A comprehensive review on phosphatidylinositol-3-kinase (PI3K) and its inhibitors bearing pyrazole or indazole core for cancer therapy.

Cancer is a complex and multifaceted group of diseases with a high mortality rate characterized by uncontrolled proliferation of abnormal cells. Dysregulation of normal signalling pathways in cancer contributes to the different hallmarks of this disease. The signalling pathway of which phosphatidylinositol 3-kinase (PI3K) is a part is not an exception. In fact, dysregulated activation of PI3K signalling pathways can result in unbridled cellular proliferation and enhanced cell survival, thereby fostering the onset and advancement of cancer. Therefore, there is substantial interest in developing targeted therapies specifically aimed at inhibiting the PI3K enzyme and its associated pathways. Also, the therapeutic interest on pyrazoles and indazoles has been growing due to their various medicinal properties, namely, anticancer activity. Derivatives of these compounds have been studied as PI3K inhibitors, and they showed promising results. There are already some PI3K inhibitors approved by Food and Drug Administration (FDA), such as Idelalisib (Zydelig®) and Alpelisib (Piqray®). In this context, this review aims to address the importance of PI3K in cellular processes and its role in cancer. Additionally, it aims to report a comprehensive literature review of PI3K inhibitors, containing the pyrazole and indazole scaffolds, published in the last fifteen years, focusing on structure-activity relationship aspects, thus providing important insights for the design of novel and more effective PI3K inhibitors.

Emerging Pro-neurogenic Therapeutic Strategies for Neurodegenerative Diseases: A Review of Pre-clinical and Clinical Research.

The neuroscience community has largely accepted the notion that functional neurons can be generated from neural stem cells in the adult brain, especially in two brain regions: the subventricular zone of the lateral ventricles and the subgranular zone in the dentate gyrus of the hippocampus. However, impaired neurogenesis has been observed in some neurodegenerative diseases, particularly in Alzheimer's, Parkinson's, and Huntington's diseases, and also in Lewy Body dementia. Therefore, restoration of neurogenic function in neurodegenerative diseases emerges as a potential therapeutic strategy to counteract, or at least delay, disease progression. Considering this, the present study summarizes the different neuronal niches, provides a collection of the therapeutic potential of different pro-neurogenic strategies in pre-clinical and clinical research, providing details about their possible modes of action, to guide future research and clinical practice.

A review of poly(ADP-ribose)polymerase-1 (PARP1) role and its inhibitors bearing pyrazole or indazole core for cancer therapy.

Cancer is a disease with a high mortality rate characterized by uncontrolled proliferation of abnormal cells. The hallmarks of cancer evidence the acquired cells characteristics that promote the growth of malignant tumours, including genomic instability and mutations, the ability to evade cellular death and the capacity of sustaining proliferative signalization. Poly(ADP-ribose) polymerase-1 (PARP1) is a protein that plays key roles in cellular regulation, namely in DNA damage repair and cell survival. The inhibition of PARP1 promotes cellular death in cells with homologous recombination deficiency, and therefore, the interest in PARP protein has been rising as a target for anticancer therapies. There are already some PARP1 inhibitors approved by Food and Drug Administration (FDA), such as Olaparib and Niraparib. The last compound presents in its structure an indazole core. In fact, pyrazoles and indazoles have been raising interest due to their various medicinal properties, namely, anticancer activity. Derivatives of these compounds have been studied as inhibitors of PARP1 and presented promising results. Therefore, this review aims to address the importance of PARP1 in cell regulation and its role in cancer. Moreover, it intends to report a comprehensive literature review of PARP1 inhibitors, containing the pyrazole and indazole scaffolds, published in the last fifteen years, focusing on structure-activity relationship aspects, thus providing important insights for the design of novel and more effective PARP1 inhibitors.

Good Syndrome in a Young Woman: An Unusual Presentation.

