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Comprehensive analysis platform to understand, remedy, and eliminate amyotrophic lateral sclerosis (CAPTURE ALS): Study protocol for a Canadian multicenter, multimodal, longitudinal observational study
No full textBACKGROUND: The marked heterogeneity of Amyotrophic Lateral Sclerosis (ALS) combined with a lack of biomarkers are key contributing factors to the lack of disease-modifying treatments. The Comprehensive Analysis Platform to Understand Remedy and Eliminate ALS (CAPTURE ALS) is a Canadian platform designed to create the most comprehensive picture of people living with ALS with the objective of facilitating ALS research initiatives worldwide. OBJECTIVES: The main aims of CAPTURE ALS include: (1) to characterize ALS and healthy controls with biosamples and data in order to provide the most comprehensive picture of individuals living with ALS to date; (2) to create a de-identified database and biosample repository linked to detailed clinical information; and (3) to develop and implement an inclusive and transparent participant engagement strategy to be active throughout all stages of CAPTURE ALS. METHODS/RESULTS: CAPTURE ALS is a prospective, multicenter, observational, longitudinal study. People living with ALS, or a related disease and healthy controls undergo a harmonized protocol including the collection of detailed clinical information, neurological and cognitive examination, speech recording, advanced magnetic resonance imaging, and biosampling. Data and samples are stored in a biobank operating under an open science governance framework. An inclusive and transparent participant engagement strategy was designed and implemented throughout all stages of CAPTURE ALS. Four sites are operating in the consortium with a fifth being onboarded. The target enrollment is 120 affected participants and 50 controls, with the first participant visit having occurred in March 2022. Recruitment is ongoing. DISCUSSION: CAPTURE ALS is a scalable clinical research platform that connects scientists and patients to facilitate efficient translational research. The unique and deeply phenotyped data and biosamples are a global resource towards the development of biomarkers and understanding ALS biology. This study is registered at clinicaltrials.gov (NCT: NCT05204017)
Neuronal gene profiling of tau oligomer-bearing cholinergic nucleus basalis neurons during the onset of Alzheimer\u27s disease
No full textSoluble tau oligomeric assemblies display neurotoxic properties and may provide a pathogenic link between neurofibrillary tangle evolution and selective neuronal vulnerability in Alzheimer\u27s disease (AD). However, the precise molecular and cellular pathways mediating tau oligomer toxicity are unclear. We combined single-neuron laser capture microdissection with custom microarrays to investigate differences in the molecular signatures of basal forebrain neurons within the nucleus basalis of Meynert (nbM) labeled for p75, a cholinergic cell marker, or dual-labeled for p75 and TOC1, a tau oligomer marker. Tissue was obtained postmortem from Rush Religious Orders Study participants who died with an antemortem clinical diagnosis of no cognitive impairment (NCI), mild cognitive impairment (MCI), or mild/moderate AD. Using clinical diagnosis as a covariate to isolate tau oligomer-specific mechanisms, we identified 140 differentially expressed genes (DEGs) in p75 + /TOC1 + cholinergic nbM neurons compared to p75 + /TOC1- neurons. STRING interactome and pathway analysis revealed that downregulated genes were associated with pre- and postsynaptic function, with additional enrichment in glutamate and acetylcholine signaling. By contrast, upregulated genes related to cellular stress responses and apoptosis were clustered with a subset of downregulated DEGs regulating mitochondrial metabolism and redox function, indicative of bioenergetic failure. Weighted gene co-expression correlation network analysis of the entire dataset revealed only two significantly correlated modules, which were either negatively correlated with the presence of TOC1 and enriched for synaptic signaling or positively correlated with TOC1 and enriched for cellular responses to hypoxia. These data show with single-neuron resolution that oligomeric tau formation in vulnerable cholinergic nbM neurons, even prior to MCI, is associated with the dysregulation of multiple classes of genes driving cell/mitochondrial stress and synaptic imbalances, which may be amenable for disease-modifying therapeutic approaches
A Systematic Review of Current Terminology for Conditions Preceding Degenerative Cervical Myelopathy: Evidence Synthesis to Inform an AO Spine Expert Opinion Statement
