# Specific radiosensitivity of brain structures (areas or regions) and cognitive impairment after focal or whole brain radiotherapy: A review

Emmanuel Mesny, Julian Jacob, Georges Noël, Marie-Odile Bernier, Damien Ricard

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Emmanuel Mesny, Julian Jacob, Georges Noël, Marie-Odile Bernier, Damien Ricard. Specific radiosensitivity of brain structures (areas or regions) and cognitive impairment after focal or whole brain radiotherapy: A review. Cancer/Radiothérapie, 2025, 29 (3), pp.104625. 10.1016/j.canrad.2025.104625. hal-05466644

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# Specific radiosensitivity of brain structures (areas or regions) and cognitive impairment after focal or whole brain radiotherapy: A review

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## Radiosensibilité spécifique des structures cérébrales et altération des fonctions neurocognitives après la radiothérapie encéphalique : revue systématique

Emmanuel Mesny<sup>a, b, *</sup>, Julian Jacob<sup>c</sup>, Georges Noël<sup>d, e, f, g</sup>, Marie-Odile Bernier<sup>h</sup>, Damien Ricard<sup>a, i, j</sup>

## INFO ARTICLE

Historique de l'article :

Reçu le 12 mars 2025

Accepté le 4 avril 2025

## ABSTRACT

Delayed neurocognitive impairment is observed following encephalic radiotherapy, including brain parts (areas), leading to a substantial deterioration of the quality of life. These delayed radiotherapy side effects are variable in terms of intensity of symptoms and time of occurrence, characterized by minor-to-severe cognitive deficits, such as attention or memory disorders and/or dysexecutive syndrome. However, the precise mechanisms leading to these cognitive disorders remain mostly unknown. Various tissue alterations have been reported after brain radiotherapy, in specific brain structures as the hippocampus, the cerebral white matter or the cerebral cortex. Sparing these structures during brain radiotherapy may be a potential approach to limit the development of late cognitive impairment; however, few dose constraints have been published regarding brain areas (regions) involved in cognitive functions. The main purposes of this literature review are to report the pathophysiological process leading to the radiation-induced cognitive impairment, to describe the tolerance and radiological modifications induced by radiation of specific healthy cerebral tissues, to better understand their radiosensitivity and to describe potential improvements.

© 2025 The Authors. Published by Elsevier Masson SAS on behalf of Société française de radiothérapie oncologique (SFRO). This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

## RÉSUMÉ

Une altération retardée des fonctions neurocognitives est observée après une radiothérapie encéphalique, affectant notamment certaines régions du cerveau, à l'origine d'une détérioration substantielle de la qualité de vie. Ces effets secondaires retardés de la radiothérapie sont variables en termes d'intensité des symptômes et du moment de leur apparition, et se caractérisent par des déficits cognitifs d'intensité variable, tels que des troubles de l'attention ou de la mémoire et/ou un syndrome dysexécutif. Cependant, les mécanismes précis conduisant à ces troubles cognitifs demeurent largement inconnus. Diverses altérations tissulaires ont été rapportées après une radiothérapie cérébrale, dans des structures cérébrales spécifiques comme l'hippocampe, la substance blanche cérébrale ou le cortex cérébral. La préservation de ces structures durant la radiothérapie cérébrale pourrait constituer une approche potentielle pour

**Keywords :**
Leukoencephalopathy
Brain radiosensitivity
Brain radiotherapy
Cognition and radiotherapy

**Mots clés :**
Radiosensibilité
Radiothérapie

<footnote><sup>a</sup> Université Paris Saclay, université Paris Cité, ENS Paris Saclay, CNRS, SSA, Inserm, centre Borelli, 91190 Gif-sur-Yvette, France</footnote>

<footnote><sup>b</sup> Radiation Oncology department, Hospices civils de Lyon, centre hospitalier Lyon Sud, Oullins-Pierre-Bénite, France</footnote>

<footnote><sup>c</sup> Sorbonne Université, hôpital de La Pitié-Salpêtrière, Department of Radiation Oncology, 47-83, boulevard de l'Hôpital, 75013 Paris, France</footnote>

<footnote><sup>d</sup> Radiotherapy Department, Institut de cancérologie Strasbourg Europe (ICANS), 17, rue Albert-Calmette, BP 23025, 67033 Strasbourg, France</footnote>

<footnote><sup>e</sup> Faculté de médecine, université de Strasbourg, 4, rue Kirschleger, 67000 Strasbourg, France</footnote>

<footnote><sup>f</sup> Europe (ICANS), Radiobiology Laboratory, Unicancer, 67000 Strasbourg, France</footnote>

<footnote><sup>g</sup> Université de Strasbourg, ICube, imagerie multimodale intégrative en santé (Imis), 300, boulevard Sébastien-Brant, 67400 Illkirch-Graffenstaden, France</footnote>

<footnote><sup>h</sup> Institut de radioprotection et de sûreté nucléaire, Fontenay-aux-Roses, France</footnote>

<footnote><sup>i</sup> Service de neurologie, Service de santé des armées, hôpital d'instruction des armées Percy, 92140 Clamart, France</footnote>

<footnote><sup>j</sup> Service de santé des armées, École du Val-de-Grâce, 75005 Paris, France</footnote>

<footnote>* Corresponding author.
Adresse e-mail : emmanuel.mesny@chu-lyon.fr (E. Mesny).</footnote>
Cerveau
Cognitif

limiter le développement de troubles cognitifs tardifs; toutefois, peu de contraintes de dose ont été
publiées concernant les régions cérébrales impliquées dans les fonctions cognitives. Les principaux
objectifs de cette revue de littérature sont de rapporter le processus physiopathologique conduisant à
l'altération cognitive induite par la radiothérapie, de décrire la tolérance et les modifications radiolo-
giques induites par l'irradiation sur les tissus cérébraux sains spécifiques, de mieux comprendre leur
radiosensibilité et de décrire les améliorations potentielles.

