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Patterns of Factors in the National Institute on Aging Health Disparities Research Framework Domains and Mild Cognitive Impairment Risk
No full textINTRODUCTION: Alzheimer\u27s disease and related dementias are public health and social care challenges. This study used the National Institute on Aging Health Disparities Research Framework to organize potential cognitive impairment risk factors. It aimed to examine patterns of environmental, sociocultural, behavioral, and biological factors and identify key components that predict mild cognitive impairment risk. METHODS: This study comprised 2,812 participants from the Mayo Clinic Study of Aging who were cognitively unimpaired at baseline (aged ≥50 years, mean age [SD]=68.9 [9.7] years, 50.4% female). Analyses utilized a 2-stage approach using factor and principal component analyses to group factors from multiple National Institute on Aging Health Disparities Research Framework domains and identify components that predict cognitive impairment risk. Using a cohort study design, the resulting composite scores were considered as covariates for incident mild cognitive impairment analysis using Cox proportional hazards models. RESULTS: Three principal components explained 40.30% of the variance and were differentially associated with mild cognitive impairment risk. One component (Principal Component 2), which included factors from all 4 domains of the National Institute on Aging Health Disparities Research Framework (including social, group, and playing game activities [sociocultural domain]; exercise and physical activity [behavioral domain]; education/occupation [environmental domain]; and absence of cardiometabolic risk factors/health self-rating [biological domain]), was associated with lower mild cognitive impairment risk (hazard ratio=0.80, 95% CI=0.73, 0.89). The other 2 principal components, also including factors from multiple framework domains, were associated with increased mild cognitive impairment risk. CONCLUSIONS: Derived principal components included factors from multiple framework domains, supporting the multietiology pathways leading to cognitive impairment. These principal components were differentially associated with mild cognitive impairment risk. Identifying key factors from multiple National Institute on Aging Health Disparities Research Framework domains associated with cognitive impairment risk has implications for effectively targeting interventions at multiple levels (e.g., medical, societal, policy) to avert or delay cognitive impairment risk
Physical activity and the outcome of cognitive trajectory: a machine learning approach
No full textBACKGROUND: Physical activity (PA) may have an impact on cognitive function. Machine learning (ML) techniques are increasingly used in dementia research, e.g., for diagnosis and risk stratification. Less is known about the value of ML for predicting cognitive decline in people with dementia (PwD). The aim of this study was to use an ML approach to identify variables associated with a multimodal PA intervention that may impact cognitive changes in PwD, i.e., by distinguishing between cognitive decliners and non-decliners. METHODS: This is a secondary, exploratory analysis using data from a Randomized Controlled Trial that included a 16-week multimodal PA intervention for the intervention group (IG) and treatment as usual for the control group (CG) in nursing homes. Predictors included in the ML models were related to the intervention (e.g., adherence), physical performance (e.g., mobility, balance), and pertinent health-related variables (e.g., health status, dementia form and severity). Primary outcomes were global and domain-specific cognitive performance (i.e., attention/ executive function, language, visuospatial skills, memory) assessed by standardized tests. A Support Vector Machine model was used to perform the classification of each primary outcome into the two classes of decline and non-decline. GridSearchCV with fivefold cross-validation was used for model training, and area under the ROC curve (AUC) and accuracy were calculated to assess model performance. RESULTS: The study sample consisted of 319 PwD (IG, N = 161; CG, N = 158). The proportion of PwD experiencing cognitive decline, in the different domains measured, ranged from 27-48% in CG, and from 23-49% in IG, with no statistically significant differences and no time*group effects. ML models