Four decades of chemotherapy-induced cognitive dysfunction: comprehensive review of clinical, animal and in vitro studies, and insights of key initiating events

Dias-Carvalho, Ana; Ferreira, Mariana; Ferreira, Rita; Bastos, Maria de Lourdes; Sá, Susana I.; Capela, João Paulo; Carvalho, Félix; Costa, Vera Marisa

doi:10.1007/s00204-021-03171-4

Cited by 14 publications

(13 citation statements)

References 325 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Objective neurocognitive data support the notion that cognitive deficits are most common in the domains of executive functioning, working memory, attentional resource mobilization, and processing speed 28. Research shows a decline in cognitive performance throughout the progression of chemotherapy for non-CNS cancers, with most taking the form of longitudinal studies 11…”

Section: Clinical Characterizationmentioning

confidence: 79%

“…Prevalence rates of self-reported cognitive complaints associated with chemotherapy are variable, ranging between 21% and 34% in patients with breast cancer 9. Despite most clinical studies investigating cognitive impairment having been conducted in chemotherapy treated breast cancer populations,11 evidence in support of chemotherapy induced cognitive impairment (CICI) spans a variety of prevalent cancers, including lung, colorectal, and gynecological cancers 121314. However, these studies are few, and a clear need exists to establish more robust evidence for CICI in cancers other than the most studied breast cancer group, especially neuroimaging studies in which sex differences can affect results.…”

Section: Epidemiologymentioning

confidence: 99%

“…Neuropsychological tests are the de facto method of objectively identifying cognitive impairment in recipients of cancer treatment 11. Methods for recognizing cognitive impairment vary considerably between studies, which has made comparison difficult 22.…”

Section: Clinical Characterizationmentioning

confidence: 99%

“…Chemotherapy related neuroinflammation may arise via several possible mechanisms 11. Elevated cerebral ROS induced by antineoplastic action in the periphery may oxidize apolipoprotein-1, inhibiting its ability to mediate the transcription 3 signaling cascade, triggering macrophage produced pro-inflammatory cytokines 73.…”

Section: Mechanisms Underlying Chemotherapy Induced Cognitive Impairmentmentioning

confidence: 99%

See 3 more Smart Citations

Cognitive impairment after cancer treatment: mechanisms, clinical characterization, and management

Fleming

Edison

Kenny

2023

BMJ

View full text Add to dashboard Cite

Cognitive impairment is a debilitating side effect experienced by patients with cancer treated with systemically administered anticancer therapies. With around 19.3 million new cases of cancer worldwide in 2020 and the five year survival rate growing from 50% in 1970 to 67% in 2013, an urgent need exists to understand enduring side effects with severe implications for quality of life. Whereas cognitive impairment associated with chemotherapy is recognized in patients with breast cancer, researchers have started to identify cognitive impairment associated with other treatments such as immune, endocrine, and targeted therapies only recently. The underlying mechanisms are diverse and therapy specific, so further evaluation is needed to develop effective therapeutic interventions. Drug and non-drug management strategies are emerging that target mechanistic pathways or the cognitive deficits themselves, but they need to be rigorously evaluated. Clinically, consistent use of objective diagnostic tools is necessary for accurate diagnosis and clinical characterization of cognitive impairment in patients treated with anticancer therapies. This should be supplemented with clinical guidelines that could be implemented in daily practice. This review summarizes the recent advances in the mechanisms, clinical characterization, and novel management strategies of cognitive impairment associated with treatment of non-central nervous system cancers.

show abstract

Section: Clinical Characterizationmentioning

confidence: 79%

Section: Epidemiologymentioning

confidence: 99%

Section: Clinical Characterizationmentioning

confidence: 99%

Section: Mechanisms Underlying Chemotherapy Induced Cognitive Impairmentmentioning

confidence: 99%

See 2 more Smart Citations

Cognitive impairment after cancer treatment: mechanisms, clinical characterization, and management

Fleming

Edison

Kenny

2023

BMJ

View full text Add to dashboard Cite

show abstract

“…Cognitive decline, a sign of brain aging, is amongst the most devastating of these adverse consequences. Increasing evidence indicates that chemotherapy for cancers outside the nervous system increases the risk of cognitive impairment [ 3 , 5 , 6 , 36 ]. Nevertheless, multiple epidemiologic studies have shown that there is an inverse relation between cancer and Alzheimer disease [ 37 – 39 ].…”