© 2025 Les Auteurs. Published by Elsevier Masson SAS au nom de Société française de radiothérapie oncologique (SFRO). Cet article est publié en Open Access sous licence CC BY (http://creativecommons.org/licenses/by/4.0/).

**1. Introduction**

Delayed neurocognitive impairment is observed following brain
radiotherapy leading to a substantial deterioration of the quality
of life of long-term surviving patients [1-3]. The delayed neuro-
cognitive effects of brain radiotherapy are variable in terms of
intensity of symptoms and time of occurrence, characterized by
minor-to-severe cognitive deficits, such as attention or memory
disorders and/or dysexecutive syndrome. In severe cases, these
effects can lead to a clinical sub cortical dementia with gait
apraxia and urinary troubles due to severe dysexecutive syn-
drome [4]. Various anatomical specific brain tissue alterations
have been reported after cerebral radiotherapy, in particular in
the hippocampus or the cerebral white matter [5]. Several mecha-
nisms implicating small vessels, mature neurons, neural precursors
or microglia have been suggested to explain radiation-induced
brain injury [6]. However, the knowledge of the cerebral areas
radiosensitivity and the brain radiation toxicities remains still
unclear. The main purposes of this literature review are to report
the physiopathological processes leading to the radiation-induced
cognitive impairment, to describe the tolerance and radiologi-
cal (post-therapeutic) modifications of specific anatomical healthy
cerebral structures exposed to radiation and to describe potential
improvements in terms of radiotherapy techniques (specific dose
constraints, protontherapy, stereotactic radiotherapy) or other
strategies to mitigate neurocognitive disorders.

**2. Methods**

The Preferred Reporting Items for Systematic Reviews and
Metaanalyses (PRISMA) reporting guidelines were used to guide
the conduct of this review [7]. The research was performed
using Medline via PubMed, Cochrane and Embase databases to
identify articles published between 2013 and October 2024. The
keywords, "brain", "encephalic radiotherapy", "radiation-induced
brain injury", "cognition", were used to select the studies dealing
with the pathophysiology of the cognitive impairment following
cranial radiotherapy. Furthermore, we searched works reporting
data about the radiosensitivity of the specific brain areas involv-
ed in cognitive functions considering the following keywords:
"hippocampus", "cerebral cortex", "cerebral white matter", "corpus
callosum", "amygdala" "cerebellum". We also aimed to describe the
clinical and technical approaches proposed to mitigate or prevent
radiation-induced cognitive impairment. In addition, bibliographic
references of the included studies were reviewed for relevant works
that would have been missed by this electronic search. The research
was limited to adult patients (over 18 years old) and paediatric
population treated with brain radiation was excluded of the ana-
lysis. Preclinical studies were also excluded from the analysis,
excepted for the pathophysiology part. The entire research process
is detailed in Fig. 1.

**3. Results**

**3.1. Physiopathology**

Various mechanisms osed to explain the late cerebral tissue
modifications and neurocognitive effects of encephalic (brain)
radiotherapy [6]. Radiotherapy induces deoxyribonucleic acid
damage leading to the death of normal cells. In the hippocam-
pus, a direct inhibition of the proliferation of neural precursors,
necessary at all ages to learn and register new memories, was sug-
gested after radiation exposure [8]. However, other studies have
questioned the adult neurogenesis activity of the hippocampus and
also suggested a difference in terms of radiosensitivity among the
neural precursors, e.g. in the dentate gyrus and the subventricular
zone, with potential delayed recovery [9,10]. Finally, it seems that
radiation-induced changes in the microenvironment play a grea-
ter role in the inhibition of neurogenesis than the direct effects
on the neural precursors [11]. Brain exposure to ionizing radia-
tion induces an inappropriate neuroinflammatory response with
activation of the oxidative stress [12]. This response is driven by
changes in the phenotype of the microglia directly induced by ioni-
zing radiation [13]. Activated microglia, through the secretion of
pro-inflammatory mediators (cytokines or chemokines) such as
tumour necrosis factor-α (TNF-α), interleukin 1β (IL-1β) or IL-6,
inhibits neurogenesis, promotes the astrocytic differentiation of
the neural precursors and the recruitment of lymphocytes and
participates to the microvascular damages [2,14]. Microvascular
damage is another more direct mechanism induced by ionizing
radiation [6]. Brain radiotherapy causes an alteration of the small
vessel architecture with the death of endothelial cells and plate-
let adherence leading to occlusion and hyalinization of vessels and
disruption of the blood barrier [15]. Encephalic radiotherapy also
impacts mature neurons with alterations of dendritic morphology
and functions [16]. These alterations of dendrites associated with
a disturbance of the neurotransmitters levels induce a global dys-
function of the synaptic response [17]. Demyelination and loss of
oligodendrocytes (involved in remyelination) are two other mecha-
nisms described in the process of neurological impairment induced
by cranial radiotherapy [18].

