9 results on '"Robert MacLachlan"'
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2. AGE-ASSOCIATED CHANGES IN THE RENIN-ANGIOTENSIN SYSTEM: IMPLICATIONS FOR FUTURE CLINICAL TRIALS
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Robert MacLachlan, Scott Miners, and Patrick Kehoe
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Specialties of internal medicine ,RC581-951 ,Neurosciences. Biological psychiatry. Neuropsychiatry ,RC321-571 - Published
- 2024
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3. THE BRAIN RENIN-ANGIOTENSIN SYSTEM IS ALTERED IN AGE AND ALZHEIMER'S DISEASE
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Robert MacLachlan, Patrick Kehoe, and Scott Miners
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Specialties of internal medicine ,RC581-951 ,Neurosciences. Biological psychiatry. Neuropsychiatry ,RC321-571 - Published
- 2024
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- View/download PDF
4. Age-related reduction in brain ACE-2 is not exacerbated by Alzheimer’s disease pathology in mouse models of Alzheimer’s disease
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Robert MacLachlan, Charles E. Evans, Siew Yeen Chai, Mark A. Good, Patrick Gavin Kehoe, and J. Scott Miners
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Ageing ,Alzheimer’s disease ,Renin-angiotensin system ,ACE-2 ,ACE-1 ,Angiotensin-II ,Neurosciences. Biological psychiatry. Neuropsychiatry ,RC321-571 - Abstract
An imbalance in the circulatory and organ-specific renin-angiotensin system (RAS) pathways is associated with age-related dysfunction and disease including cardiovascular burden and more recently Alzheimer’s disease (AD). It is currently unclear whether an age-associated imbalance in components of the RAS within the brain precedes the onset of AD or whether a RAS imbalance is associated with the onset of disease pathology and cognitive decline.Angiotensin-converting enzyme-1 (ACE-1) and -2 (ACE-2) protein (ELISA) and enzyme activity (FRET assay), markers of the classical and counter-regulatory RAS axis respectively, and Ang-II and Ang-(1–7) peptide levels (ELISA), were measured in the left cortex across four transgenic AD mouse models of amyloid pathology (5xFAD – 2, 6, and 12 months of age; Apd9 – 3-4, 12, and 18 months of age; Tg2576 – 3-4 and 24 months of age; and PDAPP – 3-4, 7, 11, 15, and 18 months of age) and littermate wild-type (WT) controls.ACE-1 level, and enzyme activity, was unaltered in relation to age in WT mice and across all four models. In contrast, ACE-2 level and enzyme activity, was reduced and Ang-II increased with ageing in both WT animals and disease models. The changes in ACE-2 and Ang-II in AD models mirrored WT mice, except for the 5xFAD model, when the reduction in ACE-2 (and elevated Ang-II) was observed at a younger age.These data indicate an age-related dysregulation of brain RAS is likely to be driven by a reduction in ACE-2. The reduction in ACE-2 occurs at a young age, coinciding with early pathological changes and the initial deposition of Aβ, and preceding neuronal loss and cognitive decline, in the transgenic AD models. However, the age-related loss was mirrored in WT mice suggesting that the change was independent of pathological Aβ deposition.
