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JMIR Aging Jun 2024Frontotemporal lobar degeneration (FTLD) is a leading cause of dementia in individuals aged <65 years. Several challenges to conducting in-person evaluations in FTLD...
BACKGROUND
Frontotemporal lobar degeneration (FTLD) is a leading cause of dementia in individuals aged <65 years. Several challenges to conducting in-person evaluations in FTLD illustrate an urgent need to develop remote, accessible, and low-burden assessment techniques. Studies of unobtrusive monitoring of at-home computer use in older adults with mild cognitive impairment show that declining function is reflected in reduced computer use; however, associations with smartphone use are unknown.
OBJECTIVE
This study aims to characterize daily trajectories in smartphone battery use, a proxy for smartphone use, and examine relationships with clinical indicators of severity in FTLD.
METHODS
Participants were 231 adults (mean age 52.5, SD 14.9 years; n=94, 40.7% men; n=223, 96.5% non-Hispanic White) enrolled in the Advancing Research and Treatment of Frontotemporal Lobar Degeneration (ARTFL study) and Longitudinal Evaluation of Familial Frontotemporal Dementia Subjects (LEFFTDS study) Longitudinal Frontotemporal Lobar Degeneration (ALLFTD) Mobile App study, including 49 (21.2%) with mild neurobehavioral changes and no functional impairment (ie, prodromal FTLD), 43 (18.6%) with neurobehavioral changes and functional impairment (ie, symptomatic FTLD), and 139 (60.2%) clinically normal adults, of whom 55 (39.6%) harbored heterozygous pathogenic or likely pathogenic variants in an autosomal dominant FTLD gene. Participants completed the Clinical Dementia Rating plus National Alzheimer's Coordinating Center Frontotemporal Lobar Degeneration Behavior and Language Domains (CDR+NACC FTLD) scale, a neuropsychological battery; the Neuropsychiatric Inventory; and brain magnetic resonance imaging. The ALLFTD Mobile App was installed on participants' smartphones for remote, passive, and continuous monitoring of smartphone use. Battery percentage was collected every 15 minutes over an average of 28 (SD 4.2; range 14-30) days. To determine whether temporal patterns of battery percentage varied as a function of disease severity, linear mixed effects models examined linear, quadratic, and cubic effects of the time of day and their interactions with each measure of disease severity on battery percentage. Models covaried for age, sex, smartphone type, and estimated smartphone age.
RESULTS
The CDR+NACC FTLD global score interacted with time on battery percentage such that participants with prodromal or symptomatic FTLD demonstrated less change in battery percentage throughout the day (a proxy for less smartphone use) than clinically normal participants (P<.001 in both cases). Additional models showed that worse performance in all cognitive domains assessed (ie, executive functioning, memory, language, and visuospatial skills), more neuropsychiatric symptoms, and smaller brain volumes also associated with less battery use throughout the day (P<.001 in all cases).
CONCLUSIONS
These findings support a proof of concept that passively collected data about smartphone use behaviors associate with clinical impairment in FTLD. This work underscores the need for future studies to develop and validate passive digital markers sensitive to longitudinal clinical decline across neurodegenerative diseases, with potential to enhance real-world monitoring of neurobehavioral change.
PubMed: 38922667
DOI: 10.2196/52831 -
JAMA Network Open Jun 2024Chronic kidney disease (CKD) is an often-asymptomatic complication of type 2 diabetes (T2D) that requires annual screening to diagnose. Patient-level factors linked to...
IMPORTANCE
Chronic kidney disease (CKD) is an often-asymptomatic complication of type 2 diabetes (T2D) that requires annual screening to diagnose. Patient-level factors linked to inadequate screening and treatment can inform implementation strategies to facilitate guideline-recommended CKD care.
OBJECTIVE
To identify risk factors for nonconcordance with guideline-recommended CKD screening and treatment in patients with T2D.