In conclusion, pathophysiology of cognitive impairment after
encephalic radiotherapy is long lasting, complex, dynamic with
multiple mechanisms involved in significant changes of the
cerebral micro-environment. Interactions between the different
involved compartments (vascular, neuronal, glial) have been repor-
ted. However, the fully understanding of these mechanisms is
not yet achieved and the reported hypotheses should be confir-
med in further studies. Development of innovative in vitro models
should be considered to better study tumour heterogeneity, spatial
physiology and effect of radiotherapy on brain tissues. Three-
dimensional in vitro models are promising candidates for this
purpose [19].
<figure><img src="image_5.png" /><figcaption>**Fig. 1.** Literature review on radiosensitivity of brain structures after brain radiotherapy: research process according to the Preferred Reporting Items for Systematic Reviews and Metaanalyses (PRISMA) reporting guidelines.</figcaption></figure>

## 3.2. Radiosensitivity of healthy cerebral tissues

### 3.2.1. Cerebral cortex

The cerebral cortex is a complex structure composed of multiple cytoarchitectural layers and subdivided in different architectural and functional areas (prefrontal, motor, parietal, visual, entorhinal) [20]. Three retrospective studies have suggested a particular radiosensitivity of cortical regions in patients treated with encephalic (or focal brain) radiotherapy for gliomas. The first study, including 54 patients, found a dose-response relationship with a significant risk of cortical thickness one year after radiotherapy for mean dose greater than 40 Gy, particularly in cortical regions involved in cognitive functions (entorhinal and inferior parietal) [21]. The second study, performed on 15 patients, also found a significant dose effect with a cortical thinning observed one year after radiotherapy, 0.0024 mm/Gy in the frontal lobe and 0.0046 mm/Gy in the temporal lobe [22]. The last study, analysing MRI data of 105 patients, have suggested significant volumetric changes of the grey matter two years after radiotherapy, with a reduction of 3.5 % of the cortical volume, more pronounced in regions involved in cognition and execution movement [23]. Based on these data, a normal tissue complication probability model has been estimated in order to design a cortex-sparing approach [24]. A dose threshold of 28.6 Gy (for normofractionated radiotherapy) was found to result in a 20 % probability of severe cortical atrophy (defined as greater than 5 %). However, it is important to note that none of these studies

have assessed the clinical relevance on cognitive functions of these results or the more precise effect of radiotherapy on each cortical layer.

### 3.2.2. Hippocampus

Since many years, the preservation of hippocampi has been a main (major) field of research in brain irradiation. Due to the neurogenic stem cell population residing in the hippocampal dentate gyrus and the central implication of hippocampus in memory functioning, it has been hypothesized that alteration of hippocampus may explain the memory impairment (at least early and early delayed) observed after encephalic radiotherapy [8,25]. In a prospective cohort with 52 brain tumours patients treated with radiotherapy, hippocampal volume was measured before and 1 year after radiotherapy [26]. Mean hippocampal dose was significantly correlated with hippocampal volume loss, with a mean hippocampal volume decrease of 6 % at 1 year after high dose radiotherapy (mean dose greater than 40 Gy). Interestingly, no changes were observed if the mean dose was inferior to 10 Gy [26,27]. In addition to morphological changes observed after brain radiotherapy, vascular alterations have been suggested [28]. The effect of radiotherapy in the hippocampal sublayers have been reported in a prospective cohort of 58 patients with nasopharyngeal carcinoma treated with radiation and matched with healthy controls [29]. A volume reduction over time (respectively 3 and 6 months after radiotherapy) was observed in the bilateral hippocampus, as
well as in the bilateral granule cell layer, bilateral cornu ammonis 1, bilateral molecular layer, and bilateral subiculum. This volume loss was correlated to the radiotherapy dose and a high volume loss in the bilateral hippocampus, bilateral granule cell layer, left subiculum, and right molecular layer were associated with a cognitive decline [29]. Many studies have reported the clinical impact of radiotherapy dose on hippocampi on the cognitive function. Gondi et al. found in a prospective cohort of 28 adult patients with benign or low-grade adult brain tumours treated by encephalic irradiation, that biologically equivalent doses in 2-Gy fractions (EQD(2)) (assuming an α/β ratio of 2 Gy for the hippocampus) to 40 % of the bilateral hippocampi greater than 7.3 Gy<sub>EQD2/α/β2Gy</sub> was associated with impairment in Wechsler Memory Scale-III Word List (WMS-WL) delayed recall. A maximal dose of 15 Gy and a dose of 6.2 Gy in more than 30 % of the left hippocampus were also associated with an altered visual integration (only in the univariable analysis) [30]. In a retrospective cohort of 158 patients with nasopharyngeal carcinoma treated with radiation, a dose to 40 % of the hippocampi greater than 15 Gy was associated with a higher probability of anxiety [31]. In a prospective cohort of 60 adults undergoing encephalic radiotherapy (prophylactic cranial irradiation or focal cranial irradiation), a dose-response of radiotherapy to the hippocampus were observed regarding decline in memory (measured by the Hopkins Verbal Learning Test-Revised [HTLV-R] Delayed Recall at 6 months). A dose to 50 % of the bilateral hippocampi of more than 22.1 Gy was associated with 20 % risk of decline [32]. Considering the radiosensitivity of the hippocampi and its clinical implications, hippocampal-sparing approaches have been developed and largely described in the literature [5,33,34]. The main results came from the NRG Oncology CC001 phase III trial that tested in 518 patients with brain metastases the impact of hippocampal avoidance-whole brain radiotherapy plus memantine versus whole brain radiotherapy plus memantine on cognition with an analysis of the individual trajectory [35]. Risk of cognitive failure, measured with battery of cognitive tests (trail making test for processing speed and executive function, HVLT-R for memory and controlled oral word association for verbal fluency), was significantly lower after hippocampal avoidance-whole brain radiotherapy plus memantine versus whole brain radiotherapy plus memantine at 6 months (adjusted hazard ratio [HR]: 0.74; 95 % confidence interval [CI]: 0.58–0.95). In a long-term analysis of the results of the trial, with follow up for more than 1 year, patients treated in the arm hippocampal avoidance – whole brain radiotherapy plus memantine showed sustained preservation of cognitive function with less cognitive symptoms over time [36]. A recent secondary analysis of the trial suggested that patients with more than 4 months survival or primary lung histology or less severe patient-reported cognitive impairment at baseline seemed to have more benefit from hippocampal avoidance-whole brain radiotherapy [37].

