Cognitive Decline following Head and Neck Cancer Radiotherapy: History
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Noor Shatirah Voon

Radiotherapy for head and neck cancers exposes small parts of the brain to radiation, resulting in radiation-induced changes in cerebral tissue. Implementation of neurocognitive assessment with advanced MRI examination in monitoring brain microstructural and functional changes of head and neck cancer patients could detect cognitive changes early. With suitable intervention, further deleterious effects on the patient’s cognition can be prevented.

  • neurocognition
  • head and neck cancer
  • magnetic resonance imaging
  • radiotherapy

1. Introduction

Radiotherapy (RT) with or without the combination of chemotherapy is the primary treatment option for head and neck cancer patients [1][2][3]. During radiation, head and neck cancer (HNC) patients were irradiated with high doses of radiation to the tumour, with normal brain tissues and sometimes crucial brain components such as temporal lobes, the brain stem and the hippocampus, are within or in close proximity to the target volume [4][5][6][7][8]. The injury to these brain compartments may increase the risk of compromised intelligence, memory impairment, and learning disabilities that would negatively impact patients’ quality of life, including diminishing work productivity, reduced engagement in social activities, and difficulties in daily living [9][10][11][12]. In addition, radiation-induced brain injury was observed in long term survivors of small cell lung carcinoma, low-grade glioma, non-parenchymal tumours, primary brain tumours, nasopharyngeal cancer, and metastatic brain tumours treated with fractionated partial or whole brain irradiation showed deficits in both anatomic and functional components [13]. Intensity--modulated radiation therapy (IMRT) was shown to reduce long-term morbidity among head and neck patients, but long-term toxicities and quality of life (QoL) impairment remained considerable with hearing toxicity, hypothyroidism, depression, fatigue, and anxiety as some of the common adverse effects [14]. The development of late radiation toxicities such as cranial neuropathies and cognitive impairment years after treatment can also induce a significant decline in QoL [15].
Nevertheless, the improved precision of radiotherapy technology has successfully reduced radiation doses in normal brain tissues, thus reducing the risk of brain tissue necrosis in patients following radiotherapy treatment [6]. Because radiation-induced brain injury at acute and early delayed periods within the first six months after radiotherapy is often not detected by routine imaging [16][17], it could potentially cause cognitive decline and exert a permanent effect [18][19]. Currently, the long-term cognitive dysfunction yielded by the incidental radiation dose to the surrounding cerebral tissues is subject to active investigations by researchers across the globe [20][21][22][23]. To monitor the cognitive functions, several neurocognitive tests can be conducted, including Montreal Cognitive Assessments (MoCA), Mini-Mental State Exam, Auditory Verbal Learning Test (AVLT), Trail Making Test A, Trail Making Test B, Rey Auditory Verbal Learning Test, Wechsler Adult Intelligence Scale, and Hopkins Verbal Learning Test. However, studies showed lower Montreal Cognitive Assessments (MoCA) scores in patients following RT even without overt cerebral injury [6][24].
In recent years, advances in brain imaging such as fibre tracking by diffusion imaging and functional mapping have shown their potential in the radiosurgical and surgical management of brain tumours [25][26][27]. These advancements could be beneficial should they be employed in the management of head and neck cancer treatment by monitoring brain microstructural changes. Functional connectivity (FC) in functional magnetic resonance imaging (fMRI) studies had been explored in measuring the correlation of synchronised signal among spatially distributed brain regions with the deduction of regions with correlated activity from functional networks [28]. In addition, functional connectivity alterations may provide valuable information on functional recovery and treatment strategies, allowing the precision of dose distribution, reliable dose constraints, and prevention or minimisation of brain damage [29]. Diffusion imaging has also shown potential as an early non-invasive indicator in predicting the early response of radiotherapy-induced white matter damage in nasopharyngeal carcinoma (NPC) [30][31]. Thus, this may provide a potential biomarker for early intervention of cognitive impairments in patients [32][33][34][35]. Ideally, these biomarkers can be traced and monitored during treatment and follow-up evaluation with cognitive assessments to evaluate clinical outcome measures.

