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Alzheimer's Research & Therapy Aug 2023The paradigm shift towards earlier Alzheimer's disease (AD) stages and personalized medicine creates new challenges for clinician-patient communication. We conducted a...
BACKGROUND
The paradigm shift towards earlier Alzheimer's disease (AD) stages and personalized medicine creates new challenges for clinician-patient communication. We conducted a survey among European memory clinic professionals to identify opinions on communication about (etiological) diagnosis, prognosis, and prevention, and inventory needs for augmenting communication skills.
METHODS
Memory clinic professionals (N = 160) from 21 European countries completed our online survey (59% female, 14 ± 10 years' experience, 73% working in an academic hospital). We inventoried (1) opinions on communication about (etiological) diagnosis, prognosis, and prevention using 11 statements; (2) current communication practices in response to five hypothetical cases (AD dementia, mild cognitive impairment (MCI), subjective cognitive decline (SCD), with ( +) or without ( -) abnormal AD biomarkers); and (3) needs for communication support regarding ten listed communication skills.
RESULTS
The majority of professionals agreed that communication on diagnosis, prognosis, and prevention should be personalized to the individual patient. In response to the hypothetical patient cases, disease stage influenced the inclination to communicate an etiological AD diagnosis: 97% would explicitly mention the presence of AD to the patient with AD dementia, 68% would do so in MCI + , and 29% in SCD + . Furthermore, 58% would explicitly rule out AD in case of MCI - when talking to patients, and 69% in case of SCD - . Almost all professionals (79-99%) indicated discussing prognosis and prevention with all patients, of which a substantial part (48-86%) would personalize their communication to patients' diagnostic test results (39-68%) or patients' anamnestic information (33-82%). The majority of clinicians (79%) would like to use online tools, training, or both to support them in communicating with patients. Topics for which professionals desired support most were: stimulating patients' understanding of information, and communicating uncertainty, dementia risk, remotely/online, and with patients not (fluently) speaking the language of the country of residence.
CONCLUSIONS
In a survey of European memory clinic professionals, we found a strong positive attitude towards communication with patients about (etiological) diagnosis, prognosis, and prevention, and personalization of communication to characteristics and needs of individual patients. In addition, professionals expressed a need for supporting tools and skills training to further improve their communication with patients.
Topics: Humans; Female; Male; Neuropsychological Tests; Prognosis; Cognitive Dysfunction; Alzheimer Disease; Communication
PubMed: 37543608
DOI: 10.1186/s13195-023-01276-9 -
JAMA Network Open Nov 2023Predictive models using machine learning techniques have potential to improve early detection and management of Alzheimer disease (AD). However, these models potentially...
IMPORTANCE
Predictive models using machine learning techniques have potential to improve early detection and management of Alzheimer disease (AD). However, these models potentially have biases and may perpetuate or exacerbate existing disparities.
OBJECTIVE
To characterize the algorithmic fairness of longitudinal prediction models for AD progression.
DESIGN, SETTING, AND PARTICIPANTS
This prognostic study investigated the algorithmic fairness of logistic regression, support vector machines, and recurrent neural networks for predicting progression to mild cognitive impairment (MCI) and AD using data from participants in the Alzheimer Disease Neuroimaging Initiative evaluated at 57 sites in the US and Canada. Participants aged 54 to 91 years who contributed data on at least 2 visits between September 2005 and May 2017 were included. Data were analyzed in October 2022.
EXPOSURES
Fairness was quantified across sex, ethnicity, and race groups. Neuropsychological test scores, anatomical features from T1 magnetic resonance imaging, measures extracted from positron emission tomography, and cerebrospinal fluid biomarkers were included as predictors.
MAIN OUTCOMES AND MEASURES
Outcome measures quantified fairness of prediction models (logistic regression [LR], support vector machine [SVM], and recurrent neural network [RNN] models), including equal opportunity, equalized odds, and demographic parity. Specifically, if the model exhibited equal sensitivity for all groups, it aligned with the principle of equal opportunity, indicating fairness in predictive performance.