DESIGN, SETTING, AND PARTICIPANTS
This retrospective cohort study was performed at 20 health care systems contributing data to the US National Patient-Centered Clinical Research Network. To evaluate concordance with CKD screening guidelines, adults with an outpatient clinician visit linked to T2D diagnosis between January 1, 2015, and December 31, 2020, and without known CKD were included. A separate analysis reviewed prescription of angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs) and sodium-glucose cotransporter 2 (SGLT2) inhibitors in adults with CKD (estimated glomerular filtration rate [eGFR] of 30-90 mL/min/1.73 m2 and urinary albumin-to-creatinine ratio [UACR] of 200-5000 mg/g) and an outpatient clinician visit for T2D between October 1, 2019, and December 31, 2020. Data were analyzed from July 8, 2022, through June 22, 2023.
EXPOSURES
Demographics, lifestyle factors, comorbidities, medications, and laboratory results.
MAIN OUTCOMES AND MEASURES
Screening required measurement of creatinine levels and UACR within 15 months of the index visit. Treatment reflected prescription of ACEIs or ARBs and SGLT2 inhibitors within 12 months before or 6 months following the index visit.
RESULTS
Concordance with CKD screening guidelines was assessed in 316 234 adults (median age, 59 [IQR, 50-67] years), of whom 51.5% were women; 21.7%, Black; 10.3%, Hispanic; and 67.6%, White. Only 24.9% received creatinine and UACR screening, 56.5% received 1 screening measurement, and 18.6% received neither. Hispanic ethnicity was associated with lack of screening (relative risk [RR], 1.16 [95% CI, 1.14-1.18]). In contrast, heart failure, peripheral arterial disease, and hypertension were associated with a lower risk of nonconcordance. In 4215 patients with CKD and albuminuria, 3288 (78.0%) received an ACEI or ARB; 194 (4.6%), an SGLT2 inhibitor; and 885 (21.0%), neither therapy. Peripheral arterial disease and lower eGFR were associated with lack of CKD treatment, while diuretic or statin prescription and hypertension were associated with treatment.
CONCLUSIONS AND RELEVANCE
In this cohort study of patients with T2D, fewer than one-quarter received recommended CKD screening. In patients with CKD and albuminuria, 21.0% did not receive an SGLT2 inhibitor or an ACEI or an ARB, despite compelling indications. Patient-level factors may inform implementation strategies to improve CKD screening and treatment in people with T2D.
Topics: Humans; Diabetes Mellitus, Type 2; Female; Male; Middle Aged; Renal Insufficiency, Chronic; Retrospective Studies; Aged; Guideline Adherence; Practice Guidelines as Topic; Mass Screening; Angiotensin-Converting Enzyme Inhibitors; Angiotensin Receptor Antagonists; Risk Factors; Sodium-Glucose Transporter 2 Inhibitors; United States; Glomerular Filtration Rate
PubMed: 38922613
DOI: 10.1001/jamanetworkopen.2024.18808 -
JAMA Psychiatry Jun 2024The emergence of psychotic symptoms in Alzheimer disease (AD) is associated with accelerated cognitive and functional decline that may be related to disease pathology.
IMPORTANCE
The emergence of psychotic symptoms in Alzheimer disease (AD) is associated with accelerated cognitive and functional decline that may be related to disease pathology.
OBJECTIVE
To investigate the longitudinal dynamics of plasma tau phosphorylated at threonine 181 (p-tau181) and neurofilament light chain protein (NfL) levels in association with the emergence of psychotic symptoms (delusions and hallucinations) in the context of AD.
DESIGN, SETTING, AND PARTICIPANTS
This cohort study used longitudinal data from the Alzheimer Disease Neuroimaging Initiative (ADNI). Baseline analyses compared patients with mild cognitive impairment (MCI) and AD (both with psychosis [AD+P] and without psychosis [AD-P]) and participants who were cognitively unimpaired (CU). For the longitudinal analysis, participants with MCI and AD were subdivided into patients with evidence of psychosis at baseline (AD+P baseline) and patients free of psychosis at baseline who showed incidence of psychosis over the course of the study (AD+P incident). Study data were analyzed between June and November 2023.
