Publications by authors named "Antoinette O'Connor"

Introduction: Alzheimer disease (AD)-modifying therapies are approved for treatment of early-symptomatic AD. Autosomal dominant AD (ADAD) provides a unique opportunity to test therapies in presymptomatic individuals.

Methods: Using data from the Dominantly Inherited Alzheimer Network (DIAN), sample sizes for clinical trials were estimated for various cognitive, imaging, and CSF outcomes.

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  • The study aims to explore patient eligibility for lecanemab therapy for Alzheimer's Disease (AD) at a Regional Specialist Memory Clinic, emphasizing the importance of timely treatment in early AD cases.
  • A retrospective analysis was conducted on 188 new patients over a year, assessing their diagnostic data and biomarker status to determine eligibility based on Appropriate Use Criteria (AUC) and clinical trial standards.
  • Results showed only 5.9% of the patients were eligible according to AUC, with a higher eligibility rate of 26.2% among those with biomarker positive Alzheimer's, highlighting major barriers like lack of biomarker confirmation and cognitive ineligibility.
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  • People with intellectual disability have a higher risk of developing dementia, which often shows different and earlier symptoms than in the general population, complicating diagnosis.
  • There is a need for specialized memory services and reliable biomarkers to improve diagnosis and treatment options for this group, but current research and services are lacking.
  • The underrepresentation of adults with intellectual disabilities in biomarker research could lead to their exclusion from effective treatments for neurodegenerative diseases, worsening existing health care inequities.
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  • Autosomal dominant Alzheimer's disease (ADAD) and Down syndrome (DS) are genetic forms of Alzheimer's that help researchers explore biomarker changes and disease progression in Alzheimer's overall.
  • The study highlights that biomarkers in genetic cases have unique characteristics and a predictable onset, making their context of use different from sporadic Alzheimer's cases.
  • Understanding these distinctions is crucial for research and clinical practices, ultimately leading to more personalized treatment strategies for individuals affected by genetically determined Alzheimer's.
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There is growing public awareness and concern regarding dementia risk. In addition, genetic testing is increasingly accessible and is at the point of being integrated into routine clinical practice. As a result, there is a pressing need for treating clinicians to have the appropriate knowledge base to request and consent for diagnostic genetic testing in cognitive clinics.

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  • Plasma p-tau217 is identified as a promising blood-based marker for detecting Alzheimer Disease (AD) pathology, particularly in memory clinic patients undergoing lumbar punctures.
  • A study involving 108 participants found that plasma p-tau217 levels were significantly higher in those with detected amyloid (Aβ) pathology compared to those without, indicating its strong potential for diagnosis.
  • The analysis showed that plasma p-tau217 had excellent performance metrics for Aβ detection (AUC: 0.91), outperforming other biomarkers and suggesting it could be a reliable tool in Alzheimer's diagnostics.
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Introduction: Familial Alzheimer's disease (fAD) is heterogeneous in terms of age at onset and clinical presentation. A greater understanding of the pathogenicity of fAD variants and how these contribute to heterogeneity will enhance our understanding of the mechanisms of AD more widely.

Methods: To determine the pathogenicity of the unclassified PSEN1 P436S mutation, we studied an expanded kindred of eight affected individuals, with magnetic resonance imaging (MRI) (two individuals), patient-derived induced pluripotent stem cell (iPSC) models (two donors), and post-mortem histology (one donor).

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Introduction: Alzheimer's disease and other dementias affect >50 million individuals globally and are characterised by broad clinical and biological heterogeneity. Cohort and biobank studies have played a critical role in advancing the understanding of disease pathophysiology and in identifying novel diagnostic and treatment approaches. However, further discovery and validation cohorts are required to clarify the real-world utility of new biomarkers, facilitate research into the development of novel therapies and advance our understanding of the clinical heterogeneity and pathobiology of neurodegenerative diseases.

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Herpes simplex virus (HSV) is one of the most common causes of viral encephalitis. Hypothalamic-pituitary dysfunction has rarely been reported in HSV encephalitis, with few reports into the longer term outcomes for these patients. A 46-year-old male presented with a 10-day history of delirium, fever, and polydipsia.

