Replacement of microglia by monocyte-derived macrophages prevents long-term memory deficits after therapeutic irradiation

AbstractResident microglia of the brain have a distinct origin compared to macrophages in other organs. Under physiological conditions, microglia are maintained by self-renewal from the local pool, independent of hematopoietic progenitors. Pharmacologic depletion of microglia during therapeutic whole-brain irradiation prevents synaptic loss and rescues recognition memory deficits but the mechanisms behind these protective effects are unknown. Here we demonstrate that after a combination of therapeutic whole-brain irradiation and microglia depletion, macrophages originating from circulating monocytes engraft into the brain and replace the microglia pool. Comparisons of transcriptomes reveal that brain-engrafted macrophages have an intermediate phenotype that resembles both monocytes and embryonic microglia. Importantly, the brain-engrafted macrophages have a reduced phagocytic activity for synaptic compartments compared to the activated microglia from irradiated brains, which in turn prevent the aberrant and chronic synapse loss that results in radiation-induced memory deficits. These results are the first to demonstrate that replacement of microglia by brain-engrafted macrophages represent a potential therapeutic avenue for the treatment of brain radiotherapy induced cognitive deficits.

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EXTH-08. REPLACEMENT OF MICROGLIA BY BRAIN-ENGRAFTED MACROPHAGES PREVENTS MEMORY DEFICITS AFTER THERAPEUTIC WHOLE-BRAIN IRRADIATION

Neuro-Oncology ◽

10.1093/neuonc/noz175.342 ◽

2019 ◽

Vol 21 (Supplement_6) ◽

pp. vi83-vi84

Author(s):

Xi Feng ◽

Sonali Gupta ◽

David Chen ◽

Zoe Boosalis ◽

Sharon Liu ◽

...

Keyword(s):

Cognitive Deficits ◽

Memory Deficits ◽

Protective Effects ◽

Whole Brain Irradiation ◽

Synaptic Loss ◽

Whole Brain ◽

Brain Irradiation ◽

Brain Radiotherapy ◽

The Brain ◽

Therapeutic Avenue

Abstract Microglia have a distinct origin compared to blood circulating myeloid cells. Under normal physiological conditions, microglia are maintained by self-renewal, independent of hematopoietic progenitors. Following genetic or pharmacologic depletion, newborn microglia derive from the local residual pool and quickly repopulate the entire brain. The depletion of brain resident microglia during therapeutic whole-brain irradiation fully prevents irradiation-induced synaptic loss and recognition memory deficits but the mechanisms driving these protective effects are unknown. Here, we demonstrate that after CSF-1R inhibitor-mediated microglia depletion and therapeutic whole-brain irradiation, circulating monocytes engraft into the brain and replace the microglia pool. These monocyte-derived brain-engrafted macrophages have reduced phagocytic activity compared to microglia from irradiated brains, but similar to locally repopulated microglia without brain irradiation. Transcriptome comparisons reveal that brain-engrafted macrophages have both monocyte and embryonic microglia signatures. These results suggest that monocyte-derived brain-engrafted macrophages represent a novel therapeutic avenue for the treatment of brain radiotherapy-induced cognitive deficits.

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SCIDOT-04. REPLACEMENT OF MICROGLIA BY BRAIN-ENGRAFTED MACROPHAGES PREVENTS MEMORY DEFICITS AFTER THERAPEUTIC WHOLE-BRAIN IRRADIATION

Neuro-Oncology ◽

10.1093/neuonc/noz175.1145 ◽

2019 ◽

Vol 21 (Supplement_6) ◽

pp. vi273-vi273

Author(s):

Xi Feng ◽

Sonali Gupta ◽

David Chen ◽

Zoe Boosalis ◽

Sharon Liu ◽

...