RESULTS
A total of 1730 participants in the cohort (mean [SD] age, 73.81 [6.92] years; 776 females [44.9%]; 69 Hispanic [4.0%] and 1661 non-Hispanic [96.0%]; 29 Asian [1.7%], 77 Black [4.5%], 1599 White [92.4%], and 25 other race [1.4%]) were included. Sensitivity for predicting progression to MCI and AD was lower for Hispanic participants compared with non-Hispanic participants; the difference (SD) in true positive rate ranged from 20.9% (5.5%) for the RNN model to 27.8% (9.8%) for the SVM model in MCI and 24.1% (5.4%) for the RNN model to 48.2% (17.3%) for the LR model in AD. Sensitivity was similarly lower for Black and Asian participants compared with non-Hispanic White participants; for example, the difference (SD) in AD true positive rate was 14.5% (51.6%) in the LR model, 12.3% (35.1%) in the SVM model, and 28.4% (16.8%) in the RNN model for Black vs White participants, and the difference (SD) in MCI true positive rate was 25.6% (13.1%) in the LR model, 24.3% (13.1%) in the SVM model, and 6.8% (18.7%) in the RNN model for Asian vs White participants. Models generally satisfied metrics of fairness with respect to sex, with no significant differences by group, except for cognitively normal (CN)-MCI and MCI-AD transitions (eg, an absolute increase [SD] in the true positive rate of CN-MCI transitions of 10.3% [27.8%] for the LR model).
CONCLUSIONS AND RELEVANCE
In this study, models were accurate in aggregate but failed to satisfy fairness metrics. These findings suggest that fairness should be considered in the development and use of machine learning models for AD progression.
Topics: Aged; Female; Humans; Alzheimer Disease; Asian; Benchmarking; Disease Progression; Machine Learning; Middle Aged; Aged, 80 and over; Male; Hispanic or Latino; Black or African American; White
PubMed: 37934495
DOI: 10.1001/jamanetworkopen.2023.42203 -
PloS One 2023This study was designed to investigate the relationship between a systematic inflammatory biomarker measure, concurrent and later cognitive performance, and future...
This study was designed to investigate the relationship between a systematic inflammatory biomarker measure, concurrent and later cognitive performance, and future dementia risk. The literature has reported the potential involvement of inflammation in cognitive performance as well as Alzheimer's Disease, but not consistently. We used a population-based cohort of 500,000 people in the UK and assessed the association between a composite inflammatory biomarker and cognitive performance measures across five domains measured concurrently and 4-13 years later, taking advantage of the large sample size. We also assessed the same biomarker's association with dementia diagnosis 3-11 years later in the initially dementia-free sample. We report small but significant associations between elevated biomarker levels and worsened cognitive performance at baseline for four cognitive tasks (OR = 1.204, p<0.001 for Prospective memory, β = -0.366, p<0.001 for Fluid intelligence, β = 8.819, p<0.001 for Reaction time, and β = -0.224, p<0.001 for Numeric memory), comparing the highest quartile of the biomarker to the lowest. We also found that for one measure (Pairs matching) higher biomarker levels were associated with fewer errors, i.e. better performance (β = -0.096, p<0.001). We also report that the 4th quartiles of the baseline biomarker levels were significantly associated with cognitive task scores assessed years later on the p< = 0.002 level, except for the Pair matching test, for which none of the quartiles remained a significant predictor. Finally, the highest biomarker quartile was significantly associated with increased dementia risk compared to the lowest quartile (HR = 1.349, p<0.001). A case-only analysis to assess disease subtype heterogeneity suggested probable differences in the association with the highest biomarker quartile between vascular dementia and Alzheimer disease subtypes (OR = 1.483, p = 0.055). Our results indicate that systemic inflammation may play a small but significant part in dementia pathophysiology, especially in vascular dementia.
Topics: Humans; Dementia, Vascular; Biological Specimen Banks; Alzheimer Disease; Biomarkers; Inflammation; United Kingdom; Cognitive Dysfunction
PubMed: 37467176
DOI: 10.1371/journal.pone.0288045 -
European Journal of Nuclear Medicine... Jan 2024Despite the revealed role of immunological dysfunctions in the development and progression of Alzheimer's disease (AD) through animal and postmortem investigations,...
PURPOSE
Despite the revealed role of immunological dysfunctions in the development and progression of Alzheimer's disease (AD) through animal and postmortem investigations, direct evidence regarding the impact of genetic factors on microglia response and amyloid-β (Aβ) deposition in AD individuals is lacking. This study aims to elucidate this mechanism by integrating transcriptomics and TSPO, Aβ PET imaging in clinical AD cohort.