However, hippocampal avoidance-whole brain radiotherapy remains controversial. Others trials (phase II and III) found no clinical benefit of the hippocampal avoidance strategy [38,39]. It may be explained because of the heterogeneity of the studied population (various histology, different dose regimen used: 25 Gy in 10 fractions or 30 Gy in ten fractions, baseline cognitive tests) and the cognitive tests used. Moreover, each hippocampus may have a functional asymmetry with different functions, making questionable dosimetric statistics on a volume that does not differentiate between the two hippocampi [27,40].

### 3.2.3. Cerebral white matter

White matter tracts participated to complex cognitive functions, supporting interactions between various distributed cognitive networks [41]. Six main white matter tracts seemed to be implicated in executive functions [41]. It has been suggested that white matter may be particularly sensitive to radiation, probably due to its

terminal vascularization, through the observation of leukoencephalopathy associated with cognitive impairment after encephalic radiotherapy [42].

Diffusion tensor imaging is an advanced MRI technique used to assess microstructural changes in white matter, with parameters reflecting the mobility of water molecules, such as mean diffusivity and fractional anisotropy, or axonal damage and demyelination, such as axial or radial diffusivities [43]. Several studies reported dose-dependent changes in white matter microstructure after encephalic radiotherapy for primary tumours. White matter damage was observed even for low doses (inferior to 10 Gy), with mean, axial and radial diffusivities increased significantly with time and dose, and associated with a decreased in fractional anisotropy [44,45]. There seems to exist a correlation between fractional anisotropy decrease and mean dose to specific white matter structures (body of corpus callosum, fornix, cingulum bundle) [46]. Significant decrease of mean diffusivity has been also observed in white matter receiving more than 20 Gy. Radiation-induced white matter damages are progressive with time and dose [47]. There is also a difference in regional radiosensitivity of white matter. In a prospective cohort of 36 glioblastomas followed with diffusion tensor imaging approaches, the internal capsule, the corona radiata, the posterior thalamic radiation, and the superior longitudinal fasciculus showed the most pronounced changes after radiotherapy with mean doses (± standard deviation) of 26.5 Gy (± 20.7), 19.0 Gy (± 17.1), 8.9 Gy (± 13.6) and 15.8 Gy (± 17.8), respectively [48]. Mean dose to bilateral perisylvian white matter regions including superficial white matter subadjacent to Broca's area and the superior temporal gyrus, inferior longitudinal fasciculus, inferior fronto-occipital fasciculus, and arcuate fasciculus, has been reported as predictive of volume loss at 6 months after radiotherapy and, decreased fractional anisotropy and increased mean diffusivity for left white matter tracts [49]. These microstructure injuries to left-sided perisylvian white matter were correlated to a decline of language fluency after radiotherapy [49]. Tringale et al. reported early microstructural alteration of the white matter underlying the anterior cingulate cortex, characterized by decreased fractional anisotropy and increased mean and radial diffusivities at 6 months after radiotherapy. These biomarkers were correlated to executive function decline (flexibility and verbal set-shifting ability) [50]. Increase of radial diffusivity and decrease of axial diffusivity during radiotherapy for benign or low-grade cranial tumours were reported to be predictive of verbal memory and verbal fluency decline 18 months after radiotherapy. In these series, increase of radial diffusivity at the end of radiotherapy to predict verbal fluency decline 18 months after treatment [51].