EXPOSURES
Plasma p-tau181 and NfL measures in individuals with MCI and AD, both with and without psychosis.
MAIN OUTCOMES AND MEASURES
Plasma p-tau181 and NfL quantifications up to 48 months and concurrent assessments of presence or absence of delusions and hallucinations via the Neuropsychiatric Inventory (NPI) questionnaire.
RESULTS
The cohort included 752 participants with AD (mean [SD] age, 74.2 [7.7] years; 434 male [57.7%]). A total of 424 CU participants had a mean (SD) age of 75.4 (6.6) years of whom 222 were female (52.4%). In the longitudinal analysis of p-tau181 trajectories of the AD+P group, the group of patients who showed incidence of psychosis over the course of follow-up (AD+P incident) demonstrated an associated increase in plasma p-tau181 levels compared with the group of patients who had psychosis at baseline (AD+P baseline) and showed an associated decrease in plasma p-tau181 levels (F4, 117 = 3.24; P = .01). The mean slope of p-tau181 change was significantly different in AD+P incident and AD+P baseline groups (F5,746 = 86.76, P < .0001) and when only individuals with amyloid-β positivity (Aβ+), which was determined using positron emission tomography, were compared (F5,455 = 84.60, P < .001). Patients who experienced psychosis at any time had increased levels of NfL relative to those who never experienced psychosis.
CONCLUSIONS AND RELEVANCE
Results of this cohort study suggest that the emergence of psychosis in AD was associated with elevations in plasma levels of p-tau181, highlighting the potential utility of plasma p-tau181 as a biomarker of neuropsychiatric illness in AD, which could have implications for predictive and treatment response strategies.
PubMed: 38922609
DOI: 10.1001/jamapsychiatry.2024.1389 -
Naunyn-Schmiedeberg's Archives of... Jun 2024Diabetes is one of the most common endocrine metabolic diseases and is associated with the accumulation of beta-amyloid plaques in the brain. Amyloid beta (Aβ) and...
Diabetes is one of the most common endocrine metabolic diseases and is associated with the accumulation of beta-amyloid plaques in the brain. Amyloid beta (Aβ) and abnormal tau proteins are effective in the development of Alzheimer's disease. The aim of this study is to investigate the therapeutic and protective effects of curcumin on beta-amyloid (Aβ) accumulation and tau protein expression levels, as well as biochemical and oxidative changes in streptozotocin-induced diabetes in rats. The study comprised five groups, each consisting of eight rats: control, diabetic, curcumin, curcumin during diabetic induction, and curcumin post-diabetic induction. Groups 2 and 4 were administered a single dose of 45 mg/kg streptozotocin on day 1, while group 5 received it on day 28. Curcumin was orally administered via gavage at a dose of 100 mg/kg/day for 35 days to the third, fourth, and fifth groups. At the end of the trial (day 35), blood sugar levels and insulin resistance were similar between the control and curcumin-treated groups but significantly higher in the diabetic groups (P < 0.05). The protective effect of curcumin is tested during induction and active diabetes. The results indicated that diabetic rats displayed increased levels of Aβ, tau protein, and total oxidant capacity (TOS) compared to the curcumin-treated groups. Additionally, the total antioxidant capacity (TAS) levels were lower in the diabetic rats (P < 0.05). Aβ protein levels are lower in both the serum and brain of rats with active diabetes and treated with curcumin compared to control rats (P > 0.05). In addition, serum TAS levels were higher in rats treated with curcumin following the induction of diabetes than pre-induction of diabetes (P > 0.05). The TOS levels in the serum were higher in the rats treated with curcumin during active diabetes compared to the rats treated prior to the induction of diabetes (P < 0.05). However, no significant difference was observed in the brain. The above results show that curcumin has an effect on reducing oxidative stress caused by diabetes and increasing antioxidant activity.