Good Syndrome is a rare disease that comprises the presence of a thymoma, immunodeficiency, and recurrent opportunistic infections. We report the case of a young woman who was diagnosed with Good Syndrome, who had a long-term history of recurrent infections, often due to atypical agents, and who also had a previous history of immunodeficiency and a B1 thymoma invading the large vessels, lung, and pericardium (Masaoka stage IV). She underwent surgical resection of the mediastinal mass, requiring vena cava superior reconstruction due to the extent of invasion, followed by adjuvant radiotherapy and immunoglobulin G supplementation. Despite relative stability in the subsequent years, without serious infections, after three years she had a thymoma recurrence requiring a new therapeutic approach. This case highlights the importance of a thorough investigation of the underlying causes of recurrent infections, which may be the result of an immunodeficiency secondary to malignancy. In young patients, early diagnosis is crucial to avoid disease progression and to reduce mortality rates. To achieve such outcomes, a multidisciplinary team and a comprehensive therapeutic strategy are necessary.

Clinical outcomes and prognostic factors in Acanthamoeba keratitis.

PURPOSE: To report clinical findings and prognostic factors for visual and morphological outcomes in patients with Acanthamoeba keratitis (AK). METHODS: Single-center, retrospective, longitudinal study of 51 cases of AK diagnosed by real-time polymerase chain reaction (RT-PCR) between March 2010 and October 2022. The primary outcome was the final best corrected visual acuity (BCVA). Poor visual outcome was defined as a final BCVA ≥ 1 logMAR unit, while good visual outcome was defined as a final BCVA < 1 logMAR unit. Eyes from these two groups were compared, regarding demographic and initial clinical variables, anti-Acanthamoeba treatment used, and complications of the disease. Early diagnosis was defined as ≤ 14 days from symptom onset to diagnostic confirmation and initiation of Acanthamoeba medical treatment. Multivariable logistic regression was used to determine predictors of poor visual outcome. RESULTS: A total of 51 eyes from 46 patients diagnosed with AK, all contact lens (CL) wearers, were included in this study. Average follow-up was 39.0 ± 30.2 [total range 14-120] months. Thirty-one eyes (60.8 %) presented good visual outcome, with a lower baseline age (30.5 ± 9.0 vs. 42.3 ± 15.8; p = 0.020), better initial BCVA (0.8 ± 0.7 logMAR units vs. 1.3 ± 0.9 logMAR units; p = 0.047), higher rate of early diagnosis (45.2 % vs. 5.6 %; p = 0.004), and higher rate of therapeutic epithelial debridement (64.5 % vs. 10 %; p < 0.001). 20 eyes (39.2 %) presented poor visual outcome, with 12 eyes undergoing evisceration/enucleation (23.5 %). These 20 eyes presented a higher rate of complications (90 % vs. 61.3 %; p = 0.031). In multivariable analysis, early diagnosis of AK (OR 19.78; 95 % CI 2.07-189.11; p = 0.010) and therapeutic epithelial debridement (OR 19.02; 95 % CI 3.27-110.57; p = 0.001) were associated with a good visual outcome. CONCLUSIONS: In the present study, poor visual outcome was present in 39 % of affected eyes. Early AK diagnosis (≤14 days from symptom onset) and therapeutic epithelial debridement were associated with good final visual outcome.

Epidemiological Changes in Respiratory Viral Infections in Children: The Influence of the COVID-19 Pandemic.

BACKGROUND: Viruses are the major cause of acute respiratory infections in children, causing important morbimortality. Before the COVID-19 pandemic, in temperate regions, respiratory viruses displayed a typical seasonality in transmission. A disruption in this pattern was observed in several countries during the pandemic, with low prevalence during the typical season, and an interseasonal rise. We evaluated the effects of the COVID-19 pandemic in the epidemiology of non-COVID viral respiratory infections in children, in a tertiary care hospital in Portugal. METHODS: Between March 2020 and August 2022, nasopharyngeal samples from children with respiratory symptoms in the Emergency Department (ED) and the Pediatric Ward were tested for RSV, influenza and other respiratory viruses, by real-time reverse transcriptase PCR (RT-PCR). RESULTS: A seasonal variation was observed from 2018 to 2020, with prevalence increasing in winter (mainly RSV and influenza). In the winter of 2020/21, when measures to mitigate SARS-CoV-2 transmission were stricter, there was a disruption of the seasonal pattern, with unusually low numbers. In the summer of 2021, when measures were being relaxed, there was an atypical rise. In June 2021, RSV was first detected and peaked in October. Influenza (Influenza A H3) was detected for the first time in February 2022, peaking in March/April. CONCLUSIONS: These findings show a disruption of the seasonality of viral respiratory infections in children during the pandemic, with a virtual elimination during the months of usually higher prevalence, and a subsequent out-of-season increase, coinciding with variations in the measures implemented to control the SARS-CoV-2 transmission, and confirming their efficacy.