Whole brain radiotherapy also induces effects on white matter. Leukoencephalopathy is a common long term side effect of whole brain radiotherapy, occurring in almost 50 % of cases 2-years after radiotherapy versus 5 % after stereotactic radiotherapy for brain metastases [52]. White matter fiber tracts implicated in the limbic circuit seem to be particularly sensitive with significant decrease of fractional anisotropy and increase of mean diffusivity observed at the end of radiotherapy and one month post-treatment in the cingulum, corpus callosum, and fornix [53]. Radiation-induced microstructural injuries in the temporal lobe white matter have been observed at 6 and 12 months after radiotherapy for nasopharyngeal carcinoma, with a correlation between diffusion metrics on diffusion tensor imaging and radiotherapy dose in the temporal white matter tracts [54]. In a longitudinal study with 146 patients nasopharyngeal carcinoma treated with radiation, white matter injuries observed in the bilateral cingulate angular bundle fibres, and characterized by a reduction of radial and mean diffusivities during the first year post-treatment, were correlated with the atrophy of the ipsilateral hippocampus and progressive cognitive impairment [55]. Time-dependent white matter atrophy was
also observed post-treatment in the right parahippocampal gyrus, right inferior temporal gyrus, right middle temporal gyrus, right fusiform gyrus, and left insular cortex in 120 patients with nasopharyngeal carcinoma. Moreover, white matter atrophy in the right parahippocampal gyrus and the right inferior temporal gyrus was correlated with the mean radiotherapy dose to the temporal lobe and progressive cognitive impairment measured by the Montreal Cognitive Assessment (MoCA) test [56].

### 3.2.4. Corpus callosum

The corpus callosum is a major white matter commissure connective the two cerebral hemispheres. Corpus callosum is implicated in many cognitive networks and cognitive function [57]. The corpus callosum demonstrated radiation dose-dependent atrophy in a prospective trial with 59 patients treated with brain irradiation: midanterior corpus callosum volume, lower fractional anisotropy in posterior, anterior and total corpus callosum, and higher mean diffusivity in anterior corpus callosum, were correlated with higher radiotherapy dose [58]. These microstructural corpus callosum injuries, combined with intrahemispheric white matter injury, were associated with a decline in attention scores and processing speed [58]. Changes in the white matter microstructure of the entire corpus callosum have been also reported 3 months after whole brain radiotherapy, with a decrease of fractional anisotropy [59].

### 3.2.5. Cerebellum

The cerebellum, initially considered as a "simple" modulator of motor functions, is now recognized as a highly interconnected brain region, participating as a modulator of cognitive and emotional activities. In a prospective study with 91 patients who had chemoradiotherapy for a glioma, a loss of cerebellar volume was observed in the follow-up after radiotherapy with correlation with age, time after radiotherapy and mean cerebellar dose [60]. In another cohort with 62 patients treated by protons for brain tumours, a moderate deterioration of the MoCA test was associated with an increase in the relative volume of the anterior cerebellum that received more than 30 Gy [61]. Lastly, an association between microstructural cerebellar injury assessed by diffusion tensor MRI after radiotherapy and processing speed was found in patients with primary brain tumours [62]. In this prospective study with 65 patients, cerebellar white matter volume significantly declined over time. Decrease of cerebellar cortex volume and cerebellar white matter mean diffusivity were associated with worse post-treatment processing speed, independently of corpus callosum and intrahemispheric white matter injuries.

### 3.2.6. Subcortical deep grey matter

Subcortical deep grey matter structures, which play a critical role in controlling the transmission and integration of information flow in cerebral networks, seem also to be affected by radiotherapy. In a study on 31 patients with glioma treated with radiation, a significant relation between radiotherapy dose and volume loss was reported for most of the subcortical deep grey matter structures such as thalamus, globus pallidus, amygdala, putamen and nucleus accumbens, with volume loss rates from 0.16 to 1.37 %/Gy [63]. This statistical association was not found with the caudate nucleus. Significant regional atrophy in the medial posterior segment of the bilateral thalamus has also been reported after radiotherapy for nasopharyngeal carcinoma [64].

The amygdala is a small subcortical structure composed of multiple nuclei and located anteriorly to the hippocampus in the medial temporal lobe. It is a critical structure of the limbic system, connected to the hippocampus, the thalamus and the cerebral cortex and playing a key role in the memory process and emotional and affective-related behaviours [65]. Hyunh-Le et al. were the

first to retrospectively report a certain sensitivity of amygdala to radiotherapy. They found a correlation between the mean amygdala dose and the volume loss on multivariable analysis with an estimated amygdala volume loss of 0.17 %/1 Gy [66]. In a recent prospective trial including 63 patients with glioma, the impact of radiotherapy on amygdala was also observed with a bilateral amygdalae atrophy described as early as 6 months after treatment with a response dose-effect [67]. After autosegmentation of both amygdalae, they have looked if at the individual nuclear level, the volume of the substructure of amygdala could predict the cognitive outcomes after radiotherapy. They found that greater left lateral, basal, central, accessory basal, and corticoamygdaloid transition nuclear volumes were each significantly associated with better performance on memory tests (verbal and visuospatial). Atrophy in amygdalae was also associated with deterioration emotional well-being and increase of anxiety [67].

The subventricular zones have an important role in cognition and neurogenesis with the presence of neural stem cells. However, subventricular zones seem to be associated with the tumorigenesis of high grade gliomas with the presence of tumoral stem cells in these areas [68]. It has been reported that patients with glioblastoma in contact with or invading the subventricular zone had poorer outcomes and a higher risk of recurrence [69]. Despite several retrospective studies have suggested favourable effect of high doses to the subventricular zone area on survival outcomes, the correlation between subventricular zone radiation dose and survival of patients with glioblastoma remains unclear [70-72]. Preliminary results of a sparing technique for nasopharyngeal carcinoma located in the subventricular zone have been reported in a small prospective study with 30 patients with glioblastomas (prescribed dose: 60 Gy in 30 fractions to the planning target volume, no constraint on the subventricular zone). No significant association was observed between the dose to the nasopharyngeal carcinoma and survival or cognitive outcomes [73].

