Cancer-related cognitive impairment and hippocampal functioning: The role of dynamin-1

Cancer-related cognitive impairment (CRCI) is a significant challenge for a substantial number of cancer survivors and may persist for many years after treatment. CRCI most frequently affects memory, executive functions, attention, and processing speed. Despite its prevalence, there is currently no established standard of care for CRCI, and the biological pathways and neural mechanisms underlying these cognitive changes are only partially understood. Consequently, a gap remains in translational research that links the neurobiological mechanisms with its cognitive and behavioral outcomes. Bridging this gap is essential, as a clearer understanding of these connections could lead to pharmacological interventions to relieve cognitive impairment. Moreover, research integrating both human subjects and animal models is sparse, further limiting our ability to comprehensively investigate CRCI's mechanisms and identify effective therapies.

Direct and Indirect Neurotoxicity

Chemotherapy can affect the brain in several ways. Studies have shown that both central nervous system (CNS) directed, and non-CNS directed chemotherapy cross the blood-brain barrier (BBB) leading to neurotoxicity and brain damage [1]. The direct toxicity of chemotherapy is evident as neuronal damage, characterized by increased apoptosis and reduced neurogenesis, contributing to cognitive impairment [2]. Chemotherapy and cancer biology can also have an indirect neurotoxic effect by triggering systemic inflammation, hormonal dysregulation, and oxidative stress [3].

Research has identified the hippocampus as a key region affected by neurotoxicity impacted by CRCI, particularly because of its critical role in memory, learning, and spatial navigation. Cancer therapies, including chemotherapy and radiotherapy, have been shown to reduce hippocampal progenitor cells and neurogenesis, diminishing hippocampal function, and contributing to cognitive deficits and reduced cognitive flexibility [4].

Lessons from Aging and Dementia Research

Several authors have pointed out similarities between CRCI and the aging brain in terms of cognitive outcomes such as working memory, attention, and processing speed [5,6]. Neuroimaging studies have found similarities between chemotherapy-exposed brains and those affected by aging, including gray and white matter loss, altered connectivity [7]. Focusing on the hippocampus, research in breast cancer survivors who received chemotherapy have shown volume loss, shape alterations, and decreased functional connectivity [[8], [9], [10]]. These hippocampal changes are consistent with patterns observed in brain aging and cognitive decline [11].

Shared biological processes, such as cellular senescence, oxidative stress, mitochondrial dysfunction, DNA damage, and shortened telomeres, have been shown to be implicated in both aging and CRCI [1]. The parallels suggest that CRCI may follow neurodegenerative pathways similar to those seen in aging, providing a basis for exploring biomarkers and therapeutic approaches from the aging literature. Hence, insights from aging could also be relevant targets for understanding and mitigating CRCI, as these fields have been studied more extensively.

Dynamin 1 as a Potential Mediator in CRCI

Dynamin 1 (DNM1) has been studied for the last decade as a mediator in dementia patients but has only recently been considered in CRCI [12]. DNM1 is a protein that is predominantly expressed in the central nervous system including the brain. DNM1 plays a crucial role in effective neurotransmission by facilitating synaptic vesicle recycling through endocytosis. This recycling process is essential for neurons to continue releasing neurotransmitters efficiently and supports synaptic plasticity. Consequently, lower DNM1 levels in extracellular vesicles (EVs) may reflect reduced neuronal activity, plasticity, and memory function. Reduced levels of DNM1 have been linked to cognitive deficits, particularly in the hippocampus where decreased DNM1 expression in aging models has been associated with declines in hippocampal-dependent memory [13]. Furthermore, experiments inhibiting DNM1 have demonstrated impaired hippocampal-dependent associative memory formation, supporting its critical role in memory [14].

Current Study

In this issue of Neurotherapeutics, Ng and colleagues investigate the role of DNM1 in CRCI by (a) examining the associations between self-reported cognitive functioning and DNM1 levels in blood in cancer patients and controls, and (b) analyzing DNM1 levels in the hippocampus of a mouse model of breast cancer treated with chemotherapy (Fig. 1) [15]. The human study includes prospective and longitudinal data from adolescent and young adult (AYA) patients with various cancer diagnoses.

Fig. 1.

Illustration of the article by Ng. et al. in the current issue of Neurotherapeutics. A. In the human study, self-perceived cognitive functioning was collected with questionnaires, and Dynamin-1 levels were measured in peripheral blood. B. The mouse model study assessed memory function and measured Dynamin-1 levels in the hippocampus. C. Simplified illustration of the mechanisms involved in cancer related cognitive impairment and, in particular, changes related to hippocampal neurotoxicity.

The authors present the first study to measure DNM1 levels in human subjects using peripheral blood samples. This was accomplished by isolating EVs—small vesicles that act as messenger carriers outside of neurons, transporting proteins and other molecules. Cancer patients treated with chemotherapy who reported CRCI showed markedly lower DNM1 levels compared to those who did not report CRCI. When participants were grouped simply as patients or controls, without considering CRCI status, no differences in DNM1 levels were observed. This is surprising given the chemotherapy exposure of the patients.

The current findings indicate that lower DNM1 expression is specifically linked to the experience of CRCI rather than to the cancer or treatment itself. Interestingly, cancer patients who did not report CRCI exhibited higher DNM1 levels than the control participants. This finding may suggest that some cancer patients maintain or even increase DNM1 levels, potentially due to individual differences in treatment response or underlying biological resilience factors such as genetics. For example, the authors found that ethnicity was associated with DNM1 levels. Such factors could be explored further in future studies.

DNM1 levels were also measured in the hippocampus of a mouse model of breast cancer receiving chemotherapy, breast cancer model mice not receiving chemotherapy, and non-cancer wild-type mice also receiving chemotherapy. The most marked decreases in DNM1 immunoreactivity were observed in the CA1 and CA3 regions of the hippocampus in breast cancer-bearing mice that received chemotherapy. Additionally, the cancer-bearing mice receiving chemotherapy performed worse on a spatial memory task compared to the control mice.

The authors focused on AYA patients to minimize the confounding effects of aging and age-related neurodegenerative diseases, which are more common in cancer types prevalent among older individuals. Future studies could investigate to what degree age interacts with DNM1 levels, considering that lower hippocampal DNM1 levels have been associated with aging [13], and dementia [16,17]. Additionally, the potential of DNM1 as a prognostic biomarker to identify patients more vulnerable to developing CRCI could be investigated further.

The study by Ng et al. also raises the possibility of using DNM1 as a biomarker for CRCI, suggesting it could have potential as a target for therapeutic interventions aimed at reducing cognitive sequalae in cancer survivors. In conclusion, this article underscores the need for research that bridges the gap between neurobiology and cognition in CRCI. By leveraging findings from aging and neurodegenerative studies, we can enhance our understanding of CRCI and develop targeted interventions to support affected individuals.

Author Contributions

BJTN: Conceptualization, Writing – Original Draft, Visualization.

LLH: Conceptualization, Writing – Review & Editing.

BJTN and LLH have read and agreed to the published version of the manuscript.

Declaration of competing interest

The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Barbara Johanne Thomas Nordhjem reports financial support was provided by The Danish Childhood Cancer Foundation. Lisa Lyngsie Hjalgrim reports financial support was provided by The Danish Childhood Cancer Foundation. Barbara Johanne Thomas Nordhjem reports financial support was provided by Novo Nordisk Foundation. Lisa Lyngsie Hjalgrim reports financial support was provided by Novo Nordisk Foundation. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.