Metabolomics to Study Human Aging: A Review.

In the last years, with the increase in the average life expectancy, the world's population is progressively aging, which entails social, health and economic problems. In this sense, the need to better understand the physiology of the aging process becomes an urgent need. Since the study of aging in humans is challenging, cellular and animal models are widely used as alternatives. Omics, namely metabolomics, have emerged in the study of aging, with the aim of biomarker discovering, which may help to uncomplicate this complex process. This paper aims to summarize different models used for aging studies with their advantages and limitations. Also, this review gathers the published articles referring to biomarkers of aging already discovered using metabolomics approaches, comparing the results obtained in the different studies. Finally, the most frequently used senescence biomarkers are described, along with their importance in understanding aging.

Protein Phosphorylation Alterations in Myotonic Dystrophy Type 1: A Systematic Review.

Among the most common muscular dystrophies in adults is Myotonic Dystrophy type 1 (DM1), an autosomal dominant disorder characterized by myotonia, muscle wasting and weakness, and multisystemic dysfunctions. This disorder is caused by an abnormal expansion of the CTG triplet at the DMPK gene that, when transcribed to expanded mRNA, can lead to RNA toxic gain of function, alternative splicing impairments, and dysfunction of different signaling pathways, many regulated by protein phosphorylation. In order to deeply characterize the protein phosphorylation alterations in DM1, a systematic review was conducted through PubMed and Web of Science databases. From a total of 962 articles screened, 41 were included for qualitative analysis, where we retrieved information about total and phosphorylated levels of protein kinases, protein phosphatases, and phosphoproteins in DM1 human samples and animal and cell models. Twenty-nine kinases, 3 phosphatases, and 17 phosphoproteins were reported altered in DM1. Signaling pathways that regulate cell functions such as glucose metabolism, cell cycle, myogenesis, and apoptosis were impaired, as seen by significant alterations to pathways such as AKT/mTOR, MEK/ERK, PKC/CUGBP1, AMPK, and others in DM1 samples. This explains the complexity of DM1 and its different manifestations and symptoms, such as increased insulin resistance and cancer risk. Further studies can be done to complement and explore in detail specific pathways and how their regulation is altered in DM1, to find what key phosphorylation alterations are responsible for these manifestations, and ultimately to find therapeutic targets for future treatments.

Automatic Text-Mining Approach to Identify Molecular Target Candidates Associated with Metabolic Processes for Myotonic Dystrophy Type 1.

Myotonic dystrophy type 1 (DM1) is an autosomal dominant hereditary disease caused by abnormal expansion of unstable CTG repeats in the 3' untranslated region of the myotonic dystrophy protein kinase (DMPK) gene. This disease mainly affects skeletal muscle, resulting in myotonia, progressive distal muscle weakness, and atrophy, but also affects other tissues and systems, such as the heart and central nervous system. Despite some studies reporting therapeutic strategies for DM1, many issues remain unsolved, such as the contribution of metabolic and mitochondrial dysfunctions to DM1 pathogenesis. Therefore, it is crucial to identify molecular target candidates associated with metabolic processes for DM1. In this study, resorting to a bibliometric analysis, articles combining DM1, and metabolic/metabolism terms were identified and further analyzed using an unbiased strategy of automatic text mining with VOSviewer software. A list of candidate molecular targets for DM1 associated with metabolic/metabolism was generated and compared with genes previously associated with DM1 in the DisGeNET database. Furthermore, g:Profiler was used to perform a functional enrichment analysis using the Gene Ontology (GO) and REAC databases. Enriched signaling pathways were identified using integrated bioinformatics enrichment analyses. The results revealed that only 15 of the genes identified in the bibliometric analysis were previously associated with DM1 in the DisGeNET database. Of note, we identified 71 genes not previously associated with DM1, which are of particular interest and should be further explored. The functional enrichment analysis of these genes revealed that regulation of cellular metabolic and metabolic processes were the most associated biological processes. Additionally, a number of signaling pathways were found to be enriched, e.g., signaling by receptor tyrosine kinases, signaling by NRTK1 (TRKA), TRKA activation by NGF, PI3K-AKT activation, prolonged ERK activation events, and axon guidance. Overall, several valuable target candidates related to metabolic processes for DM1 were identified, such as NGF, NTRK1, RhoA, ROCK1, ROCK2, DAG, ACTA, ID1, ID2 MYOD, and MYOG. Therefore, our study strengthens the hypothesis that metabolic dysfunctions contribute to DM1 pathogenesis, and the exploitation of metabolic dysfunction targets is crucial for the development of future therapeutic interventions for DM1.

