Plasma ADAM10 Levels and Their Association with Alzheimer's Disease Diagnosis in Older Adults with Fewer Years of Formal Education.

INTRODUCTION: Low educational attainment is a potential risk factor for Alzheimer's disease (AD) development. Alpha-secretase ADAM10 plays a central role in AD pathology, attenuating the formation of beta-amyloid peptides and, therefore, their aggregation into senile plaques. This study seeks to investigate ADAM10 as a blood-based biomarker in mild cognitive impairment (MCI) and AD in a diverse group of community-dwelling older adults, focusing on those with limited educational attainment. METHODS: Participants were recruited from public health services. Cognition was evaluated using Mini-Mental State Examination (MMSE) and Addenbrooke's Cognitive Examination - Revised (ACE-R) batteries. Blood samples were collected to analyze plasma ADAM10 levels. A logistic regression was conducted to verify the influence of plasma ADAM10 on the AD diagnosis. RESULTS: Significant differences in age, years of education, prescribed medications, and cognitive test scores were found between the MCI and AD groups. Regarding cognitive performance, both ACE-R and MMSE scores displayed significant differences between groups, with post hoc analyses highlighting these distinctions, particularly between AD and cognitively unimpaired individuals. Elevated plasma ADAM10 levels were associated with a 4.5-fold increase in the likelihood of a diagnosis of MCI and a 5.9-fold increase in the likelihood of a diagnosis of AD. These findings suggest ADAM10 levels in plasma as a valuable biomarker for assessing cognitive status in older individuals with low education attainment. CONCLUSION: This study underscores the potential utility of plasma ADAM10 levels as a blood-based biomarker for cognitive status, especially in individuals with low educational backgrounds, shedding light on their relevance in AD development and diagnosis.

A systematic review and meta-analysis on cognitive frailty in community-dwelling older adults: risk and associated factors.

OBJECTIVES: To identify which factors are associated with cognitive frailty (CF), as well as the impact of CF on the incidence of dementia and mortality. METHODS: A systematic review with meta-analysis was carried out using papers that enrolled a total of 75,379 participants and were published up to January 2020. RESULTS: Of the 558 identified records, 28 studies met the inclusion criteria and were included in the review. The meta-analysis of cross-sectional studies showed that CF has a significant association of having an older age and a history of falls. In longitudinal studies, the analysis showed a significant increase in risk of mortality and dementia for those with CF. DISCUSSION: This is the first systematic review and meta-analysis on CF, which addressed a wide variety of factors associated with the theme and which pointed out some as a potential target for prevention or management with different interventions or treatments, showing the clinical importance of its identification in the most vulnerable and susceptible groups.

Metformin a Potential Pharmacological Strategy in Late Onset Alzheimer's Disease Treatment.

Alzheimer's disease (AD) is one of the most devastating brain disorders. Currently, there are no effective treatments to stop the disease progression and it is becoming a major public health concern. Several risk factors are involved in the progression of AD, modifying neuronal circuits and brain cognition, and eventually leading to neuronal death. Among them, obesity and type 2 diabetes mellitus (T2DM) have attracted increasing attention, since brain insulin resistance can contribute to neurodegeneration. Consequently, AD has been referred to "type 3 diabetes" and antidiabetic medications such as intranasal insulin, glitazones, metformin or liraglutide are being tested as possible alternatives. Metformin, a first line antihyperglycemic medication, is a 5'-adenosine monophosphate (AMP)-activated protein kinase (AMPK) activator hypothesized to act as a geroprotective agent. However, studies on its association with age-related cognitive decline have shown controversial results with positive and negative findings. In spite of this, metformin shows positive benefits such as anti-inflammatory effects, accelerated neurogenesis, strengthened memory, and prolonged life expectancy. Moreover, it has been recently demonstrated that metformin enhances synaptophysin, sirtuin-1, AMPK, and brain-derived neuronal factor (BDNF) immunoreactivity, which are essential markers of plasticity. The present review discusses the numerous studies which have explored (1) the neuropathological hallmarks of AD, (2) association of type 2 diabetes with AD, and (3) the potential therapeutic effects of metformin on AD and preclinical models.

COVID Health Structure Index: The Vulnerability of Brazilian Microregions.

