7202 research outputs found
Sort by
Clinical effect of occipitocervical and subaxial cervical fusion constructs on range of motion: comprehensive guide based on biomechanical cadaveric testing on 1009 motion segments
No full textOBJECTIVE: Understanding the relative contribution of each cervical motion segment is vital for assessing the effect of fusion constructs on range of motion (ROM). Many spine surgeons are familiar with the work of Panjabi and White, from which these values have historically been cited. However, their data were obtained from a limited number of subjects, and methodological shortcomings have since been identified. In this study, the authors sought to improve understanding of segmental ROM using data from standardized biomechanical tests involving a large number of intact cervical spine specimens. METHODS: Flexibility data from 1009 cervical spine motion segments from 286 cadaveric spine specimens spanning the occiput (Occ)-T1 were analyzed. Specimens were subjected to standardized pure moment flexibility tests and loaded to 1.5 Nm in 3 anatomical axes: flexion-extension, axial rotation, and lateral bending. Intervertebral ROM was measured optoelectronically. Hypothetical ROM values of various fusion constructs were calculated, assuming complete loss of segmental ROM across treated segments and lack of compensatory changes in ROM for unfused segments. RESULTS: The overall mean ROM values for the entire cervical spine (Occ-T1) in flexion-extension, axial rotation, and lateral bending were 109.8°, 79.3°, and 37.7°, respectively. The greatest segmental contribution to flexion-extension ROM was the Occ-C1 joint (24% of overall ROM) at a mean (SD) of 26.4° (6.4°), which differed significantly from the values of all other levels (p \u3c 0.001). In axial rotation, C1-2 contributed 53% of overall ROM (41.6° [14.7°]) (all p \u3c 0.001). C3-4 accounted for 16% of lateral bending ROM (5.9° [1.9°]). Cervical ROM after hypothetical Occ-C2 fusion was 59% of the ROM of the unfused spine in flexion-extension, 36% in axial rotation, and 76% in lateral bending. Fusion from C2 to T1 maintained 41% of ROM in flexion-extension, 64% in axial rotation, and 24% in lateral bending. Increasing the length of a subaxial fusion construct leads to a steady decrease in the remaining ROM in all 3 planes of movement. CONCLUSIONS: This study demonstrates the segmental ROM values of the intact cervical spine and evaluates the calculated effects of cervical instrumentation on regional ROM based on data from the largest reported number of similarly tested cervical motion segments. These findings can help surgeons to plan surgery and counsel patients regarding the clinical effect of cervical fusion on ROM
Detection of Epileptogenic Focal Cortical Dysplasia Using Graph Neural Networks: A MELD Study.
No full textIMPORTANCE: A leading cause of surgically remediable, drug-resistant focal epilepsy is focal cortical dysplasia (FCD). FCD is challenging to visualize and often considered magnetic resonance imaging (MRI) negative. Existing automated methods for FCD detection are limited by high numbers of false-positive predictions, hampering their clinical utility.
OBJECTIVE: To evaluate the efficacy and interpretability of graph neural networks in automatically detecting FCD lesions on MRI scans.
DESIGN, SETTING, AND PARTICIPANTS: In this multicenter diagnostic study, retrospective MRI data were collated from 23 epilepsy centers worldwide between 2018 and 2022, as part of the Multicenter Epilepsy Lesion Detection (MELD) Project, and analyzed in 2023. Data from 20 centers were split equally into training and testing cohorts, with data from 3 centers withheld for site-independent testing. A graph neural network (MELD Graph) was trained to identify FCD on surface-based features. Network performance was compared with an existing algorithm. Feature analysis, saliencies, and confidence scores were used to interpret network predictions. In total, 34 surface-based MRI features and manual lesion masks were collated from participants, 703 patients with FCD-related epilepsy and 482 controls, and 57 participants were excluded during MRI quality control.
MAIN OUTCOMES AND MEASURES: Sensitivity, specificity, and positive predictive value (PPV) of automatically identified lesions.