METHODS
We analyzed 85 patients with PET/MR imaging for microglial activation (TSPO, [F]DPA-714) and Aβ ([F]AV-45) within the prospective Alzheimer's Disease Immunization and Microbiota Initiative Study Cohort (ADIMIC). Immune-related differentially expressed genes (IREDGs), identified based on AlzData, were screened and verified using blood samples from ADIMIC. Correlation and mediation analyses were applied to investigate the relationships between immune-related genes expression, TSPO and Aβ PET imaging.
RESULTS
TSPO uptake increased significantly both in aMCI (P < 0.05) and AD participants (P < 0.01) and showed a positive correlation with Aβ deposition (r = 0.42, P < 0.001). Decreased expression of TGFBR3, FABP3, CXCR4 and CD200 was observed in AD group. CD200 expression was significantly negatively associated with TSPO PET uptake (r =-0.33, P = 0.013). Mediation analysis indicated that CD200 acted as a significant mediator between TSPO uptake and Aβ deposition (total effect B = 1.92, P = 0.004) and MMSE score (total effect B =-54.01, P = 0.003).
CONCLUSION
By integrating transcriptomics and TSPO PET imaging in the same clinical AD cohort, this study revealed CD200 played an important role in regulating neuroinflammation, Aβ deposition and cognitive dysfunction.
Topics: Humans; Alzheimer Disease; Amyloid beta-Peptides; Gene Expression Profiling; Neuroinflammatory Diseases; Positron-Emission Tomography; Prospective Studies; Receptors, GABA
PubMed: 37801139
DOI: 10.1007/s00259-023-06446-3 -
Cells Nov 2023Alzheimer's disease (AD) is a well-known chronic neurodegenerative disorder that leads to the progressive death of brain cells, resulting in memory loss and the loss of... (Review)
Review
Alzheimer's disease (AD) is a well-known chronic neurodegenerative disorder that leads to the progressive death of brain cells, resulting in memory loss and the loss of other critical body functions. In March 2019, one of the major pharmaceutical companies and its partners announced that currently, there is no drug to cure AD, and all clinical trials of the new ones have been cancelled, leaving many people without hope. However, despite the clear message and startling reality, the research continued. Finally, in the last two years, the Food and Drug Administration (FDA) approved the first-ever medications to treat Alzheimer's, aducanumab and lecanemab. Despite researchers' support of this decision, there are serious concerns about their effectiveness and safety. The validation of aducanumab by the Centers for Medicare and Medicaid Services is still pending, and lecanemab was authorized without considering data from the phase III trials. Furthermore, numerous reports suggest that patients have died when undergoing extended treatment. While there is evidence that aducanumab and lecanemab may provide some relief to those suffering from AD, their impact remains a topic of ongoing research and debate within the medical community. The fact is that even though there are considerable efforts regarding pharmacological treatment, no definitive cure for AD has been found yet. Nevertheless, it is strongly believed that modern nanotechnology holds promising solutions and effective clinical strategies for the development of diagnostic tools and treatments for AD. This review summarizes the major hallmarks of AD, its etiological mechanisms, and challenges. It explores existing diagnostic and therapeutic methods and the potential of nanotechnology-based approaches for recognizing and monitoring patients at risk of irreversible neuronal degeneration. Overall, it provides a broad overview for those interested in the evolving areas of clinical neuroscience, AD, and related nanotechnology. With further research and development, nanotechnology-based approaches may offer new solutions and hope for millions of people affected by this devastating disease.
Topics: Aged; Humans; United States; Alzheimer Disease; Medicare; Brain; Nanotechnology
PubMed: 38067098
DOI: 10.3390/cells12232669 -
Neurology Oct 2023The capacity of specialty memory clinics in the United States is very limited. If lower socioeconomic status or minoritized racial group is associated with reduced use... (Observational Study)
Observational Study
BACKGROUND AND OBJECTIVES
The capacity of specialty memory clinics in the United States is very limited. If lower socioeconomic status or minoritized racial group is associated with reduced use of memory clinics, this could exacerbate health care disparities, especially if more effective treatments of Alzheimer disease become available. We aimed to understand how use of a memory clinic is associated with neighborhood-level measures of socioeconomic factors and the intersectionality of race.