Many developing countries have highly unequal health systems across their regions. The pandemic of COVID-19 brought an additional challenge, as hospital structures equipped with doctors, intensive care units and respirators are not available to a sufficient extent in all regions. Using Data Envelopment Analysis, we create a COVID Index to verify whether the hospital structures in 543 Brazilian microregions are adequate to deal with COVID-19 and to verify whether public policies were implemented in the right direction. The results indicate that hospital structures in the poorest microregions were the most vulnerable, although the peak of COVID-19 occurred in the richest microregions (Sao Paulo). The Southeast states could relocate hospital resources or even patients between their regions. The relocation was not possible in many states in the Northeast, as the health system poorly assisted the interior of these states. These findings reveal that the heterogeneity of microregions' hospital structures follows the patterns of socioeconomic inequalities. We conclude that it is easier for the wealthier regions to reallocate hospital resources internally than for the poorest regions. By using the COVID Index, policymakers and hospital managers have straightforward information to decide which regions must receive new investments and reallocate underutilized resources.

ADAM10 Plasma and CSF Levels Are Increased in Mild Alzheimer's Disease.

ADAM10 is the main α-secretase that participates in the non-amyloidogenic cleavage of amyloid precursor protein (APP) in neurons, inhibiting the production of ß-amyloid peptide (Aß) in Alzheimer's disease (AD). Strong recent evidence indicates the importance of the localization of ADAM10 for its activity as a protease. In this study, we investigated ADAM10 activity in plasma and CSF samples of patients with amnestic mild cognitive impairment (aMCI) and mild AD compared with cognitively healthy controls. Our results indicated that plasma levels of soluble ADAM10 were significantly increased in the mild AD group, and that in these samples the protease was inactive, as determined by activity assays. The same results were observed in CSF samples, indicating that the increased plasma ADAM10 levels reflect the levels found in the central nervous system. In SH-SY5Y neuroblastoma cells, ADAM10 achieves its major protease activity in the fraction obtained from plasma membrane lysis, where the mature form of the enzyme is detected, confirming the importance of ADAM10 localization for its activity. Taken together, our results demonstrate the potential of plasma ADAM10 to act as a biomarker for AD, highlighting its advantages as a less invasive, easier, faster, and lower-cost processing procedure, compared to existing biomarkers.

ADAM10: Biomarker of mild cognitive impairment but not of cognitive frailty.

Mild cognitive impairment (MCI) associated with physical frailty gave rise to the new concept of cognitive frailty. Previous studies have suggested that MCI may represent a condition that precedes Alzheimer's disease (AD), in view of its higher conversion rate to dementia, when compared with the conversion rate of cognitively healthy older adults. Therefore, and considering that MCI represents a reversible condition, the identification of biomarkers for this condition is imperative to early diagnosis. Accordingly, this study aimed to assess whether the platelet and plasma levels of ADAM10 could be related with the concomitant conditions of MCI and physical frailty, in order to support a new blood-based biomarker for the construct of cognitive frailty. Sixty-one adults aged 60 years or older participated in this study. The results showed that ADAM10 levels are reduced in platelets (p < 0.05) and increased in plasma (p < 0.05) of older adults with MCI compared to healthy controls, regardless of the physical frailty condition. The analysis of the ROC curve of ADAM10 in platelets showed sensitivity and specificity of 72.7 and 73.9%, respectively, to correct differentiate between participants with preserved cognition from those with MCI. For plasma samples, ADAM10 presented 62.5 and 90.0%, sensitivity and specificity respectively, to differentiate the aforementioned conditions. Together with other clinical criteria blood ADAM10 could be a relevant, low-invasive, low-cost and fast processing biomarker tool to help in the early and accurate diagnosis of MCI, however this marker was not able to identify cognitive frailty.

