Cross-translational models of late-onset cognitive sequelae and their treatment in pediatric brain tumor survivors

Dahhan, Noor Z. Al; Cox, Elizabeth; Nieman, Brian J.; Mabbott, Donald

doi:10.1016/j.neuron.2022.04.009

Cited by 11 publications

(10 citation statements)

References 268 publications

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“…Long-term difficulties are likely to profoundly affect participation for these children, at home, school and later in the workplace, likely resulting in poorer long-term educational and employment outcomes [13, 14]. This results in persistent burden for families and healthcare systems [15]. Whilst survival must always be the utmost priority, research aimed at limiting this cognitive morbidity in this group is now needed to ensure likelihood of reaching their potential, despite their illness [16].…”

Section: Introductionmentioning

confidence: 99%

Limited Research Investigating the Value of MRI in Predicting Future Cognitive Morbidity in Survivors of Paediatric Brain Tumours: A Call to Action for Clinical Neuroimaging Researchers

Griffiths-King,

Delivett,

Peet

et al. 2024

Preprint

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Survivors of pediatric brain tumour patients are at high risk of cognitive morbidity. There is clinical benefit in being able to reliably predict, at the individual patient level, whether a patient will experience these difficulties or not, the degree of impairment, and the domains affected. Whilst established risk factors exist, quantitative analysis of MRI could provide added predictive value towards this goal, above and beyond existing clinical risk models. The current systematic review aims to answer the question; Do MRI markers predict future cognitive functioning in pediatric brain tumour survivors?. Studies of pediatric brain tumour patients which test the value of MRI variables in predicting later neuropsychological outcomes were searched up to July 2022. Only included were studies where MRI scans were acquired at an earlier timepoint and used to predict a child's performance on cognitive tests at a later timepoint. Surprisingly few studies were identified by the search process which specifically investigated MRI measures of cerebellar and white matter damage as features in predicting cognitive outcomes. However, the important finding of this review is that the current literature is limited and those identified had small sample sizes and were rated as poor quality for the purposes of prediction. Overall, current findings are at high risk of bias and thus the quality and impact of conclusions are limited. Given the significant impact for this clinical population that predictive models would enable, the current review affirms the need for a call-to-action for medical imaging researchers in pediatric neuro-oncology.

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Section: Introductionmentioning

confidence: 99%

Limited Research Investigating the Value of MRI in Predicting Future Cognitive Morbidity in Survivors of Paediatric Brain Tumours: A Call to Action for Clinical Neuroimaging Researchers

Griffiths-King,

Delivett,

Peet

et al. 2024

Preprint

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“…Notably, the prognosis of GBM patients worsens with age (Kim et al., 2021 ; Ladomersky et al., 2020 ; Lowry et al., 1998 ). Nearly all patients with primary brain tumors develop debilitating neurocognitive dysfunction, resulting in a reduced quality of life, and educational and occupational attainment (Al Dahhan et al., 2022 ; Liu et al., 2009 ; Lustberg et al., 2023 ). Importantly, this impairment in neurocognitive function is irreversible and progressive in nature, in some cases developing long after completion of treatment (Al Dahhan et al., 2022 ; Makale et al., 2017 ).…”

Section: Introductionmentioning

confidence: 99%

“…Nearly all patients with primary brain tumors develop debilitating neurocognitive dysfunction, resulting in a reduced quality of life, and educational and occupational attainment (Al Dahhan et al., 2022 ; Liu et al., 2009 ; Lustberg et al., 2023 ). Importantly, this impairment in neurocognitive function is irreversible and progressive in nature, in some cases developing long after completion of treatment (Al Dahhan et al., 2022 ; Makale et al., 2017 ). It affects various neurocognitive domains, in particular memory, processing speed, and executive function, resulting in dementia in 5% of cases (Ajithkumar et al., 2017 ; DeAngelis et al., 1989 ).…”

Section: Introductionmentioning

confidence: 99%

Glioblastoma and its treatment are associated with extensive accelerated brain aging