METHODS
We conducted an observational cross-sectional study using electronic health record data to compare the neighborhood advantage of patients seen at the Washington University Memory Diagnostic Center with the catchment area using a geographical information system. Furthermore, we compared the severity of dementia at the initial visit between patients who self-identified as Black or White. We used a multinomial logistic regression model to assess the Clinical Dementia Rating at the initial visit and tests to compare neighborhood characteristics, including Area Deprivation Index, with those of the catchment area.
RESULTS
A total of 4,824 patients seen at the memory clinic between 2008 and 2018 were included in this study (mean age 72.7 [SD 11.0] years, 2,712 [56%] female, 543 [11%] Black). Most of the memory clinic patients lived in more advantaged neighborhoods within the overall catchment area. The percentage of patients self-identifying as Black (11%) was lower than the average percentage of Black individuals by census tract in the catchment area (16%) ( < 0.001). Black patients lived in less advantaged neighborhoods, and Black patients were more likely than White patients to have moderate or severe dementia at their initial visit (odds ratio 1.59, 95% CI 1.11-2.25).
DISCUSSION
This study demonstrates that patients living in less affluent neighborhoods were less likely to be seen in one large memory clinic. Black patients were under-represented in the clinic, and Black patients had more severe dementia at their initial visit. These findings suggest that patients with a lower socioeconomic status and who identify as Black are less likely to be seen in memory clinics, which are likely to be a major point of access for any new Alzheimer disease treatments that may become available.
Topics: Aged; Female; Humans; Male; Alzheimer Disease; Black People; Cross-Sectional Studies; Racial Groups; Socioeconomic Factors; United States; Memory Disorders; White People; Neighborhood Characteristics; Middle Aged; Aged, 80 and over
PubMed: 37532510
DOI: 10.1212/WNL.0000000000207674 -
Aging and Disease May 2024An essential regulator of neurodegenerative conditions like Alzheimer's disease (AD) is the gut microbiota. Alterations in intestinal permeability brought on by gut... (Review)
Review
An essential regulator of neurodegenerative conditions like Alzheimer's disease (AD) is the gut microbiota. Alterations in intestinal permeability brought on by gut microbiota dysregulation encourage neuroinflammation, central immune dysregulation, and peripheral immunological dysregulation in AD, as well as hasten aberrant protein aggregation and neuronal death in the brain. However, it is unclear how the gut microbiota transmits information to the brain and how it influences brain cognition and function. In this review, we summarized the multiple pathways involved in the gut microbiome in AD and provided detailed treatment strategies based on the gut microbiome. Based on these observations, this review also discusses the problems, challenges, and strategies to address current therapeutic strategies.
Topics: Alzheimer Disease; Humans; Gastrointestinal Microbiome; Brain-Gut Axis; Brain; Animals; Dysbiosis
PubMed: 37728579
DOI: 10.14336/AD.2023.0823-2 -
International Journal of Molecular... Apr 2024The insulin-like growth factor (IGF) system has paracrine and endocrine roles in the central nervous system. There is evidence that IGF signalling pathways have roles in... (Review)
Review
The insulin-like growth factor (IGF) system has paracrine and endocrine roles in the central nervous system. There is evidence that IGF signalling pathways have roles in the pathophysiology of neurodegenerative disease. This review focusses on Alzheimer's disease and Parkinson's disease, the two most common neurodegenerative disorders that are increasing in prevalence globally in relation to the aging population and the increasing prevalence of obesity and type 2 diabetes. Rodent models used in the study of the molecular pathways involved in neurodegeneration are described. However, currently, no animal model fully replicates these diseases. Mice with triple mutations in , and show promise as models for the testing of novel Alzheimer's therapies. While a causal relationship is not proven, the fact that age, obesity and T2D are risk factors in both strengthens the case for the involvement of the IGF system in these disorders. The IGF system is an attractive target for new approaches to management; however, there are gaps in our understanding that first need to be addressed. These include a focus beyond IGF-I on other members of the IGF system, including IGF-II, IGF-binding proteins and the type 2 IGF receptor.