Autocompaixão e ações de promoção à saúde mental como moderadores da ansiedade entre idosos institucionalizados / Self-compassion and mental health promotion actions as moderators of anxiety among institutionalized older adults

Objetivou-se verificar a relação entre ansiedade, autocompaixão e ações de promoção à saúde mental de idosos residentes em Instituições de Longa Permanência. Estudo exploratório, transversal e quantitativo, realizado com 88 idosos residentes em seis instituições de cinco cidades do interior do Estado de São Paulo, entre 2016 e 2017, utilizando um questionário de caracterização dos participantes, o Mini exame do Estado Mental, o Inventário de Ansiedade de Beck e a Escala de Autocompaixão. Foram realizadas análises descritivas, correlacionais e de regressão linear múltipla pelos mínimos quadrados ordinários. Todos os cuidados éticos foram respeitados. Para cada um ponto de aumento nos escores de autocompaixão houve redução de 1,11% nos escores de ansiedade (p=0,005). Ações de promoção à saúde mental reduziram em 0,54% (p=0,043) os escores de ansiedade. Concluiu-se que a autocompaixão e as ações de promoção à saúde mental reduziram a ansiedade em idosos institucionalizados.

The objective of this study has been to verify the relationship between anxiety, self-compassion, and actions to promote mental health of older adults living in long-term facilities. This is an exploratory, cross-sectional, and quantitative study, carried out with 88 older adults living in six institutions in five cities in the state of São Paulo, Brazil, between 2016 and 2017, using a questionnaire to characterize the participants, the Mini-Mental State Examination, the Beck Anxiety Inventory, and the Self-Compassion Scale. Descriptive, correlational, and multiple linear regression analyses were performed using ordinary least squares. All ethical precautions were followed. For each point of increase in self-compassion scores, there was a 1.11% decrease in anxiety scores (p = 0.005). Actions to promote mental health reduced anxiety scores by 0.54% (p = 0.043). Thus, this study concludes that self-compassion and mental health promotion actions reduced anxiety in institutionalized older adults.

A metabolic perspective of late onset Alzheimer's disease.

After decades of research, the molecular neuropathology of Alzheimer's disease (AD) is still one of the hot topics in biomedical sciences. Some studies suggest that soluble amyloid ß (Aß) oligomers act as causative agents in the development of AD and could be initiators of its complex neurodegenerative cascade. On the other hand, there is also evidence pointing to Aß oligomers as mere aggravators, with an arguable role in the origin of the disease. In this line of research, the relative contribution of soluble Aß oligomers to neuronal damage associated with metabolic disorders such as Type 2 Diabetes Mellitus (T2DM) and obesity is being actively investigated. Some authors have proposed the endoplasmic reticulum (ER) stress and the induction of the unfolded protein response (UPR) as important mechanisms leading to an increase in Aß production and the activation of neuroinflammatory processes. Following this line of thought, these mechanisms could also cause cognitive impairment. The present review summarizes the current understanding on the neuropathological role of Aß associated with metabolic alterations induced by an obesogenic high fat diet (HFD) intake. It is believed that the combination of these two elements has a synergic effect, leading to the impairement of ER and mitochondrial functions, glial reactivity status alteration and inhibition of insulin receptor (IR) signalling. All these metabolic alterations would favour neuronal malfunction and, eventually, neuronal death by apoptosis, hence causing cognitive impairment and laying the foundations for late-onset AD (LOAD). Moreover, since drugs enhancing the activation of cerebral insulin pathway can constitute a suitable strategy for the prevention of AD, we also discuss the scope of therapeutic approaches such as intranasal administration of insulin in clinical trials with AD patients.

ADAM10 in Alzheimer's disease: Pharmacological modulation by natural compounds and its role as a peripheral marker.

Alzheimer's disease (AD) represents a global burden in the economics of healthcare systems. Amyloid-ß (Aß) peptides are formed by amyloid-ß precursor protein (AßPP) cleavage, which can be processed by two pathways. The cleavage by the α-secretase A Disintegrin And Metalloprotease 10 (ADAM10) releases the soluble portion (sAßPPα) and prevents senile plaques. This pathway remains largely unknown and ignored, mainly regarding pharmacological approaches that may act via different signaling cascades and thus stimulate non-amyloidogenic cleavage through ADAM10. This review emphasizes the effects of natural compounds on ADAM10 modulation, which eventuates in a neuroprotective mechanism. Moreover, ADAM10 as an AD biomarker is revised. New treatments and preventive interventions targeting ADAM10 regulation for AD are necessary, considering the wide variety of ADAM10 substrates.

Benzodiazepines and Related Drugs as a Risk Factor in Alzheimer's Disease Dementia.