Keyword(s):

Cognitive Deficits ◽

Memory Deficits ◽

Protective Effects ◽

Whole Brain Irradiation ◽

Synaptic Loss ◽

Whole Brain ◽

Brain Irradiation ◽

Brain Radiotherapy ◽

The Brain ◽

Therapeutic Avenue

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An Updated Review on Memantine Efficacy in Reducing Cognitive Dysfunction of Whole-brain Irradiation for Adult Patients with Brain metastasis

International Journal of Cancer Management ◽

10.5812/ijcm.111966 ◽

2021 ◽

Vol In Press (In Press) ◽

Author(s):

Anya jafari ◽

Zahra Siavashpour ◽

Mohammad Houshyari

Keyword(s):

Brain Metastasis ◽

Verbal Learning ◽

Whole Brain Radiotherapy ◽

Protective Effects ◽

Whole Brain Irradiation ◽

Whole Brain ◽

Brain Irradiation ◽

Brain Radiotherapy ◽

Delayed Recognition

Context: Increased survival of patients with cancer raises the need to pay attention to long-term side effects. Patients with brain metastasis experienced cognition failure after whole-brain radiotherapy. This review aimed at concluding the efficacy of Memantine in preserving cognitive function by reducing the brain toxicity of whole-brain radiotherapy for metastatic brain cancers. Evidence Acquisition: Published studies evaluating memantine protective effects during brain metastasis radiotherapy were searched for in scientific databases (e.g., Embase, PubMed, Cochrane database, Google Scholar, Scopus) using keywords including whole-brain radiotherapy and Memantine. Results: A total of 4 prospective clinical trials were included in the review. Effects of Memantine on cognition tests were evaluated in these trials. A significantly better Hopkins Verbal Learning Test-Revised (HVLT-R) delayed recognition at months 6 was achieved in RTOG 0614 and NRG CC001. Longer time to cognitive decline was found in the memantine arm of the RTOG trial and was statistically significant. Memantine effects were not statistically significant before 2 months. Conclusions: It seems reasonable to consider Memantine during radiation to prevent long-term cognitive failure in patients with brain metastasis due to the current results. Memantine improves cognition function during whole-brain radiotherapy (WBRT) without adding irreparable complications.

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Whole-brain irradiation differentially modifies neurotransmitters levels and receptors in the hypothalamus and the prefrontal cortex

Radiation Oncology ◽

10.1186/s13014-020-01716-y ◽

2020 ◽

Vol 15 (1) ◽

Author(s):

Javier Franco-Pérez ◽

Sergio Montes ◽

Josué Sánchez-Hernández ◽

Paola Ballesteros-Zebadúa

Keyword(s):

Prefrontal Cortex ◽

Gabaa Receptor ◽

Whole Brain Radiotherapy ◽

Gabab Receptors ◽

Gamma Aminobutyric Acid ◽

Secondary Effects ◽

Whole Brain Irradiation ◽

Whole Brain ◽

Brain Irradiation ◽

Brain Radiotherapy

Abstract Background Whole-brain radiotherapy is a primary treatment for brain tumors and brain metastasis, but it also induces long-term undesired effects. Since cognitive impairment can occur, research on the etiology of secondary effects has focused on the hippocampus. Often overlooked, the hypothalamus controls critical homeostatic functions, some of which are also susceptible after whole-brain radiotherapy. Therefore, using whole-brain irradiation (WBI) in a rat model, we measured neurotransmitters and receptors in the hypothalamus. The prefrontal cortex and brainstem were also analyzed since they are highly connected to the hypothalamus and its regulatory processes. Methods Male Wistar rats were exposed to WBI with 11 Gy (Biologically Effective Dose = 72 Gy). After 1 month, we evaluated changes in gamma-aminobutyric acid (GABA), glycine, taurine, aspartate, glutamate, and glutamine in the hypothalamus, prefrontal cortex, and brainstem according to an HPLC method. Ratios of Glutamate/GABA and Glutamine/Glutamate were calculated. Through Western Blott analysis, we measured the expression of GABAa and GABAb receptors, and NR1 and NR2A subunits of NMDA receptors. Changes were analyzed comparing results with sham controls using the non-parametric Mann–Whitney U test (p < 0.05). Results WBI with 11 Gy induced significantly lower levels of GABA, glycine, taurine, aspartate, and GABAa receptor in the hypothalamus. Also, in the hypothalamus, a higher Glutamate/GABA ratio was found after irradiation. In the prefrontal cortex, WBI induced significant increases of glutamine and glutamate, Glutamine/Glutamate ratio, and increased expression of both GABAa receptor and NMDA receptor NR1 subunit. The brainstem showed no statistically significant changes after irradiation. Conclusion Our findings confirm that WBI can affect rat brain regions differently and opens new avenues for study. After 1 month, WBI decreases inhibitory neurotransmitters and receptors in the hypothalamus and, conversely, increases excitatory neurotransmitters and receptors in the prefrontal cortex. Increments in Glutamate/GABA in the hypothalamus and Glutamine/Glutamate in the frontal cortex indicate a neurochemical imbalance. Found changes could be related to several reported radiotherapy secondary effects, suggesting new prospects for therapeutic targets.