Section: Discussionmentioning

confidence: 99%

Nasal administration of mesenchymal stem cells prevents accelerated age-related tauopathy after chemotherapy in mice

et al. 2023

View full text Add to dashboard Cite

Background There is increasing concern that cancer and cancer treatment accelerate aging and the associated cognitive decline. We showed recently that treatment of 9-month-old male mice with cisplatin causes cognitive deficits that are associated with formation of tau deposits in the hippocampus. Here we explored the capacity of mesenchymal stem cells (MSC) given via the nose to prevent age-related brain tau deposits. Moreover, we more closely examined the cellular distribution of this hallmark of accelerated brain aging in response to treatment of 9-month-old female and male mice with cisplatin. Results We show that cisplatin induces tau deposits in the entorhinal cortex and hippocampus in both sexes. The tau deposits colocalize with syndecan-2. Astrocytes surrounding tau deposits have increased glial fibrillary acidic protein glial fibrillary acidic protein (GFAP) expression. Most of the cisplatin-induced tau deposits were located in microtubule associated protein-2 (MAP-2)+ neurons that were surrounded by aquaporin 4+ (AQP4)+ neuron-facing membrane domains of astrocytes. In addition, some tau deposits were detected in the perinuclear region of GFAP+ astrocytes and in CD31+ endothelial cells. There were no morphological signs of activation of ionized calcium binding adaptor molecule-1+ (Iba-1)+ microglia and no increases in brain cytokine production. Nasal administration of MSC at 48 and 96 hours after cisplatin prevented formation of tau deposits and normalized syndecan-2 and GFAP expression. Behaviorally, cisplatin-induced tau cluster formation was associated with reduced executive functioning and working/spatial memory and nasal administration of MSC at 48 and 96 hours after cisplatin prevented these cognitive deficits. Notably, delayed MSC administration (1 month after cisplatin) also prevented tau cluster formation and cognitive deficits, in both sexes. Conclusion In summary, nasal administration of MSC to older mice at 2 days or 1 month after completion of cisplatin treatment prevents the accelerated development of tau deposits in entorhinal cortex and hippocampus and the associated cognitive deficits. Since MSC are already in clinical use for many other clinical indications, developing nasal MSC administration for treatment of accelerated brain aging and cognitive deficits in cancer survivors should be feasible and would greatly improve their quality of life.

show abstract

DNMT3a Downregulation Ttriggered Upregulation of GABA_A Receptor in the mPFC Promotes Paclitaxel‐Induced Pain and Anxiety in Male Mice

Tian,

Li,

Zhao

et al. 2024

Advanced Science

View full text Add to dashboard Cite

Chemotherapeutic agents, such as paclitaxel (PTX), induce neuroplastic changes and alter gene expression in the prefrontal cortex (PFC), which may be associated with chemotherapy‐induced pain and negative emotions. Notably, DNA methylation undergoes adaptive changes in neurological disorders, emerging as a promising target for neuromodulation. In this study, systemic administration of PTX leads to a decrease in the expression of the DNA methyltransferase DNMT3a, while concurrently upregulating the expression of Gabrb1 mRNA and its encoded GABAARβ1 protein in the medial PFC (mPFC) of male mice. Overexpression of DNMT3a in the mPFC alleviates PTX‐induced pain hypersensitivity, and anxiety‐like behavior in these mice. Additionally, it reverses the PTX‐induced increase in inhibitory synaptic transmission in the pyramidal neurons of the mPFC. Mechanistically, the upregulation of GABAARβ1 in the mPFC is linked to the reduced expression of DNMT3a and DNA hypomethylation at the promoter region of the Gabrb1 gene. Furthermore, a long‐term diet rich in methyl donors alleviates PTX‐induced pain hypersensitivity and anxiety‐like behavior in mice. These findings suggest that the DNMT3a‐mediated upregulation of GABAARβ1 in the mPFC contributes to PTX‐induced neuropathic pain and anxiety, highlighting DNA methylation‐dependent epigenetic regulation as a potential therapeutic target for addressing chemotherapy‐induced cortical dysfunction.

show abstract

Four decades of chemotherapy-induced cognitive dysfunction: comprehensive review of clinical, animal and in vitro studies, and insights of key initiating events

Cited by 14 publications

References 325 publications

Cognitive impairment after cancer treatment: mechanisms, clinical characterization, and management

Cognitive impairment after cancer treatment: mechanisms, clinical characterization, and management

Nasal administration of mesenchymal stem cells prevents accelerated age-related tauopathy after chemotherapy in mice

DNMT3a Downregulation Ttriggered Upregulation of GABA_A Receptor in the mPFC Promotes Paclitaxel‐Induced Pain and Anxiety in Male Mice

Contact Info

Product

Resources

About

Four decades of chemotherapy-induced cognitive dysfunction: comprehensive review of clinical, animal and in vitro studies, and insights of key initiating events

Cited by 14 publications

References 325 publications

Cognitive impairment after cancer treatment: mechanisms, clinical characterization, and management

Cognitive impairment after cancer treatment: mechanisms, clinical characterization, and management

Nasal administration of mesenchymal stem cells prevents accelerated age-related tauopathy after chemotherapy in mice

DNMT3a Downregulation Ttriggered Upregulation of GABAA Receptor in the mPFC Promotes Paclitaxel‐Induced Pain and Anxiety in Male Mice

Contact Info

Product

Resources

About

DNMT3a Downregulation Ttriggered Upregulation of GABA_A Receptor in the mPFC Promotes Paclitaxel‐Induced Pain and Anxiety in Male Mice