PubMed: 38922352
DOI: 10.1007/s00210-024-03231-3 -
Environmental Health Perspectives Jun 2024Evidence linking gaseous air pollution to late-life brain health is mixed.
Association of Gaseous Ambient Air Pollution and Dementia-Related Neuroimaging Markers in the ARIC Cohort, Comparing Exposure Estimation Methods and Confounding by Study Site.
BACKGROUND
Evidence linking gaseous air pollution to late-life brain health is mixed.
OBJECTIVE
We explored associations between exposure to gaseous pollutants and brain magnetic resonance imaging (MRI) markers among Atherosclerosis Risk in Communities (ARIC) Study participants, with attention to the influence of exposure estimation method and confounding by site.
METHODS
We considered data from 1,665 eligible ARIC participants recruited from four US sites in the period 1987-1989 with valid brain MRI data from Visit 5 (2011-2013). We estimated 10-y (2001-2010) mean carbon monoxide (CO), nitrogen dioxide (), nitrogen oxides (), and 8- and 24-h ozone () concentrations at participant addresses, using multiple exposure estimation methods. We estimated site-specific associations between pollutant exposures and brain MRI outcomes (total and regional volumes; presence of microhemorrhages, infarcts, lacunes, and severe white matter hyperintensities), using adjusted linear and logistic regression models. We compared meta-analytically combined site-specific associations to analyses that did not account for site.
RESULTS
Within-site exposure distributions varied across exposure estimation methods. Meta-analytic associations were generally not statistically significant regardless of exposure, outcome, or exposure estimation method; point estimates often suggested associations between higher and smaller temporal lobe, deep gray, hippocampal, frontal lobe, and Alzheimer disease signature region of interest volumes and between higher CO and smaller temporal and frontal lobe volumes. Analyses that did not account for study site more often yielded significant associations and sometimes different direction of associations.
DISCUSSION
Patterns of local variation in estimated air pollution concentrations differ by estimation method. Although we did not find strong evidence supporting impact of gaseous pollutants on brain changes detectable by MRI, point estimates suggested associations between higher exposure to CO, , and and smaller regional brain volumes. Analyses of air pollution and dementia-related outcomes that do not adjust for location likely underestimate uncertainty and may be susceptible to confounding bias. https://doi.org/10.1289/EHP13906.
Topics: Humans; Air Pollutants; Air Pollution; Male; Magnetic Resonance Imaging; Female; Environmental Exposure; Dementia; Neuroimaging; Aged; Middle Aged; Nitrogen Oxides; Cohort Studies; Brain; Nitrogen Dioxide; Ozone; United States
PubMed: 38922331
DOI: 10.1289/EHP13906 -
Toxics Jun 2024Long-term exposure to lead (Pb) can result in chronic damage to the body through accumulation in the central nervous system (CNS) leading to neurodegenerative diseases,...
