Levels of Alzheimer Beta-Amyloid Precursor Protein (APP) in Children With Severely Autistic Behavior and Aggression

Deborah K. Sokol PhD, MD; Demao Chen PhD; Martin R.Farlow MD; David W. Dunn MD; Bryan Maloney BA; Jennifer A. Zimmer MD; Debomoy K. Lahiri PhD

Disclosures

J Child Neurol. 2006;21(6):444-449. 

In This Article

Results

The mean age of children with autism was 8.8 years (SD 4.7 years). The mean age of children in the control group was 9.2 years (SD 4.8 years). The mean head circumference percentile was 54.6 (SD 32.8) for children with autism and 54.5 (SD 27.7) for the control group. No significant difference in age or head circumference was seen between these groups as measured via t-test analysis.

Seven of the 10 children with autism scored in the mild to moderate range and the other three scored in the severely autistic range of symptoms as measured by the Childhood Autism Rating Scale. A separate analysis was done for three children who displayed "severe autism with aggression." Examples of aggression were based on the following clinical reports: one patient hit others and broke furniture at home, another hit others and engaged in repetitive head banging, and a third repeatedly engaged in "ripping out his sister's hair." All of the 11 medical control subjects scored within the "nonautistic range" on the Childhood Autism Rating Scale.

Assay of acetylcholinesterase activity was performed in all subjects, and the result suggests that no apparent difference exists in acetylcholinesterase according to the severity of autism (Figure 1).

Relative acetylcholinesterase according to the severity of autism.

Plasma levels of soluble secreted beta-amyloid precursor protein were measured in two different ways. First, total levels of secreted beta-amyloid precursor protein were measured by Western immunoblotting technique with 22C11 monoclonal antibody. The total secreted beta-amyloid precursor protein detects and represents various species: α, β, and γ proteins. Second, the level of secreted beta-amyloid precursor protein α species was determined exclusively. Both methods yielded a consistent result, suggesting that the most predominant secreted beta-amyloid precursor protein species is α. The assay detected a wide range of secreted b-amyloid precursor protein a levels in these subjects, from 200 to 1200 pg/mL. Waller-Duncan multiple-range tests showed that children with severe autism and aggression expressed secreted beta-amyloid precursor protein (1200 pg/mL) at two or more times the levels than that of children without autism (500 pg/mL) and up to four times more than children with mild autism (P < .05; Figure 2). The differences between children with severe autism and aggression and both children without or with mild autism are significant at P < .05 (Waller-Duncan). The difference between children without and with mild autism was not significant.

Relative secreted beta-amyloid precursor protein levels according to the severity of autism.

Segregating by both age and autism reemphasized (see Figure 2) that, within each age group, low secreted beta-amyloid precursor protein levels were seen when comparing children with and without autism, whereas higher levels of secreted beta-amyloid precursor protein were found comparing either of the previous groups with children with severe autism and aggression (P < .05; Figure 3). Within severity levels, secreted beta-amyloid precursor protein was lower for children 10 years and older than for children 7 years and younger. These differences are not, however, more than weakly significant. The category of severe autism, over 10 years of age, was excluded from analysis because of the small sample size (n = 1).

Relative secreted beta-amyloid precursor protein levels according to age and the severity of autism (note that the letters A, B, and C indicate Waller-Duncan categories.)

Levels of amyloid-beta 40 varied in inverse relationship to the severity of autism (Figure 4). However, the differences were not statistically significant. This was also true for amyloid-beta 42 levels. Segregating by age and the severity of autism revealed no statistically significant differences. Thus, there were no significant differences for amyloid-beta 40 or for amyloid-beta 42 for groups according to age and the severity of autism.

Relative amyloid-beta 40 levels according to the severity of autism.

Acetylcholinesterase varied somewhat over age and autism, with a drop in acetylcholinesterase levels between autistic and nonautistic patients within an age group, but this was not statistically significant (Waller-Duncan). Acetylcholinesterase levels in patients with severe autism under 7 years of age were 24% lower than in patients with autism over 10 years of age, and this was significant at P < .05, which was also true comparing nonautistic patients under 7 years of age with the higher acetylcholinesterase group (Figure 5). The category of severe autism, over 10 years, was excluded from this analysis because of the small sample size (n = 1). .

Relative acetylcholinesterase according to age and the severity of autism (note that the letters A, B, and C indicate Waller-Duncan categories).

There were significant negative correlations between beta-amyloid precursor protein and acetylcholinesterase (-0.5014; P < .05) and between age and beta-amyloid precursor protein (-0.4815) for the entire sample. There was a significant positive correlation between age and acetylcholinesterase (0.57311; P < .05). When segregating by age and the severity of autism, only the positive correlation between age and acetylcholinesterase was again demonstrated (0.66685; P < .05), but this time, a positive correlation existed between beta-amyloid precursor protein and acetylcholinesterase for the young children without autism (0.93941; P < .05). When segregating by the presence of seizures and the severity of autism, among those with seizures (n = 8), there was a significant correlation between age and amyloid beta 40 (0.78846; P < .05). The magnitude and direction of correlations for those without seizures (n = 13) followed those seen for the overall group: significant negative correlations between beta-amyloid precursor protein and acetylcholinesterase (-0.7908; P < .05) and between age and beta-amyloid precursor protein (0.6854; P < .05) and a positive correlation between age and acetylcholinesterase (0.650565; P < .05). The magnitude and direction of correlations for those without autism and without seizures (n = 6) also followed those of the overall group: a significant negative correlation between secreted beta-amyloid precursor protein and acetylcholinesterase (-0.9700; P < .05) and between age and secreted beta-amyloid precursor protein (-0.0497; P < .05) and a significant positive correlation between age and acetylcholinesterase (0.91028; P < .05). The children with mild autism but no seizures also showed a negative correlation between age and beta-amyloid precursor protein (-0.9497; P < .05) but a positive correlation between beta-amyloid precursor protein and amyloid-beta 40 (0.97109; P < .05). No other associations were significant. Amyloid-beta 42 was too low to be detected in these samples.

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