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- 2023
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5. Elevated late-life blood pressure may maintain brain oxygenation and slow amyloid-β accumulation at the expense of cerebral vascular damage
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Hannah M Tayler, Robert MacLachlan, Özge Güzel, J Scott Miners, and Seth Love
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Cellular and Molecular Neuroscience ,Psychiatry and Mental health ,Neurology ,Biological Psychiatry - Abstract
Hypertension in midlife contributes to cognitive decline and is a modifiable risk factor for dementia. The relationship between late-life hypertension and dementia is less clear. We have investigated the relationship of blood pressure and hypertensive status during late life (after 65 years) to post-mortem markers of Alzheimer’s disease (amyloid-β and tau loads); arteriolosclerosis and cerebral amyloid angiopathy; and to biochemical measures of ante-mortem cerebral oxygenation (the myelin-associated glycoprotein:proteolipid protein-1 ratio, which is reduced in chronically hypoperfused brain tissue, and the level of vascular endothelial growth factor-A, which is upregulated by tissue hypoxia); blood–brain barrier damage (indicated by an increase in parenchymal fibrinogen); and pericyte content (platelet-derived growth factor receptor β, which declines with pericyte loss), in Alzheimer’s disease (n = 75), vascular (n = 20) and mixed dementia (n = 31) cohorts. Systolic and diastolic blood pressure measurements were obtained retrospectively from clinical records. Non-amyloid small vessel disease and cerebral amyloid angiopathy were scored semiquantitatively. Amyloid-β and tau loads were assessed by field fraction measurement in immunolabelled sections of frontal and parietal lobes. Homogenates of frozen tissue from the contralateral frontal and parietal lobes (cortex and white matter) were used to measure markers of vascular function by enzyme-linked immunosorbent assay. Diastolic (but not systolic) blood pressure was associated with the preservation of cerebral oxygenation, correlating positively with the ratio of myelin-associated glycoprotein to proteolipid protein-1 and negatively with vascular endothelial growth factor-A in both the frontal and parietal cortices. Diastolic blood pressure correlated negatively with parenchymal amyloid-β in the parietal cortex. In dementia cases, elevated late-life diastolic blood pressure was associated with more severe arteriolosclerosis and cerebral amyloid angiopathy, and diastolic blood pressure correlated positively with parenchymal fibrinogen, indicating blood–brain barrier breakdown in both regions of the cortex. Systolic blood pressure was related to lower platelet-derived growth factor receptor β in controls in the frontal cortex and in dementia cases in the superficial white matter. We found no association between blood pressure and tau. Our findings demonstrate a complex relationship between late-life blood pressure, disease pathology and vascular function in dementia. We suggest that hypertension helps to reduce cerebral ischaemia (and may slow amyloid-β accumulation) in the face of increasing cerebral vascular resistance, but exacerbates vascular pathology.
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- 2023
6. Dysregulation of ACE-1 in Normal Aging and the Early Stages of Alzheimer's Disease
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Robert MacLachlan, Patrick Gavin Kehoe, and J Scott Miners
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Renin-Angiotensin System ,Aging ,Alzheimer Disease ,Angiotensin II ,Humans ,Geriatrics and Gerontology ,Peptidyl-Dipeptidase A - Abstract
An imbalance in the renin–angiotensin system (RAS) is associated with cognitive decline and disease pathology in Alzheimer’s disease (AD). In this study, we have investigated changes in the brain angiotensin-converting enzyme-1 (ACE-1) and angiotensin-II (Ang-II), and the counter-regulatory angiotensin-converting enzyme-2 (ACE-2), in the frontal and temporal cortex during normal aging and in the early stages of AD. We studied a cohort of normal aging (n = 121; 19–95 years age-at-death) from the Sudden Death Brain Bank, University of Edinburgh, United Kingdom, and AD and age-matched controls (n = 60) from the South West Dementia Brain Bank, University of Bristol, United Kingdom, stratified according to Braak tangle stage (BS): 0–II, III–IV (intermediate disease), and V–VI (end-stage disease). ACE-1 and ACE-2 enzyme activity were measured using fluorogenic peptide activity assays. ACE-1, ACE-2, and Ang-II protein level were measured by enzyme-linked immunosorbent assay (ELISA). In both regions, ACE-1 protein and Ang-II levels correlated positively with age whereas ACE-1 enzyme activity was inversely related to age. ACE-1 protein correlated positively with Ang-II, whilst ACE-1 activity correlated inversely with Ang-II in normal aging. ACE-1 enzyme activity was elevated at an early/intermediate stage, BS III–IV compared to BS 0–II in the temporal cortex in AD. ACE-2 protein and enzyme activity were unchanged with aging and in AD. In conclusion, ACE-1 activity is induced in the early stages of AD independently from normal physiological age-related changes in ACE-1 protein.