Topics: Humans; Animals; Neurodegenerative Diseases; Alzheimer Disease; Signal Transduction; Insulin-Like Growth Factor I; Somatomedins; Disease Models, Animal; Parkinson Disease; Insulin-Like Growth Factor Binding Proteins; Insulin-Like Peptides
PubMed: 38674097
DOI: 10.3390/ijms25084512 -
Redox Biology Nov 2023Alzheimer's disease (AD) is an age-dependent neurodegenerative disorder and the most common cause of cognitive decline. The alarming epidemiological features of... (Meta-Analysis)
Meta-Analysis
Alzheimer's disease (AD) is an age-dependent neurodegenerative disorder and the most common cause of cognitive decline. The alarming epidemiological features of Alzheimer's disease, combined with the high failure rate of candidate drugs tested in the preclinical phase, impose more intense investigations for new curative treatments. NRF2 (Nuclear factor-erythroid factor 2-related factor 2) plays a critical role in the inflammatory response and in the cellular redox homeostasis and provides cytoprotection in several diseases including those in the neurodegeneration spectrum. These roles suggest that NRF2 and its directly associated proteins may be novel attractive therapeutic targets in the fight against AD. In this study, through a systemics perspective, we propose an in silico drug repurposing approach for AD, based on the NRF2 interactome and regulome, with the aim of highlighting possible repurposed drugs for AD. Using publicly available information based on differential expressions of the NRF2-neighborhood in AD and through a computational drug repurposing pipeline, we derived to a short list of candidate repurposed drugs and small molecules that affect the expression levels of the majority of NRF2-partners. The relevance of these findings was assessed in a four-step computational meta-analysis including i) structural similarity comparisons with currently ongoing NRF2-related drugs in clinical trials ii) evaluation based on the NRF2-diseasome iii) comparison of relevance between targeted pathways of shortlisted drugs and NRF2-related drugs in clinical trials and iv) further comparison with existing knowledge on AD and NRF2-related drugs in clinical trials based on their known modes of action. Overall, our analysis yielded in 5 candidate repurposed drugs for AD. In cell culture, these 5 candidates activated a luciferase reporter for NRF2 activity and in hippocampus derived TH22 cells they increased NRF2 protein levels and the NRF2 transcriptional signatures as determined by increased expression of its downstream target heme oxygenase 1. We expect that our proposed candidate repurposed drugs will be useful for further research and clinical translation for AD.
Topics: Humans; Alzheimer Disease; NF-E2-Related Factor 2; Drug Repositioning; Hippocampus
PubMed: 37696195
DOI: 10.1016/j.redox.2023.102881 -
Journal of Nanobiotechnology Mar 2024Alzheimer's disease (AD) is a neurodegenerative disorder with complex pathogenesis and effective clinical treatment strategies for this disease remain elusive.... (Review)
Review
Alzheimer's disease (AD) is a neurodegenerative disorder with complex pathogenesis and effective clinical treatment strategies for this disease remain elusive. Interestingly, nanomedicines are under extensive investigation for AD management. Currently, existing redox molecules show highly bioactive property but suffer from instability and high production costs, limiting clinical application for neurological diseases. Compared with natural enzymes, artificial enzymes show high stability, long-lasting catalytic activity, and versatile enzyme-like properties. Further, the selectivity and performance of artificial enzymes can be modulated for neuroinflammation treatments through external stimuli. In this review, we focus on the latest developments of metal, metal oxide, carbon-based and polymer based nanozymes and their catalytic mechanisms. Recent developments in nanozymes for diagnosing and treating AD are emphasized, especially focusing on their potential to regulate pathogenic factors and target sites. Various applications of nanozymes with different stimuli-responsive features were discussed, particularly focusing on nanozymes for treating oxidative stress-related neurological diseases. Noninvasiveness and focused application to deep body regions makes ultrasound (US) an attractive trigger mechanism for nanomedicine. Since a complete cure for AD remains distant, this review outlines the potential of US responsive nanozymes to develop future therapeutic approaches for this chronic neurodegenerative disease and its emergence in AD management.
Topics: Humans; Nanostructures; Alzheimer Disease; Neurodegenerative Diseases; Catalysis; Metals
PubMed: 38555420
DOI: 10.1186/s12951-024-02406-7