Cognitive outcomes in early-treated adults with phenylketonuria (PKU): A comprehensive picture across domains.

Working memory/short-term memory

This is the capacity which allows us to keep in mind, manipulate and refresh the information necessary to complete a task (see Baddeley, 1986 ; McCabe, Roediger, McDaniel, Balota, & Hambrick, 2010 ). Typical tasks used to tap this function are forward and backward digit span tasks (where sequences of digits have to be repeated back in the order in which they were presented or in reverse order). The Corsi Block test is a typical visuospatial working memory task (it requires participants to touch a sequence of blocks in the same order in which they were touched by the examiner or in reverse order). Most studies have reported working memory to be impaired in AwPKU ( Bik-Multanowski, Pietrzyk, & Mozrzymas, 2011 ; Brumm et al., 2004 ; Channon et al., 2004 ; Channon, Goodman, Zlotowitz, Mockler, & Lee, 2007 ; Channon, Mockler, & Lee, 2005 ; but see Moyle, Fox, Bynevelt, et al., 2007 for negative results).

Sustained attention

This is the capacity to keep in mind target information for a sustained amount of time in spite of interfering information being presented ( Sarter, Givens, & Bruno, 2001 ; Wilkins, Shallice, & McCarthy, 1987 ). Typical tasks used to tap this function are the continuous performance task or the rapid visual information processing task, in which participants are presented with sequences of digits and must detect target sequences. Sustained attention has been reported to be impaired in AwPKU ( Bik-Multanowski et al., 2011 ; Schmidt at al., 1994 ; Weglage et al., 2013 ).

Inhibitory control

This refers to the ability to flexibly modify answers and inhibit inappropriate responses depending on task demands (e.g., Latzman & Markon, 2010 ; Miyake et al., 2000 ). A prototypical task tapping this ability is the Stroop Test where participants have to name the ink color of words whose meaning refers to a different color (say “yellow” for the word “red” written with yellow ink), thus, suppressing the tendency to read the word. Impairments have been reported in children with PKU, but only sporadically in adults (for a review of children studies, see DeRoche & Welsh, 2008 ; AwPKU impaired in Sundermann et al., 2011 , N = 17; current Phe average 1140 μmol/L; not impaired in Brumm et al., 2004 ; Feldmann, Denecke, Grenzebach, & Weglage, 2005 ). No impairment has also been reported in other tasks tapping inhibitory control such as the Hayling Sentence Completion Test which involves completing sentences as quickly as possible with nonsensical words ( Channon et al., 2004 ) and the Flanker Test in which participants have to respond to the direction of a central arrow, ignoring flanker arrows that may point in opposite ways ( Channon et al., 2005 ).

Impairments in Speed of Processing

As evident from the review above, results in the assessment of executive functions have been mixed, in spite of groups being similar for Phe levels at the time of testing (although historical Phe are not always reported and could be responsible for variations). Negative findings are particularly evident for inhibitory control, which is considered a typical executive function. These mixed results have lead some authors to suggest that the main residual deficit in AwPKU in one of speed of processing with deficits in executive tasks being largely resolved (e.g., Channon et al., 2005 , 2007 ; Moyle, Fox, Bynevelt, et al., 2007 ; Feldmann et al., 2005 ). Channon et al. (2005 , 2007 ), for example, compared the performance of 25 AwPKU (concurrent Phe level 221–1233 μmol/L) and 25 matched controls on two executive tasks tapping working memory ( n -back; Braver et al., 1997 ) and inhibition (Flanker inhibitory task), and two nonexecutive tasks (one involving learning an object location, and one involving categorizing objects for shape or function). AwPKU showed only a speed deficit in the working memory task and performed normally in the other tasks, prompting the conclusion that the only remaining deficit is one of speed. This conclusion, however, may be premature. Although inhibitory control may normalize in adulthood, other executive functions may remain suboptimal.