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Metabolic and histopathological changes in the brain and plasma of rats exposed to fractionated whole-brain irradiation

Brain Research ◽

10.1016/j.brainres.2018.12.022 ◽

2019 ◽

Vol 1708 ◽

pp. 146-159 ◽

Cited By ~ 1

Author(s):

Soňa Bálentová ◽

Petra Hnilicová ◽

Dagmar Kalenská ◽

Eva Baranovičová ◽

Peter Muríň ◽

...

Keyword(s):

Histopathological Changes ◽

Whole Brain Irradiation ◽

Whole Brain ◽

Brain Irradiation ◽

The Brain

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Dosimetric study of whole-brain irradiation with high-energy photon beams for dose reduction to the scalp

British Journal of Radiology ◽

10.1259/bjr.20200159 ◽

2020 ◽

Vol 93 (1114) ◽

pp. 20200159

Author(s):

Masafumi Sawada ◽

Etsuo Kunieda ◽

Takeshi Akiba ◽

Shigeto Kabuki ◽

Ryuta Nagao ◽

...

Keyword(s):

High Energy ◽

High Energy Photon ◽

Photon Beams ◽

Whole Brain Irradiation ◽

Energy Photon ◽

Whole Brain ◽

Brain Irradiation ◽

Brain Surface ◽

The Mean ◽

The Brain

Objective: To evaluate the efficiency of high-energy photons for mitigating alopecia due to whole-brain irradiation (WBRT). Methods: Planning CT data from 10 patients who received WBRT were collected. We prepared 4 WBRT plans that used 6 or 15 MV photon beams, with or without use of a field-in-field (FiF) technique, and compared outcomes using a treatment planning system. The primary outcome was dose parameters to the scalp, including the mean dose, maximum dose, and dose received to 50% scalp (D50%). Secondary outcomes were minimum dose to the brain surface. Results: Using FiF, the mean doses were 24.4–26.0 and 22.4–24.1 Gy, and the maximum doses were 30.5–32.1 and 28.5–30.8 Gy for 6 and 15 MV photon beams, respectively. Without FiF, the mean doses were 24.6–26.9 and 22.6–24.5 Gy, and the maximum doses were 30.8–34.6 and 28.6–32.4 Gy for 6 and 15 MV photon beams. The 15 MV plan resulted in a lower scalp dose for each dose parameter (p < 0.001). Using FiF, the minimum doses to the brain surface for the 6 and 15 MV plans were 28.9 ± 0.440 and 29.0 ± 0.557 Gy, respectively (p = 0.70). Without FiF, the minimum doses to the brain surface for the 6 and 15 MV plans were 28.9 ± 0.456 and 29.0 ± 0.529, respectively (p = 0.66). Conclusion: Compared with the 6 MV plan, the 15 MV plan achieved a lower scalp dose without impairing the brain surface dose. Advances in knowledge: High-energy photon WBRT may mitigate alopecia of patients who receiving WBRT.