RESULTS: In the test dataset, the MELD Graph had a sensitivity of 81.6% in histopathologically confirmed patients seizure-free 1 year after surgery and 63.7% in MRI-negative patients with FCD. The PPV of putative lesions from the 260 patients in the test dataset (125 female [48%] and 135 male [52%]; mean age, 18.0 [IQR, 11.0-29.0] years) was 67% (70% sensitivity; 60% specificity), compared with 39% (67% sensitivity; 54% specificity) using an existing baseline algorithm. In the independent test cohort (116 patients; 62 female [53%] and 54 male [47%]; mean age, 22.5 [IQR, 13.5-27.5] years), the PPV was 76% (72% sensitivity; 56% specificity), compared with 46% (77% sensitivity; 47% specificity) using the baseline algorithm. Interpretable reports characterize lesion location, size, confidence, and salient features.
CONCLUSIONS AND RELEVANCE: In this study, the MELD Graph represented a state-of-the-art, openly available, and interpretable tool for FCD detection on MRI scans with significant improvements in PPV. Its clinical implementation holds promise for early diagnosis and improved management of focal epilepsy, potentially leading to better patient outcomes
A Critical Appraisal of the Application of Frailty and Sarcopenia in the Spinal Oncology Population
No full textSTUDY DESIGN: Systematic review and clinimetric analysis. OBJECTIVES: Frailty and sarcopenia predict worse surgical outcomes among spinal degenerative and deformity-related populations; this association is less clear in the context of spinal oncology. Here, we sought to identify frailty and sarcopenia tools applied in spinal oncology and appraise their clinimetric properties. METHODS: A systematic review was conducted from January 1, 2000, until June 2022. Study characteristics, frailty tools, and measures of sarcopenia were recorded. Component domains, individual items, cut-off values, and measurement techniques were collected. Clinimetric assessment was performed according to Consensus-based Standards for Health Measurement Instruments. RESULTS: Twenty-two studies were included (42 514 patients). Seventeen studies utilized 6 frailty tools; the three most employed were the Metastatic Spine tumor Frailty Index (MSTFI), Modified Frailty Index-11 (mFI-11), and the mFI-5. Eight studies utilized measures of sarcopenia; the three most common were the L3-Total Psoas Area (TPA)/Vertebral Body Area (VBA), L3-TPA/Height, and L3-Spinal Muscle Index (L3-Cross-Sectional Muscle Area/Height). Frailty and sarcopenia measures lacked or had uncertain content and construct validity. Frailty measures were objective except the Johns-Hopkins Adjusted Clinical Groups. All tools were feasible except the Hospital Frailty Risk Score (HFRS). Positive predictive validity was observed for the HFRS and in select studies employing the mFI-5, MSTFI, and L3-TPA/VBA. All frailty tools had floor or ceiling effects. CONCLUSIONS: Existing tools for evaluating frailty and sarcopenia among patients undergoing surgery for spinal tumors have poor clinimetric properties. Here, we provide a pragmatic approach to utilizing existing frailty and sarcopenia tools, until more clinimetrically robust instruments are developed
Motor correlates of finger tapping variability in subjective memory complaints, mild cognitive impairment and probable Alzheimer\u27s disease
No full textBACKGROUND: Variability of finger tapping speeds, especially in the non-dominant hand, has been reported in individuals with amnestic mild cognitive impairment (MCI-A) and dementia of the Alzheimer\u27s type (AD). An explanation of this finding, however, has not appeared. OBJECTIVE: The aim of this study was to investigate possible motor correlates of finger tapping variability in normal older healthy controls (HC), persons with subjective memory complaints (SMC), MCI-A and probable AD. METHODS: Using a modified version of the Halstead Finger Tapping Test (HFTT), individual finger tapping movements were classified as valid (i.e., advanced the number on a mechanical counter) or invalid (i.e., did not advance the number). Failures at selective motor inhibition and learning and fatigue effects were also measured. RESULTS: Finger tapping variability was significantly greater in the non-dominant hand in probable AD patients compared to HC and SMC patients. MCI-A and probable AD patients did not differ on this measure. Finger tapping variability was significantly correlated (ρ = + 0.65) with the number of invalid tapping responses but not with selective motor inhibition failures. A small but significant correlation of dominant hand learning effect with finger tapping variability was found. Invalid tapping responses were significantly greater in MCI and probable AD groups compared to HC and SMC groups. CONCLUSIONS: Frequency of invalid tapping responses strongly correlated with finger tapping variability. The number of invalid tapping responses may have diagnostic and prognostic significance when evaluating older individuals with known or suspected memory impairment of a neurodegenerative type