Language processing, and memory and learning

Impairments in these domains have been reported less frequently in early treated PKU children (for a review see Janzen & Nguyen, 2010 ). In AwPKU, results are inconsistent. Typical tasks include learning a list of words across trials (e.g., Rey Word Test), learning the positions of shapes (e.g., paired associated visual learning) or drawing a complex picture from memory (Rey–Osterrieth Complex Figure). No memory impairment was reported by Griffiths et al. (1995) in the verbal domain and by Channon et al. (2004) in the visuospatial domain. In contrast, memory impairments have been reported by Brumm et al. (2004) and Smith et al. (1996) across domains and by Griffiths et al. (1995) in the visuospatial domain. 1 In addition, Brumm et al. (2004) have reported impairments in expressive naming (Boston Naming Test), but not in receptive vocabulary (Peabody Picture Vocabulary Test).

Plan of Study and Data Analyses

In sum, for most cognitive functions including complex executive functions, visuomotor coordination, language processing, and memory and learning, results have been mixed. Deficits have been reported more consistently for working memory and sustained attention and normal performance for inhibitory control. Some authors have suggested that only deficits of speed of processing characterize AwPKU.

Our study will establish the cognitive profile of a group of 37 AwPKU with better metabolic control than reported in previous studies (average 432 μmol/L, in childhood; <850 μmol/L later on). Our study is similar to Brumm et al. (2004) in assessing a large number of functions and using a variety of tests for each function to reduce error. Differently from Brumm et al., we have decomposed executive functions in a number of subtypes, assessed visuospatial attention as a separate domain, and included assessment of orthographic skills.

Besides performance in individual tasks and functions, we will consider two general measures of performance across domains: (a) an overall standard score, which averages across cognitive tests and measures (RTs and accuracy); and (b) the proportion of impaired scores. This second measure is also very important because good performance in a number of tasks may counterbalance and mask severe impairments in others and result in an overall score which is normal or close to normal. Therefore, we will also consider, for each PKU participant, the number of cognitive domains/measure where severe difficulties are encountered. Even control participants are anticipated to demonstrate some poor scores, but this number may be much higher in AwPKU. For these measures (overall standardized score and rate of impaired scores) we will report both group averages and proportions of individuals impaired. To be conservative, we will consider impaired scores which deviate 2 or more standard deviations from the mean of a control group that we tested for comparison and was matched to the AwPKU for age and education (z scores = >2). We will consider scores which are within 0.5 standard deviations from the control mean (z scores = <.05) to be clearly normal.

Tasks

IQ was measured using the Wechsler Abbreviated Scale of Intelligence (WASI; Wechsler, 1999 ), which includes the following subtests: Vocabulary, Block Design, Similarities, and Matrix Reasoning. These subtests are similar in format to their WISC–III and WAIS–III counterparts. They are those with the highest loadings on general intellectual functioning ( Wechsler, 1991 , 1997 ) and allow estimates of both Verbal and Performance IQ. In addition, participants were given an extensive neuropsychological battery. Tasks are briefly described below. A more extensive description is provided in the supplementary materials.

This included measures from 6 tasks: (a) Simple Detection : Press a response button as soon as a ladybird appeared on the screen; (b) Detection with Distractors : Press a button whenever a ladybird appeared on the screen alone or with a green bug; in the second part of the task the instruction was changed to press a button whenever a green bug appeared on the screen alone or with a ladybird; (c) Choice Reaction Time : Press either a left or right response key consistent with the direction of an arrow centrally presented; (d) Feature Search : Detect a target among distractors not sharing features by pressing a ‘yes’ or ‘no’ button (e.g., a red ladybird among green bugs); and (e) Conjoined Search : Detect a target among distractors sharing features (e.g., red ladybird among red bugs and green ladybirds). Both RTs (reaction time (RT) from now on) and accuracy measures (error rates) were taken.

Visuomotor coordination

This included measures from 2 tasks: (a) Grooved Pegboard Test : Put pegs into the holes of a board using only one hand as quickly as possible and (b) Digit Symbol Task : Fill as many boxes as possible with symbols corresponding with numbers in 90 s.