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- 2021
7. Variability in Reassessment of Left Ventricular Ejection Fraction After Myocardial Infarction in the Acute Myocardial Infarction Quality Assurance Canada Study
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Luc Harvey, E. Marc Jolicoeur, Stephen B. Wilton, Wei Qi, Camille Galloway, Sarah Singh, Rebecca Fromm, Benoit Plourde, Peter Leong-Sit, Rozsa Sas, Brady Robinson, Chantale Mercure, Matthew T. Bennett, Umjeet S Jolly, Lynn Nymann, Isabelle Roy, Marina Sanchez, Nancy Hiltz, Bernice Tsang, Erick Schampaert, Marc W. Deyell, Mary Radyk, Stephanie J. Frisbee, Vincent Spagnoli, Robert MacLachlan, Ratika Parkash, Sabrina Wall, Evan Lockwood, Katherine M. Kavanagh, Jaimie Manlucu, Nicole Ell, Derek S. Chew, Frank Halperin, Elisa Ramser, and C. Seifer
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Male ,medicine.medical_specialty ,Canada ,Time Factors ,medicine.medical_treatment ,Cardiology ,Myocardial Infarction ,Revascularization ,Ventricular Function, Left ,Sudden cardiac death ,Cohort Studies ,Ventricular Dysfunction, Left ,Risk Factors ,Internal medicine ,medicine ,Humans ,Myocardial infarction ,cardiovascular diseases ,Cardiac imaging ,Cardiac catheterization ,Original Investigation ,Ejection fraction ,business.industry ,Research ,Stroke Volume ,General Medicine ,Middle Aged ,medicine.disease ,Prognosis ,humanities ,Online Only ,Treatment Outcome ,Heart failure ,cardiovascular system ,Female ,business ,circulatory and respiratory physiology ,Cohort study - Abstract
Key Points Question What proportion of patients with left ventricular dysfunction identified during hospitalization for acute myocardial infarction have follow-up assessment of left ventricular ejection fraction (LVEF)? Findings In this cohort study of 501 patients, 303 patients had undergone LVEF reassessment by 6 months, with significant variability according to patient-level and site-level characteristics. Meaning These findings suggest that programs to improve the quality of post–myocardial infarction care should include measures to ensure that indicated repeat cardiac imaging is performed., This cohort study assesses adherence with guideline-recommended left ventricular ejection fraction (LVEF) reassessment after myocardial infarction and studies the evolution of LVEF over 6 months of follow-up in the Acute Myocardial Infarction Quality Assurance (AMIQA) Canada study., Importance Persistently depressed left ventricular ejection fraction (LVEF) after myocardial infarction (MI) is associated with adverse prognosis and directs the use of evidence-based treatments to prevent sudden cardiac death and/or progressive heart failure. Objective To assess adherence with guideline-recommended LVEF reassessment and to study the evolution of LVEF over 6 months of follow-up. Design, Setting, and Participants This was a multicenter cohort study at Canadian academic and community hospitals with on-site cardiac catheterization services. Patients with type 1 acute MI and LVEF less than or equal to 45% during the index hospitalization were enrolled between January 2018 and August 2019 and were followed-up for 6 months. Data analysis was performed from May 2020 to September 2021. Exposures Baseline clinical factors, in-hospital care and LVEF, and site-specific features. Main Outcomes and Measures The main outcomes were receipt of repeat LVEF assessment by 6 months and the presence of a persistent LVEF reduction at 2 thresholds: LVEF less than or equal to 40%, prompting consideration of additional medical therapy for heart failure, or LVEF less than or equal to 35%, prompting referral for implanted cardioverter defibrillator in addition to medical therapy. Results This study included 501 patients (mean [SD] age, 63.3 [13.0] years; 113 women [22.6%]). Overall, 370 patients (73.4%) presented with STEMI, and 454 (90.6%) had in-hospital revascularization. The median (IQR) baseline LVEF was 40% (34%-43%). Of 458 patients (91.4%) who completed the 6-month follow-up, 303 (66.2%; 95% CI, 61.7%-70.5%) had LVEF reassessment, with a range of 46.7% to 90.0% across sites (χ213 = 19.6; P = .11). Participants from community hospitals were more likely than those from academic hospitals to undergo LVEF reassessment (73.6% vs 63.2%; χ21 = 4.50; P = .03), as were those with worse LVEF at baseline. Follow-up LVEF improved by an absolute median (IQR) of 8% (3%-15%). However, 103 patients (34.1%) met the definitions of clinically relevant LVEF reduction, including 52 patients (17.2%) with LVEF less than or equal to 35% and 51 patients (16.9%) with LVEF of 35.1% to 40.0%. Conclusions and Relevance In this cohort study, approximately 1 in 3 patients with at least mild LVEF reduction after acute MI did not undergo indicated LVEF reassessment within 6 months, suggesting that programs to improve the quality of post-MI care should include measures to ensure that indicated repeat cardiac imaging is performed. In those with follow-up imaging, clinically relevant persistent LVEF reduction was identified in more than one-third of patients.