Benzodiazepines (BZDs) and Z-drugs are compounds widely prescribed in medical practice due to their anxiolytic, hypnotic, and muscle relaxant properties. Yet, their chronic use is associated with cases of abuse, dependence, and relapse in many patients. Furthermore, elderly people are susceptible to alterations in pharmacodynamics, pharmacokinetics as well as to drug interaction due to polypharmacy. These situations increase the risk for the appearance of cognitive affectations and the development of pathologies like Alzheimer's disease (AD). In the present work, there is a summary of some clinical studies that have evaluated the effect of BZDs and Z-drugs in the adult population with and without AD, focusing on the relationship between their use and the loss of cognitive function. Additionally, there is an assessment of preclinical studies focused on finding molecular proof on the pathways by which these drugs could be involved in AD pathogenesis. Moreover, available data (1990-2019) on BZD and Z-drug use among elderly patients, with and without AD, was compiled in this work. Finally, the relationship between the use of BZD and Z-drugs for the treatment of insomnia and the appearance of AD biomarkers was analyzed. Results pointed to a vicious circle that would worsen the condition of patients over time. Likewise, it put into relevance the need for close monitoring of those patients using BZDs that also suffer from AD. Consequently, future studies should focus on optimizing strategies for insomnia treatment in the elderly by using other substances like melatonin agonists, which is described to have a much more significant safety profile.

Factors associated with cognitive performance in elderly caregivers.

OBJECTIVE: To explore the socioeconomic, demographic and psychosocial factors associated with cognitive performance in elderly caregivers from Brazil. METHODS: We evaluated 351 Brazilian elderly caregivers attending primary healthcare services regarding sociodemographic and care variables. Addenbrooke's Cognitive Examination-Revised (ACE-R) domains of orientation/attention, memory, verbal fluency, language and visuospatial were used as dependent variables in the Tobit model. RESULTS: Literacy and family income were positively associated with all ACE-R domains. Age, gender, time of care (days/week) were negatively associated with some cognitive domains. Moreover, receiving emotional help and the level of hope were positively associated with specific domains. DISCUSSION: The results may be useful for planning interventions aimed at elderly caregivers in order to prevent deficits in the different cognitive domains.

Factors associated with cognitive performance in elderly caregivers / Principais fatores associados aos domínios cognitivos em cuidadores idosos

Abstract Objectives: To explore the socioeconomic, demographic and psychosocial factors associated with cognitive performance in elderly caregivers from Brazil. Methods: We evaluated 351 Brazilian elderly caregivers attending primary healthcare services regarding sociodemographic and care variables. Addenbrooke's Cognitive Examination-Revised (ACE-R) domains of orientation/attention, memory, verbal fluency, language and visuospatial were used as dependent variables in the Tobit model. Results: Literacy and family income were positively associated with all ACE-R domains. Age, gender, time of care (days/week) were negatively associated with some cognitive domains. Moreover, receiving emotional help and the level of hope were positively associated with specific domains. Discussion: The results may be useful for planning interventions aimed at elderly caregivers in order to prevent deficits in the different cognitive domains.

RESUMO Objetivos: explorar os fatores socioeconômicos, demográficos e psicossociais associados ao desempenho cognitivo em idosos cuidadores do Brasil. Métodos: Avaliamos 351 idosos cuidadores da atenção primária à saúde em relação a variáveis sociodemográficas e de contexto do cuidado. Os domínios da Escala Cognitiva de Addenbrooke Revisada (ACE-R) - orientação/atenção, memória, fluência verbal, linguagem e visuo-espacial - foram utilizados como variáveis dependentes no modelo de Tobit. Resultados: Alfabetização e renda familiar foram positivamente associados a todos os domínios ACE-R. A idade, o sexo, o tempo de atendimento (dias/semana) foram associados negativamente com alguns domínios cognitivos. Além disso, receber ajuda emocional e nível de esperança foram positivamente associados a domínios específicos. Discussão: os resultados podem ser úteis para o planejamento de intervenções voltadas para cuidadores idosos, a fim de prevenir déficits nos diferentes domínios cognitivos.

Alpha-Secretase ADAM10 Regulation: Insights into Alzheimer's Disease Treatment.