Non-COVID-19 respiratory viral infection.

Implemented control measures brought about by the coronavirus disease 2019 (COVID-19) pandemic have changed the prevalence of other respiratory viruses, often relegating them to a secondary plan. However, it must not be forgotten that a diverse group of viruses, including other human coronaviruses, rhinoviruses, respiratory syncytial virus, human metapneumoviruses, parainfluenza and influenza, continue to be responsible for a large burden of disease. In fact, they are among the most common causes of acute upper and lower respiratory tract infections globally. Viral respiratory infections can be categorised in several ways, including by clinical syndrome or aetiological agent. We describe their clinical spectrum. Distinctive imaging features, advances in microbiological diagnosis and treatment of severe forms are also discussed. Educational aims: To summarise the knowledge on the spectrum of disease that respiratory viral infections can cause and recognise how often they overlap.To learn the most common causes of respiratory viral infections and acknowledge other less frequent agents that may target certain key populations (e.g. immunocompromised patients).To improve awareness of the recent advances in diagnostic methods, including molecular assays and helpful features in imaging techniques.To identify supportive care strategies pivotal in the management of severe respiratory viral infections.

Monkeypox after Occupational Needlestick Injury from Pustule.

We report a case of monkeypox in a physician after an occupational needlestick injury from a pustule. This case highlights risk for occupational transmission and manifestations of the disease after percutaneous transmission: a short incubation period, followed by a solitary lesion at the injured site and later by systemic symptoms.

Different Strategies to Attenuate the Toxic Effects of Zinc Oxide Nanoparticles on Spermatogonia Cells.

Zinc oxide nanoparticles (ZnO NPs) are one of the most used nanoparticles due to their unique physicochemical and biological properties. There is, however, a growing concern about their negative impact on male reproductive health. Therefore, in the present study, two different strategies were used to evaluate the recovery ability of spermatogonia cells from the first stage of spermatogenesis (GC-1 spg cell line) after being exposed to a cytotoxic concentration of ZnO NPs (20 µg/mL) for two different short time periods, 6 and 12 h. The first strategy was to let the GC-1 cells recover after ZnO NPs exposure in a ZnO NPs-free medium for 4 days. At this phase, cell viability assays were performed to evaluate whether this period was long enough to allow for cell recovery. Exposure to ZnO NPs for 6 h and 12 h induced a decrease in viability of 25% and 41%, respectively. However, the recovery period allowed for an increase in cell viability from 16% to 25% to values as high as 91% and 84%. These results strongly suggest that GC-1 cells recover, but not completely, given that the cell viability does not reach 100%. Additionally, the impact of a synthetic chalcone (E)-3-(2,6-dichlorophenyl)-1-(2-hydroxyphenyl)prop-2-en-1-one (1) to counteract the reproductive toxicity of ZnO NPs was investigated. Different concentrations of chalcone 1 (0-12.5 µM) were used before and during exposure of GC-1 cells to ZnO NPs to mitigate the damage induced by NPs. The protective ability of this compound was evaluated through viability assays, levels of DNA damage, and cytoskeleton dynamics (evaluating the acetylated α-tubulin and ß-actin protein levels). The results indicated that the tested concentrations of chalcone 1 can attenuate the genotoxicity induced by ZnO NPs for shorter exposure periods (6 h). Chalcone 1 supplementation also increased cell viability and stabilized the microtubules. However, the antioxidant potential of this compound remains to be elucidated. In conclusion, this work addressed the main cytotoxic effects of ZnO NPs on a spermatogonia cell line and analyzed two different strategies to mitigate this damage, which represent a significant contribution to the field of male fertility.

The Long-Term Culture of Human Fibroblasts Reveals a Spectroscopic Signature of Senescence.

