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Effects of BDNF and COMT variants on cognitive decline in Early‐Onset Alzheimer’s Disease
No full textBackground:
Early‐Onset Alzheimer’s Disease (EOAD) is a rare condition that affects only 5% of patients with Alzheimer’s Disease (AD). At present, only basic information is known about the impact of AD risk variants on EOAD, and the effects of more subtle genetic contributions to cognitive decline have yet to be investigated. Genetic variants for brain derived neurotrophic factor (BDNF) and catechol‐O‐methyltransferase (COMT) have both been implicated in cognitive change (Fiocco et al., 2010; Ferrer et al., 2019), consequently the aim of the current study was to examine the role of these genetic variants on cognitive decline in EOAD.
Method:
Data from 88 amyloid‐positive EOAD participants enrolled in the Longitudinal Early Onset Alzheimer’s Disease Study (LEADS; aged 40‐64) were analyzed. Exploratory multivariate analyses of covariance (MANCOVA) were conducted to investigate differences in 12‐month cognitive decline as a function of BDNF rs6265 (p.V66M) and COMT rs4680 (p.V158M) variants using dominant genetic models (Val/Val versus Val/Met or Met/Met). Cox Regression analyses were also conducted to consider the effect of genetic variants on age of onset.
Result:
See Table 1 for demographic characteristics of our sample. MANCOVA, controlling for age, education, sex, and race/ethnicity, showed significant effects for BDNF p.V66M on domains of Memory (p<0.001) and Executive Functioning (p = 0.04; Table 2). Specifically, greater 12‐month cognitive decline was observed for the CRAFT Immediate and Delayed Story Memory, with worse performance associated with BDNF minor alleles (ps. = 0.007 to 0.02). Conversely, worse decline was observed for the reference group for RAVLT Immediate Memory (p<0.006) and Digit Span Backwards (p<0.02). No significant effects were evident for domains of Language, Speed/Attention, or Visuospatial skills (ps = 0.34‐0.97), nor for any analyses of COMT carrier status (ps = 0.26‐0.87). Cox Regression analyses, controlling for race and ethnicity, were not significant for BDNF or COMT carrier status (ps = 0.59‐0.64; Figure 1).
Conclusion:
Results suggest subtle effects of BDNF p.V66M carrier status on memory decline in EOAD participants, which was not observed for disease progression/age‐of‐onset. No effects for COMT p.V158M carrier status were observed. Future investigation will replicate these effects in larger samples, permitting stratification of additional covariates including APOE genotype
Generation of Retinal Ganglion Cells from Reprogrammed Keratocytes of Non‐Glaucoma and Glaucoma Donors
No full textHuman induced pluripotent stem cell (hiPSC)-based disease modeling can be successfully recapitulated to mimic disease characteristics across various human pathologies. Glaucoma, a progressive optic neuropathy, primarily affects the retinal ganglion cells (RGCs). While multiple groups have successfully generated RGCs from non-diseased hiPSCs, producing RGCs from glaucomatous human samples holds significant promise for understanding disease pathology by revealing patient-specific disease signatures. Given that keratocytes originate from the neural crest and previous reports suggest that ocular fibroblasts from glaucomatous donors carry pathogenic signatures, it is highly plausible that these signatures imprinted within the keratocytes will also be present in the derived RGCs. Thus, we aimed to generate RGCs from both glaucomatous and non-glaucomatous donor keratocytes and validate disease-specific signatures in 3D retinal organoids and in isolated RGCs. Our protocol describes the generation of iPSCs from keratocytes of both glaucomatous and non-glaucomatous donors, followed by their differentiation into retinal organoids. Subsequent isolation and culturing of RGCs were performed. Disease signatures in the RGCs were validated in both 3D retinal organoids (ROs) and 2D RGC cultures, and glaucomatous RGCs in 3D and 2D cultures demonstrated increased cleaved CASP3 and significant RGC loss, indicating disease imprints in the hiPSC-derived RGCs. This model offers a venue and high throughput platform for studying glaucomatous disease pathology and holds significant potential for drug discovery using RGCs derived from human donors
Two-stage revision anterior cruciate ligament reconstruction reduces failure risk but leads to lesser clinical outcomes than single-stage revision after primary anterior cruciate ligament graft failure: a retrospective cohort study
No full textBackground: There are no studies that compare the outcomes and complications of single-versus two-stage revision anterior cruciate ligament reconstruction (ACLR) after primary ACLR failure. This purpose of this study is to examine clinical and functional outcomes and complications associated with single and two-stage revision ACLR after primary ACLR failure.