No full textStudy DesignSystematic review.ObjectivesThe pre-symptomatic state of Degenerative Cervical Myelopathy (DCM), wherein degenerative changes and spinal cord compression are seen without clinical findings, is poorly understood and inconsistently categorised. Clear identification may elucidate the temporality of DCM development. Therefore, a systematic assessment was undertaken of current terminology for pre-DCM states, with the objective of standardising definitions and informing an AO Spine expert position statement.MethodsMedline and Embase were searched for all studies on asymptomatic spinal compression or clinical findings preceding DCM, returning 3585 studies. After screening, 96 studies were included in the final analysis. The terminology used for pre-DCM states and their definitions were extracted, along with their frequencies or speciality/country of author in the literature.ResultsMultiple terms were used to represent pre-DCM stages, including asymptomatic (86 studies), non-myelopathic (26 studies), without myelopathy (15 studies), pre-symptomatic (9 studies) and sub-clinical (7 studies). asymptomatic was associated with the greatest inconsistency. Some defined this as patients with radiological signs of spinal degeneration with/without spinal cord compression but no clinical signs of myelopathy, whereas others used the term synonymously with healthy controls. This inconsistency is particularly challenging in clinical studies in which DCM patients are compared to those with pre-DCM states and/or healthy volunteers.ConclusionThere is substantial inconsistency in the terms used to describe pre-DCM states. There is no clear relationship between the terms used and the country or speciality of the main author. Standardised definitions for these disease states should be agreed and used in future studies
Repeatability and reliability of cerebrovascular reactivity in young adults using multi-echo, multi-contrast MRI
No full textCerebrovascular reactivity (CVR) shows promise as a biomarker of vascular integrity and may benefit from a repeatable, reliable, and microvasculature-sensitive acquisition. A combined spin- and gradient-echo (SAGE) functional MRI (fMRI) acquisition may improve repeatability and reliability compared to single spin- (SE) and gradient-echo (GRE) fMRI and provide a microvascular-weighted analysis. The most repeatable and reliable MRI acquisition CVR maps were compared across three CVR paradigms: a breath-hold task, a breath modulation task, and a resting state acquisition. SAGE-fMRI data was acquired in fifteen young adults at two timepoints. Mean gray matter (GM) within-subject coefficient of variation (wCV) and intraclass correlation coefficient (ICC) were compared within the quantitative and weighted SAGE-fMRI CVR maps and single GRE- and SE-fMRI CVR. Total and microvascular MRI inputs with lowest wCV and highest ICC were used to compare three CVR paradigms. Total and microvascular weighted SAGE-fMRI CVR had the lowest wCV and highest ICC across paradigms. The breath-hold paradigm produced significantly higher GM CVR estimates. SAGE repeatably and reliably measures CVR and offers a simultaneous, complementary analysis on total and microvascular scales. The breath-hold paradigm showed significantly higher CVR estimates, but less compliance-dependent protocols may be ideal for applications in patient populations
Predicting Post-Mortem α-Synuclein Pathology by the Combined Presence of Probable REM sleep behavior disorder and Hyposmia.
No full textBACKGROUND: Idiopathic rapid eye movement sleep behavior disorder (RBD) is a strong known predictor of a final clinicopathological diagnosis of a Lewy type α-synucleinopathy (LTS). Olfactory dysfunction is an early symptom of synucleinopathies and has been repeatedly associated with the presence of post-mortem LTS.
OBJECTIVE: To assess the combined value of a clinician diagnosis of probable RBD (PRBD) and hyposmia in predicting the post-mortem presence of LTS in a broader, less-selected, volunteer elderly population.
METHODS: We studied 652 autopsied subjects from the Arizona Study of Aging and Neurodegenerative Disorders, which were evaluated for PRBD, had completed annual movement and cognitive assessments, and had at least one the University of Pennsylvania Smell Identification Test (UPSIT) olfactory test.
RESULTS: Histological evidence of LTS was significantly more frequent in those who had PRBD (112/152: 73.7%) than those without (177/494: 35.8%) (P \u3c 0.001). LTS was more frequent in cases with PRBD and a low UPSIT score (90.8%) compared to cases with PRBD only (73.7%) (P \u3c 0.001) or cases with a low UPSIT score only (69.4%) (P \u3c 0.001). Sensitivity of PRBD diagnosis for predicting LTS was 38.8% and specificity 88.8%, whereas sensitivity of a low UPSIT score was 74.4% and specificity 73.4% (Youden\u27s index = 0.276 for PRBD, 0.478 for UPSIT). When combining both measures, sensitivity was 34.3% and specificity increased to 97.2%.
CONCLUSION: PRBD, diagnosed without sleep study confirmation, combined with a reduced olfactory performance is highly specific for predicting post-mortem presence of LTS. The combination of both measures may provide a cost-effective means of predicting LTS in a broader community
Histopathological analysis of duragen collagen matrix over time in humans.