ADAM (a disintegrin and metalloproteinase) is a family of widely expressed, transmembrane and secreted proteins of approximately 750 amino acids in length with functions in cell adhesion and proteolytic processing of the ectodomains of diverse cell-surface receptors and signaling molecules. ADAM10 is the main α-secretase that cleaves APP (amyloid precursor protein) in the non-amyloidogenic pathway inhibiting the formation of ß-amyloid peptide, whose accumulation and aggregation leads to neuronal degeneration in Alzheimer's disease (AD). ADAM10 is a membrane-anchored metalloprotease that sheds, besides APP, the ectodomain of a large variety of cell-surface proteins including cytokines, adhesion molecules and notch. APP cleavage by ADAM10 results in the production of an APP-derived fragment, sAPPα, which is neuroprotective. As increased ADAM10 activity protects the brain from ß-amyloid deposition in AD, this strategy has been proved to be effective in treating neurodegenerative diseases, including AD. Here, we describe the physiological mechanisms regulating ADAM10 expression at different levels, aiming to propose strategies for AD treatment. We report in this review on the physiological regulation of ADAM10 at the transcriptional level, by epigenetic factors, miRNAs and/or translational and post-translational levels. In addition, we describe the conditions that can change ADAM10 expression in vitro and in vivo, and discuss how this knowledge may help in AD treatment. Regulation of ADAM10 is achieved by multiple mechanisms that include transcriptional, translational and post-translational strategies, which we will summarize in this review.

Serotoninergic antidepressants positively affect platelet ADAM10 expression in patients with Alzheimer's disease.

BACKGROUND: Studies have demonstrated a decreased platelet ADAM10 expression in patients with Alzheimer's Disease (AD), classifying this protein as a blood-based AD biomarker. About 50% of the patients with AD are diagnosed with depression, which is commonly treated with tricyclic and tetracyclic antidepressants, monoaminoxidade (MAO) inhibitors and, more preferably, with selective serotonin reuptake inhibitors (SSRIs). Considering that a large proportion of patients with AD takes antidepressant medications during the course of the disease we investigated the influence of this medication on the expression of platelet ADAM10, which is considered the main α-secretase preventing beta-amyloid (ßA) formation. METHODS: Blood was collected for protein extraction from platelets. ADAM10 was analyzed by using western blotting and reactive bands were measured using ß-actin as endogenous control. RESULTS: Platelet ADAM10 protein expression in patients with AD was positively influenced by serotoninergic medication. CONCLUSION: More studies on the positive effects of serotonergic antidepressants on ADAM10 platelet expression should be performed in order to understand its biological mechanisms and to verify whether these effects are reflected in the central nervous system. This work represents an important advance for the study of AD biomarkers, as well as for more effective pharmacological treatment of patients with AD and associated depression.

BACE1 levels are increased in plasma of Alzheimer's disease patients compared with matched cognitively healthy controls.

AIM: BACE1 is the secretase that acts in Aß production in Alzheimer's disease (AD). MATERIALS & METHODS: We investigated mRNA expression in total blood and the levels of plasma protein BACE1 in AD patients compared with cognitively healthy subjects. Probable AD (n = 47) and non-AD control group (n = 32) were evaluated for mRNA expression for BACE1 using reverse transcription-qPCR. A subsample of n = 21 AD and n = 20 non-AD had plasma BACE1 levels analyzed, using ELISA. RESULTS: No differences were found on BACE1 mRNA between groups. However, higher levels of BACE1 were detected in plasma of AD patients. DISCUSSION: Blood-based diagnostic tools are desired to improve AD diagnosis. BACE1 plasma levels could provide an additional diagnostic tool for AD in association with neuropsychological tests.

ADAM10 gene expression in the blood cells of Alzheimer's disease patients and mild cognitive impairment subjects.

ADAM10 is a potential biomarker for Alzheimer's disease (AD). ADAM10 protein levels are reduced in platelets of AD patients. The aim was to verify the total blood and platelet ADAM10 gene expression in AD patients and to compare with mild cognitive impairment (MCI) and healthy subjects. No significant differences in ADAM10 gene expression were observed. Therefore, the decrease of ADAM10 protein in platelets of AD patients is not caused by a reduction in ADAM10 mRNA. Further studies must be performed to investigate other pathways in the down regulation of ADAM10 protein.