Methods: All patients who underwent single or two-stage revision ACLR after primary ACLR failure between 2012 and 2021 with a minimum of a 2 year follow-up were included. Patients were excluded if they were not treated at our single academic institution, had inadequate follow-up, or had incomplete medical records. Revision intraoperative data, concomitant injuries, and complications were collected by chart review. Return to sport, numerical pain rating scale (NPRS) score, Knee injury and Osteoarthritis Outcome Score (KOOS), and Veteran Rands 12-item health survey (VR-12 scores) were collected.
Results: The final analysis included 176 patients. A total of 147 (83.5%) had a single-stage revision ACLR (87 male, 60 female), and 29 (16.5%) had a two-stage revision ACLR (13 male, 16 female). Two-stage revision ACLR was significantly associated with anterior knee pain [odds ratio (OR) 4.36; 95% confidence interval (CI) 1.5 to 12.65; P = 0.007] but with lower failure rates (OR 0.12, 95% CI 0.02 to 0.9; P = 0.04). On multivariate analysis, a two-stage revision ACLR reduced the risk of graft failure by 85% (OR 0.15; 95% CI 0.02 to 1.17; P = 0.07). Two-stage revision ACLR was significantly associated with a lower KOOS pain score (OR -11.7; 95% CI -22.35 to -1.04; P = 0.031), KOOS symptoms score (OR -17.11; 95% CI -28.85 to -5.36; P = 0.004), KOOS Activities of Daily Living (ADL) score (OR -11.15; 95% CI -21.71 to -0.59; P = 0.039) and Veterans RAND 12-Item Health Survey (VR-12) physical component score (OR -9.99; 95% CI -15.77 to -4.22; P = 0.001).
Conclusions: The clinical outcomes and subjective patient scores significantly differed between the single-stage and two-stage revision ACLR after primary ACLR failure. Patients with a two-stage revision ACLR had a significantly reduced risk of revision graft failure but higher rates of postoperative anterior knee pain, lower pain scores, and lesser knee functional scores than single-stage revision patients
Optimal Transport‐Based Transcriptomic Mapping Revealed Atypical Disease Progression Subtypes in Living Alzheimer’s Disease Patients
No full textBackground:
Alzheimer’s disease (AD) exhibits substantial heterogeneity in its disease trajectory. A subset of AD patients with unmatched cognitive decline/tauopathy severity has not been well studied. We identified such atypical subgroups in post‐mortem AD brain studies. However, such atypical subtypes may not be easily identified in living patients, as obtaining brain samples are unfeasible, and NFT measurement is not accurate. In this study, we utilize the matched transcriptomic data from both brain and blood of ROSMAP cohort to identify such atypical AD groups in the blood transcriptomic data of live patients in other cohorts using transfer learning‐based approach, to uncover distinct molecular signatures and biomarkers for earlier and more accurate disease subtyping and prognosis in living AD patients.
Method:
Three subgroups were defined from ROSMAP cohort with the blood and brain RNA‐seq data based on the clinical information of their tauopathies and disease progression, namely, Asymptomatic AD, Low‐NFT AD, Typical AD, plus normal Control, which serves as our training dataset for a supervised transfer learning. Then, the labels were transferred to the blood RNA‐seq samples from two new cohorts, ADNI and ANMerge using optimal transport. Next, we identify the genes consistently expressed in three independent cohorts for that specific AD subtype. Lastly, the diffusion pseudo‐time analysis infers the temporal order of the gene expression patterns within each subgroups. Dominant genes with a consistent expression pattern across cohorts are considered as the signature for each subgroup, and their relevance to AD pathology is analyzed.
Result:
We identified distinctive genes with consistent expression patterns across cohorts for each AD subgroup. Remarkably, our analysis also reveals the temporal gene expression dynamics differs for sex, age (late/early onset), and onset pattern (sudden/gradual) across the cohorts.