No full textDuraGen is a widely used type I collagen matrix derived from bovine Achilles tendon that promotes fibroblast ingrowth and neovascularization. However, it remains unknown the time required for dura regeneration and reabsorption of the graft. We evaluate the histopathological characteristics of implanted DuraGen in humans across multiple time points. Patients who underwent a decompressive craniectomy and duraplasty with DuraGen at our institution between January 2020 and September 2021 were prospectively enrolled. At the time of the subsequent surgery, including cranioplasty, DuraGen and associated tissues removed from patients were sent for histopathological analysis. For each patient, time from index surgery to subsequent surgery was categorized into three groups: early (0-20 days), intermediate (21-30 days), and late (\u3e 30 days). Baseline characteristics, primary disease, operative time, complication rate, and histopathological findings were compared between groups. A total of 28 patients were enrolled in the study. Seven specimens (25.0%) were collected within 20 days after craniectomy, 9 specimens (35.7%) between 21 and 30 days, and 12 specimens (39.3%) over 31 days. Histopathologically, implanted collagen matrix, erythrocyte infiltration, and fibrin layer decreased over time, whereas fibroblasts and endogenous collagen increased. Receiver operating characteristic analysis showed that the cut-off time post-implantation for presence of endogenous collagen was 34 days after DuraGen implantation (area under the curve = 0.810). We found that DuraGen was replaced by fibroblast-derived endogenous collagen as early as 34 days post-implantation. Although certain findings remain to be further validated, the present study substantiates DuraGen as a reliable substitute, with findings derived from clinical outcomes and histopathological changes
Visual-Guided Transillumination Method for Accurate Percutaneous Tracheal Tube Placement
No full textBACKGROUND: Percutaneous tracheostomy (PT) is generally considered a safe procedure, but complications such as malpositioning, bleeding, and tracheal ring rupture remain concerns, particularly during initial needle insertion. This study investigates the feasibility, ease of use, and safety of a novel device and technique for bedside PT, named the Illuminated Tracheal Alignment Guide (iTAG). METHODS: An interventional pilot study evaluated the feasibility and safety of the iTAG device and method. The study was approved by our local institutional review board and a Food and Drug Administration waiver was granted for use of our device. Patients in a neurocritical care unit requiring tracheostomy were screened and consented for inclusion. Exclusion criteria included significant vascular overlap and specific ventilator settings. The iTAG method involves a laser light source and a needle guide with a hard stop, used in conjunction with standard PT equipment. Data on demographics, procedure details, and early complications were collected and compared with historical control data from patients who underwent standard tracheostomy (ST). RESULTS: From January 2023 to July 2024, 30 patients underwent PT using the iTAG device. The mean time from intubation to tracheostomy was 15.53 days, with a mean ICU length of stay of 31.14 days. The iTAG group experienced significantly fewer early complications compared with the historical ST control group, including reduced hemorrhage, and there were no instances of tracheal ring fracture, posterior wall injury, or pneumothorax. The iTAG method allowed for safe PT in all patients. CONCLUSIONS: The iTAG device enhances the safety and efficacy of PT by providing precise visualization and limiting needle penetration, reducing early complications. Its use expands patient candidacy for PT and offers a valuable tool for training less-experienced practitioners. Further research with larger cohorts and randomized controlled trials is needed to confirm these findings and establish the iTAG method as a standard of care for PT
A Rare Case of Microscopic Polyangitis With Associated Transient Hypophysitis
No full textGranulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA) are rare forms of antineutrophil cytoplasmic antibody-associated vasculitides, characterized by systemic inflammation and necrosis of small blood vessels, which can lead to multiorgan damage. GPA is identified by the presence of granulomas and serine proteinase-3 positivity, while MPA is marked by necrotizing vasculitis without granulomas and is associated with myeloperoxidase (MPO) positivity. Central nervous system involvement is more frequent in GPA, affecting 7% to 10% of patients, compared to its occurrence in approximately 1% of MPA cases. In this case report, we present a 41-year-old woman who exhibited symptoms of pituitary mass effect, initially suspected to be a macroadenoma. Further investigation revealed pituitary enlargement due to MPA, confirmed by positive MPO antibodies and lung biopsy findings consistent with MPA. After treatment with prednisone and rituximab, the patient\u27s pituitary gland returned to its normal size, with significant improvement in her symptoms. This case highlights the diagnostic complexities in differentiating MPA from more common causes of pituitary enlargement and underscores the necessity of considering vasculitic origins in similar clinical scenarios. Further research is essential to deepen the understanding of the pathophysiology and to optimize the management of pituitary involvement in MPA
Neuropsychological correlates of reduced self-awareness of functional competency in persons with subjective memory complaints, mild cognitive impairment, and early probable Alzheimer\u27s dementia
No full textOlder adults with subjective memory complaints (SMC) often underestimate their cognitive and related functional competencies, while patients with mild cognitive impairment (MCI) or early probable Alzheimer\u27s disease dementia (AD) often overestimate their cognitive and functional abilities. We predicted that both cognitive (i.e., executive and memory) and non-cognitive (i.e., affective and motor) test performance of patients would be associated with reduced awareness of their functional limitations. Ten participants with SMC, 16 with MCI, and 10 with probable early AD were compared on measures of self and relatives\u27 perceptions of their daily functional capacities. Reduced self-awareness was behaviorally assessed by subtracting the patient\u27s subjective ratings of their functional abilities from the relatives\u27 (or significant others\u27) ratings of their functional abilities. Reduced self-awareness of functional competencies correlated with measures of language and calculation skills, memory, affect perception and expression, finger tapping movements, and overall cognitive status. The tendency to overestimate functional competences was associated with greater cognitive, affective, and motor impairments