showed accuracy and AUC values ranging from 40.6-75.6. The strongest predictors of cognitive decline or non-decline were performance of activities of daily living in IG and CG, and adherence and mobility in IG. CONCLUSIONS: ML models showed moderate performance, suggesting that the selected variables only had limited value for classification, with adherence and performance of activities of daily living appearing to be predictors of cognitive decline. While the study provides preliminary evidence of the potential use of ML approaches, larger studies are needed to confirm our observations and to include other variables in the prediction of cognitive decline, such as emotional health or biomarker abnormalities
Polygenic Vulnerability to Intracranial Hypertension, Hemorrhage Progression, and Outcome in Traumatic Brain Injury
No full textOBJECTIVE: Growing evidence underscores the importance of host-response/secondary-injury-likely influenced by genetics-in outcome variability post-traumatic brain injury (TBI). Intracranial hypertension and hemorrhage progression are critical secondary injuries in severe TBI; these are mediated by the SUR1-TRPM4 channel (a target in clinical trials). We aimed to deconstruct the complex network surrounding SUR1-TRPM4 and define the cumulative impact of key genetic variants on mechanistically connected secondary injuries/outcomes after severe TBI. METHODS: This exploratory study analyzed 492 prospectively enrolled patients with severe TBI. A network of regulators, mediators, and effectors upstream/downstream of SUR1-TRPM4 was bioinformatically constructed. Single nucleotide variants (SNVs) were evaluated for multivariable model association with intracranial pressure, intraparenchymal hemorrhage progression, and Glasgow Outcome Scale (GOS) score. Weighted/unweighted polygenic-risk scores (PRS) were constructed and interrogated. Spatial modeling and functional predictions were determined. Single-cell cortical transcriptomic differences were assessed in a parallel murine TBI model. RESULTS: Ninety-seven genes (625 SNVs) were analyzed. Nineteen genes contained variants associated with all outcomes (intracranial pressure, hemorrhage progression, and GOS score; p \u3c 0.05). Twenty-two genes (42 SNVs) retained significance for ≥ 1 outcome, with overlap across outcomes. Functions included Ca-transport/signaling, glutamate-clearance, neuroinflammation, and cell death. Single-cell analyses revealed cell-specific gene-expression differences. SNVs were brain-specific cis-expression quantitative trait locus (eQTLs)/missense/frameshift mutations suggesting high likelihood of biological impact. PRSs were associated with all outcomes with large effects, and markedly improved model explanatory power/performance (R, receiver operating characteristic [ROC]). INTERPRETATION: Polygenic variability in key nodes linked to SUR1-TRPM4 were associated with mechanistically related secondary injuries and outcome after severe TBI; findings suggest a major role of heritability. Functional implications indicate biological plausibility and identify novel targets. The data, whereas requiring validation, support a shift toward incorporating biologically relevant genetics in advancing precision medicine. ANN NEUROL 2025
Real-world use of diagnostic tests for mild cognitive impairment, Alzheimer\u27s disease, and other dementias in Medicare fee-for-service beneficiaries
No full textINTRODUCTION: This study assessed real-world use of diagnostic tests, such as neuroimaging (e.g., magnetic resonance imaging [MRI], or positron emission tomography [PET]), and computed tomography (CT), cerebrospinal fluid (CSF) biomarker, and blood tests for mild cognitive impairment (MCI), Alzheimer\u27s disease (AD), and other dementias in a large US elderly population. METHODS: Medicare fee-for-service data (2015-2020) were used to identify patients aged ≥ 67 newly diagnosed with MCI, AD, or other dementias. Descriptive analyses were conducted to understand the test use within 1 year before disease diagnosis and trends. RESULTS: Among 653,420 patients (9.1% MCI, 30.3% AD, 60.6% other dementias), 71.9% had blood tests, 53.9% neuroimaging (46.4% CT, 17.7% MRI, and 0.7% PET), and 2.2% CSF test. Test use slightly increased from 2015 to 2020. DISCUSSION: Findings from this study suggest low use of diagnostic tests, especially PET and CSF. HIGHLIGHTS: Blood tests, magnetic resonance imaging, and computed tomography were predominant for diagnosing mild cognitive impairment, Alzheimer\u27s disease, or other dementias prior to the arrival of disease-modifying therapies.Cerebrospinal fluid biomarker and positron emission tomography tests were infrequently used despite their diagnostic value.The study indicates a modest increase in diagnostic test usage over 6 years between 2015 and 2020.Patients often received combined or repeated diagnostic tests
