Effects of chemotherapy for acute lymphoblastic leukemia on cognitive function in animal models of contemporary protocols: A systematic literature review

Abstract

Survival rates of childhood acute lymphoblastic leukemia (ALL) have improved greatly due to advanced therapies and supportive care. Intrathecal chemotherapy replaced cranial radiation due to radiation-induced neurotoxicity and late-effects. Survivors treated with chemotherapy-only experience neurologic and cognitive problems following cessation of treatment. Very long-term cognitive outcomes remain unclear. Animal models are being generated to assess late-effects of chemotherapy on cognitive function. Although, few address juvenile models of chemotherapy-induced cognitive impairment (CICI) and developing brain, results of this review outline neurocognitive effects of chemotherapy consistent with childhood ALL therapy. Studies demonstrate deficits across cognitive domains including spatial memory, executive function, short-term memory, anxiety and depression. Inflammation, oxidative stress, excitotoxity, and other metabolic disruptions may lead to neurodegeneration associated with cognitive impairment observed in ALL survivors. Interventions directly targeting these mechanisms may prevent and/or promote recovery of cognitive function and improve long-term outcomes. Evidence suggests success of anti-inflammatory and antioxidant treatments in reducing cognitive decline. Animal models provide basis for assessing effects of chemotherapy on neurologic processes to guide future clinical investigations.

Keywords: Acute lymphoblastic leukemia; Animal models; Chemobrain; Childhood cancer; Survivorship.

Figure 1:

Results of literature review

Figure 2:

Mechanisms of chemotherapy-induced cognitive impairment form a complex network that contribute to sustained neurologic injury in childhood cancer survivors. Inflammation, oxidative stress, metabolic disruption and excitotoxicity all contribute to chemotherapy-induced cognitive impairment. Interactions across mechanisms may exacerbate or prolong cognitive impact of cancer therapy. Inflammation: Damage to cellular structures releases damage associated molecular patterns which can activate innate immunity and ultimately, microglia. Activated microglia release cytokines that can destabilize mitochondria resulting in oxidative stress and apoptosis. Metabolism: Disruption of the folate pathway by methotrexate can lead to folate depletion and inflammatory activation. Excitotoxicity: Dexamethasone-induced overexcitation of neurons can lead to oxidative stress and neuronal apoptosis. Methotrexate has been shown to raise homocysteine and excitatory neurotransmitter levels. Overexcitation of glutamate receptors can lead to mitochondrial destabilization and neuronal apoptosis. Oxidative stress: Release of reactive oxygen species after mitochondrial destabilization leads oxidation of cellular structures. Pro-apoptotic signaling molecules are also released from dysfunctional mitochondria.