Long-term exposure to lead (Pb) can result in chronic damage to the body through accumulation in the central nervous system (CNS) leading to neurodegenerative diseases, such as Alzheimer's disease (AD). This study delves into the intricate role of miR-671/CDR1as regulation in the etiology of AD-like lesions triggered by chronic Pb exposure in adult mice. To emulate the chronic effects of Pb, we established a rodent model spanning 10 months of controlled Pb administration, dividing 52 C57BL/6J mice into groups receiving varying concentrations of Pb (1, 2, or 4 g/L) alongside an unexposed control. Blood Pb levels were monitored using serum samples to ensure accurate dosing and to correlate with observed toxicological outcomes. Utilizing the Morris water maze, a robust behavioral assay for assessing cognitive functions, we documented a dose-dependent decline in learning and memory capabilities among the Pb-exposed mice. Histopathological examination of the hippocampal tissue revealed tell-tale signs of AD-like neurodegeneration, characterized by the accumulation of amyloid plaques and neurofibrillary tangles. At the molecular level, a significant upregulation of AD-associated genes, namely amyloid precursor protein (APP), β-secretase 1 (BACE1), and tau, was observed in the hippocampal tissue of Pb-exposed mice. This was accompanied by a corresponding surge in the protein levels of APP, BACE1, amyloid-β (Aβ), and phosphorylated tau (p-tau), further implicating Pb in the dysregulation of these key AD markers. The expression of CDR1as, a long non-coding RNA implicated in AD pathogenesis, was found to be suppressed in Pb-exposed mice. This observation suggests a potential mechanistic link between Pb-induced neurotoxicity and the dysregulation of the CDR1as/miR-671 axis, which warrants further investigation. Moreover, our study identified a dose-dependent alteration in the intracellular and extracellular levels of the transcription factor nuclear factor-kappa B (NF-κB). This finding implicates Pb in the modulation of NF-κB signaling, a pathway that plays a pivotal role in neuroinflammation and neurodegeneration. In conclusion, our findings underscored the deleterious effects of Pb exposure on the CNS, leading to the development of AD-like pathology. The observed modulation of NF-κB signaling and miR-671/CDR1as regulation provides a plausible mechanistic framework for understanding the neurotoxic effects of Pb and its potential contribution to AD pathogenesis.
PubMed: 38922090
DOI: 10.3390/toxics12060410 -
Nanomaterials (Basel, Switzerland) Jun 2024Chrysin is hypothesized to possess the ability to prevent different illnesses, such as diabetes, cancer, and neurodegenerative disorders. Nonetheless, chrysin has a low...
Chrysin is hypothesized to possess the ability to prevent different illnesses, such as diabetes, cancer, and neurodegenerative disorders. Nonetheless, chrysin has a low solubility under physiological conditions, resulting in limited bioavailability. In a previous study, we utilized an oil-in-water emulsion system (chrysin-ES or chrysin-NE) to encapsulate chrysin, thereby increasing its bioaccessibility and preserving its antioxidant and anti-Alzheimer's properties. To promote the chrysin-ES as a supplementary and functional food, it was obligatory to carry out a safety assessment. Cytotoxicity testing showed that chrysin-ES was harmless, with no killing effect on 3T3-L1 (adipocytes), RAW 264.7 (macrophages), HEK293 (kidney cells), and LX-2 (hepatic stellate cells). The acute toxicity evaluation demonstrated that the 50% lethal dose (LD) for chrysin-ES was greater than 2000 mg/kg BW. Genotoxicity assessments found that chrysin-ES did not induce DNA mutations in vitro or in vivo. Furthermore, chrysin and chrysin-ES exhibited anti-mutagenic properties against PhIP-induced and IQ-induced mutagenesis in the Ames test, while they inhibited urethane-, ethyl methanesulfonate-, mitomycin C-, and -nitrosomethylurea-mediated mutations in . The present study illustrates the safety and anti-genotoxicity properties of chrysin-ES, allowing for the further development of chrysin-based food supplements and nutraceuticals.
PubMed: 38921877
DOI: 10.3390/nano14121001 -
Residual-Based Multi-Stage Deep Learning Framework for Computer-Aided Alzheimer's Disease Detection.Journal of Imaging Jun 2024Alzheimer's Disease (AD) poses a significant health risk globally, particularly among the elderly population. Recent studies underscore its prevalence, with over 50% of...
