Plausible biochemical mechanisms of chemotherapy-induced cognitive impairment (“chemobrain”), a condition that significantly impairs the quality of life of many cancer survivors

Ren, Xiaojia; Boriero, Diana; Chaiswing, Luksana; Bondada, Subbarao; Clair, Daret K. St.; Butterfield, D. Allan

doi:10.1016/j.bbadis.2019.02.007

Cited by 94 publications

(70 citation statements)

References 152 publications

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“…This conclusion follows comparison of final and time-averaged dementia rates born in the originally cognitively normal population. On the other hand, the rates of the conversion to dementia among patients in pre-existing MCI were higher than that in cognitively normal participants, in agreement with the previous reports [54] and were less amenable to delay by the combinations of protectants.…”

Section: Dem Av: ¼ Dem E X ðTe à Tdþ=ðte à Tbþsupporting

confidence: 91%

“…Thus, PDE5 inhibitors [42], antiplatelet [43,44], vasodilators [43,45], antimigraine [38,39], antivirals [46], probiotics [47], magnesium [48,49], transdermal oestrogen ( Table 2) and possibly metformin [40,41,50,51] are the agents of interest to perhaps combine with the multivitamin-multimineral formulas of Table 2. Conversely, the signals by corticosteroids [52,53], anti-cancer therapies [54,55], anti-acid drugs [56,57], infections underlying use of antibiotics and antifungals [58], the link between dementia and respiratory deficiency [59], between dementia and cardiac arrythmia [44] mostly align with outside evidence of involvement in neurodegeneration. Effects of statins are likely due to underlying conditions outweighing the effects of medications (cardiovascular disease, metabolic syndrome), not unlike the insulin case described above.…”

Section: Screening Of Individual Pharmacological Mechanisms For Corrementioning

confidence: 99%

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Pharmacological signatures of the reduced incidence and the progression of cognitive decline in ageing populations suggest the protective role of beneficial polypharmacy

Mayburd

Koivogui²,

Baranova

2019

PLoS ONE

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Preventive treatments for dementia are warranted. Here we show that utilization of certain combinations of prescription medications and supplements correlates with reduced rates of cognitive decline. More than 1,900 FDA-approved agents and supplements were collapsed into 53 mechanism-based groups and traced in electronic medical records (EMRs) for >50,000 patients. These mechanistic groups were aligned with the data presented in more than 300 clinical trials, then regression model was built to fit the signals from EMRs to clinical trial performance. While EMR signals of each single agents correlated with clinical performance relatively weakly, the signals produced by combinations of active compounds were highly correlated with the clinical trial performance (R = 0.93, p = 3.8 x10^-8). Higher ranking pharmacological modalities were traced in patient profiles as their combinations, producing protective complexity estimates reflecting degrees of exposure to beneficial polypharmacy. For each age strata, the higher was the protective complexity score, the lower was the prevalence of dementia, with maximized life-long effects for the highest regression score /diversity compositions. The connection was less strong in individuals already diagnosed with cognitive impairment. Confounder analysis confirmed an independent effect of protective complexity in multivariate context. A sub-cohort with lifelong odds of dementia decreased > 5-folds was identified; this sub-cohort should be studied in further details, including controlled clinical trials. In short, our study systematically explored combinatorial preventive treatment regimens for age-associated multi-morbidity, with an emphasis on neurodegeneration, and provided extensive evidence for their feasibility.Funding: AM is the Founder of Neurocombinatorix LLC, and MK is affiliated with the organization. Neurocombinatorix LLC does not conduct commercial activity and did not provide any funds for research. The authors volunteered to the effort without any salaries, no other parties have a role in the study design, data collection and analysis, Recent decreases in the rate of dementia and a shift to later ages of onset are encouraging [4]. However, in a first quartile of life expectancy, dementia still accounts for 1 in every 6 deaths, and is a major source of disability [1]. While multiple clinical trials for single dementia combating agents are ongoing [5], earlier stages of neurodegeneration process largely remain unexplored in humans.On the other hand, recent studies in model animals are encouraging. Particular successful efforts in visible rejuvenation of already differentiated tissues are reviewed in [6]). NAD+ supplementation has been associated with an extension of murine lifespan by 10-15% [7,8] through the mechanism likely related to overall brain function. The maintenance of microvasculature [9,10], the clearance of misfolded proteins [11], the neuroprotection [12,13], and the regulation of cholinesterase [13] were shown to be comparably important for the prevention...

