First described by Dr. Leo Kanner, autism is a pervasive developmental disorder (PDD) characterized by the presence of limited interests and activities, as well as by impairments in socialization and communication [1
]. Despite the fact that there are many suggestions for the causes of this disorder, including, but not limited to, genetics, the environment, and vaccinations, there is no one cause of autism [3
]. With the advent of electroencephalography (EEG), observations of aberrant patterns in autistic patients contributed the contemporary understanding of the syndrome as a brain-based disorder [4
]. The heterogeneity of the clinical syndrome would seem to indicate that the disorder termed autism may arise from a constellation of different etiologies [5
]. For example, about one quarter of autistic patients have comorbid epilepsy [7
]. Studies suggest another subgroup, some 40 - 55% of autistic patients, suffers mental retardation [8
]. Furthermore, even though the heritability of autism is relatively high, only some 10% of cases can be attributed to a known genetic aberration [5
Although there are diagnostic criteria listed in the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV), the International Statistical Classification of Diseases and Related Health Problems (ICD-10), the Autism Diagnostic Observation Schedule (ADOS) and the Autism Diagnostic Interview-Revised (ADIR), the disorder is currently diagnosed solely using core behavioral criteria selected to define autism, typically during the toddler or preschool years at the earliest [11
]. There is presently no clinical laboratory test for diagnosing autism [12
]. To begin intervention at the earliest possible time, the development of biological quantitative methods to predict the presence or risk of autism is necessary.
A common biological correlate of autism, which may be used in the future as a quantitative diagnostic tool, is abnormal brain overgrowth [13
]. Macrocephaly is said to occur in 15–35% of autistic children [10
]. Specifically, observations of brain volume through magnetic resonance imaging (MRI) as well as head circumference studies suggest that regulation of brain growth is abnormal in autism, as indicated by early brain overgrowth followed by abnormally slow brain growth [14
]. Moreover a positive association between increasing radiate white matter volume and motor skill impairment in children with autism has also been shown [17
]. However, brain overgrowth observations by way of head circumference or brain volume measurements via MRI would be an inaccurate method of diagnosis for autism.
Brain overgrowth may be detected by looking for signs of a central nervous system (CNS) anabolic state during childhood. Indeed this has been suggested by studies of brain-derived neurotrophic growth factor (BDNF, a modulator of neuronal development and maintenance) levels in both brain and blood of autistic children [18
]. Observed BDNF levels were three times as high in basal forebrain of autistic patients compared to adults of comparable age [19
]. Likewise, Nelson and colleagues found elevated neonatal concentrations of BDNF in autistic spectrum children compared to controls [21
]. It has been suggested that serum levels of BDNF, in addition to another neurotrophin, NT-4, be measured in order to aid in the diagnosis of autism and mental retardation [22
]. Conversely, a later study reports a delayed increase in serum BDNF levels of autism patients with development [23
]. This inconsistency implies that BDNF is not the best candidate for a peripheral biomarker that can be used in autism diagnosis.
Proteolytic cleavage of amyloid precursor protein (APP) by the sequential actions of β-and γ-secretases form the neurotoxic amyloid beta (Aβ) peptide, which typically consists of 40 or 42 amino acid residues (the amyloidogenic pathway). On the other hand the non-amyloidogenic pathway consists of APP cleavage by α-secretase [24
] which yields the neurotrophic product, secreted APP-α (sAPP-α). As α-secretase cleaves APP within the Aβ sequence, Aβ formation is subsequently prevented. In a recent report Sokol and colleagues demonstrated, in children with severe autism and aggressive behavior, that serum sAPP-α levels were more than twice that of children without autism and up to four times higher than observed in children with mild autism [18
Based on the Sokol study, we speculated that sAPP-α is a peripheral biomarker that can be used for the diagnosis of autism. In addition, we have recently developed a sensitive enzyme-linked immunosorbent assay (ELISA) to specifically measure sAPP-α secretion in human plasma and umbilical cord blood and we hypothesize that this ELISA will show a significant difference in sAPP-α levels of autistic patients when compared to healthy individuals. Our goal is to design a laboratory tool for early diagnosis of autism.