Memantine for Mitigation of Neurocognitive Toxicity Following Radiation to the Brain.
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ABSTRACT:
SUBMITTER: Cunningham DA
PROVIDER: S-EPMC8081539 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Preserving cognitive functions is a priority for most patients with brain metastases. Knowing the mechanisms of hyperglutamatergic neurotoxicity and the role of some hippocampal areas in cognitive decline (CD) led to testing both the antiglutamatergic pharmacological prophylaxis and hippocampal-sparing whole-brain radiotherapy (WBRT) techniques. These studies showed a relative reduction in CD four to six months after WBRT. However, the failure to achieve statistical significance in one study that tested memantine alone (RTOG 0614) led to widespread skepticism about this drug in the WBRT setting. Moreover, interest grew in the reasons for the strong patient dropout rates in the first few months after WBRT and for early CD onset. In fact, the latter can only partially be explained by subclinical tumor progression. An emerging interpretation of the (not only) cognitive impairment during and immediately after WBRT is the dysfunction of the limbic and hypothalamic system with its immune and hormonal consequences. This new understanding of WBRT-induced toxicity may represent the basis for further innovative trials. These studies should aim to: (i) evaluate in greater detail the cognitive effects and, more generally, the quality of life impairment during and immediately after WBRT; (ii) study the mechanisms producing these early effects; (iii) test in clinical studies, the modern and advanced WBRT techniques based on both hippocampal-sparing and hypothalamic-pituitary-sparing, currently evaluated only in planning studies; (iv) test new timings of antiglutamatergic drugs administration aimed at preventing not only late toxicity but also acute effects.
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Project description:BackgroundHippocampal avoidance whole-brain radiotherapy (HA-WBRT) shows potential for neurocognitive preservation. This study aimed to evaluate whether HA-WBRT or conformal WBRT (C-WBRT) is better for preserving neurocognitive function.MethodsThis single-blinded randomized phase II trial enrolled patients with brain metastases and randomly assigned them to receive HA-WBRT or C-WBRT. Primary endpoint is decline of the Hopkins Verbal Learning Test-Revised (HVLT-R) delayed recall at 4 months after treatment. Neurocognitive function tests were analyzed with a mixed effect model. Brain progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method.ResultsFrom March 2015 to December 2018, seventy patients were randomized to yield a total cohort of 65 evaluable patients (33 in the HA-WBRT arm and 32 in the C-WBRT arm) with a median follow-up of 12.4 months. No differences in baseline neurocognitive function existed between the 2 arms. The mean change of HVLT-R delayed recall at 4 months was -8.8% in the HA-WBRT arm and +3.8% in the C-WBRT arm (P = 0.31). At 6 months, patients receiving HA-WBRT showed favorable perpetuation of HVLT-R total recall (mean difference = 2.60, P = 0.079) and significantly better preservation of the HVLT-R recognition-discrimination index (mean difference = 1.78, P = 0.019) and memory score (mean difference = 4.38, P = 0.020) compared with patients undergoing C-WBRT. There were no differences in Trail Making Test Part A or Part B or the Controlled Oral Word Association test between the 2 arms at any time point. There were no differences in brain PFS or OS between arms as well.ConclusionPatients receiving HA-WBRT without memantine showed better preservation in memory at 6-month follow-up, but not in verbal fluency or executive function.
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Project description:After surgery, radiation is the most effective treatment for the majority of brain tumors in both children and adults. Although improvements in radiotherapy delivery and targeting have resulted in reduction in neurologic morbidity, radiotherapy is still associated with acute and late toxicities that are dependent on a variety of treatment- and patient-specific variables. Variables of treatment include radiation dose, fractionation, volume, technique, photons or protons, and concomitant or adjuvant chemotherapy. Patient- and tumor-specific variables include tumor type, location and patient age. Side effects of treatment are also variable and can range from mild fatigue to significant memory difficulties and even death. This review will focus on the hypothesized mechanisms of cognitive dysfunction after radiation therapy and will discuss possible intervention strategies including behavioral and pharmacological prevention and treatment.