Blarcamesine for the treatment of Early Alzheimer\u27s Disease: Results from the ANAVEX2-73-AD-004 Phase IIB/III trial
No full textBACKGROUND: There are no approved oral disease-modifying treatments for Alzheimer\u27s disease (AD). OBJECTIVES: The objective of this study was to assess efficacy and safety of blarcamesine (ANAVEX®2-73), an orally available small-molecule activator of the sigma-1 receptor (SIGMAR1) in early AD through restoration of cellular homeostasis including autophagy enhancement. DESIGN: ANAVEX2-73-AD-004 was a randomized, double-blind, placebo-controlled, 48-week Phase IIb/III trial. SETTING: Multicenter - 52 medical research centers/hospitals in 5 countries. INTERVENTION: 508 participants with early AD (Stage 3) were randomized to receive either blarcamesine (n = 338) in medium dose group 30 mg or in high dose group 50 mg or placebo (n = 170) oral capsules once daily for 48 weeks. Participants in these groups were offered to enroll into the open-label-extension study ATTENTION-AD, which completed June 2024, ClinicalTrials.gov Identifier NCT04314934. MEASUREMENTS: The co-primary cognitive and functional outcomes were assessed as change in ADAS-Cog13 and ADCS-ADL from baseline to 48 weeks. The outcomes include the secondary outcome CDR-SB and biomarkers from the A/T/N spectrum, plasma Aβ42/40-ratio and global brain volume changes measured by MRI. All clinical endpoints were analyzed using mixed model for repeated measures (MMRM), plasma biomarker measurements were analyzed by Welch\u27s t-test, and volumetric MRI scans were analyzed by general linear model. RESULTS: Among 462 randomized participants in the intent-to-treat population (mean age, 73.7 years; 225 [48.7%] women), 338 (73.2%) completed the trial. The co-primary outcome was met under the multiplicity control rule, since the differences in the least-squares mean (LSM) change from baseline to 48 weeks between the prespecified blarcamesine and placebo groups for ADAS-Cog13 was significant at a level of P \u3c 0.025 and for CDR-SB was significant at a level of P \u3c 0.025, while ADCS-ADL did not reach significance at Week 48 (ADAS-Cog13 difference of -2.027 [95% CI -3.522 to -0.533]; P = 0.008; CDR-SB difference of -0.483 [95% CI -0.853 to -0.114]; P = 0.010; ADCS-ADL difference of 0.775 [95%CI -0.874 to 2.423]; P = 0.357). Plasma Aβ42/40-ratio increased significantly with blarcamesine group vs. placebo, (P = 0.048) and whole brain volume loss was significantly decreased (P = 0.002). Participants in the full safety population with ≥1 serious treatment-emergent adverse events (TEAEs) occurred in 56 participants (16.7%) in the blarcamesine and 17 (10.1%) in the placebo group. Common TEAEs included dizziness, which was transient and mostly mild to moderate in severity. One death in the blarcamesine group and 1 in the placebo group were both not considered treatment related. CONCLUSIONS: Blarcamesine, demonstrating a safety profile with no associated neuroimaging adverse events, significantly slowed clinical progression by 36.3% at 48 weeks with blarcamesine group as well as the individual 30 mg (by 34.6%) and 50 mg (by 38.5%) blarcamesine groups vs. placebo on the prespecified primary cognitive endpoint ADAS-Cog13. The prespecified secondary endpoint CDR-SB, which is used as the sole primary endpoint in recent successful AD drug submissions, is significantly improved at Week 48 with blarcamesine relative to placebo. The findings are supported by biomarkers from the A/T/N spectrum, including plasma Aβ42/40-ratio and reduction of whole brain atrophy. Additionally, the prespecified SIGMAR1 gene variant subgroup analysis confirmed beneficial clinical effect of blarcamesine group through upstream SIGMAR1 activation - subjects with the common SIGMAR1 wild-type gene (excluding carriers of the mutated SIGMAR1 rs1800866 variant) experienced an even greater significant clinical benefit with slowed clinical progression by 49.8% at 48 weeks on the prespecified primary cognitive endpoint ADAS-Cog13. Oral once daily blarcamesine could represent a novel treatment in early AD and be complementary or alternative to anti-beta amyloid drugs
