FIGURE 20.3. Cognitive abilities in DS. Individuals with DS have relative strengths in global processing but show impairments in local processing (Bihrle et al., 1989). Reprinted with permission by the Salk Institute.

FIGURE 20.3. Cognitive abilities in DS. Individuals with DS have relative strengths in global processing but show impairments in local processing (Bihrle et al., 1989). Reprinted with permission by the Salk Institute.

cannot be mapped to any one region of chromosome 21 but rather that genes from many different parts of the chromosome are involved (Korenberg et al., 1994). How then can researchers begin to identify the genes responsible for mental retardation in DS?

To do this, we must first delineate a series of measurable cognitive features that clearly distinguish individuals with DS from the larger human population. Cognitive features include defects in auditory and visual spatial processing and in short-term memory, although there are relative strengths in visual-spatial short-term memory. One of the most specific cognitive features is the preservation of global versus the impairment of local processing (Bihrle et al., 1989; see Fig. 20.3), an example of the type of definable feature that may be amenable to mapping in partially trisomic individuals. Other DS cognitive features are less specific and thus would be difficult to map directly but may be related to mappable structural alterations in the brain. Thus it may be possible to map cognitive features indirectly, through understanding associated neurological, neuroanatomic, or functional changes in the brain. Structural abnormalities of the brain in DS include regression and distortion of the dendritic tree beginning after 4 months of age, a mean decrease in brain weight of 10-20% that begins after 6 months of age (Becker

Normar ~DS

FIGURE 20.4. The development of the dendritic tree, part of the nervous system involved in sending and receiving signals, is impaired in individuals with DS, which may underlie some aspects of DS cognitive defects (Becker et al., 1993).

et al., 1993; see Fig. 20.4), abnormal formation of the sulci and gyri, and defective lamination of the cortex coupled with reduced cortical thickness (Golden and Hyman, 1994). Adults with DS also have substantially smaller cerebral and cerebellar hemispheres and hippocampal formations than the rest of the population (Pinter et al., 2001; see Fig. 20.5). Individuals with DS exhibit particular defects in speech and language that may involve regions of the prefrontal cortex, hippocampus and cerebellum and deficits in executive functions that may be associated with basal ganglia dysfunction (Pennington and Bennetto, 1996). Thus it may be possible, by uncovering the pathways that link these structural defects to cognitive function, to begin to map DS cognitive deficits to specific regions of chromosome 21. It is now important to understand the cognitive deficits seen in DS individuals in detail and to correlate these with detailed structural and functional studies employing new approaches to brain imaging [magnetic resonance imaging (MRI), functional MRI, and event-related potentials] variations in the brain. With this new level of information, it may be possible to correlate gene function with deficits in specific domains seen in persons with DS.

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FIGURE 20.5. The hippocampus, a region of the brain central to learning and memory, tends to be smaller in individuals with DS (Pinter et al., 2001), which may contribute to the learning difficulties associated with DS. This was determined by measuring the boundaries of the amygdala (A and superior structures in B) and hippocampus (C and inferior structures in B).

Although none of the genes on chromosome 21 can as yet be related to these structural defects, genes expressed in the developing and adult brain are good candidates. These include DSCAM (Down syndrome cell adhesion molecule), which codes for a neural cell adhesion molecule mapping in 21q22 (Yamakawa et al., 1998). DSCAM is expressed in the developing central and peripheral nervous systems from early in the development of the fetal brain (Yamakawa et al., 1998) and continues to be expressed in the brain throughout adult life (Barlow et al., 2001b). Within the brain, DSCAM is expressed in the cerebral cortex, hippocampus, and cerebellum (Barlow et al., 2001b; see Fig. 20.6), all of which are affected in DS (Jernigan et al., 1993; Golden and Hyman 1994; Raz et al., 1995). In particular, the hippocampus is important for learning and memory as well as for retaining and possibly processing sensory inputs before transferring them to the cortex for long-term memory storage (Kandel et al., 1995), which are affected in individuals with DS (Pennington and Benetto, 1996). This pattern of DSCAM expression in the adult brain therefore suggests that DSCAM may play a role in the ongoing defects of learning and memory associated with DS.

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