Conclusion:
Through a deep transfer learning‐based approach on the blood and brain transcriptomic data, we successfully identified the atypical disease progression subgroups among live AD patient cohorts in ADNI and ANMerge with promising biomarkers/gene signatures. The molecular signatures identified in this study not only enhance our comprehension of the underlying pathophysiological mechanisms but also hold promise for developing early prognosis and effective personalized treatments for AD and related tauopathies
Fit for purpose high‐throughput absolute quantitation of chimeric aducanumab in mouse cortex and plasma
No full textBackground:
Although pharmacokinetics and pharmacodynamics of biotherapeutics are commonly studied through ELISAs; however, the extremely strong binding of modern antibody‐based therapeutics result in background, inability of secondary antibody binding, and nonlinear response curves. The selectivity and specificity imparted through the use of liquid chromatography‐targeted mass spectrometry (LC‐MS/MS) allows for absolute quantitation of chosen peptides. For MODEL‐AD, here we present a high‐throughput workflow for absolute quantification of chimeric aducanumab from cortex and plasma of 5XFAD mice.
Methods:
A targeted MS assay for quantitation of aducanumab was designed utilizing guidelines described by the National Cancer Institute’s Clinical Proteomic Tumor Analysis Consortium. Proteotryptic peptides unique for chimeric aducanumab were selected, and stable isotope versions were purchased as spike in controls. Given that aducanumab was present in mouse cortex at very low levels, a high sensitivity and high throughput methodology was optimized with Protein A enrichment, reduction, alkylation, trypsin digestion, loading samples onto Evotips using an AssayMap Bravo (Agilent). Evosep LC was paired with a Lumos Tribrid orbitrap (Thermo Fisher Scientific) and data were analyzed in Skyline (MacCoss lab) with a concentration curve of pure protein in matrix normalized to spike in stable isotope labeled peptides.
Results:
The three tryptic peptides used for quantitation of aducanumab had lower limits of detection and quantification of 1‐500 Amol pure peptide on column and 2‐5 ng aducanumab/uL in plasma and 0.225 ng/ug brain homogenate. This assay was sensitive and linear over 1 to 500,000 Amol range with high reproducibility (CV 3‐10%). Using a protein A purification, the lower limit of quantification was decreased by 100 fold. This assay was micronized for 96 sample formats, where a single plate could be analyzed in 48‐72 hours.
Conclusions:
Although unique peptides will vary, we anticipate this general workflow will allow for quantitation of AD focused biotherapeutics. As part of the open science framework, this methodology will be made available to the broader research community to facilitate broad application
High-Riding Innominate Artery: Booby Trap for ICU Tracheotomy
No full textDespite tracheotomy being a routine procedure, it is not rare to encounter anatomic irregularities that can compromise its success. In this report, we describe a case in which a high riding innominate artery was identified within the surgical trajectory moments before incision, which ultimately necessitated airway securement using an alternative laryngological procedure
Understanding the cellular responses to anti‐Abeta antibodies to gain insights into mechanisms of ARIA
No full textAnti‐amyloid immunotherapy holds great promise for our patients and their families as the first disease‐modifying therapy for the treatment of Alzheimer’s disease (AD) to be approved. Positive clinical trials for lecanamab and donanemab showed significant and rapid lowering of brain amyloid burden and a significant slowing of cognitive decline. Amyloid‐related imaging abnormalities (ARIA) in the form of vasogenic edema (ARIA‐E) and micro ‐ and macro‐ hemorrhages (ARIA‐H) remain the major obstacle to broad use of these agents. Significant cerebrovascular pathology precludes treatment due to enhanced risk of ARIA. In addition, it is known that ApoE4 carriers are at a significantly increased risk of ARIA incidence, with 25‐40% of homozygotes developing ARIA. Understanding the mechanisms underlying ARIA is of critical importance to increase safety and broaden the use of anti‐amyloid immunotherapy.
Using mouse models of amyloid deposition, we have performed systemic and intracranial anti‐beta‐amyloid antibody administration to study the potential mechanisms of both amyloid clearance and cerebrovascular disruptions that lead to ARIA. We have found that microglial activation is present along the vessels that are laden with cerebral amyloid angiopathy (CAA). Furthermore, coincident with microhemorrhage occurrence is increased expression and activity of matrix metalloproteinases (MMPs) MMP9 and MMP3. MMPs are known to degrade basement membranes and tight junction proteins that could lead to disruption of the blood‐brain barrier and, ultimately, edema and hemorrhage. in fact, it has long been understood that MMP9 plays a critical role in the hemorrhagic transformation of ischemic stroke. We have performed single‐cell transcriptomic analysis to examine the glial responses following a single anti‐amyloid immunotherapy and we find significant microglial population shifts and also enhanced signaling from microglia to perivascular macrophages, potentially implicating these cells as a key player in the development of ARIA.