Alzheimer's Disease (AD) poses a significant health risk globally, particularly among the elderly population. Recent studies underscore its prevalence, with over 50% of elderly Japanese facing a lifetime risk of dementia, primarily attributed to AD. As the most prevalent form of dementia, AD gradually erodes brain cells, leading to severe neurological decline. In this scenario, it is important to develop an automatic AD-detection system, and many researchers have been working to develop an AD-detection system by taking advantage of the advancement of deep learning (DL) techniques, which have shown promising results in various domains, including medical image analysis. However, existing approaches for AD detection often suffer from limited performance due to the complexities associated with training hierarchical convolutional neural networks (CNNs). In this paper, we introduce a novel multi-stage deep neural network architecture based on residual functions to address the limitations of existing AD-detection approaches. Inspired by the success of residual networks (ResNets) in image-classification tasks, our proposed system comprises five stages, each explicitly formulated to enhance feature effectiveness while maintaining model depth. Following feature extraction, a deep learning-based feature-selection module is applied to mitigate overfitting, incorporating batch normalization, dropout and fully connected layers. Subsequently, machine learning (ML)-based classification algorithms, including Support Vector Machines (SVM), Random Forest (RF) and SoftMax, are employed for classification tasks. Comprehensive evaluations conducted on three benchmark datasets, namely ADNI1: Complete 1Yr 1.5T, MIRAID and OASIS Kaggle, demonstrate the efficacy of our proposed model. Impressively, our model achieves accuracy rates of 99.47%, 99.10% and 99.70% for ADNI1: Complete 1Yr 1.5T, MIRAID and OASIS datasets, respectively, outperforming existing systems in binary class problems. Our proposed model represents a significant advancement in the AD-analysis domain.
PubMed: 38921618
DOI: 10.3390/jimaging10060141 -
Biomimetics (Basel, Switzerland) Jun 2024The brain is the most complex organ in the human body and, as such, its study entails great challenges (methodological, theoretical, etc.). Nonetheless, there is a... (Review)
Review
The brain is the most complex organ in the human body and, as such, its study entails great challenges (methodological, theoretical, etc.). Nonetheless, there is a remarkable amount of studies about the consequences of pathological conditions on its development and functioning. This bibliographic review aims to cover mostly findings related to changes in the physical distribution of neurons and their connections-the connectome-both structural and functional, as well as their modelling approaches. It does not intend to offer an extensive description of all conditions affecting the brain; rather, it presents the most common ones. Thus, here, we highlight the need for accurate brain modelling that can subsequently be used to understand brain function and be applied to diagnose, track, and simulate treatments for the most prevalent pathologies affecting the brain.
PubMed: 38921242
DOI: 10.3390/biomimetics9060362 -
Journal of Chemical Information and... Jun 2024The coexistence of amyloid-β (Aβ) and human islet amyloid polypeptide (hIAPP) in the brain and pancreas is associated with an increased risk of Alzheimer's disease...
The coexistence of amyloid-β (Aβ) and human islet amyloid polypeptide (hIAPP) in the brain and pancreas is associated with an increased risk of Alzheimer's disease (AD) and type 2 diabetes (T2D) due to their coaggregation and cross-seeding. Despite this, the molecular mechanisms underlying their interaction remain elusive. Here, we systematically investigated the cross-talk between Aβ and hIAPP using atomistic discrete molecular dynamics (DMD) simulations. Our results revealed that the amyloidogenic core regions of both Aβ (Aβ and Aβ) and hIAPP (hIAPP and hIAPP), driving their self-aggregation, also exhibited a strong tendency for cross-interaction. This propensity led to the formation of β-sheet-rich heterocomplexes, including potentially toxic β-barrel oligomers. The formation of Aβ and hIAPP heteroaggregates did not impede the recruitment of additional peptides to grow into larger aggregates. Our cross-seeding simulations demonstrated that both Aβ and hIAPP fibrils could mutually act as seeds, assisting each other's monomers in converting into β-sheets at the exposed fibril elongation ends. The amyloidogenic core regions of Aβ and hIAPP, in both oligomeric and fibrillar states, exhibited the ability to recruit isolated peptides, thereby extending the β-sheet edges, with limited sensitivity to the amino acid sequence. These findings suggest that targeting these regions by capping them with amyloid-resistant peptide drugs may hold potential as a therapeutic approach for addressing AD, T2D, and their copathologies.
PubMed: 38921060
DOI: 10.1021/acs.jcim.4c00859