2. Cognitive Decline following Head and Neck Cancer Radiotherapy

2.1. Neurocognitive Assessments in Detecting Cognitive Changes

Two neurocognitive tests were used in the studies evaluated, i.e., MoCA and AVLT [36], to detect cognitive changes following radiation treatment in head and neck cancer. The MoCA is a rapid screening instrument for mild cognitive dysfunction that assesses various cognitive domains: attention and concentration, executive functions, memory, language, visuo-constructional skills, conceptual thinking, calculations, and orientation. It is a brief 30-question test that takes about 10 to 12 min to administer with a scoring range from zero to 30. The average and range of MoCA scores for the studies are reported in Table 1. From the findings, most studies reported a MoCA score <26 to define cognitive impairment. Only one study [37] adjusted for patient’s education and age. All studies also reported changes in the post-MRI findings corresponding to lower MoCA scores post-RT (Table 1).
Table 1. MoCA scores and changes in MRI findings.
First Author, Year Average MoCA Post-RT (Range, Bonus Point) Pre-MRI Findings Post-MRI Findings Study Limitations
Ma Q, 2016 [38] 24.2 (22–27)   45 altered FC compared to untreated NPC group Heterogeneous treatment protocol, combined both non-irradiated and irradiated subjects, varied sample size, lack of new and larger sample, and between-subject variance
Qiu Y, 2017 [29] NR Functional network connectivity for NPC patients pre- and post-RT shared similar connectivity Weaker intra-network connectivity with lower mean connectivity correlation than baseline Heterogeneous treatment protocols, between-subject variance
Ma Q, 2017 [39] 24.2 (22–27)   Altered FC between cerebellar seeds and relative brain clusters Heterogeneous treatment protocol, combined both non-irradiated and irradiated subjects, varied sample size, lack of new and larger sample, and between-subject variance
Guo Z, 2018 [40] <26 No differences in cerebral volume of pre-NPC to controls Decrease in brain macrostructural volume Combined both non-irradiated and irradiated subjects, short time interval, and varied sample size
Lv X, 2018 [41] NR No significant differences in volumes of hippocampus and hippocampal subfields between groups Significant volume reductions in bilateral hippocampus and hippocampal subfields Combined both non-irradiated and irradiated subjects and varied sample size
Ren WT, 2019 [36] 27 (24–29) No significant changes in regional cerebral and connectivity before RT Reduced regional cerebral and neural network functions Comparison to healthy controls and small sample size, short time interval
Wu G, 2020 [37] <26
(<12 years education and >65 years age)		 Baseline of kurtosis and diffusivity does not show significant difference Significantly lower kurtosis and diffusivity of white matter Heterogeneous treatment protocols, comparison between different marker groups, and between subject-variance

2.2. Relationship of Neurocognitive Assessments to Magnetic Resonance Imaging (MRI)

According to Ma et al. [38], five functional connections were significantly correlated with MoCA overall scores with the attention domain also being significantly correlated to functional connectivity between vermis and hippocampus (r = 0.43, p < 0.001). This relationship was further explored by Ma et al. [39] and it was found that altered cerebellar-cerebral FCs were also significantly correlated to MoCA and attention scores, one of the seven subscores in MoCA, although results obtained were negatively correlated. From the findings, the change of correlation from negative to positive may implicate that the RT process might have impaired the anticorrelation between the two networks of NPC patients. The impaired anticorrelation between the dorsal attention and default networks may suggest deficits in cognitive and attention processing of NPC patients after RT [41]. In contrast, no correlation was found between network-level functional connectivity and cognition in Qiu et al. [29] (Table 2), although significantly reduced FC (p < 0.005) in the left anterior cingulate cortex (ACC), the right insular and bilateral executive control network (ECN) to MoCA scores three months post-RT were reported compared to pre-RT.
No significant correlations between FC and MoCA tests and no significant changes in MoCA scores between pre-and post-RT and healthy controls were shown in Ren et al. [36]. Nevertheless, seven weeks post-RT, FC was significantly reduced in several cortical regions of DMN, including the precuneus, posterior cingulate cortex, medial prefrontal cortex, and other regions such as parahippocampus, cuneus, lingual gyrus, fusiform gyri, and calcarine sulcus [36]. Significant reduction in connectivity was also shown in post-RT patients compared to controls in multiple cerebellar-cerebral regions including the cerebellum, parahippocampal gyrus, hippocampus, fusiform gyrus, inferior frontal gyrus, inferior occipital gyrus, precuneus, and cingulate cortex [36].
In terms of volume, a significant negative correlation was reported between the reduced MoCA scores and expansion of ventricles [40] (Table 2). Significant volume losses in the bilateral hippocampus, bilateral GCL, left subiculum (SUB), and the right molecular layer was correlated with rapid cognitive function decline [41]. According to Wu et al. [37], Kurtosis mean-1 of white matter could predict late delayed neurocognitive impairment through changes in MoCA scores post-RT with the sensitivity of 84.2% and specificity of 87.5% in the receiver operating (ROC) curve. However, the study done by Sharma et al. [42] displayed voluminous, diffuse, radiation-induced white matter hyperintensities; changes were not associated with any neurocognitive assessments.
Table 2. Relationship of neurocognitive outcome to MRI findings.
First Author, Year Score Functional Connectivity or Volume Significant Relationships and Prediction Details Summary
Functional connectivity
Ma Q, 2016 [38] MoCA Vermis and hippocampus r = 0.4440,
p = 0.00043		 ↓ FC   ↓ MoCA score
  Attention r = 0.4282,
p = 0.00072		 ↓ FC   ↓ Attention score
  MoCA Cerebellum lobule VI and dIPFC r = −0.4343,
p = 0.00059		 ↑ FC   ↓ MoCA score
    Precuneus and dFC r = 0.4622,
p = 0.00023		 ↓ FC   ↓ MoCA score
    Cuneus and middle occipital lobe r = 0.4282,
p = 0.00071		 ↓ FC   ↓ MoCA score
    Anterior insula and cuneus r = 0.4569,
p = 0.00028		 ↓ FC   ↓ MoCA score
Qiu Y, 2017 [29] MoCA Left anterior cingulate cortex within the default mode network (DMN)   No significant correlation
    Right insular within salience network (SN)   No significant correlation
    Bilateral executive control network (ECN)   No significant correlation
Ma Q, 2017 [39] MoCA Right cerebellar lobule VIIb and right fusiform gyrus r = −0.34,
p = 0.008		 ↑ FC   ↓ MoCA score
  Attention r = −0.41,
p = 0.002		 ↑ FC   ↓ Attention score
  MoCA Left cerebellar lobule VIII and right crus I r = −0.30,
p = 0.021		 ↑ FC   ↓ MoCA score
  Attention r = −0.32,
p = 0.001		 ↑ FC   ↓ Attention score
  Attention Left cerebellar lobule VIII and right MFG r = −0.27,
p = 0.040		 ↑ FC   ↓ Attention score
Ren WT, 2019 [36] MoCA Default mode network (DMN)   No significant correlation
Volume
Guo Z, 2018 [40] MoCA Ventricular bβvolume = −4.63 × 10−4,
p = 0.007		 ↓ Volume   ↓ MoCA score
Lv X, 2018 [41] MoCA Left hippocampus bβvolume = 0.010,
p = 0.017		 ↓ Volume   ↓ MoCA score
    Right Hippocampal bβvolume = 0.013,
p = 0.002		 ↓ Volume   ↓ MoCA score
    Left Subiculum bβvolume = 0.061,
p = 0.018		 ↓ Volume   ↓ MoCA score
    Left Granule cell layer (GCL) bβvolume = 0.102,
p = 0.011		 ↓ Volume   ↓ MoCA score
    Right Granule cell layer (GCL) bβvolume = 0.158,
p = 0.022		 ↓ Volume   ↓ MoCA score
    Right molecular layer (ML) bβvolume = 0.285,
p = 0.002		 ↓ Volume   ↓ MoCA score
Kurtosis
Wu G, 2020 [37] MoCA Hippocampal r = 0.76, p < 0.05 Kurtosis mean-1 best in predicting MoCA scores decline