Assessment of microstructural changes in white matter hyperintensities in aging and mild cognitive impairment revealed by advanced diffusion MRI
No full textBACKGROUND: White matter hyperintensities (WMHs) are common in older adults and appear as abnormal signal on T2-weighted or fluid-attenuated inversion recovery (FLAIR) magnetic resonance imaging (MRI). They are often linked to demyelination, axonal damage, and gliosis, as well as vascular changes. WMHs occur in both normal aging and mild cognitive impairment (MCI), where they may contribute to cognitive decline. OBJECTIVE: The study objectives were to determine whether advanced diffusion MRI (dMRI) techniques can detect distinct microstructural changes within WMHs in individuals with MCI compared to healthy controls and to evaluate relationships between these measures and cognitive performance. METHODS: Advanced dMRI techniques were used to assess WMH microstructural changes in normal aging (n = 55) and MCI (n = 46) participants from the ADNI database. WMHs and their surrounding penumbra were identified using an automated approach. Microstructural characteristics, derived from free-water (FW) diffusion tensor imaging and diffusion kurtosis imaging, were evaluated between groups and white matter regions. Associations between these measures and cognitive performance (assessed by the Mini-Mental State Exam) were examined. RESULTS: Across both groups, WMHs showed higher FW and lower FW-fractional anisotropy and kurtosis metrics compared to normal-appearing white matter, indicating widespread microstructural alterations. No groupwise microstructural differences were observed within corresponding tissue types. In the MCI group, kurtosis metrics within WMHs correlated with cognitive performance. CONCLUSIONS: These findings highlight the complexity of WMH-related microstructural changes and suggest that advanced dMRI biomarkers may offer valuable insights into the role of white matter changes in aging and cognitive decline
Frontal cortex pyramidal neuron expression profiles differentiate the prodromal stage from progressive degeneration across the Alzheimer\u27s disease spectrum
No full textINTRODUCTION: Underlying causes of Alzheimer\u27s disease (AD) remain unknown, making it imperative to identify molecular mechanisms driving the pathobiology of AD onset and progression. METHODS: Laser capture microdissection was used to isolate layer III pyramidal neurons from post mortem human prefrontal cortex (Brodmann area 9). Single population RNA sequencing was conducted using tissue from subjects with no cognitive impairment (NCI), mild cognitive impairment (MCI), and AD. Differentially expressed genes (DEGs) were compared across groups. RESULTS: DEGs increased from prodromal (MCI vs. NCI) to progression (AD vs. MCI) to frank AD (AD vs. NCI). The majority of DEGs and pathways shared between prodromal and progression exhibited a change in the direction of dysregulation unlike pathways between progression and frank AD. DISCUSSION: Candidate genes and pathways were identified that demarcate early-stage AD onset from AD progression, providing a roadmap to study cortical cellular vulnerability and key targets for intervention at early stages of AD. HIGHLIGHTS: Pyramidal neuron differentially expressed genes (DEGs) are directionally divergent between prodromal, progression, and frank Alzheimer\u27s disease (AD). Pyramidal neuron DEGs are directionally convergent between progression and frank AD. Dysfunctional bioenergetic pathways increased dysregulation as the AD spectrum progressed. Immune response pathways were more dysregulated in frank AD than prodromal stages. DEGs, = biological pathways, and interactomes demarcate specific stages across the AD spectrum
Optimization of 3D-printed titanium interbody cage design. Part 2: An in vivo study of spinal fusion in sheep
