Early-life gastrointestinal inflammation and the developing brain: Unravelling the pathways to long-term cognitive dysfunction

Table 5 Summary of studies: Celiac disease and cognitive/neurological outcomes

Ref.	Study type/population	Key cognitive/symptomatic findings	Key structural/mechanistic findings	Effect of GFD
Edwards George et al[148], 2022	Nationwide online survey (CD and NCGS patients)	89% of CD and 95% of NCGS reported GINI (brain fog). Most common symptoms: Difficulty concentrating, forgetfulness, and grogginess	High prevalence suggests GINI is a genuine and common symptom complex	N/A (focus on symptoms after exposure)
Croall et al[149], 2020	United Kingdom biobank (population-based cohort)	Significant deficits in reaction time. Increased rates of self-reported anxiety and depression	Widespread white matter changes (increased axial diffusivity) observed via diffusion tensor imaging	N/A (cross-sectional comparison)
Croall et al[153], 2020	Pilot study (newly diagnosed vs established CD vs controls)	Underperformed relative to controls in visual and verbal memory (established at diagnosis)	Dysfunction appears established at the point of diagnosis	Cognitive deficit stabilizes but does not necessarily fully reverse, implying a benefit against further decline
Lichtwark et al[152], 2014	Longitudinal pilot study (newly diagnosed CD, 12-month follow-up)	Cognitive tests (verbal fluency, attention, motoric function) showed significant improvement over 12 months	Cognitive improvement strongly correlated with mucosal healing (Marsh score) and decreased tissue transglutaminase antibodies	Improved cognitive performance in parallel with resolution of intestinal inflammation
Casella et al[150], 2012	Case-control study (elderly CD patients on GFD vs controls)	Worse cognitive performance in CD patients despite long-term GFD, including lower scores on Mini Mental Test Examination, Semantic Fluency, and Digit Symbol Test	Emphasizes the risk of irreversible effects from diagnostic delay and prolonged gluten exposure	Suggests long-term GFD may not fully restore function if diagnosis is late
Hu et al[154], 2006	Case series (patients with cognitive decline associated with CD)	Presentation included amnesia, acalculia, and confusion. Average impairment was in the moderately impaired range. Ataxia common (10/13 patients)	Frequent deficiencies in folate, vitamin B12, or vitamin E. Brain magnetic resonance imaging often showed non-specific white matter hyperintensities	Three patients improved or stabilized cognitively with gluten withdrawal
Lanza et al[146], 2018 and Pennisi et al[147], 2017	Review of neurophysiological studies (TMS, electroencephalography)	Adult CD patients often report “brain fog” to overt dementia	Evidence suggests a profile of “hyperexcitable celiac brain” (measured by TMS) which is a feature also reported in degenerative/vascular dementia	Hyperexcitability partially reverts back after long-term gluten restriction
Lebwohl et al[155], 2016	Population-based cohort study (age $\geq$ 50 years)	No increased overall risk for dementia in CD patients over the long term	Subgroup analysis showed a non-significant trend for increased risk of vascular dementia (hazard ratio = 1.28) but not Alzheimer’s	N/A (population risk analysis)
Beas et al[151], 2024	Systematic review and meta-analysis	Confirmed a significant association between CD and insomnia. Provided valuable insight into studies on cognitive impairment	N/A (meta-analysis of existing literature)	N/A (meta-analysis)

It summarizes key findings from clinical studies investigating the neurological and cognitive manifestations of celiac disease. The evidence consistently demonstrates objective cognitive deficits (memory, reaction time, attention), subjective symptoms (brain fog/gluten-induced neurocognitive impairment), and associated brain pathology (white matter changes, cerebral hyperexcitability). Findings highlight the critical importance of a timely diagnosis, as the effectiveness of the gluten-free diet may vary between reversing new symptoms and stabilizing or failing to fully resolve deficits established during chronic, untreated inflammation. CD: Celiac disease; GINI: Gluten-induced neurocognitive impairment; GFD: Gluten-free diet; NCGS: Non-celiac gluten sensitivity; N/A: Not applicable; TMS: Transcranial magnetic stimulation.