2.3. Effect of Radiotherapy Treatment Dose to Brain Structural and Functional Changes

Brain structure and function changes were apparent in patients treated with NPC radiotherapy compared to untreated patients or healthy controls. This was reported in Ma et al. [38] (Table 3) with changes of the cerebellum, sensorimotor and cingulo-opecular FC shown in irradiated patients with altered cerebral-cerebral FCs within dorsal attention, frontal-parietal [39], and default-mode networks [36][39].
Table 3. Dose-dependent changes with brain microstructure or functional connectivity.
First Author, Year Dose-Dependent Changes
Ma Q, 2016 [38] Functional connectivity pattern in NPC treated patients was significantly impaired compared to NPC untreated with changes shown in cerebellum, sensorimotor, and cingulo-opercular.
Qiu Y, 2017 [38] Changes in right insular functional connectivity were negatively correlated with dose of right temporal lobe.
Ma Q, 2017 [39] Altered cerebral-cerebral functional connectivity within dorsal attention, default, and frontoparietal networks shown in NPC treated patients.
Guo Z, 2018 [40] Significantly decrease volume in bilateral temporal lobe with increased mean dose to this region.
Lv X, 2018 [41] Volume deficits in the bilateral hippocampus, bilateral granule cell layer, and right molecular layer negatively correlates with the mean dose to ipsilateral hippocampus.
Ren WT, 2019 [36] Decreased connectivity in multiple cerebellar-cerebellar regions mainly in the default-mode networks likely because of radiation dose.
Wu G, 2020 [37] Significant radiation-induced changes in both white and gray matter of the temporal lobes due to the high radiation dose received.
The findings showed that greater FC corresponded to lower MoCA and attention scores. Furthermore, the medial frontal gyrus within the default-mode networks is considered to be associated with executive function and decision making, which propagates information for higher-level processing response [38][39]. Abnormal connection of sensorimotor and cingulo-opercular networks with cerebellum shown might also imply the radiation-induced motor deficits and cognitive function abnormalities, especially attention changes [38]. Significant reduction in bilateral temporal lobe volume after RT [40] and differences in its white and grey matters among the neurocognitive function decline (NFD) group [37] suggests the dependency of changes in brain microstructure on radiation dose. Negative correlations were also displayed between the volume of the bilateral hippocampus, bilateral granule cell layer (GCL), and right middle lobe (ML) to mean dose of the ipsilateral hippocampus [41] and maximum irradiation dose of the right temporal lobe to the right insular FC within the salience network [29] (Table 3). No studies reported on the normal tissue compilation probability (NTCP) modelling for the temporal lobe.

