**5. Effect of brain RT on cognition**

**4. Brain tumor surgery and cognition**

246 Neurooncology - Newer Developments

**•** Does brain surgery improve cognitive deficit?

rapid growth, and the infiltrative nature.

executive functions, and intelligence) [49].

tumor lateralization [53].

than to discrete focal injury.

effect [54].

than in the extensive temporal lobe surgery [50].

not significantly lower than the preoperative.

visuomotor function, problem-solving, and affective disorders.

In brain tumors, the first treatment modality is surgery. The aim was to balance the neurolog‐

Surgery for brain tumors improves the cognitive function due to the reduction of compres‐ sion as after removal of noninvasive tumors, such as meningiomas, improvement of atten‐ tional function occur [42]. Patients with high-grade glioma have worse cognitive dysfunction than patients with low-grade glioma (LGG) [47]. The worse cognitive deficits in patients with high-grade gliomas have been attributed to higher incidence of intracranial hypertension, the

Sweet et al. [48] reported that the localization is associated with cognitive effects. Tumors of the pineal region associated with memory impairment, visuospatial function, attention,

Medial temporal lobe epilepsy caused by tumor is associated with cognitive deficit (long-term memory dysfunction, difficulties in learning, attention, naming, visuospatial abilities,

Less extensive surgery of the mesiotemporal structures correlates with better memory outcome

Verbal memory decline was observed in dominant temporal lobe resection [51], while visuospatial memory decline associated with nondominant temporal lobe resection [52].

Cognitive improvement has been observed after tumor resection, and improvement of verbal memory has been observed after LGG resections in frontal premotor and anterior temporal areas [4], usually after a transient postoperative worsening. This improvement was related to

Some studies reported postoperative cognitive worsening in (38%) of patients versus 24% rate of improved patients. Worsening associated with executive functions while improvement was observed with memory function. This worsening may correlate to volume of the operated area (tumor size) rather than the location. The postoperative improvement of memory function, the most frequent preoperative cognitive deficit, occurs due to release of the mass

Teixidor et al. [4] reported immediate postoperative worsening for working memory in 96% of cases, and Giovagnoli et al. [55] reported that postoperative scores for cognitive tests were

Talacchi et al. [5] found unexpected low incidence of additional deficits (38%) immediate postoperative and a considerable rate of early improvement (24%), and this correlated with tumor size and histology. This study reported also that postoperative worsening seems to be due to a generic mechanical effect and to manipulation/removal of tumor periphery rather

ical outcomes (minimize the neurological deficits) and oncological outcome [2].

Cognitive deficits following RT are irreversible and progressive complication that may follow RT by several months to many years. These deficits may be due to vascular injury, local radionecrosis, and cerebral atrophy, the severity ranges from mild or moderate to progres‐ sive mental slowing, occurring in at least 12% of patients who were treated with radiation therapy [59].

#### **5.1. Hypothesis of radiation-induced cognitive impairment**

There are many hypotheses that explain how the cognitive deficits following radiation therapy occur, direct damage and subsequent death of parenchymal cells (oligodendrocytes, neu‐ rons, astrocytes, and microglia) or indirect through reactive oxygen species (ROS) production.

Dynamic interactions between the multiple cell types (astrocytes, endothelial cells, microglia, neurons, and oligodendrocytes) within the brain may be the cause of radiation-induced cognitive impairment [60]. Another hypothesis is that the RT can inhibit hippocampal neurogenesis causing the cognitive impairment.

Irradiation of the hippocampus results in loss of neuronal stem cells (NSCs) which are responsible on self-renewal and generating neurons, astrocytes, and oligodendrocytes [61]. The radiation injury to NSCs is dose-dependent [62] and results in decrease in proliferation of NSCs and decrease in its differentiation into neurons [63]. Radiation therapy for brain tumors may lead to a significant reduction in the number of neurogenic cells [64].

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

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 postirradiation complications [71].

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 breakdown [72].

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

The severity of cognitive deficit following radiation therapy appears to be proportional to the dose of radiation therapy received by the hippocampus region [74].