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- 2021
8. Mediators of cerebral hypoperfusion and blood-brain barrier leakiness in Alzheimer's disease, vascular dementia and mixed dementia
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J Scott Miners, Seth Love, Robert MacLachlan, Ozge Guzel, and Hannah Tayler
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Male ,blood‐brain barrier ,0301 basic medicine ,Pathology ,medicine.medical_specialty ,Arteriolosclerosis ,Plaque, Amyloid ,Blood–brain barrier ,Pathology and Forensic Medicine ,mixed dementia ,White matter ,03 medical and health sciences ,0302 clinical medicine ,Alzheimer Disease ,mental disorders ,medicine ,Humans ,Dementia ,Cerebral perfusion pressure ,Vascular dementia ,cerebral hypoperfusion ,Research Articles ,pathophysiology ,Aged ,Aged, 80 and over ,Amyloid beta-Peptides ,business.industry ,Dementia, Vascular ,General Neuroscience ,Brain ,vascular dementia ,blood-brain barrier ,Alzheimer's disease ,medicine.disease ,Cerebral Amyloid Angiopathy ,Cerebrovascular Disorders ,030104 developmental biology ,medicine.anatomical_structure ,Blood-Brain Barrier ,Cerebral cortex ,Female ,Neurology (clinical) ,Cerebral amyloid angiopathy ,business ,Alzheimer’s disease ,030217 neurology & neurosurgery ,Research Article - Abstract
In vascular dementia (VaD) and Alzheimer’s disease (AD), cerebral hypoperfusion and blood‐brain barrier (BBB) leakiness contribute to brain damage. In this study, we have measured biochemical markers and mediators of cerebral hypoperfusion and BBB in the frontal (BA6) and parietal (BA7) cortex and underlying white matter, to investigate the pathophysiology of vascular dysfunction in AD, VaD and mixed dementia. The ratio of myelin‐associated glycoprotein to proteolipid protein‐1 (MAG:PLP1), a post‐mortem biochemical indicator of the adequacy of ante‐mortem cerebral perfusion; the concentration of fibrinogen adjusted for haemoglobin level, a marker of blood‐brain barrier (BBB) leakiness; the level of vascular endothelial growth factor‐A (VEGF), a marker of tissue hypoxia; and endothelin‐1 (EDN1), a potent vasoconstrictor, were measured by ELISA in the frontal and parietal cortex and underlying white matter in 94 AD, 20 VaD, 33 mixed dementia cases and 58 age‐matched controls. All cases were assessed neuropathologically for small vessel disease (SVD), cerebral amyloid angiopathy (CAA) severity, Aβ and phospho‐tau parenchymal load, and Braak tangle stage. Aβ40 and Aβ42 were measured by ELISA in guanidine‐HCl tissue extracts. We found biochemical evidence of cerebral hypoperfusion in AD, VaD and mixed dementia to be associated with SVD, Aβ level, plaque load, EDN1 level and Braak tangle stage, and to be most widespread in mixed dementia. There was evidence of BBB leakiness in AD—limited to the cerebral cortex and related to EDN1 level. In conclusion, abnormalities of cerebral perfusion and BBB function in common types of dementia can largely be explained by a combination of arteriolosclerosis, and Aβ‐, tau‐ and endothelin‐related vascular dysfunction. The relative contributions of these processes vary considerably both between and within the diseases., Tayler et al. used post‐mortem biochemical methods to determine the severity of chronic and acute hypoperfusion of the cerebral cortex and white matter in Alzheimer's disease (AD), vascular dementia (VaD) and mixed dementia (Mixed). The two myelin proteins myelin‐associated protein (MAG) and proteolipid protein‐1 (PLP‐1), which have a similar slow turnover in vivo, are differentially susceptible to changes in tissue oxygenation such that a fall in the ratio of these proteins indicates reduced perfusion of the tissue over a period of several months prior to death. In contrast, vascular endothelial growth factor‐A (VEGF‐A) is upregulated acutely in response to tissue hypoxia. By measuring these proteins, the authors showed the severity of cerebral hypoperfusion in AD, VaD and mixed dementia to be associated with multiple factors (small vessel disease severity, Aβ level, plaque load, endothelin‐1 level and Braak tangle stage) and to be most widespread in mixed dementia.
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- 2021
9. Abstract 14586: Variability in Indicated Left Ventricular Function Reassessment After Mi: The Acute Myocardial Infarction Quality Assurance (AMIQA) Canada Multicenter Prospective Study
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Stephanie J. Frisbee, Amiqa Canada Investigators, Derek S. Chew, Rozsa Sas, Frank Halperin, Matthew T. Bennett, Jaimie Manlucu, Robert MacLachlan, Sarah Singh, Umjeet S Jolly, Peter Leong-Sit, Katherine M. Kavanagh, Ratika Parkash, Stephen B. Wilton, and M. Jolicoeur
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medicine.medical_specialty ,Ejection fraction ,Ventricular function ,business.industry ,medicine.disease ,Sudden death ,Sudden cardiac death ,Physiology (medical) ,Heart failure ,Internal medicine ,cardiovascular system ,Cardiology ,Medicine ,cardiovascular diseases ,Myocardial infarction ,Cardiology and Cardiovascular Medicine ,business ,Prospective cohort study ,Cardiac imaging ,circulatory and respiratory physiology - Abstract
Introduction: Persistently reduced LVEF after acute MI predicts adverse prognosis and directs use of evidence-based treatments to prevent sudden death (SCD) and/or progressive heart failure. We conducted a multicentre, prospective, observational study to assess adherence with guideline recommendations to repeat imaging assessment post-MI in those with initially depressed LVEF. Methods: We enrolled 501 patients with type 1 acute MI and LVEF ≤45% during the index hospitalization, from 14 Canadian sites. Outcomes were the proportion having a repeat LVEF assessment by 6 months and the proportion with an actionable reduced LVEF in follow-up: Results: Mean age was 63.3 ± 13.0, and 113 (22.6%) were female. Overall, 370 (73.4%) presented with STEMI, and 454 (91.6%) had one or more in-hospital revascularization procedures. The mean baseline LVEF was 36.9% ± 6.7%. Over a median follow-up of 198 days, 18 (3.6%) patients died and 27 (5.3%) were lost to follow-up. Of 456 remaining patients, 303 (66.5%) had LVEF reassessment and significant variation was observed across sites (range 46.7-90.0%; p=0.035). Patients from community vs academic hospitals were more likely to undergo LVEF reassessment (73.6% vs. 63.2%, p=0.034), as were those with worse LVEF at baseline ( Figure, panel A ). In those with follow-up LVEF (n=302), 61.6% had an actionable persistent LVEF reduction: 13.9% had LVEF Figure, Panel B ). Conclusions: One in three patients with at least mild LVEF reduction after acute MI did not undergo indicated LVEF reassessment within 6 months. In those with follow-up imaging, clinically actionable persistent LVEF reduction was identified in over one quarter of patients.
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- 2020
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