Although the published clinical data are heterogeneous in terms of populations, total doses, fractionation and neuropsychological assessments, evidence tend to highlight specific cerebral areas sensitivity to ionizing radiation involved in post-treatment cognition deterioration. Table 1 summarize suggested published dosimetric constraints associated with clinical or radiological impact after radiotherapy for adult patients. The neurophysiology of some white matter areas, mainly the cingulum, corpus callosum, fornix, but also cerebellar white matter, or cortical areas seems to be significantly altered by radiotherapy in a dose-dependent manner. MR imaging is an essential tool to detect and monitor radiation-induced brain injuries. Brain diffusion MRI biomarkers change during or after radiotherapy seems to be predictive of cognitive decline with frequently a decrease of fractional anisotropy and an increase of radial and mean diffusivities [60]. The microstructural modifications reported with diffusion tensor imaging can occur in the year post-treatment, however the reversibility of these changes remain uncertain. For white matter, diffusion tensor imaging changes, especially decreased fractional anisotropy in specific regions (corpus callosum or cingulum), were associated with cognitive decline in several studies [61]. Vascular and metabolic changes measured with MRI (spectroscopy, perfusion- and susceptibility-weighted imaging) or brain metabolism measured with (¹⁸F)-fluorodeoxyglucose positron emission tomography (PET)/computed tomography (CT) are other biomarkers to evaluate the impact of radiotherapy on healthy cerebral structures [74,75].

### 3.3. Relationship between function and brain radiosensitivity

In practice, studying the impact of radiotherapy individually on a specific brain structure, which participates in several cerebral networks involved in different cognitive functions, seems com-
<caption>**Table 1**</caption>

Literature review on radiosensitivity of brain structures after brain radiotherapy: summary of suggested dosimetric constraints in specific brain structures associated with radiological or clinical changes in adult patients.

<table><thead><tr><th>Brain structure</th><th>Dosimetric constraints</th><th>Radiological or clinical impact</th></tr></thead><tbody><tr><td><strong>Hippocampus</strong><br>Two hippocampi + 5 mm (hippocampal avoidance whole brain radiotherapy)</td><td>D100 % &lt; 9 Gy<br>Dmax &lt; 16 Gy [34,76-78]</td><td>Preservation of memory and quality of life<br>4-6 months after whole brain radiotherapy [76-78]<br>Less deterioration in executive function at 4 months and learning and memory at 6 months after whole brain radiotherapy (+ memantine) [34]</td></tr><tr><td>Sum of the two hippocampi</td><td>D50 % &lt; 22.1 Gy EQD2<br>D40 % ≤ 7.3 Gy EQD2 [26,29]</td><td>Probability of HVLT-R DR decline &lt; 20 %<br>Long-term impairment in list-learning delayed recall for fractionated encephalic radiotherapy if D40 % &gt; 7.3 Gy [79]<br>Less probability for anxiety after radiotherapy<br>Hippocampus atrophy &lt; 6 % one year after radiotherapy [25]<br>Neurocognitive preservation indicated by the immediate recall of WMS-WL [80]</td></tr><tr><td>Hippocampus (individually)</td><td>D40 % &lt; 15 Gy<br>Dmean &lt; 40 Gy [25]</td><td></td></tr><tr><td>Left hippocampus</td><td>D0 % &lt; 12.6 Gy EQD2 [80]</td><td></td></tr><tr><td>Cortex</td><td>D10 % &lt; 8.81 Gy EQD2 [80]</td><td></td></tr><tr><td>Cerebellum</td><td>D50 % &lt; 7.45 Gy EQD2 [80]</td><td></td></tr><tr><td>Amygdala</td><td>D80 % &lt; 5.83 Gy EQD2 [80]</td><td></td></tr><tr><td></td><td>V55 Gy &lt; 0 % [81]</td><td>Postradiation impairment (HVLT-R ≤ 15) &lt; 14.9 %</td></tr><tr><td></td><td>Dmean &lt; 30 Gy EQD2 [82]</td><td>Drop of IQ &lt; 10 % at 3 years after radiotherapy [82]</td></tr><tr><td></td><td>Dmean &lt; 28.6-30 Gy EQD2 [23]</td><td>Severe atrophy (&gt; 5 %) &lt; 20 % [23]</td></tr><tr><td></td><td>Dmean &lt; 10 Gy [59]</td><td>Loss of cerebellar volume less than 3.2 %, 3.6 % and 4.0 %, respectively for patients aged of 30, 55 and 88 years, 2 years after radiotherapy [59]</td></tr><tr><td></td><td>Dmean &lt; 34.6 Gy EQD2 [65]</td><td>Reduction of volume (−5.74 %) if &gt; 34.6 Gy EQD2 [65]</td></tr></tbody></table>

Dx %: dose in x % of the volume; Dmax: maximal dose; Dmean: mean dose; EQD2: biologically equivalent doses in 2-Gy fractions assuming an α/β ratio of 2 Gy; HVLT-R: Hopkins Verbal Learning Test-Revised; IQ: intellectual quotient; WMS-WL: Wechsler Memory Scale-III Word List.