Aging is a complex process which leads to progressive loss of fitness/capability/ability, increasing susceptibility to disease and, ultimately, death. Regardless of the organism, there are some features common to aging, namely, the loss of proteostasis and cell senescence. Mammalian cell lines have been used as models to study the aging process, in particular, cell senescence. Thus, the aim of this study was to characterize the senescence-associated metabolic profile of a long-term culture of human fibroblasts using Fourier Transform Infrared and Nuclear Magnetic Resonance spectroscopy. We sub-cultivated fibroblasts from a newborn donor from passage 4 to passage 17 and the results showed deep changes in the spectroscopic profile of cells over time. Late passage cells were characterized by a decrease in the length of fatty acid chains, triglycerides and cholesterol and an increase in lipid unsaturation. We also found an increase in the content of intermolecular ß-sheets, possibly indicating an increase in protein aggregation levels in cells of later passages. Metabolic profiling by NMR showed increased levels of extracellular lactate, phosphocholine and glycine in cells at later passages. This study suggests that spectroscopy approaches can be successfully used to study changes concomitant with cell senescence and validate the use of human fibroblasts as a model to monitor the aging process.

Nuclear Envelope Alterations in Myotonic Dystrophy Type 1 Patient-Derived Fibroblasts.

Myotonic dystrophy type 1 (DM1) is a hereditary and multisystemic disease characterized by myotonia, progressive distal muscle weakness and atrophy. The molecular mechanisms underlying this disease are still poorly characterized, although there are some hypotheses that envisage to explain the multisystemic features observed in DM1. An emergent hypothesis is that nuclear envelope (NE) dysfunction may contribute to muscular dystrophies, particularly to DM1. Therefore, the main objective of the present study was to evaluate the nuclear profile of DM1 patient-derived and control fibroblasts and to determine the protein levels and subcellular distribution of relevant NE proteins in these cell lines. Our results demonstrated that DM1 patient-derived fibroblasts exhibited altered intracellular protein levels of lamin A/C, LAP1, SUN1, nesprin-1 and nesprin-2 when compared with the control fibroblasts. In addition, the results showed an altered location of these NE proteins accompanied by the presence of nuclear deformations (blebs, lobes and/or invaginations) and an increased number of nuclear inclusions. Regarding the nuclear profile, DM1 patient-derived fibroblasts had a larger nuclear area and a higher number of deformed nuclei and micronuclei than control-derived fibroblasts. These results reinforce the evidence that NE dysfunction is a highly relevant pathological characteristic observed in DM1.

Outcome measures frequently used to assess muscle strength in patients with myotonic dystrophy type 1: a systematic review.

Measurement of muscle strength is fundamental for the management of patients with myotonic dystrophy type 1 (DM1). Nevertheless, guidance on this topic is somewhat limited due to heterogeneous outcome measures used. This systematic literature review aimed to summarize the most frequent outcome measures to assess muscle strength in patients with DM1. We searched on Pubmed, Web of Science and Embase databases. Observational studies using measures of muscle strength assessment in adult patients with DM1 were included. From a total of 80 included studies, 24 measured cardiac, 45 skeletal and 23 respiratory muscle strength. The most common method and outcome measures used to assess cardiac muscle strength were echocardiography and ejection fraction, for skeletal muscle strength were quantitative muscle test, manual muscle test and maximum isometric torque and medical research council and for respiratory muscle strength were manometry and maximal inspiratory and expiratory pressure. We successfully gathered the more consensual methods and measures to evaluate muscle strength in future clinical studies, particularly to test muscle strength response to treatments in patients with DM1. Future consensus on a set of measures to evaluate muscle strength (core outcome set), is important for these patients.

Early Gestational Diagnosis of Lethal Skeletal Dysplasias: A 15 Year Retrospective Cohort Reviewing Concordance between Ultrasonographic, Genetic and Morphological Features.

Aim: We evaluated the diagnostic accuracy of ultrasound, postmortem and genetic studies in classifying skeletal dysplasias in the first vs second trimester of pregnancy. Methods: We retrospectively gathered data from a 15 year period of all the prenatal ultrasounds, autopsies, and available genetic studies on fetuses with skeletal dysplasias from our institution. Results: Five (23%) and 17 (77%) fetuses were diagnosed during the first and second trimester of pregnancy respectively. Only partial characterization was possible with ultrasound in the first trimester. Complete characterization was established in five cases (30%) in the second trimester with ultrasound alone. Pathology provided an additional diagnostic yield of 40% and 47% and genetics an additional 40% and 11% in the first and second trimesters respectively. Conclusion: Ultrasound is an effective screening but not a diagnostic tool. Complete characterizations of dysplasia increased from 22% by ultrasound alone to 86% with pathology and genetics.