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Colony-stimulating factor 1 receptor blockade prevents fractionated whole-brain irradiation-induced memory deficits

Journal of Neuroinflammation ◽

10.1186/s12974-016-0671-y ◽

2016 ◽

Vol 13 (1) ◽

Cited By ~ 32

Author(s):

Xi Feng ◽

Timothy D. Jopson ◽

Maria Serena Paladini ◽

Sharon Liu ◽

Brian L. West ◽

...

Keyword(s):

Memory Deficits ◽

Receptor Blockade ◽

Colony Stimulating Factor ◽

Whole Brain Irradiation ◽

Whole Brain ◽

Brain Irradiation ◽

Stimulating Factor

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Whole-brain irradiation differentially modifies neurotransmitters levels and receptors in the hypothalamus and the prefrontal cortex.

10.21203/rs.3.rs-42436/v2 ◽

2020 ◽

Author(s):

JAVIER FRANCO PEREZ ◽

SERGIO MONTES ◽

JOSUE SANCHEZ-HERNANDEZ ◽

PAOLA BALLESTEROS-ZEBADUA

Keyword(s):

Prefrontal Cortex ◽

Gabaa Receptor ◽

Whole Brain Radiotherapy ◽

Gabab Receptors ◽

Gamma Aminobutyric Acid ◽

Secondary Effects ◽

Whole Brain Irradiation ◽

Whole Brain ◽

Brain Irradiation ◽

Brain Radiotherapy

Abstract Background: Whole-brain radiotherapy is a primary treatment for brain tumors and brain metastasis, but it also induces long-term undesired effects. Since cognitive impairment can occur, research on the etiology of secondary effects has focused on the hippocampus. Often overlooked, the hypothalamus controls critical homeostatic functions, some of which are also susceptible after whole-brain radiotherapy. Therefore, using whole-brain irradiation (WBI) in a rat model, we measured neurotransmitters and receptors in the hypothalamus. The prefrontal cortex and brainstem were also analyzed since they are highly connected to the hypothalamus and its regulatory processes.Methods: Male Wistar rats were exposed to WBI with 11 Gy (Biologically Equivalent Dose= 72Gy). After one month, we evaluated changes in gamma-aminobutyric acid (GABA), glycine, taurine, aspartate, glutamate, and glutamine in the hypothalamus, prefrontal cortex, and brainstem according to an HPLC method. Ratios of Glutamate/GABA and Glutamine/Glutamate were calculated. Through Western Blott analysis, we measured the expression of GABAa and GABAb receptors, and NR1 and NR2A subunits of NMDA receptors. Changes were analyzed comparing results with sham controls using the non-parametric Mann-Whitney U test (p<0.05).Results: WBI with 11Gy induced significantly lower levels of GABA, glycine, taurine, aspartate, and GABAa receptor in the hypothalamus. Also, in the hypothalamus, a higher Glutamate/GABA ratio was found after irradiation. In the prefrontal cortex, WBI induced significant increases of glutamine and glutamate, Glutamine/Glutamate ratio, and increased expression of both GABAa receptor and NMDA receptor NR1 subunit. The brainstem showed no statistically significant changes after irradiation.Conclusion: Our findings confirm that WBI can affect rat brain regions differently and opens new avenues for study. After one month, WBI decreases inhibitory neurotransmission in the hypothalamus and, conversely, increases excitatory neurotransmission in the prefrontal cortex. Increments in Glutamate/GABA in the hypothalamus and Glutamine/Glutamate in the frontal cortex indicate a neurochemical imbalance. Found changes could be related to several reported radiotherapy secondary effects, suggesting new prospects for therapeutic targets.

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Chemotherapy for patients with brain metastases from melanoma.

Journal of Clinical Oncology ◽

10.1200/jco.2012.30.15_suppl.e19012 ◽

2012 ◽

Vol 30 (15_suppl) ◽

pp. e19012-e19012

Author(s):

David R. Naskhletashvili ◽

Vera A. Gorbunova ◽

Mark B. Bychkov ◽

Ali H. Bekyashev ◽

Vladislav B. Karahan ◽

...