3. Summary

Studies indicate a cut-off point of 26 in MoCA assessments to define cognitive impairments. Though changes in MoCA scores were associated with MRI outcomes, the cut-off may be too stringent and not optimal among minorities [43] and certain health condition populations [44]. Additionally, the cut-off is also too high for cognitively normal older adults, even those who are highly educated [45]. Nevertheless, the use of MoCA is shown to be efficient in screening for mild cognitive impairment among the Chinese population [46][47] with the Cantonese Chinese MoCA being a consistent and reliable instrument [48]. Therefore, it is crucial to use age [45], education [43][45], and race or ethnicity [43][49] in correcting the cut-off scores to avoid misdiagnosis of cognitive decline. A lower MoCA cut-off score 23/30 yielded an overall better diagnostic accuracy with a lower false positive rate and excellent sensitivity (96%) and specificity (95%), thus, is recommended as the new MoCA cut-off score [49][50].

The neurocognitive assessment has shown the likelihood to be associated with MRI outcome following head and neck cancer radiotherapy, especially for the temporal region. Focus is given to the region due to its proximity to the target volume and would inevitably be incorporated into the treatment field, which exceeds the tolerance limit. Changes in functional connectivity (FC) and brain volume were significantly correlated with MoCA scores in most studies [38][37][40][41]. From the findings, the change of correlation from negative to positive may implicate that the RT process might have impaired the anticorrelation between the two networks of NPC patients. The impaired anticorrelation between the dorsal attention and default networks may suggest deficits in cognitive and attention processing of NPC patients after RT [39]. The correlation may also be inferred to be due to the radiation-induced cognitive impairment of domains such as short-term memory, visual memory, language ability, attention, and executive function [38][39]. In terms of volume, longitudinal changes in MoCA scores were associated with the longitudinal changes in total grey matter and bilateral temporal and ventricular volumes.

Radiation-induced changes were also observed throughout the studies investigated. The early changes are closely related to vascular damage shown by vessel dilation, endothelial cells loss, nuclei enlargement, vessel wall thickening, increased vessel permeability, and decreased vessel density and length [19][51]. Resultant functional connectivity and brain volumes from irradiation were observed in multiple cerebellar regions. This was shown with the altered correlation between brain networks observed in NPC patients following RT, which may imply deficits in cognitive and attention processing [38][39]. In addition, the demonstrated differences in the FC pattern also suggests that radiation-induced changes may not be bound to the exposed area only, but other encephalic regions such as the cerebellum, sensorimotor, and cingulo-opercular areas [38]. This shows that the incidental radiation received by the brain during treatment of HNC could contribute to cognitive impairment [52]. The findings suggest that early microstructural injury of the temporal lobe has a direct contributory relation to the delayed neurocognitive decline with lower MoCA scores shown post-radiotherapy [37]. Specifically, an increased radiation dose to the temporal lobes and cerebellum were significantly associated with worse memory performance and motor coordination, respectively [52]. In addition, a higher radiation dose (30 Gy) induced earlier and more severe histological changes than a lower dose that were reflected with changes in diffusivity and perfusion [53][54][55]. Nevertheless, in the study done by Zer et al. [56], no significant correlation was shown to suggest the risk of treatment parameters, such as chemotherapy regimen or radiation dose, to greater cognitive decline.

Radiation-induced atrophy was also demonstrated in the bilateral hippocampus, bilateral GCL, and right molecular layer [17][41][57], suggesting the atrophy of the subfields is primarily induced by radiation that might be associated with early radiation effects on vascular injury, reduced molecular layer volume, and disruption of neuronal structure and synaptic integrity [41]. The elevated volume losses in these areas were associated with a rapid cognitive function decline evaluated by MoCA in irradiated patients [41], indicating dose-dependent atrophy. Additionally, altered FC within the default-mode and salience networks also indicates high-order cognition impairment, especially memory and attention [29]. According to Wen et al. [58], limiting the dose delivered to 0.5-cm3 temporal lobe volume (D0.5cc) to less than 65.06 Gy may be advisable during IMRT for NPC patients, as it decreases the risk of temporal lobe injury (TLI) in older patients with advanced tumour stage. Thus, the implementation of NTCP modelling could potentially predict TLI and allow individualised follow-up management. Therefore, a clinically appropriate and safe dose is crucial in protecting these vulnerable regions.

This entry is adapted from the peer-reviewed paper 10.3390/cancers13246191

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