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Cortical tau accumulation is a key pathological event that partly defines Alzheimer's disease (AD) onset and is associated with cognitive decline and future disease progression. However, an improved understanding of the timing and pattern of early tau deposition in AD and how this may be tracked in vivo is needed. Data from 59 participants involved in two longitudinal cohort studies of autosomal dominant AD (ADAD) were used to investigate whether tau PET can detect and track presymptomatic change; seven participants were symptomatic, and 52 were asymptomatic but at a 50% risk of carrying a pathogenic mutation.

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Familial Alzheimer's disease (FAD), caused by mutations in Presenilin (PSEN1/2) and Amyloid Precursor Protein (APP) genes, is associated with an early age at onset (AAO) of symptoms. AAO is relatively consistent within families and between carriers of the same mutations, but differs markedly between individuals carrying different mutations. Gaining a mechanistic understanding of why certain mutations manifest several decades earlier than others is extremely important in elucidating the foundations of pathogenesis and AAO.

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Visual short-term memory (VSTM) deficits including VSTM binding have been associated with Alzheimer's disease (AD) from preclinical to dementia stages, cross-sectionally. Yet, longitudinal investigations are lacking. The objective of this study was to evaluate VSTM function longitudinally and in relation to expected symptom onset in a cohort of familial Alzheimer's disease.

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In vitro studies of autosomal dominant Alzheimer's disease implicate longer amyloid-β peptides in disease pathogenesis; however, less is known about the behaviour of these mutations in vivo. In this cross-sectional cohort study, we used liquid chromatography-tandem mass spectrometry to analyse 66 plasma samples from individuals who were at risk of inheriting a mutation or were symptomatic. We tested for differences in amyloid-β (Aβ)42:38, Aβ42:40 and Aβ38:40 ratios between presenilin 1 (PSEN1) and amyloid precursor protein (APP) carriers.

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The basis of visual short-term memory (VSTM) impairments in preclinical Alzheimer's disease (AD) remains unclear. Research suggests that eye movements may serve as indirect surrogates to investigate VSTM. Yet, investigations in preclinical populations are lacking.

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Cognitive resilience is an important modulating factor of cognitive decline in Alzheimer's disease, but the functional brain mechanisms that support cognitive resilience remain elusive. Given previous findings in normal ageing, we tested the hypothesis that higher segregation of the brain's connectome into distinct functional networks represents a functional mechanism underlying cognitive resilience in Alzheimer's disease. Using resting-state functional MRI, we assessed both resting-state functional MRI global system segregation, i.

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Mutations in the Presenilin 1 (PSEN1) gene are the most common cause of autosomal dominant familial Alzheimer's disease. We report the clinical, imaging and postmortem findings of kindred carrying a novel duplication mutation (Ile168dup) in the PSEN1 gene. We interpret the pathogenicity of this novel variant and discuss the additional neurological features (pyramidal dysfunction, myoclonus and seizures) that accompanied cognitive decline.

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Objective: To investigate the inherent clinical risks associated with the presence of cerebral microhemorrhages (CMHs) or cerebral microbleeds and characterize individuals at high risk for developing hemorrhagic amyloid-related imaging abnormality (ARIA-H), we longitudinally evaluated families with dominantly inherited Alzheimer disease (DIAD).

Methods: Mutation carriers (n = 310) and noncarriers (n = 201) underwent neuroimaging, including gradient echo MRI sequences to detect CMHs, and neuropsychological and clinical assessments. Cross-sectional and longitudinal analyses evaluated relationships between CMHs and neuroimaging and clinical markers of disease.

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Objective: To use survival modeling to estimate disease duration in autosomal dominant familial Alzheimer disease (ADAD) and ascertain whether factors influencing age at onset also affect survival.

Methods: Symptomatic mutation carriers (201 presenilin 1 [] and 55 amyloid precursor protein []) from ADAD families referred to the Dementia Research Centre, between 1987 and 2019, were included. Survival was assessed with respect to age at onset, year of birth, ε4 status, cognitive presentation, and sex using multilevel mixed-effects Weibull survival models.

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