plex and illusory. That is why a cognitive function-based analysis, with description of fibre tracts and cerebral structures involved, might be more relevant [83]. Hardy et al. have reported an association of radiation dose to the cerebral network implicated in the emotion recognition function, which is a crucial function for social cognition, involving the amygdala, the medial and lateral orbitofrontal cortex. Patients with higher radiotherapy doses on these specific structures had a significant longer median response time on an emotional recognition task [84]. Connor et al. have recently reported the first normal tissue complication probability models for fine motor skill decline after brain radiotherapy [85]. They found that dose to several motor function-associated regions of interest, including thalamus, cerebellum, white matter corticospinal tracts, caudate nucleus, motor cortex, was correlated with a decline in dominant-hand fine motor dexterity.

Others associations between specific brain structures participating in complex networks and altered cognitive functions after encephalic radiotherapy have been highlighted: processing speed and corpus callosum/cerebellum/intrahemispheric white matter [58,62]; attention and corpus callosum [58]; memory and amygdala/hippocampus/parahippocampal [46,67]; language fluency and left perisylvian white matter tracts [49]; flexibility and cingulum [50]. However, these preliminary results should be confirmed in larger studies.

Cancer related fatigue is a common patient reported symptom after encephalic radiotherapy and can participate to the cognitive decline [86]. Studies have reported a correlation between patient reported fatigue (acute or late) and higher mean radiotherapy dose on specific brain structures (total brain, brainstem, posterior fossa, cerebellum, basal ganglia, hippocampi and pituitary) for patients irradiated for primary brain tumours or head and neck cancers [87,88]. More recently, a study reported the fatigue after proton beam radiotherapy and found a correlation at 12 months post-treatment between higher mean dose to the brain, brainstem, hippocampi and pituitary and physical fatigue (measured by Multidimensional Fatigue Inventory [MFI-20]). They observed also a

reduced motivation according to MFI correlated with higher radiotherapy dose to the brainstem and the pituitary gland [89].

Moreover, the global brain radiosensitivity is variable between individuals reflecting the presence of probable individual risk factors. Recently, the age at encephalic radiotherapy, smoking status and the germline SNP rs2120825 on the PPARg locus have been suggested as risk factor of radiation-induced leukopenia in a retrospective analysis of a cohort of gliomas long-term survivors [42]. Several studies suggested a genetic predisposition for cognitive decline after radiotherapy [90,91]. Indeed, the APOE ε4 carriers with brain metastases exhibited greater decline in learning and memory, executive function, after whole brain radiotherapy (with or without memantine) in a prospective trial [92]. In an observational cohort of more than 1000 patients with nasopharyngeal carcinoma treated with radiation, the presence of a variant of the gene CP128 was associated with temporal lobe injury [93]. These results could open new selective drug strategies to mitigate radiation-induced cognitive impairment. For example, a PPARg agonist (pioglitazone) has been tested recently as neuroprotective agent in patients receiving encephalic radiotherapy, with good results in terms of safety [94].

It is important to highlight that other cofactors are susceptible to favour the occurrence of neurocognitive disorders after radiotherapy (for example chemotherapy, antiepileptic drugs, cardiovascular risk factors, tumour progression) [95].

Finally, most studies evaluated neurocognitive decline at a population-scale. Analysing the individual cognitive trajectory of each patient may facilitate the evaluation of inter-individual variability of cognitive deterioration after radiotherapy and to determine predictive biomarkers (dosimetric, radiological or biological) [96,97]. The early detection and management of depression and anxiety symptoms associated with the disease and the treatment is also crucial as these symptoms can amplify cognitive disorders and compromise the patient's quality of life [98].
### 3.4. Perspectives to reduce cognitive impairment after brain radiotherapy

To reduce the exposure of healthy brain to radiotherapy and thus the reduce cognitive impairment, various strategies have been developed.

#### 3.4.1. Limit or differ the brain radiotherapy indication

For patients with benign tumours or low-grade glioma, in whom prolonged survival is expected and thus a greater risk to develop delayed radiation-induced cognitive disorders, brain radiotherapy may be differed as possible. Two randomized trials are testing this hypothesis in the population of 1p19q codeleted oligodendroglioma (grade 2 and grade 3 respectively) with a primary endpoint defined as survival without cognitive deterioration [99,100]. In isocitrate dehydrogenase mutant gliomas, selective isocitrate dehydrogenase inhibitors (vorasidenib) have shown efficacy and safety, and may allow to differ the use of radiotherapy [101]. For grade 2 gliomas, the prescribed dose recommended to the planning target volume is 50.4 to 54 Gy [102]. An European Organisation for Research and Treatment of Cancer (EORTC) randomized trial had showed that maybe these tumours could response to lower dose (45 Gy) [103]. However, the trial is relatively old, using old technique of radiotherapy and larger volumes than currently recommended. These findings need to be confirmed in more recent cohort with advanced radiotherapy techniques.

