and epilepsy, and the possibility of occurrence increases with age. The chances of seizure are high for patients with mild cognitive impairment and Alzheimer's disease. So, there is a bidirectional association between Alzheimer's and epilepsy, as both affect the neurodegenerative processes. Electroencephalogram (EEG) is a possible non-invasive measurement technique widely used to measure the variations in brain signals. EEG signal is analyzed to discriminate the Alzheimer and epilepsy. Numerous research works evaluated the clinical relevance of Alzheimer's and epilepsy. Specifically, machine learning-based evaluation models developed recently bring the facts by extracting features from the EEG signals. However, machine learning-based models lag in performance due to high dimensional EEG features. For initial feature selection particle swarm optimization is included in the proposed model and to reduce the computation complexity of the classifier, kernel PCA is incorporated for dimensionality reduction. Experimentations using benchmark Bon and Dementia datasets confirms the proposed model better performances in terms of precision, recall, f1-score and accuracy. The attained accuracy of 94% is much better than existing Gaussian Mixture Model (GMM), Relevance Vector Machine (RVM), Support Vector Machine (SVM), and Artificial Neural Network (ANN) methods. [ABSTRACT FROM AUTHOR]

Background and Purpose: The effect of physical activity and living in enriched environment on some cognitive mechanisms in Alzheimer's disease (AD) is not yet well understood. Therefore, this study aimed to investigate the effect of aerobic training along with enriched environment on spatial memory and brainderived neurotrophic factor in the Hippocampal tissue of elderly female Wistar rats with Alzheimer's disease. Materials and Methods: In this experimental study, 30 elderly female Wistar rats with twenty-one-monthold and average weight of 260±20 grams were used and divided into 6 groups: control-healthy, Alzheimer's, sham group, Alzheimer's + aerobic exercise (treadmill), Alzheimer's + enriched environment, Alzheimer's + enriched environment + aerobic exercise (treadmill). Rats in the training groups performed two 15-min sessions with 5-minute passive rest at a speed of 10 m/min in the first and second weeks. In the third week, they performed three sessions at a speed of 15 m/min with a 5-min break, and in the fourth week, four sessions per day at a speed of 15 m/min with a 5-min break. In the enriched environment group, the animals were kept in a plexiglass material larger than the standard cage (60 x 50 x 70 cm³). In these cages, devices such as ladders, hollow pipes, wooden blocks and plastic toys were placed. In Alzheimer's groups, rats were anesthetized by intraperitoneal injection of ketamine (80 mg/kg) and xylazine (20 mg/kg). Then, Alzheimer's Aβ was induced by intracerebroventricular injections (10μg/rat). Spatial memory was measured by Morris water maze, barin derived neurotrophic factor (BDNF) and Trk-B by western blot. In a pilot study in order to evaluate the spatial memory of rats, one week after beta-amyloid injection, all rats were divided into Alzheimer's and control groups. Rats were trained in the maze for four days and the mean percentage permanence in the platform area was recorded. The results of the independent t-test showed that there is a significant difference between the control group and Alzheimer's group (P=0.0152). Therefore, One-way analysis of variance with Tukey's post-hoc test (P<0.05) were used to analyze the data. Results: BDNF increased in all groups significantly (P<0.001), and comparisons between groups were significant except for control vs sham (P=0.27) and Alzheimer's vs Aerobic Alzheimer's (P=0.20) groups. Trk-B increased in all groups and between-group comparisons were significant except for control vs sham (P=0.22), aerobic Alzheimer's vs Alzheimer's enriched environment (P=0.32). However, for spatial memory only between-group comparisons for Alzheimer's vs control (P=0.02), and Alzheimer's vs Alzheimer's + enriched environment + aerobic training (P<0.001) groups were significant. Conclusion: Based on the findings, it can be concluded that aerobic exercise and living in enriched environment can be effective on the spatial memory of elderly Alzheimer's rats through the increase of neurotrophic factors [ABSTRACT FROM AUTHOR]

Copyright of Kranion is the property of Publicidad Permanyer SLU and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Copyright of Gaceta Médica de Caracas is the property of Academia Nacional de Medicina and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Copyright of Journal of Family & Community Medicine is the property of Wolters Kluwer India Pvt Ltd and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Gamma‐hydroxy‐butyric acid (GABA) and glutamate are neurotransmitters with essential importance for cognitive processing. Here, we investigate relationships between GABA, glutamate, and brain ß‐amyloid (Aß) burden before clinical manifestation of Alzheimer's disease (AD). Thirty cognitively healthy adults (age 69.9 ± 6 years) received high‐resolution atlas‐based 1H‐magnetic resonance spectroscopic imaging (MRSI) at ultra‐high magnetic field strength of 7 Tesla for gray matter‐specific assessment of GABA and glutamate. We assessed Aß burden with positron emission tomography and risk factors for AD. Higher gray matter GABA and glutamate related to higher Aß‐burden (ß = 0.60, p < 0.05; ß = 0.64, p < 0.02), with positive effect modification by apolipoprotein‐E‐epsilon‐4‐allele (APOE4) (p = 0.01‐0.03). GABA and glutamate negatively related to longitudinal change in verbal episodic memory performance (ß = ‐0.48; p = 0.02; ß = ‐0.50; p = 0.01). In vivo measures of GABA and glutamate reflect early AD pathology at old age, in an APOE4‐dependent manner. GABA and glutamate may represent promising biomarkers and potential targets for early therapeutic intervention and prevention. Highlights: Gray matter‐specific metabolic imaging with high‐resolution atlas‐based MRSI at 7 Tesla.Higher GABA and glutamate relate to ß‐amyloid burden, in an APOE4‐dependent manner.Gray matter GABA and glutamate identify older adults with high risk of future AD.GABA and glutamate might reflect altered synaptic and neuronal activity at early AD. [ABSTRACT FROM AUTHOR]

