Neurocognitive Decline After Radiotherapy

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Radiotherapy to the brain can impair cognitive function by damaging healthy neural tissue. The hippocampus, which plays a key role in memory, is particularly sensitive.

Common symptoms:

• Memory loss (especially short-term)
• Difficulty concentrating
• Slowed thinking
• Word-finding problems
• Executive dysfunction

• High total radiation dose
• Large treatment fields
• Fractionation schedule
• Age (older patients more vulnerable)
• Concurrent chemotherapy
• Pre-existing cognitive impairment

• Clinical evaluation – Neurological and cognitive examination.
• Neuropsychological testing – To quantify affected domains.
• MRI brain – To rule out recurrence or radionecrosis.
• Functional imaging – Optional (e.g., PET, SPECT).

• Hippocampal-sparing radiotherapy – Protects memory circuits.
• Proton therapy – More precise dose distribution.
• Limit radiation dose and field when feasible.
• Cognitive rehabilitation – Exercises, compensatory strategies.
• Pharmacologic agents:
  1. Memantine (some benefit in delaying cognitive decline)
  2. Donepezil, methylphenidate (off-label use)

• Regular monitoring
• Referral to neuropsychology or cognitive therapy
• Patient and caregiver education
• Lifestyle interventions: exercise, sleep hygiene, mental stimulation

Sleurs et al. and Karin Gehring from the Department of Neurosurgery, Elisabeth-TweeSteden Hospital, Tilburg, The Netherlands, conducted prospective Cognitive assessments (Controlled Word Association (COWA), Hopkins Verbal Learning (HVLT-R), and Trail Making Tests (TMT A, B) before, 6 months, and 1 year post-RT in 111 intracranial tumor patients (18- 80 years). Reliable change indices indicated cognitive changes across timepoints. CT and T1-weighted MRI scans acquired at diagnosis were co-registered, normalized to standard space, and smoothed. Voxel-wise permutation-based regression analyses examined the relationship between RT dose and cognitive decline (α<.05 at the cluster level).

Images of 111 patients (Mdn age = 55.39 years; 47% male; lesions were gliomas (61%), meningiomas (18%), other (21%); in frontal (33%), temporal (25%), other location (42%)) were analyzed. Reliable decline was most pronounced at 6 months, particularly on the TMT A (25.77%), TMT B (24.21%), and HVLT immediate recall (21%). At 1 year, 20% of patients continued to show decline in TMT B. Higher RT doses to frontal gyri, temporal, occipital, and para-central regions were associated with declines in verbal fluency, memory, processing speed, and flexibility at both peak- and cluster-level.

Differential voxel-wise RT dose effects at peak versus cluster level suggest local and network-based recruitment of diverse functional regions and vulnerability to cranial RT. These insights may help redefine key regions at risk from a network-based perspective, preserving cognition in future RT planning ¹⁾.

The study by Sleurs et al. (2025) is a prospective cohort study that investigates neurocognitive decline in adult patients with intracranial tumors using cognitive testing and voxel-based analysis. Below is a critical review of its methodology and findings.

1. Prospective Design and Timepoints Cognitive assessments were performed at baseline, 6 months, and 12 months post-radiotherapy (RT), allowing temporal tracking of cognitive changes.

2. Use of Reliable Change Indices (RCIs) RCIs were employed to detect significant cognitive decline across timepoints, increasing measurement precision and reducing bias from practice effects.

3. Selection of Cognitive Tests The study used validated tools:

• Controlled Word Association (COWA) – verbal fluency
• Hopkins Verbal Learning Test-Revised (HVLT-R) – memory
• Trail Making Tests A & B (TMT A, B) – processing speed and executive function

4. Voxel-wise Dose Mapping CT and MRI images were co-registered and analyzed using permutation-based voxel-wise regression. Results identified RT dose-response effects at both peak and cluster levels, mapping vulnerable brain regions.

5. Clinical Relevance Cognitive decline was most pronounced at 6 months (e.g., TMT A: 25.77%). At 1 year, 20% of patients showed continued decline in TMT B. High-dose regions included frontal, temporal, occipital, and paracentral areas—informing future RT planning.

1. Limited Cognitive Battery The study did not assess visuospatial skills, working memory beyond TMT B, or emotional cognition, which may also be affected by RT.

2. No Functional Imaging The voxel-based analysis focused solely on structural imaging. Functional data (e.g., fMRI) would have strengthened claims about network-level vulnerability.

3. Heterogeneous Sample Participants had different tumor types (gliomas 61%, meningiomas 18%, others 21%) and lesion locations. This heterogeneity could confound the findings.

4. Absence of a Control Group No matched control group was used to compare natural cognitive aging versus RT-induced decline. RCIs help address this, but external validity may still be limited.

The study reinforces the need for region- and network-sensitive radiotherapy planning. Voxel-wise mapping may help preserve critical cognitive functions, especially verbal fluency, memory, and executive skills, by sparing vulnerable regions like the frontal gyri and hippocampus.