Ainslie,

Klaver,

Voshart

et al. 2024

Aging Cell

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Progressive neurocognitive dysfunction is the leading cause of a reduced quality of life in patients with primary brain tumors. Understanding how the human brain responds to cancer and its treatment is essential to improve the associated cognitive sequelae. In this study, we performed integrated transcriptomic and tissue analysis on postmortem normal‐appearing non‐tumor brain tissue from glioblastoma (GBM) patients that had received cancer treatments, region‐matched brain tissue from unaffected control individuals and Alzheimer's disease (AD) patients. We show that normal‐appearing non‐tumor brain regions of patients with GBM display hallmarks of accelerated aging, in particular mitochondrial dysfunction, inflammation, and proteostasis deregulation. The extent and spatial pattern of this response decreased with distance from the tumor. Gene set enrichment analyses and a direct comparative analysis with an independent cohort of brain tissue samples from AD patients revealed a significant overlap in differentially expressed genes and a similar biological aging trajectory. Additionally, these responses were validated at the protein level showing the presence of increased lysosomal lipofuscin, phosphorylated microtubule‐associated protein Tau, and oxidative DNA damage in normal‐appearing brain areas of GBM patients. Overall, our data show that the brain of GBM patients undergoes accelerated aging and shared AD‐like features, providing the basis for novel or repurposed therapeutic targets for managing brain tumor‐related side effects.

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“…In adult cases the median overall survival ranges between 14.6 months for grade IV glioblastoma (GBM) to 13.8 years for lower grade II glioma 3 , while in the paediatric population the 5-year survival rate has increased to over 75% 4 . Nearly all patients with primary brain tumours develop debilitating neurocognitive dysfunction, resulting in a reduced quality of life, and educational and occupational attainment 5,6 . Importantly, this impairment in neurocognitive function is irreversible and progressive in nature, in some cases developing long after completion of treatment 6,7 .…”

Section: Introductionmentioning

confidence: 99%

“…Nearly all patients with primary brain tumours develop debilitating neurocognitive dysfunction, resulting in a reduced quality of life, and educational and occupational attainment 5,6 . Importantly, this impairment in neurocognitive function is irreversible and progressive in nature, in some cases developing long after completion of treatment 6,7 . It affects various neurocognitive domains, in particular memory, processing speed and executive function, resulting in dementia in 5% of cases 8,9 .…”

Section: Introductionmentioning

confidence: 99%

Glioblastoma is associated with extensive accelerated brain ageing

Ainslie

Klaver

Voshart

et al. 2022

Preprint

View full text Add to dashboard Cite

Progressive neurocognitive dysfunction is the leading cause of a reduced quality of life in patients with primary brain tumours. Understanding the mechanisms underlying cognitive impairments that occur in response to a brain tumour and its treatment is essential to improve patients′ quality of life. Here, we show that normal-appearing non-tumour brain regions of patients with glioblastoma display hallmarks of accelerated ageing and share multiple features with Alzheimer′s disease patients. Integrated transcriptomic and tissue analysis shows that normal-appearing brain tissue from glioblastoma patients has a significant overlap with brain tissue from Alzheimer′s disease patients, revealing shared mitochondrial and neuronal dysfunction, and proteostasis deregulation. Overall, the brain of glioblastoma patients undergoes Alzheimer′s disease-like accelerated ageing, providing novel or repurposed therapeutic targets for managing brain cancer-related side effects.

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Cross-translational models of late-onset cognitive sequelae and their treatment in pediatric brain tumor survivors

Cited by 11 publications

References 268 publications

Limited Research Investigating the Value of MRI in Predicting Future Cognitive Morbidity in Survivors of Paediatric Brain Tumours: A Call to Action for Clinical Neuroimaging Researchers

Limited Research Investigating the Value of MRI in Predicting Future Cognitive Morbidity in Survivors of Paediatric Brain Tumours: A Call to Action for Clinical Neuroimaging Researchers

Glioblastoma and its treatment are associated with extensive accelerated brain aging

Glioblastoma is associated with extensive accelerated brain ageing

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