Differences in neuropsychological and behavioral parameters and brain structure in patients with familial adenomatous polyposis: a sibling-paired study

Abstract

BackgroundFamilial adenomatous polyposis (FAP) is an autosomal dominant hereditary colon cancer syndrome caused by mutations in adenomatous polyposis coli (APC) with both colonic and extra-colonic manifestations. Case reports have noted an association with FAP and intellectual disability and animal studies have shown that APC is implicated in neural development and function, but no studies have investigated neuropsychological, behavioral, or structural brain characteristics of patients with FAP.MethodsWe undertook a pilot, sibling-pair study comparing three patients with FAP to their sex-matched siblings without FAP. Each sibling pair underwent neuropsychological testing by a blinded examiner, high resolution brain MRI scans, and the mother of each pair rated her children’s adaptive life skills and behavioral and emotional characteristics. Given the small number of study participants in this pilot study, quantitative comparisons of results were made by subtracting the score of the non-FAP sibling from the FAP patient on the various neuropsychological tests and parent rating questionnaires to calculate a difference, which was then divided by the standard deviation for each individual test to determine the difference, corrected for the standard deviation. Diffusion numbers in multiple regions of the brain as assessed by MRI were calculated for each study participant.ResultsWe found similarity between siblings in all three pairs on a wide range of neuropsychological measures (general intelligence, executive function, and basic academic skills) as tested by the psychologist as well as in descriptions of adaptive life skills as rated by mothers. However, mothers’ ratings of behavioral and emotional characteristics of two of the three pairs showed differences between the siblings, specifically that the patients with FAP were found to have more behavioral and emotional problems compared to their siblings. No differences in brain structure were identified by MRI.ConclusionWe report the first study exploring neuropsychological, behavioral, emotional, and structural brain characteristics of patients with FAP and found subjective differences as assessed by maternal perception in behavioral and emotional characteristics in patients with FAP compared to their siblings. Larger studies are needed to elucidate the relationship, if any, between FAP and brain function.

Ubiquitous neurocognitive dysfunction in familial adenomatous polyposis: proof-of-concept of the role of APC protein in neurocognitive function

“…Interestingly, there were no group differences noted on the adult selfratings (BRIEF questionnaire) of executive functions, perhaps secondary to self-perceptions not recognizing the subtle differences that might be present when compared to their peers. Original observations describing intellectual disabilities among individuals with FAP were limited to case reports [4,5,7]. Patients with FAP were shown to perform lower on test of intellectual capacity, particularly on verbal tasks, when compared to patients with ulcerative colitis [14].…”

“…Despite these known linkages few empirical findings examining the relationship between the expression of the APC protein and neurocognitive and behavioral functioning in individuals with APC mutations exist [4][5][6][7]. To date, animal studies have associated APC dysfunction with altered synaptic function in APC cKO mice, which plays a critical role in learning and memory [8].…”

Altered neural networks and cognition in a hereditary colon cancer

“…A 2010 study by researchers at the Cleveland Clinic reported that though FAP patients have IQs parallel with the general population, hearing/language-dependent verbal scores were significantly lower than those without the mutation ( O'Malley et al, 2010 ). Preliminary data in a small sample, sibling-paired pilot study suggested that siblings who are FAP positive are more likely to suffer from behavioral and emotional problems than their healthy siblings ( Azofra et al, 2016 ), and a prior study reported a high incidence of formal psychiatric diagnoses (especially anxiety diagnoses) in FAP adolescents ( Gjone et al, 2011 ). The most recent investigation of neurocognitive function of FAP patients identified and characterized robust deficits in several cognitive measures (particularly long term retrieval and cognitive fluency), suggesting that APC protein plays a critical role in cognition ( Cruz-Correa et al, 2020 ).…”

Altered Resting State Brain Networks and Cognition in Familial Adenomatous Polyposis

“…A 2010 study by researchers at the Cleveland Clinic reported that though FAP patients have IQs parallel with the general population, hearing/language-dependent verbal scores were significantly lower than those without the mutation (O’Malley et al, 2010). Preliminary data in a small sample, sibling-paired pilot study suggested that siblings who are FAP positive are more likely to suffer from behavioral and emotional problems than their healthy siblings (Azofra et al, 2016), and a prior study reported a high incidence of formal psychiatric diagnoses (especially anxiety diagnoses) in FAP adolescents (Gjone, Diseth, Fausa, Nøvik, & Heiberg, 2011). The most recent investigation of neurocognitive function of FAP patients identified and characterized robust deficits in several cognitive measures (particularly long term retrieval and cognitive fluency), suggesting that APC protein plays a critical role in cognition (M. R. Cruz-Correa et al, 2020).…”