FTIR Spectroscopy as a Tool to Study Age-Related Changes in Cardiac and Skeletal Muscle of Female C57BL/6J Mice.

Studying aging is important to further understand the molecular mechanisms underlying this physiological process and, ideally, to identify a panel of aging biomarkers. Animals, in particular mice, are often used in aging studies, since they mimic important features of human aging, age quickly, and are easy to manipulate. The present work describes the use of Fourier Transform Infrared (FTIR) spectroscopy to identify an age-related spectroscopic profile of the cardiac and skeletal muscle tissues of C57BL/6J female mice. We acquired ATR-FTIR spectra of cardiac and skeletal muscle at four different ages: 6; 12; 17 and 24 months (10 samples at each age) and analyzed the data using multivariate statistical tools (PCA and PLS) and peak intensity analyses. The results suggest deep changes in protein secondary structure in 24-month-old mice compared to both tissues in 6-month-old mice. Oligomeric structures decreased with age in both tissues, while intermolecular ß-sheet structures increased with aging in cardiac muscle but not in skeletal muscle. Despite FTIR spectroscopy being unable to identify the proteins responsible for these conformational changes, this study gives insights into the potential of FTIR to monitor the aging process and identify an age-specific spectroscopic signature.

Pheochromocytomas and paragangliomas in von Hippel-Lindau disease: not a needle in a haystack.

OBJECTIVE: Pheochromocytomas are a hallmark feature of von Hippel-Lindau disease (vHL). To our knowledge, this is the first systematic review with meta-analysis evaluating the frequency of pheochromocytomas and/or paragangliomas (PPGLs) in patients with vHL, as well as among patients with different vHL subtypes. DESIGN: Systematic review with meta-analysis. METHODS: We searched on MEDLINE, Scopus, and Web of Science. We included primary studies assessing participants with vHL and reporting on the frequency of PPGL. We performed random-effects meta-analysis to quantitatively assess the frequency of PPGL, followed by meta-regression and subgroup analysis. Risk of bias analysis was performed to assess primary studies' methodological quality. RESULTS: We included 80 primary studies. In 4263 patients with vHL, the pooled frequency of PPGL was 19.4% (95% CI = 15.9-23.6%, I2 = 86.1%). The frequency increased to 60.0% in patients with vHL type 2 (95% CI = 53.4-66.3%, I2 = 54.6%) and was determined to be of 58.2% in patients with vHL type 2A (95% CI = 49.7-66.3%, I2 = 36.2%), compared to 49.8% in vHL type 2B (95% CI = 39.9-59.7%, I2 = 42.7%), and 84.1% in vHL type 2C (95% CI = 75.1-93.1%, I2 = 0%). In meta-regression analysis, more recent studies were associated with a higher frequency of PPGL. All studies had at least one internal validity item classified as 'high risk of bias,' with 13% studies having low risk of bias in all external validity items. CONCLUSIONS: PPGLs are a common manifestation of vHL. Despite methodological limitations and differences across primary studies, our results point to the importance of PPGL screening in patients with vHL.

The role of the integral type II transmembrane protein BRI2 in health and disease.

BRI2 is a type II transmembrane protein ubiquitously expressed whose physiological function remains poorly understood. Although several recent important advances have substantially impacted on our understanding of BRI2 biology and function, providing valuable information for further studies on BRI2. These findings have contributed to a better understanding of BRI2 biology and the underlying signaling pathways involved. In turn, these might provide novel insights with respect to neurodegeneration processes inherent to BRI2-related pathologies, namely Familial British and Danish dementias, Alzheimer's disease, ITM2B-related retinal dystrophy, and multiple sclerosis. In this review, we provided a state-of-the-art outline of BRI2 biology, both in physiological and pathological conditions, and discuss the proposed molecular underlying mechanisms. Overall, the BRI2 knowledge here reviewed is of extreme importance and may contribute to propose BRI2 and/or BRI2 proteolytic fragments as novel therapeutic targets for neurodegenerative diseases, such as Alzheimer's disease.