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  • Oxford University Press (OUP)  (5)
  • 1
    Online Resource
    Online Resource
    Structural progression of Alzheimer’s disease over decades: the MRI staging scheme
    Oxford University Press (OUP) ; 2022
    In:  Brain Communications Vol. 4, No. 3 ( 2022-05-02)
    Details
    In: Brain Communications, Oxford University Press (OUP), Vol. 4, No. 3 ( 2022-05-02)
    Abstract: The chronological progression of brain atrophy over decades, from pre-symptomatic to dementia stages, has never been formally depicted in Alzheimer’s disease. This is mainly due to the lack of cohorts with long enough MRI follow-ups in cognitively unimpaired young participants at baseline. To describe a spatiotemporal atrophy staging of Alzheimer’s disease at the whole-brain level, we built extrapolated lifetime volumetric models of healthy and Alzheimer’s disease brain structures by combining multiple large-scale databases (n = 3512 quality controlled MRI from 9 cohorts of subjects covering the entire lifespan, including 415 MRI from ADNI1, ADNI2 and AIBL for Alzheimer’s disease patients). Then, we validated dynamic models based on cross-sectional data using external longitudinal data. Finally, we assessed the sequential divergence between normal aging and Alzheimer’s disease volumetric trajectories and described the following staging of brain atrophy progression in Alzheimer’s disease: (i) hippocampus and amygdala; (ii) middle temporal gyrus; (iii) entorhinal cortex, parahippocampal cortex and other temporal areas; (iv) striatum and thalamus and (v) middle frontal, cingular, parietal, insular cortices and pallidum. We concluded that this MRI scheme of atrophy progression in Alzheimer’s disease was close but did not entirely overlap with Braak staging of tauopathy, with a ‘reverse chronology’ between limbic and entorhinal stages. Alzheimer’s disease structural progression may be associated with local tau accumulation but may also be related to axonal degeneration in remote sites and other limbic-predominant associated proteinopathies.
    Type of Medium: Online Resource
    ISSN: 2632-1297
    URL: Article
    DOI: 10.1093/braincomms/fcac109
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2022
    detail.hit.zdb_id: 3020013-1
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  • 2
    Online Resource
    Online Resource
    Key questions for the evaluation of anti-amyloid immunotherapies for Alzheimer’s disease
    Oxford University Press (OUP) ; 2023
    In:  Brain Communications Vol. 5, No. 3 ( 2023-05-02)
    Details
    In: Brain Communications, Oxford University Press (OUP), Vol. 5, No. 3 ( 2023-05-02)
    Abstract: The clinical benefit associated with anti-amyloid immunotherapies, a new class of drugs for the treatment of Alzheimer’s disease, is predicated on their ability to modify disease course by lowering brain amyloid levels. At the time of writing, two amyloid-lowering antibodies, aducanumab and lecanemab, have obtained United States Food and Drug Administration accelerated approval, with further agents of this class in the Alzheimer’s disease treatment pipeline. Based on limited published clinical trial data to date, regulators, payors and physicians will need to assess their efficacy, clinical effectiveness and safety, as well as cost and accessibility. We propose that attention to three important questions related to treatment efficacy, clinical effectiveness and safety should guide evidence-based consideration of this important class of drugs. These are: (1) Were trial statistical analyses appropriate and did they convincingly support claims of efficacy? (2) Do reported treatment effects outweigh safety concerns and are they generalizable to a representative clinical population of people with Alzheimer’s disease? and (3) Do the data convincingly demonstrate disease course modification, suggesting that increasing clinical benefits beyond the duration of the trials are likely? We suggest specific approaches to interpreting trial results for these drugs and highlight important areas of uncertainty where additional data and a cautious interpretation of existing results is warranted. Safe, effective and accessible treatments for Alzheimer’s disease are eagerly awaited by millions of patients and their caregivers worldwide. While amyloid-targeting immunotherapies may be promising disease-modifying Alzheimer’s disease treatments, rigorous and unbiased assessment of clinical trial data is critical to regulatory decision-making and subsequently determining their provision and utility in routine clinical practice. Our recommendations provide a framework for evidence-based appraisal of these drugs by regulators, payors, physicians and patients.
    Type of Medium: Online Resource
    ISSN: 2632-1297
    URL: Article
    DOI: 10.1093/braincomms/fcad175
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2023
    detail.hit.zdb_id: 3020013-1
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  • 3
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    Online Resource
    Staging of progressive supranuclear palsy-Richardson syndrome using MRI brain charts for the human lifespan
    Oxford University Press (OUP) ; 2024
    In:  Brain Communications
    Details
    In: Brain Communications, Oxford University Press (OUP)
    Abstract: Brain charts for the human lifespan have been recently proposed to build dynamic models of brain anatomy in normal aging and various neurological conditions. They offer new possibilities to quantify neuroanatomical changes from preclinical stages to death, where longitudinal MRI data are not available. In this study, we used brain charts to model the progression of brain atrophy in progressive supranuclear palsy – Richardson syndrome (PSP-RS). We combined multiple datasets (n = 8170 quality controlled MRI of healthy subjects from 22 cohorts covering the entire lifespan, and n = 62 MRI of PSP-RS patients from the 4 Repeat Tauopathy Neuroimaging Initiative) to extrapolate lifetime volumetric models of healthy and PSP-RS brain structures. We then mapped in time and space the sequential divergence between healthy and PSP-RS charts. We found six major consecutive stages of atrophy progression: (i) ventral diencephalon (including subthalamic nuclei, substantia nigra, and red nuclei), (ii) pallidum, (iii) brainstem, striatum and amygdala, (iv) thalamus, (v) frontal lobe and (vi) occipital lobe. The three structures with most severe atrophy over time were the thalamus, followed by the pallidum and the brainstem. These results match the neuropathological staging of tauopathy progression in PSP-RS, where the pathology is supposed to start in the pallido-nigro-luysian system and spreads rostrally via the striatum and the amygdala to the cerebral cortex, and caudally to the brainstem. This study supports the use of brain charts for the human lifespan to study the progression of neurodegenerative diseases, especially in the absence of specific biomarkers as in PSP.