For brain metastases, it has been demonstrated that stereotactic radiotherapy preserved the cognitive function compared to whole brain radiotherapy [104,105]. The indication of whole brain radiotherapy should be limited to selected indication and associated to hippocampal avoidance if possible and/or relevant [106]. For patients treated with systemic therapies with an high intracranial level penetrance (EGFR+ or ALK+ non-small cell lung cancer for example), radiotherapy may not be proposed as an upfront local treatment due to the high intracranial efficacy of these therapies [107]. However, their impact on cognition at long term is unknown.

#### 3.4.2. Technological advances

Proton beam radiotherapy is a technique that has been developed to reduce the dose to nontarget irradiated normal tissue, due to its "near zero" exit dose (versus conformal radiotherapy with X photons). Proton beam radiotherapy is now largely recommended to treat children with brain tumours in order to limit the long term neurocognitive decline [108]. In adults, no clinical benefit has been demonstrated for proton beam radiotherapy yet. Data are often monocentric, retrospective, with small samples. In a cohort of 123 adults patients treated with proton beams for intracranial tumours (mainly meningiomas), this technique offered good clinical results and was associated with a preservation of neurocognition in more than 90 % of cases at one year [109]. However, there was no comparison with photon beam radiotherapy. Anatomical changes on MRI after proton beam radiotherapy seemed to be inferior to those observed after photon beam radiotherapy [97,110]. In high grade gliomas, a phase II trial compared the efficacy of proton beam radiotherapy versus intensity modulated radiotherapy in 90 patients [111]. Proton beam radiotherapy was not associated with a delay in time to cognitive failure but reduced patient-reported fatigue (24 % versus 58 %). Ongoing trials are investigating the role of proton beam radiotherapy for benign tumours (COG-PROTON01) and low-grade gliomas in adults [112,113].

It is important to note that most studies reporting cognitive decline after photon radiotherapy were performed with "old" techniques (two-dimensional or three-dimensional conformational radiotherapy). Advance radiotherapy techniques (intensity-modulated radiotherapy, volumetric modulated arctherapy) make it possible to perform dosimetric sparing of specific regions of inter-

rest in the healthy brain. Hippocampal avoidance (detailed above) is the most documented in the literature. The recommendation of dosimetric indicators for other critical brain structures is complex due to the heterogeneity of data (techniques, concomitant chemotherapy, variability of the cognitive testing leading to the results). The majority of dosimetric indicators reported are not correlated with clinical benefit and have not been validated in an independent cohort. For example, Perlow et al. have described an interesting strategy of sparing a "memory region" during whole brain radiotherapy, including hippocampi, amygdalae, corpus callosum, and fornix [114]. The clinical value of such strategy is still unknown.

A novel modality of irradiation delivered at ultra-high dose rate, named flash radiotherapy, is currently tested in preclinical models and showed promising results in reducing neurocognitive side effects and sparing cerebral plasticity in rodent models [115,116].

#### 3.4.3. Pharmacological and non-pharmacological approaches

Several drugs have been tested to prevent or reduce radiation-induced cognitive impairment with a limited effectiveness so far.

Memantine is a N-methyl-D-aspartate (NMDA) receptor antagonist with a demonstrated neuroprotective effect in patient with vascular dementia [117]. Memantine has been tested to prevent cognitive impairment after whole brain radiotherapy in two randomized trials. In the study of Brown et al., there was a tendency for less decline in delayed recall in the memantine arm at 24 weeks (primary endpoint), but the difference was not statistically significant. For secondary outcomes, patients treated with memantine showed better cognitive function over time and a reduced rate of decline in memory, executive function, and processing speed after whole brain radiotherapy [118]. The second trial by Laack et al., found no benefit of the adjunction of memantine during whole brain radiotherapy [119]. However, patient attrition and poor testing compliance were two major issues of these two trials limiting their statistic power.

Donepezil, a reversible inhibitor of the acetylcholine esterase used to improve cognitive functioning in several neurodegenerative disease, have been tested in a randomized trial versus placebo in 198 patients with brain tumour survivors at least 6 months after partial or whole brain radiotherapy to reduce cognitive impairment [120]. The study was negative for the primary endpoint (overall composite score including eight individual test scores representing the major cognitive domains), but a benefit for donepezil was observed by looking specifically to memory and motor speed, with a benefit greater for those who were more cognitively impaired before study treatment. Methylphenidate and modafinil are two psychostimulants that have been tested to improve cognitive functioning and symptoms in brain tumour patients receiving radiotherapy, with no clear benefit found [121,122].

Non-pharmacological therapy, as cognitive rehabilitation, seems to be relevant to limit neurocognitive impact of radiotherapy [76]. In a randomized trial with 140 patients with gliomas (two third having received radiotherapy), the cognitive rehabilitation program showed significant benefit on both short-term and longer-term cognitive performance and mental fatigue [77].

### 4. Conclusion

Encephalic radiotherapy leads to anatomical changes in key brain components for cognition. Multiple brain regions are radiosensitive and may constitute "weak links" in functional networks that may explain cognitive decline. Dose constraints on brain tissues involved in cognitive functions have yet to be defined. Individual susceptibility exists, but clear predictive biomarkers remain
to be found. There are several cofactors (comorbidities, chemotherapy, tumour progression) that may participate to cognitive decline after radiotherapy. The place of protontherapy, cognitive remodulation and pharmacological preventive drugs need to be more investigated in large clinical trials.

## Author contributions

The authors did not provide this information.

## Disclosure of interest

The authors did not disclose their relationships/activities/interests.

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