No full textBACKGROUND CONTEXT: 3D-printed titanium cage designs can incorporate complex, porous features for bone ingrowth and a greater surface area for minimizing subsidence. In a companion study (Part 1), we determined that increased surface area leads to decreased subsidence; however, it remains unclear how increasing the cage surface area, resulting in a smaller graft aperture, influences fusion. PURPOSE: We evaluated the effects of surface area of 3D-printed titanium cages and the use of autologous bone grafts on spinal fusion in sheep. STUDY DESIGN: In vivo large animal study in 12 sheep. METHODS: Interbody fusion was performed in 12 adult sheep at 24 levels (L2-3 and L4-5) using 3D-printed titanium cages with bilateral pedicle screw fixation. The cage designs varied in aperture: standard (low endplate surface area), small (medium endplate surface area), or none (high endplate surface area). These cages were packed with autologous iliac crest bone grafts (ICBG). A fourth group was implanted without bone grafts, using the no-aperture cage. Fusion was evaluated at 16 weeks via manual palpation, microcomputed tomography (microCT), histology, and histomorphometry. RESULTS: Standard, small, and no-aperture cages packed with ICBG resulted in high fusion rates (80%, 100%, and 83%, respectively) at 16 weeks by manual palpation, and these results were not significantly different. Implantation without ICBG was associated with a significantly lower fusion rate (33%, p\u3c.05). Histological, histomorphometry, and microCT results supported the findings obtained by manual palpation; findings from these modalities showed new bone spanning the vertebral endplates in the spines graded as fused by manual palpation. CONCLUSIONS: Similar fusion results for standard, small, and no-aperture cage designs packed with ICBG suggest that aperture size does not influence fusion results in the sheep model. However, without ICBG grafting, fusion was significantly decreased, suggesting that graft material is necessary to predictably obtain fusion in this model. When the in vitro subsidence data (companion study, Part 1) is considered with the in vivo fusion data described here, porous 3D-printed titanium cages with maximal surface endplate contact and bone grafting perform favorably, resulting in low subsidence and high fusion rates. CLINICAL SIGNIFICANCE: 3D-printed porous titanium interbody cages are novel devices with increasing clinical use. The study results show that the aperture size of the interbody cage did not influence fusion in a large animal (sheep) model. The use of bone graft material was the most important variable affecting fusion. These data suggest that the clinical use of 3D Ti cages without graft material should be avoided
Suppression of Paclitaxel-Induced Neuropathy and Ovarian Tumor Growth by Mn Porphyrin, MnTnBuOE-2-PyP (BMX-001)
No full textNumerous cellular and animal studies demonstrated the ability of redox-active Mn(III) N-alkyl- and N-alkoxyalkylpyridyporphyrins (MnPs) to protect normal tissue while suppressing tumor growth. The mechanism primarily involves the modulation of NF-кB and Nrf2 signaling pathways via catalysis of MnP/HO-driven protein thiol oxidation. Such differential protection/suppression effects have paved the way of Mn porphyrins (commonly known as mimics of superoxide dismutase) into clinical trials, therefore introducing new line of therapeutics that are affecting cellular redox status/oxidative stress, rather than specific proteins. The most clinically advanced Mn porphyrin, Mn(III) meso-tetrakis(N-n-butoxyethyl-2-pyridyl) porphyrin (MnTnBuOE-2-PyP, BMX-001) has progressed into five Phase II clinical trials, two of those related to the injuries of central nervous system. Currently, no efficient treatment for chemotherapy-induced neuropathy is available in clinics. We therefore employed BMX-001 to assess its effect on paclitaxel (PTX)-induced neuropathy. Mechanical (Von-Frey filaments) and thermal (hot plate) stimulation, toxicity (body weight), muscular coordination and general physical condition (rotarod) of female CD-1 mice were evaluated over 3 weeks with 2 mg/kg daily dosing and also at clinically relevant dosing of 0.8 mg/kg given subcutaneously (SC) twice weekly after 1.6 mg/kg loading dose. Data revealed a significant ability of BMX-001 to suppress peripheral neuropathy and neuroinflammation. Importantly, while protecting peripheral tissue, BMX-001 suppressed the tumor growth of CAOV2 high-grade serous ovarian cancer in a mouse subcutaneous xenograft model. Previously, the strong anticancer effect was only seen when Mn porphyrins were combined with radiation, chemotherapy, and ascorbate (Asc). Our data further demonstrate that high-grade serous ovarian cancer is the first in vivo cancer thus far studied where redox-active Mn porphyrin, as a single agent, exhibits strong anticancer effect, comparable to that of PTX. The effect is presumably due to high tumor levels of BMX-001 and high oxidative stress specific to the aggressive chemoresistant CAOV2 cell line. Such a strong anticancer effect of BMX-001 would allow for lowering the dosing of PTX and reducing the neuropathy. The combined neuropathy protection and anticancer efficacy demonstrate, therefore, strong therapeutic potential of BMX-001 for gynecological cancers. Moreover, the ability of BMX-001 to suppress neuropathy may be relevant for all types of cancer where chemotherapeutics that induce neuropathy are used as a standard-of-care
Awake versus asleep deep brain stimulation for Parkinson\u27s disease: a comprehensive systematic review and meta-analysis
No full textOBJECTIVE: Deep brain stimulation (DBS) has become an effective and safe treatment in patients with Parkinson\u27s disease (PD) not responding to conventional treatments. With the growing body of literature regarding the use of DBS in different movement disorders, there remain controversies regarding performing awake or asleep DBS. This systematic review provides the most comprehensive review of the literature comparing the two techniques from various aspects in detail. METHODS: A systematic review of the PubMed, Scopus, Web of Science, and Cochrane Library databases was conducted. All studies comparing any aspects of asleep and awake DBS were included. Risk of bias was assessed using the Risk of Bias in Non-Randomized Studies of Interventions tool. Meta-analysis was conducted with consideration of baseline characteristics. RESULTS: Thirty-one studies with 2563 PD patients were included. A total of 1423 patients underwent asleep DBS. The two groups were comparable regarding their baseline characteristics. The follow-up ranged from 3 to 60 months. The two DBS techniques were comparable in terms of motor symptom improvements and levodopa equivalent daily doses. However, the asleep technique showed slightly better improvements in Mattis Dementia Rating Scale and Parkinson\u27s Disease Questionnaire scores. Moreover, the asleep technique was associated with more surgical adverse events, whereas pneumocephalus and psychological disorders such as mood, affect, and cognitive disorders were more common in the awake technique. Subgroup analyses revealed no significant differences in outcomes between asleep and awake DBS when categorized by targeted brain nuclei, use of intraoperative or preoperative imaging, and whether microelectrode recordings were used. CONCLUSIONS: These findings suggest comparable clinical outcomes between the two DBS approaches. The two methods had their salient differences in terms of lead passes and specific adverse events. The decision to perform awake or asleep DBS should be based on the patient\u27s preference, the surgeon\u27s experience, the availability of advanced intraoperative imaging, and the patient\u27s tolerance for specific adverse events
Tau, amyloid-β and α-synuclein co-pathologies synergistically enhance neuroinflammation and neuropathology
No full textAlzheimer\u27s (AD) and Parkinson disease (PD) pathology often co-occur. Amyloid-β and phosphorylated tau are found in 30-50% of idiopathic PD cases, while α-synuclein inclusions are present in 50% of AD cases. These co-pathologies are linked to increased mortality and earlier onset of cognitive decline. Immune activation is a hallmark of these neurodegenerative diseases, but current models primarily examine each pathology in isolation. How these co-pathologies drive inflammation and neuronal loss remains poorly understood. We therefore developed a mouse model combining tau, amyloid-β, and α-synuclein. We found that co-pathologies synergistically trigger an amplified neuroimmune response, with expanded populations of CD4 and CD8 tissue-resident memory T cells and CD68 microglia, compared to single pathologies. These changes were abundant in the hippocampus and cortex, regions with elevated protein pathology load and enhanced neuronal loss. Our findings demonstrate that co-pathologies enhance proteinopathy and synergistically enhance immune activation and neurodegeneration, suggesting that combinatorial therapeutic strategies that target both co-pathologies and inflammation, may be disease modifying