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Project description:Total body irradiation (TBI) can induce lethal myelosuppression, due to the sensitivity of proliferating hematopoietic stem/progenitor cells (HSPCs) to ionizing radiation (IR). No effective therapy exists to mitigate the hematologic toxicities of TBI. Here, using selective and structurally distinct small molecule inhibitors of cyclin-dependent kinase 4 (CDK4) and CDK6, we have demonstrated that selective cellular quiescence increases radioresistance of human cell lines in vitro and mice in vivo. Cell lines dependent on CDK4/6 were resistant to IR and other DNA-damaging agents when treated with CDK4/6 inhibitors. In contrast, CDK4/6 inhibitors did not protect cell lines that proliferated independently of CDK4/6 activity. Treatment of wild-type mice with CDK4/6 inhibitors induced reversible pharmacological quiescence (PQ) of early HSPCs but not most other cycling cells in the bone marrow or other tissues. Selective PQ of HSPCs decreased the hematopoietic toxicity of TBI, even when the CDK4/6 inhibitor was administered several hours after TBI. Moreover, PQ at the time of administration of therapeutic IR to mice harboring autochthonous cancers reduced treatment toxicity without compromising the therapeutic tumor response. These results demonstrate an effective method to mitigate the hematopoietic toxicity of IR in mammals, which may be potentially useful after radiological disaster or as an adjuvant to anticancer therapy.
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Project description:Cortical spreading depolarization (CSD) is a promising target for neuroprotective therapy in traumatic brain injury (TBI). We explored the effect of NMDA receptor antagonism on electrically triggered CSDs in healthy and brain-injured animals. Rats received either one moderate or four daily repetitive mild closed head impacts (rmTBI). Ninety-three animals underwent craniectomy with electrocorticographic (ECoG) and local blood flow monitoring. In brain-injured animals, ketamine or memantine inhibited CSDs in 44 to 88% and 50 to 67% of cases, respectively. Near-DC/AC-ECoG amplitude was reduced by 44 to 75% and 52 to 67%, and duration by 39 to 87% and 61 to 78%, respectively. Daily memantine significantly reduced spreading depression and oligemia following CSD. Animals (N = 31) were randomized to either memantine (10 mg/kg) or saline with daily neurobehavioral testing. Memantine-treated animals had higher neurological scores. We demonstrate that memantine improved neurovascular function following CSD in sham and brain-injured animals. Memantine also prevented neurological decline in a blinded, preclinical randomized rmTBI trial.
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Project description:William Morton introduced the world to ether anesthesia for use during surgery in the Bullfinch Building of the Massachusetts General Hospital on October 16, 1846. For nearly two centuries, the prevailing wisdom had been that the effects of general anesthetics were rapidly and fully reversible, with no apparent long-term adverse sequelae. Despite occasional concerns of a possible association between surgery and anesthesia with dementia since 1887 (Savage, 1887), our initial belief was robustly punctured following the publication in 1998 of the International Study of Post-Operative Cognitive Dysfunction [ISPOCD 1] study by Moller et al. (1998) in The Lancet, in which they demonstrated in a prospective fashion that there were in fact persistent adverse effects on neurocognitive function up to 3 months following surgery and that these effects were common. Since the publication of that landmark study, significant strides have been made in redefining the terminology describing cognitive dysfunction, identifying those patients most at risk, and establishing the underlying etiology of the condition, particularly with respect to the relative contributions of anesthesia and surgery. In 2018, the International Nomenclature Consensus Working Group proposed new nomenclature to standardize identification of and classify perioperative cognitive changes under the umbrella of perioperative neurocognitive disorders (PND) (Evered et al., 2018a). Since then, the new nomenclature has tried to describe post-surgical cognitive derangements within a unifying framework and has brought to light the need to standardize methodology in clinical studies and motivate such studies with hypotheses of PND pathogenesis. In this narrative review, we highlight the relevant literature regarding recent key developments in PND identification and management throughout the perioperative period. We provide an overview of the new nomenclature and its implications for interpreting risk factors identified by clinical association studies. We then describe current hypotheses for PND development, using data from clinical association studies and neurophysiologic data where appropriate. Finally, we offer broad clinical guidelines for mitigating PND in the perioperative period, highlighting the role of Brain Enhanced Recovery After Surgery (Brain-ERAS) protocols.