Keyword(s):

Partial Response ◽

Brain Metastases ◽

Metastatic Melanoma ◽

Objective Response ◽

Complete Response ◽

Combined Chemotherapy ◽

Whole Brain Irradiation ◽

Whole Brain ◽

Brain Irradiation ◽

The Brain

e19012 Background: There have not been standards of chemo- and chemo-radiotherapy for treatment for patients with brain metastases. The patients (pts) with brain metastases (BM) from melanoma have poor prognoses. The main goal of this trial is to assess the efficacy of nitrosoureas (CCNU or FCNU), temozolomide (TMZ) as monotherapy, TMZ combined with whole brain irradiation (WBI), or combined chemotherapy of TMZ and cisplatin in pts with BM from melanoma. Methods: 78 pts were included in this study. 21 pts were treated with WBI (3Gy/30Gy) and concomitant TMZ therapy (75 mg/m2/day orally on days 1-14), 19 pts were treated with TMZ (150 mg/m2/day orally on days 1-5, every 4 weeks) as monotherapy, 17 pts pts were treated with nitrosoureas (CCNU or FCNU), 21 pts were treated with combined chemotherapy of TMZ (150/mg/m2/day orally on days 1-5, every 4 weeks) + cisplatin (20/mg/m2/day intravenous on days 1-5, every 4 weeks). The main aims of this study were objective response (OR) – complete response (CR) + partial response (PR) in the brain and in the extracranial sites (ES), median of survival (mOS), 1-year and 2-year survival. Results: Observations were as follows: in the TMZ + WBI treated pts, 4 OR (19,0%) in 21 pts group in the brain and 1 OR (6,7%) in 15 pts group in ES. The mOS was 6.0 months, 1-year survival was 23,8%. In the TMZ monotherapy treated pts there were 5 OR (26,3%) in 19 pts group in the brain and no OR in 13 pts group in ES. The mOS was 6 months, 1-year survival was 21,1%. In the nitrisoureas treated pts we achieved 2 OR (11,8%) in 17 pts group in the brain and 1 OR (9,1%) in 11 pts group in ES. The mOS was 5 months, 1-year survival was 17,6%. In the TMZ + cisplatin treated pts there were 7 OR (33.3%) in 21 pts group in the brain and 7 OR (35,0%) in 20 pts group in ES. The mOS was 8 months, 1-year survival was 33,3%. 2-year survival (19,0%) was achieved only in TMZ and cisplatin group. Conclusions: Previous results of our study showed promising higher efficacy of TMZ and cisplatin, especially in OR in ES (p<0.05) and in 2-year survival (p<0.05), in comparison with TMZ alone, nitrosoureas or TMZ with whole brain irradiation in patients with metastatic melanoma with BM. Control of extracranial lesions is important factor for patients with BM. Further investigation is to be expected.

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Are there still indications for whole brain irradiation in 2021?

memo - Magazine of European Medical Oncology ◽

10.1007/s12254-021-00710-8 ◽

2021 ◽

Author(s):

Karin Dieckmann ◽

Harald Herrmann

Keyword(s):

Brain Metastases ◽

Whole Brain Radiotherapy ◽

Whole Brain Irradiation ◽

Whole Brain ◽

Brain Irradiation ◽

Patients With Cancer ◽

Brain Radiotherapy ◽

Precision Therapy ◽

Randomized Control ◽

Neurocognitive Decline

SummaryBrain metastases (BM) are the most frequent intracranial tumors in adults. About 10–20% of the patients with cancer will develop them. Historically, most of the patients with brain metastases were treated with whole brain radiotherapy (WBRT). The intention was to control the metastases and to eliminate distant micrometastases. Randomized control trials showed no difference in survival in patients with single and oligometastases treated with WBRT compared with stereotactic radiosurgery (SRS). To avoid treatment-related toxicities with neurocognitive decline, indications for WBRT are changing. High precision therapy with SRS or postoperative stereotactic treatments have become increasingly important. Only in exceptional cases is WBRT still the treatment of choice.

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