Objectives: To assess the factors associated with desire for hastened death and depression in early-stage dementia as well as the association between them. Also, to explore the mediator and moderator role of age in the relationship between depression and desire for hasten death. Methods: A prospective cross-sectional study including 100 patients diagnosed with early-stage dementia from a rehabilitation center between December 2018 and July 2019. Measurement tools used were the Mini-Mental State Examination, the Greek Montreal Cognitive Assessment, the Greek Schedule of Attitudes toward Hastened Death, and the Geriatric Depression Scale-15 item. Patients diagnosed with dementia as a result of Stroke history were excluded. Results: Factors of multifactorial analysis significantly associated with desire for hastened death were as follows: age (p  = 0.009), marital status (p  = 0.001), and depression (p  < 0.001). The factor significantly associated with depression was age (p  = 0.001). Also, a mediation/moderation analysis has shown that depression and age are significant predictors of desire for hasten death. Significance of results: The desire for hastened death and depression in people diagnosed with early-stage dementia includes many components. Younger patients, men, higher educated patients, single, childless, and those with higher depression scores had higher desire for hastened death, while men and older patients had higher scores of desire for depression. Our study provides important information about the desire for hastened death and depression in early-stage dementia, their risk factors, and their association. [ABSTRACT FROM AUTHOR]

Two phase-III clinical trials with anti-amyloid peptide antibodies have met their primary goal, i.e. slowing of Alzheimer's disease (AD) progression. However, antibody therapy may not be the optimal therapeutic modality for AD prevention, as we will discuss in the context of the earlier small molecules described as "γ-secretase modulators" (GSM). We review here the structure, function, and pathobiology of γ-secretases, with a focus on how mutations in presenilin genes result in early-onset AD. Significant progress has been made in generating compounds that act in a manner opposite to pathogenic presenilin mutations: they stabilize the proteinase-substrate complex, thereby increasing the processivity of substrate cleavage and altering the size spectrum of Aβ peptides produced. We propose the term "γ-secretase allosteric stabilizers" (GSAS) to distinguish these compounds from the rather heterogenous class of GSM. The GSAS represent, in theory, a precision medicine approach to the prevention of amyloid deposition, as they specifically target a discrete aspect in a complex cell biological signalling mechanism that initiates the pathological processes leading to Alzheimer's disease. This review explains how allosteric stabilizers of γ-secretase may prevent Alzheimer's disease by specifically exerting opposite effects as pathogenic presenilin mutations. [ABSTRACT FROM AUTHOR]

Extensive research into dementia has more recently honed in on several key areas. These areas include the advancement of techniques such as the accumulation of amyloid-β and tau proteins, the monitoring of cerebral hypometabolism rates etc. The primary objective of this study is to explore the intricate interplay between Alzheimer's disease (AD)—other dementias (D) and various chronic illnesses in terms of time, intensity, and connectivity. In this context, we retrospectively examined data of 149,786 individuals aged 65 and above who received diagnoses of AD and D in the year 2020. At first, logistic regression (LR) analysis has been made with "sex", "age" and "foreigner" (citizenship status) independent variables for AD and D. The LR models shows that while "sex" and "age" variables have a small rate on the risk of developing AD/D, it is detected that being a foreigner increase the risk of AD and D as 69.8% and 88.5% respectively. Besides, the LR models have middle-level success prediction rate for both of the two dependent variables. Additionally, we used the parallel coordinates graphs method within the R Studio to visualize their relationships and connections. The findings of this investigation strongly suggest that AD/D don't stand as isolated conditions, but rather stem from intricate interactions and progressive processes involving diverse chronic diseases over time. Notably, ailments including hypertension, coronary artery disease, diabetes, hyperlipidemia, and psychological disorders, contribute substantially to the emergence of both AD and D. This study highlights that the fight against AD/D can only be possible with next-generation prophylactic interventions that can predict and manage risks. Such an approach holds the potential to potentially lower AD and dementia to levels that are amenable to treatment. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is the most common type of dementia with millions of affected patients worldwide. Currently, there is still no cure and AD is often diagnosed long time after onset because there is no clear diagnosis. Thus, it is essential to study the physiology and pathogenesis of AD, investigating the risk factors that could be strongly connected to the disease onset. Despite AD, like other complex diseases, is the result of the combination of several factors, there is emerging agreement that environmental pollution should play a pivotal role in the causes of disease. In this work, we implemented an Artificial Intelligence model to predict AD mortality, expressed as Standardized Mortality Ratio, at Italian provincial level over 5 years. We employed a set of publicly available variables concerning pollution, health, society and economy to feed a Random Forest algorithm. Using methods based on eXplainable Artificial Intelligence (XAI) we found that air pollution (mainly O 3 and N O 2 ) contribute the most to AD mortality prediction. These results could help to shed light on the etiology of Alzheimer's disease and to confirm the urgent need to further investigate the relationship between the environment and the disease. [ABSTRACT FROM AUTHOR]