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Section: Dem Av: ¼ Dem E X ðTe à Tdþ=ðte à Tbþsupporting

confidence: 91%

Section: Screening Of Individual Pharmacological Mechanisms For Corrementioning

confidence: 99%

Pharmacological signatures of the reduced incidence and the progression of cognitive decline in ageing populations suggest the protective role of beneficial polypharmacy

Mayburd

Koivogui²,

Baranova

2019

PLoS ONE

View full text Add to dashboard Cite

show abstract

“…standard fluid intelligence tests) may be related to a higher degree of global functional connectivity in the lateral prefrontal cortex. Importantly, fluid intelligence tests and the TMT are all based on visual information, for which patients receiving ACBC are found to have an impaired processing [47]. Over this set of the findings related to chemotherapy neurotoxicity, preclinical studies have elicited that melatonin effects can modulate the neuroplastic processes implied in cognitive impairment [48].…”

Section: Discussionmentioning

confidence: 99%

Clinical impact of melatonin on breast cancer patients undergoing chemotherapy; effects on cognition, sleep and depressive symptoms: A randomized, double-blind, placebo-controlled trial

et al. 2020

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This randomized, double-blinded, placebo-controlled trial tested the hypothesis that 20mg of melatonin before and during the first cycle of adjuvant chemotherapy for breast cancer (ACBC) reduced the side effects associated with cognitive impairment. We evaluated the effects of melatonin on cognition, depressive symptoms and sleep quality, and whether these effects were related to serum levels of Brain Derived Neurotrophic Factor (BDNF) and its receptor, tropomyosin kinase B (TrkB). Thirty-six women were randomly assigned to receive melatonin or placebo for 10 days. To evaluate cognitive performance, we used the Trail-Making-Test Parts A and B (A-B), Rey Auditory-Verbal Learning Test (RAVLT), Controlled Oral Word Association Test (COWAT) and an inhibitory task type Go / No-Go. Our results revealed that melatonin improved executive function on TMT scores, enhanced episodic memory (immediate and delayed) and recognition on RAVLT, and increased verbal fluency in the orthographic COWAT. The TMT-A-B(A-B) were negatively correlated with baseline levels of TrkB and BDNF, respectively. At the end of treatment, changes in TrkB and BDNF were inversely associated with depressive symptoms and sleep quality, but not with the TMT scores. These results suggest a neuroprotective effect of melatonin to counteract the adverse effects of ACBC on cognitive function, sleep quality and depressive symptoms.

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“…However, there is currently little evidence that the treatments caused amyloid‐beta accumulation or triggered AD‐like dementia. Instead, the cognitive decline is attributed to damage to the BBB, oxidative stress, and cytokine dysregulation; thus, this chemobrain phenomenon is believed to be mechanistically closer to vascular dementia (Ren et al, ; Ren, St Clair, & Butterfield, ). Consistently, severe chemobrain is associated with cytotoxic DNA‐damaging drugs, rather than CDK inhibitors.…”

Section: Concerns To Be Addressedmentioning

confidence: 99%

“Amyloid‐beta accumulation cycle” as a prevention and/or therapy target for Alzheimer's disease

et al. 2020

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The cell cycle and its regulators are validated targets for cancer drugs. Reagents that target cells in a specific cell cycle phase (e.g., antimitotics or DNA synthesis inhibitors/replication stress inducers) have demonstrated success as broad‐spectrum anticancer drugs. Cyclin‐dependent kinases (CDKs) are drivers of cell cycle transitions. A CDK inhibitor, flavopiridol/alvocidib, is an FDA‐approved drug for acute myeloid leukemia. Alzheimer's disease (AD) is another serious issue in contemporary medicine. The cause of AD remains elusive, although a critical role of latent amyloid‐beta accumulation has emerged. Existing AD drug research and development targets include amyloid, amyloid metabolism/catabolism, tau, inflammation, cholesterol, the cholinergic system, and other neurotransmitters. However, none have been validated as therapeutically effective targets. Recent reports from AD‐omics and preclinical animal models provided data supporting the long‐standing notion that cell cycle progression and/or mitosis may be a valid target for AD prevention and/or therapy. This review will summarize the recent developments in AD research: (a) Mitotic re‐entry, leading to the “amyloid‐beta accumulation cycle,” may be a prerequisite for amyloid‐beta accumulation and AD pathology development; (b) AD‐associated pathogens can cause cell cycle errors; (c) thirteen among 37 human AD genetic risk genes may be functionally involved in the cell cycle and/or mitosis; and (d) preclinical AD mouse models treated with CDK inhibitor showed improvements in cognitive/behavioral symptoms. If the “amyloid‐beta accumulation cycle is an AD drug target” concept is proven, repurposing of cancer drugs may emerge as a new, fast‐track approach for AD management in the clinic setting.

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Plausible biochemical mechanisms of chemotherapy-induced cognitive impairment (“chemobrain”), a condition that significantly impairs the quality of life of many cancer survivors

Cited by 94 publications

References 152 publications

Pharmacological signatures of the reduced incidence and the progression of cognitive decline in ageing populations suggest the protective role of beneficial polypharmacy

Pharmacological signatures of the reduced incidence and the progression of cognitive decline in ageing populations suggest the protective role of beneficial polypharmacy

Clinical impact of melatonin on breast cancer patients undergoing chemotherapy; effects on cognition, sleep and depressive symptoms: A randomized, double-blind, placebo-controlled trial

“Amyloid‐beta accumulation cycle” as a prevention and/or therapy target for Alzheimer's disease

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