| S-EPMC9363758 | biostudies-literature
Project description:IntroductionNeurocognitive problems associated with posttraumatic stress disorder (PTSD) can interact with impairment resulting from traumatic brain injury (TBI).Research questionWe aimed to identify neurocognitive problems associated with probable PTSD following TBI in a civilian sample.Material and methodsThe study is part of the CENTER-TBI project (Collaborative European Neurotrauma Effectiveness Research) that aims to better characterize TBI. For this cross-sectional study, we included patients of all severities aged over 15, and a Glasgow Outcome Score Extended (GOSE) above 3. Participants were assessed at six months post-injury on the PTSD Checklist-5 (PCL-5), the Trail Making Test (TMT), the Rey Auditory Verbal Learning Test (RAVLT) and the Cambridge Neuropsychological Test Automated Battery (CANTAB). Primary analysis was a complete case analysis. Regression analyses were performed to investigate the association between the PCL-5 and cognition.ResultsOf the 1134 participants included in the complete case analysis, 13.5% screened positive for PTSD. Probable PTSD was significantly associated with higher TMT-(B-A) (OR = 1.35, 95% CI: 1.14-1.60, p < .001) and lower RAVLT-delayed recall scores (OR = 0.74, 95% CI: 0.61-0.91, p = .004) after controlling for age, sex, psychiatric history, baseline Glasgow Coma Scale and education.Discussion and conclusionPoorer performance on cognitive tests assessing task switching and, to a lesser extent, delayed verbal recall is associated with probable PTSD in civilians who have suffered TBI.
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Project description: Not available
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Project description:BackgroundAlthough radiation (RT) is standard treatment for many brain tumors, it may contribute to neurocognitive decline. The objective of this study was to investigate associations between RT dose to circumscribed brain regions and specific neurocognitive domains in patients with meningioma.MethodsWe undertook a retrospective study of 40 patients with meningioma who received RT and underwent an in-depth clinical neurocognitive assessment. Radiation dosimetry characteristics were delineated based on treatment planning computerized tomography co-registered with contrast-enhanced 3D T1-weighted magnetic resonance imaging. Principal components analysis was applied to organize neurocognitive test scores into factors, and multivariate multiple linear regression models were undertaken to examine if RT dose to circumscribed brain regions is associated with specific neurocognitive outcomes.ResultsRadiation dose to brain regions was associated with neurocognitive functions across a number of domains. High dose to the parietal-occipital region was associated with slower visuomotor processing speed (mean dose, β = -1.100, P = .017; dose to 50% of the region [D50], β = -0.697, P = .049). In contrast, high dose to the dorsal frontal region was associated with faster visuomotor processing speed (mean dose, β = 0.001, P = .036).ConclusionsThese findings suggest that RT delivered to brain regions (ie, parietal-occipital areas) may contribute to poor neurocognitive outcomes. Given that modern radiotherapy techniques allow for precise targeting of dose delivered to brain regions, prospective trials examining relations between dose and neurocognitive functions are warranted to confirm these preliminary results.
| S-EPMC9113401 | biostudies-literature
Project description:Highlights • Successful implementation of standardized neurocognitive testing within the radiotherapy clinic.• High patient compliance >75% after 1 year.• 1 year after treatment significant changes in cognitive performance is observed.• Data collection is ongoing, long-term follow-up will be performed. Background Radiotherapy induced impairment of cognitive function can lead to a reduced quality of life. The aim of this study was to describe the implementation and compliance of standardized neurocognitive assessment. In addition, the first results of cognitive changes for patients receiving a radiation dose to the brain are described. Materials and methods Patients that received radiation dose to the brain (neuro, head and neck and prophylactic cranial irradiation between April-2019 and Dec-2021 were included. Three neuro cognitive tests were performed a verbal learning and memory test, the Hopkins Verbal Learning Test; a verbal fluency test, the Controlled Oral Word Association Test and a speed and cognitive flexibility test, the Trail Making Test A&B. Tests were performed before the start of radiation, 6 months (6 m) and 1 year (1y) after irradiation. The Reliable Change Index (RCI) between baseline and follow-up was calculated using reference data from literature. Results 644 patients performed the neurocognitive tests at baseline, 346 at 6 months and 205 at 1y after RT, with compliance rates of 90.4%, 85.6%, and 75.3%, respectively. Reasons for non-compliance were: 1. Patient did not attend appointment (49%), 2. Patient was unable to perform the test due to illness (12%), 3. Patient refused the test (8 %), 4. Various causes, (31%). A semi-automated analysis was developed to evaluate the test results. In total, 26% of patients showed a significant decline in at least one of variables at 1y and 11% on at least 2 variables at 1y. However, an increase in cognitive performance was observed in 49% (≥1 variable) and 22% (≥2 variables). Conclusion Standardized neurocognitive testing within the radiotherapy clinic was successfully implemented, with a high patient compliance. A semi-automatic method to evaluate cognitive changes after treatment was defined. Data collection is ongoing, long term follow-up (up to 5 years after treatment) and dose–effect analysis will be performed.
| S-EPMC10413416 | biostudies-literature