Platelet a disintegrin and metallopeptidase 10 expression correlates with clock drawing test scores in Alzheimer's disease.

OBJECTIVE: Earlier studies have demonstrated that a disintegrin and metallopeptidase 10 (ADAM10) levels are reduced in Alzheimer's disease (AD) patients compared with healthy subjects. The objective of this study was to evaluate whether platelet ADAM10 levels correlates with the clock drawing test (CDT) scores, which is a simple and a reliable measure of visuospatial ability and executive function in AD patients. METHODS: Thirty elderly patients with probable AD and 25 healthy patients forming the control group, matched by age, gender, and educational level, were evaluated. Platelet proteins were analyzed by sodium dodecyl sulfate polyacrylamide gel electrophoresis, and ADAM10 was identified by western blotting. The Spearman's correlation coefficient between ADAM10 and CDT was obtained for each group. The areas under the curves were used to compare the receiver operating characteristic curves. RESULTS: The CDT scores and platelet ADAM10 expression were significantly different between patients with AD and controls and also along the disease's progression. In AD patients, there was a positive correlation between ADAM10 expression and CDT scores. Among non-AD subjects, no correlation was found. The combination of ADAM10 and CDT was significantly better to confirm the AD diagnosis than the AUCs of ADAM10 and CDT separately. CONCLUSIONS: The association of blood-based biomarkers, such as ADAM10, and cognitive tests may be helpful for a more reliable AD diagnosis.

Correlation between mini-mental state examination and platelet ADAM10 expression in Alzheimer's disease.

BACKGROUND: Previous studies have demonstrated a decrease in platelet ADAM10 expression among patients with Alzheimer's disease (AD) and healthy matched subjects. The association between cognitive tests and molecular biomarkers, such as platelet ADAM10, may contribute to an accurate AD diagnosis. OBJECTIVE: The aim of this research was to investigate whether cognitive deficits in AD, assessed by Mini-Mental State Exam (MMSE), correlate with ADAM10 platelet levels and if that contributes to a more effective AD diagnosis. METHODS: Elderly patients with probable AD (n = 30) and a non-AD control group (n = 25), matched by age, gender, and education level were evaluated. Platelet proteins were analyzed on SDS-PAGE (10%) and ADAM10 expression was identified by western blotting. ß-actin was used as the endogenous control. The Spearman correlation coefficient between ADAM10 and MMSE ratio was obtained for each group. RESULTS: The MMSE ratio of AD subjects (0.45 ± 0.32) was significantly different (p < 0.001) compared to the non-AD group (1.14 ± 0.07). The relationship between MMSE ratio and ADAM10 expression was significant (r = 0.62, p = 0.0003) for the AD group. The combination of ADAM10 and MMSE at a cutoff ≤ 0.87 presented a sensitivity of 85%, and a specificity of 97% (AUC 0.99, 95% CI 0.92 -1.00), which was significantly better for AD diagnosis than the AUCs of MMSE (p = 0.05) and ADAM10 expression (p = 0.18) separately. CONCLUSIONS: The association of MMSE and ADAM10 expression was significantly better compared with MMSE and ADAM10 expression separately, thus providing and additional diagnostic tool for AD.

ADAM10 as a biomarker for Alzheimer's disease: a study with Brazilian elderly.

Alzheimer's disease (AD) is the most common cause of dementia in people above age 65. Platelet studies with ADAM10 have shown that its expression is reduced in AD patients. The aim of this research was to compare the platelet levels of ADAM10 protein in two Brazilian elderly groups, considering the stages of the disease. The SDS-PAGE technique followed by Western blotting was used. Data were analyzed using comparison, correlation and association statistical methods. The results showed reduced platelet ADAM10 levels in AD elderly compared to non-AD subjects. The disease progression intensified this reduction. ADAM10 was the only statistically significant variable (p = 0.01) to increase the AD occurrence probability. The cutoff value of 0.4212 in the receiver operating characteristic curve captured sensitivity and specificity of 70 and 80.77%, respectively. Together with other clinical criteria, ADAM10 seems to be a relevant biomarker tool for early and accurate AD diagnosis.