Cropland associated with risk of Parkinson\u27s disease in the northern Great Plains
No full textINTRODUCTION: We sought to identify regional associations between cropland density and crop types and PD in the U.S. METHODS: We conducted a population-based study of 21,639,190 Medicare beneficiaries, 89,790 with incident PD in 2009. We used county-level geographic weighted regression (GWR) to identify region(s) of the U.S. where the association between PD RR and cropland density was strongest. In a broad region identified by GWR in which cropland density was associated with PD, we performed logistic regression using individual-level beneficiary data (2733 cases and 805,984 non-cases) with high-resolution cropland density data. We adjusted for age, sex, race, smoking, healthcare utilization, and PM (particulate matter \u3c2.5 μm). We then explored PD-cropland associations for each type of crop within a subregion, in which the association was the strongest. RESULTS: GWR identified a 9-state region in the Great Plains in which county-level cropland density and PD RR were associated. Within this region, the strongest GWR coefficients centered around the Williston Basin. High-resolution analysis demonstrated an association between cropland density within a 5-mile radius of residential zip+4 and PD. When comparing the highest to lowest quartile of cropland density, the odds ratio (OR) for PD was 1.14 (95 % confidence interval [CI] 1.01-1.27) in the 9-state region and 1.99 (95 % CI 1.09-3.61) in the Williston Basin. In the Williston Basin, percentage of sunflowers, winter wheat, and alfalfa within 5 miles of a beneficiary\u27s zip+4 was associated with PD. CONCLUSION: We identified a region-specific association between cropland and crop type and PD in the Williston Basin
Hippocampal Atrophy on Magnetic Resonance Imaging as a Surrogate Marker for Clinical Benefit and Neurodegeneration in Early Symptomatic Alzheimer\u27s Disease: Synthesis of Evidence from Observational and Interventional Trials
No full textAmyloid-plaque reduction is currently the only recognized surrogate outcome for Alzheimer\u27s disease (AD) trials, allowing accelerated approval of plaque-clearing amyloid antibodies. However, plaque reduction does not facilitate the development of new non-plaque-clearing treatments. The hippocampus is among the first brain regions affected by AD pathology, exhibiting synaptic dysfunction and neurodegeneration that manifests as hippocampal atrophy and memory decline. We evaluated hippocampal volume (HV) as a potential surrogate outcome that can predict clinical benefit in disease-modification trials. Using published data from observational and interventional studies that examined both cognition and HV on volumetric magnetic resonance imaging (vMRI), we evaluated the cross-sectional correlations of HV to cognitive performance, the longitudinal correlations of HV atrophy to cognitive decline, HV sensitivity to drug effects, and the correlations between drug effects on HV atrophy and cognitive decline. We also examined the magnitude of HV protection that corresponds to meaningful clinical benefit. Analyses from 30 observational studies encompassing 13,187 individuals (2633 cognitively normal; 10,554 early AD) showed significant cross-sectional correlations between baseline HV and cognition, and longitudinal correlations between HV atrophy and cognitive decline over ≥ 1 year. The relationship of HV-cognitive drug effects was examined at the group level in nine placebo-controlled trials of five antiamyloid agents that evaluated HV in early AD trials of at least 18 months\u27 duration. These trials included four amyloid antibodies (aducanumab, lecanemab, donanemab, and gantenerumab) and one oral anti-oligomer agent (valiltramiprosate). Individual-level HV-cognition relationships were examined in two valiltramiprosate studies, one of which included diffusion tensor imaging (DTI) providing microstructural correlates of HV drug effects and helping distinguish neuroprotection from brain edema. Across these anti-amyloid drug trials (total N ~10,000), there was a linear relationship between drug effects on slowing of cognitive decline and slowing of HV atrophy. Two anti-oligomer trials (valiltramiprosate) reported significant subject-level correlations between drug effects on HV and cognition over 18-24 months (r = -0.40 to -0.44, p \u3c 0.005, N = 50/69), with significant correlations of drug effects on brain microstructure (decreased mean diffusivity) with both HV and cognitive