    Type of Medium: Online Resource
    ISSN: 2632-1297
    URL: Article
    DOI: 10.1093/braincomms/fcae055
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2024
    detail.hit.zdb_id: 3020013-1
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  • 4
    Online Resource
    Online Resource
    Viral Coinfections in Hospitalized Coronavirus Disease 2019 Patients Recruited to the International Severe Acute Respiratory and Emerging Infections Consortium WHO Clinical Characterisation Protocol UK Study
    Oxford University Press (OUP) ; 2022
    In:  Open Forum Infectious Diseases Vol. 9, No. 11 ( 2022-11-02)
    Details
    In: Open Forum Infectious Diseases, Oxford University Press (OUP), Vol. 9, No. 11 ( 2022-11-02)
    Abstract: We conducted this study to assess the prevalence of viral coinfection in a well characterized cohort of hospitalized coronavirus disease 2019 (COVID-19) patients and to investigate the impact of coinfection on disease severity. Methods Multiplex real-time polymerase chain reaction testing for endemic respiratory viruses was performed on upper respiratory tract samples from 1002 patients with COVID-19, aged & lt;1 year to 102 years old, recruited to the International Severe Acute Respiratory and Emerging Infections Consortium WHO Clinical Characterisation Protocol UK study. Comprehensive demographic, clinical, and outcome data were collected prospectively up to 28 days post discharge. Results A coinfecting virus was detected in 20 (2.0%) participants. Multivariable analysis revealed no significant risk factors for coinfection, although this may be due to rarity of coinfection. Likewise, ordinal logistic regression analysis did not demonstrate a significant association between coinfection and increased disease severity. Conclusions Viral coinfection was rare among hospitalized COVID-19 patients in the United Kingdom during the first 18 months of the pandemic. With unbiased prospective sampling, we found no evidence of an association between viral coinfection and disease severity. Public health interventions disrupted normal seasonal transmission of respiratory viruses; relaxation of these measures mean it will be important to monitor the prevalence and impact of respiratory viral coinfections going forward.
    Type of Medium: Online Resource
    ISSN: 2328-8957
    URL: Article
    DOI: 10.1093/ofid/ofac531
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2022
    detail.hit.zdb_id: 2757767-3
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  • 5
    Online Resource
    Online Resource
    Tau seeds from patients induce progressive supranuclear palsy pathology and symptoms in primates
    Oxford University Press (OUP) ; 2023
    In:  Brain Vol. 146, No. 6 ( 2023-06-01), p. 2524-2534
    Details
    In: Brain, Oxford University Press (OUP), Vol. 146, No. 6 ( 2023-06-01), p. 2524-2534
    Abstract: Progressive supranuclear palsy is a primary tauopathy affecting both neurons and glia and is responsible for both motor and cognitive symptoms. Recently, it has been suggested that progressive supranuclear palsy tauopathy may spread in the brain from cell to cell in a ‘prion-like’ manner. However, direct experimental evidence of this phenomenon, and its consequences on brain functions, is still lacking in primates. In this study, we first derived sarkosyl-insoluble tau fractions from post-mortem brains of patients with progressive supranuclear palsy. We also isolated the same fraction from age-matched control brains. Compared to control extracts, the in vitro characterization of progressive supranuclear palsy-tau fractions demonstrated a high seeding activity in P301S-tau expressing cells, displaying after incubation abnormally phosphorylated (AT8- and AT100-positivity), misfolded, filamentous (pentameric formyl thiophene acetic acid positive) and sarkosyl-insoluble tau. We bilaterally injected two male rhesus macaques in the supranigral area with this fraction of progressive supranuclear palsy-tau proteopathic seeds, and two other macaques with the control fraction. The quantitative analysis of kinematic features revealed that progressive supranuclear palsy-tau injected macaques exhibited symptoms suggestive of parkinsonism as early as 6 months after injection, remaining present until euthanasia at 18 months. An object retrieval task showed the progressive appearance of a significant dysexecutive syndrome in progressive supranuclear palsy-tau injected macaques compared to controls. We found AT8-positive staining and 4R-tau inclusions only in progressive supranuclear palsy-tau injected macaques. Characteristic pathological hallmarks of progressive supranuclear palsy, including globose and neurofibrillary tangles, tufted astrocytes and coiled bodies, were found close to the injection sites but also in connected brain regions that are known to be affected in progressive supranuclear palsy (striatum, pallidum, thalamus). Interestingly, while glial AT8-positive lesions were the most frequent near the injection site, we found mainly neuronal inclusions in the remote brain area, consistent with a neuronal transsynaptic spreading of the disease. Our results demonstrate that progressive supranuclear palsy patient-derived tau aggregates can induce motor and behavioural impairments in non-human primates related to the prion-like seeding and spreading of typical pathological progressive supranuclear palsy lesions. This pilot study paves the way for supporting progressive supranuclear palsy-tau injected macaque as a relevant animal model to accelerate drug development targeting this rare and fatal neurodegenerative disease.
    Type of Medium: Online Resource
    ISSN: 0006-8950 , 1460-2156
    URL: Article
    DOI: 10.1093/brain/awac428
    RVK:
    XA 10000
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2023
    detail.hit.zdb_id: 1474117-9
    SSG: 12
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