**5.3. Neuropsychological assessments**

Direct damage of parenchymal brain cells due to RT and subsequent death of these leads to cognitive impairment; damage to oligodendrocytes, responsible for myelination, has been thought to play a role [65]. Neuronal irradiation of rodent causes altered expression of the gene activity-regulated cytoskeleton-associated protein, N-methyl-D-aspartate (NMDA) receptors,

Disruption of the blood–brain barrier (BBB) as a result of brain RT has been associated with impaired cognition. This disruption and alteration of the BBB is likely due to imbalance between matrix metalloproteinase-2 and the metalloproteinase-2 tissue inhibitor levels [67], activation of microglial cells plays an important role in phagocytosis of dead cells, sustained activation is thought to contribute to a chronic inflammatory state in the brain [68]. Subse‐ quent inflammation following RT and cell death usually associated with up regulation of cytokines, which are thought to be expressed by microglia, and pro-inflammatory transcrip‐ tion factors in the brain which contribute to endothelial cell dysfunction [69]. Glial and endothelial cells appear to have independent and overlapping roles in the pathogenesis.

Ionizing radiation produces its effect by direct DNA damage or indirect through generating ROS, leading to DNA damage to and activation of early response transcription factors and signal transduction pathways [70]. Activation of these pathways leads to the following: changes in cytokine milieu; the activation/influx of inflammatory cells, particularly micro‐ glia; marked increase in expression of the pro-inflammatory genes tumor necrosis factor (TNF) α, interleukin (IL)-1β, IL-6, and Cox-2, and the chemokines, Monocyte Chemoattractant Protein-1 (MCP-1), intercellular adhesion molecule (ICAM)-1 and the development of post-

Radiation injury to astrocytes makes them to undergo proliferation, exhibit hypertrophic nuclei/cell bodies, and show increased expression of glial fibrillary acidic protein .These reactive astrocytes secrete a host of pro-inflammatory mediators such as cyclooxygenase (Cox)-2 and the ICAM-1, which may lead to infiltration of leukocytes into the brain via BBB

RT affects large- and medium-sized blood vessels of the brain. Vascular hypothesis predicts that blood-vessel dilatation, wall thickening with hyalinization, endothelial cell loss and a

The severity of cognitive deficit following radiation therapy appears to be proportional to the

Older ages more than 60 years and in some studies more than 40 years old have increased risk to develop leukoencephalopathy specifically in patients with genetic predisposition to leukoencephalopathy [75] with subsequent cognitive deficit. Also patient with white matter disease such as multiple sclerosis have increased risk, also vascular diseases such as hyper‐

decrease in vessel density, all these finally lead to white-matter necrosis [73].

dose of radiation therapy received by the hippocampus region [74].

irradiation complications [71].

248 Neurooncology - Newer Developments

breakdown [72].

**5.2. Predisposing factors**

tention carry risk [76].

glutaminergic transmission, and also hippocampal long-term potentiation [66].

Folstein MMSE is brief test that assess delirium or significant dementia. It does not adequate‐ ly measure all the cognitive areas affected by radiation, and it is not a sensitive tool for detecting cognitive impairment in patients receiving RT [79].

Among the patients who have impaired cognitive function by neuropsychological testing, only 50% were considered abnormal on the MMSE [80].

The National Cancer Institute (NCI) Radiation Oncology Branch adapted the Meyers et al. [45] test battery by adding few measures to assess processing speed, working memory, and attention, which are functions that can be affected by RT [81].

Measurement of quality of life and daily activities of living is an important issue beside the neuropsychological testes, such as the Barthel index to assess the daily living skills and the Functional Assessment of Cancer Therapy-Brain (FACT-Br), to address the quality of life issues concerning brain tumor patients undergoing treatment The Barthel Index assesses daily living skills [82], and the FACT-Br was developed specifically to address the quality of life issues concerning brain tumor patients undergoing treatment [83].

### **5.4. Cognitive impairment following RT**

RT is the leading cause of cognitive deficits involving multiple domains, including memory, attention, executive function, and intelligence.

Patients who received RT performed worse in measures of executive function and informa‐ tion processing speed. Worse cognitive functioning also observed with white-matter hyper‐ intensities and global cortical atrophy [84].

Several studies assed cognitive defects to specific tumor-type and tumor location. Aarsen et al. [85] reported cognitive deficit, with sustained speech and speed of speech in children treated with RT for pilocytic astrocytoma, 60% of patients had difficulty with academics 3 years after treatment.

Cognitive impairment observed in children with medulloblastoma who had treated with RT. These deficits were prominent attention deficits correlated with impaired math and reading performance [86].

Hoppe-Hirsch et al. [87] conducted a study comparing intellectual outcomes of children diagnosed with ependymomas or medulloblastomas, treated with whole-brain radiotherapy (WBRT), and found that only 10% of medulloblastoma patients had an IQ above 90 after 10 years compared to 60% of ependymoma patients, and this result attributed to cerebral hemisphere radiation.

Posteroir fossa irradiation with 35 Gy was associated with lower cognitive scores than that irradiated with a dose 25 Gy, and IQ and verbal comprehension seems to be dose-dependent in posterior fossa tumors [88].

Large-sample controlled clinical trial conducted by Klein et al. [75] assed mid-term and longterm neuropsychological function following the RT in LGG. In the study, 195 patients with LGG compared with 195 healthy controls and 100 patients with hematological malignancies with mean follow-up period of 6 years. The results revealed that patients with LGG had lower scores in all cognitive domains than the controls and hematological patients, and the main cause of cognitive deficits was the tumor, but cognitive deficits of memory domain was observed only in patients who received RT with dose per fraction more than 2 Gy.

Another study was conducted on those patients after 12-year follow-up and found that the attentional deficits deteriorated in patients who received RT. The progressive decline was found even in patients received <2 Gy dose per fraction [89].

Decline in nonverbal memory was observed in patients with LGGs years post-RT, despite the long-term improvements which observed in verbal memory, attention, and executive function [84]. Postoperative RT in LGG was found to have a significant risk of long-term leukoencephalopathy and cognitive impairment [90].

The irradiated volume of brain tissue has great impact on cognition. A study conducted by Jalali et al. [91] reported that patients who treated with stereotactic conformal RT presented with unchanged overall mean full-scale IQ, while one third of patients showed a >10% decline in full-scale IQ as compared to baseline.

Chang et al. [92] found that cognitive deficits after the treatment with sterotactic radiosur‐ gery (SRS) had lower incidence than that in patients treated with whole-brain radiotherapy (WBRT). The cognitive deficit in learning and memory function was (24%) in patients treated with SRS and (52%) in patients treated with WBRT and SRS.

Intensity-modulated radiotherapy (IMRT) is a type RT technique in which more sparing of normal brain tissue can be achieved and precise contouring to the tumor tissue.

Hippocampal sparing with IMRT reduced doses delivered to hippocampus by 87% (0.49 Gy) and 81% (0.73 Gy) [93].

Proton beam therapy results in greater sparing of healthy brain tissue and allows for a moretargeted delivery of radiation and smaller penetration of tissue beyond the tumor [94]. The

mean dose of radiation to the hippocampus could be reduced much more, and it could be half that of IMRT and consequently reduce the risk of cognitive deficit after RT [95].