benefits, supporting reduced neurodegeneration. The minimal HV preservation at the mild cognitive impairment (MCI) stage that is associated with clinical benefit is estimated to be ≥ 40 mm or ≥ 10% of atrophy in the placebo arm over 18 months. Our findings demonstrate that hippocampal atrophy is an early indicator of cognitive decline in AD, linked to amyloid and tau-related neurodegeneration. HV on standardized vMRI is sensitive to anti-amyloid treatments, demonstrating strong correlations between slowed hippocampal atrophy and slowed cognitive decline. Data from over 23,000 subjects over three decades support HV as a surrogate marker for predicting clinical benefit in early symptomatic AD
Multicenter Expanded Access Protocol for Research Through Access to Trehalose in People With Amyotrophic Lateral Sclerosis
No full textINTRODUCTION/AIMS: Expanded access protocols (EAPs) allow individuals ineligible for clinical trials to receive investigational products. EAP data can be collected in parallel to randomized clinical trials (RCTs) and serve as a source of evidence in clinical practice. Here, we present the results of a National Institutes of Health (NIH)-funded EAP for amyotrophic lateral sclerosis (ALS). METHODS: Participants received trehalose, a drug studied in a parallel RCT, for up to 24 weeks; clinical and biomarker data were collected throughout the study. RESULTS: Seventy participants were enrolled at 20 study centers across the United States. Treatment with trehalose did not affect the levels of neurofilament light chain [estimated flat slope per month was -0.005, SE = 0.0078; 95% CI (-0.021, 0.011)] or disease progression [estimated least square mean change of the ALS Functional Rating Scale-Revised total score and slow vital capacity (percent predicted) from baseline to Week 24 were -5.6 (0.67); 95% CI (-7.0, -4.3) and -4.53 (4.308); 95% CI (-13.55, 4.48)], respectively. No unexpected treatment-related risks were identified. Serious adverse events were deemed not related to trehalose (20 occurrences in 13 [18.6%] participants with eight deaths). DISCUSSION: This EAP establishes a framework for implementing multi-center EAPs that complement data collected from RCTs. Additional NIH-funded EAPs are currently underway. Data and additional serum samples collected in this study are available to the research community for further study. TRIAL REGISTRATION: ClinicalTrials.gov: NCT05597436
MyEveryCise: A method for everyday exercise using \u27an activity of daily living\u27 as a cue
No full textRegular engagement in physical activity is recognized as an effective prevention strategy for both cognitive and physical decline. We developed MyEveryCise, an exercise program that uses an activity of daily living as a cue to encourage regular physical exercise. This exploratory study assessed the effectiveness of MyEveryCise in increasing the persistence in light exercise in twenty persons with low physical activity in a one-month intervention. Using the physical activity questionnaire, we observed a significant increase in the frequency and duration of light physical exercise after the intervention, suggesting that MyEveryCise is a useful method to maintain a daily exercise routine
Perspective: Minimally clinically important symptomatic benefit associated with disease modification resulting from anti-amyloid immunotherapy
No full textUNLABELLED: Despite some skepticism regarding the amyloid hypothesis, there is growing evidence that clearing amyloid by targeting specific species of amyloid (plaque, oligomers, fibrils, and protofibrils) for removal has therapeutic benefits. Specifically, there is growing evidence that, in mild cognitive impairment and mild dementia due to Alzheimer\u27s disease (AD), robust and aggressive removal of amyloid can slow cognitive decline as measured by global instruments, composite measures, and cognitive testing. Furthermore, clinical efficacy signals coupled with clear biomarker changes provide the first evidence of disease modification. This effect seems to be in addition to symptomatic treatments and opens speculation that the effect of anti-amyloid monoclonal antibodies might be clinically meaningful through symptomatic amelioration that is a result of disease modification. HIGHLIGHTS: Clearance of brain amyloid plaques may lead to a clinical benefit in patients with early AD.Aggregated Aβ may play a role in both disease expression and progression.Anti-amyloid monoclonal antibodies might be clinically meaningful through symptomatic amelioration resulting from disease modification