Ultimately, discovering the mechanisms of ARIA will result in the development of safer, next‐generation antibody therapy that has reduced ARIA risk, and also could lead to the identification of adjunct treatments that can be co‐administered with the anti‐amyloid immunotherapy to prevent the occurrence of ARIA in those at risk
Optimizing primary care for cognitive impairment screening using agile implementation
No full textBackground:
Screening for cognitive impairment in primary care faces challenges, including time constraints, provider apprehension, and limited diagnostic confidence. An effective initiative for improving screening must include strategies to foster behavioral change, and active provider engagement. Agile implementation science integrates findings from behavioral economics, complexity science, and network science, to address these challenges by confirming the demand to solve the problem; local solution adaptation; and the iterative ‘sprints’, or tests of change, that are focused on execution. This study, which is part of the Davos Alzheimer’s Collaborative (DAC) Early Detection Health System Preparedness Flagship program, explored workflows to support Digital Cognitive Assessment (DCA) in primary care, enhancing early detection of mild cognitive impairment (MCI) and dementia.
Methods:
Between June 1, 2022, and May 31, 2023, seven diverse primary care clinics participated in the DAC program. The initiative’s core was the integration of offering and performing Linus Health Core Cognitive Evaluation Digital Cognitive Assessment (DCA) for patients aged 65 and above. The selection of the digital screening tool, process workflows, and improvement cycles were co‐designed by the primary care providers, clinic staff, the Patient Advisory Council, and the implementation team using Agile Implementation. A Brain Health Navigator (BHN) role was designed to fill workflow gaps in primary care evaluation of abnormal screening and facilitate specialty care transition for patients needing referral.
Results:
Among the seven sites, five sites engaged in agile implementation and had similar performances, with an increase in DCA completion observed. A total of 1808 DCA screenings were performed on 1722 unique patients. The agile implementation process facilitated clinic‐specific adaptations, which resulted in an increase in the overall number of eligible patients completing the DCA screening.
Conclusions:
The adoption of an agile implementation process increased DCA screening uptake in primary care settings. The integration of a BHN and streamlined workflows proved crucial in enhancing the screening, diagnosis, and referral journey. This integration aligns with the principles of person‐centered care and facilitates service coordination. It also supports workforce initiatives and advances the field of health services research, ensuring that each step in the patient’s journey is both effective and efficient
Pharmacokinetic, Safety, and Pharmacodynamic Profiles of Saroglitazar Magnesium in Cholestatic Cirrhosis With Hepatic Impairment and Participants With Renal Impairment
No full textSaroglitazar magnesium, a dual PPAR α/γ agonist, currently in Phase III for treating primary biliary cholangitis (PBC), was evaluated for its pharmacokinetic (PK) profile, safety, and pharmacodynamics in participants with cholestatic liver disease (CLD) across different levels of hepatic impairment (HI) and participants with severe renal impairment (RI). Three PK studies comparing saroglitazar with healthy controls were conducted: Study 1 involved daily oral doses of 1 or 2 mg for 4 weeks in 12 PBC cirrhosis participants with mild or moderate HI; Study 2 assessed single-dose PK (2 or 4 mg) in eight non-cirrhotic CLD participants; Study 3 evaluated single-dose PK (2 mg) in eight participants with severe RI. On day 1, saroglitazar exposure increased by 14.6-42% in mild HI vs. normal, but by day 28, levels were similar, indicating no accumulation. In moderate HI, exposure was significantly increased by 50.4-85% on days 1 and 28, with 34-46% lower clearance despite a similar half-life. The moderate HI group had a 59% higher exposure than the non-cirrhotic group. Saroglitazar (1 and 2 mg) reduced alkaline phosphatase (ALP) levels by 17-40% after 4 weeks in participants with abnormal baseline ALP. Single-dose PK in non-cirrhotic CLD (2 and 4 mg) and severe RI (2 mg) was comparable to matched controls without significant safety issues. Overall, saroglitazar (1 and 2 mg) was safe and well-tolerated in cholestatic cirrhosis with mild HI and participants with severe RI without major PK changes. Moderate HI increased exposure and decreased clearance without any safety concerns