Identifying Neurocognitive Phenotypes

Drawing on results from cognitive, electrophysiological, cerebrovascular, and neuroimaging evaluations, researchers have attempted to delineate one or more distinct neurocognitive phenotypes characteristic of patients with diabetes (46). At the present time this effort may best be considered as a "work in progress" because the accuracy of any phenotype is completely dependent on the comprehensiveness of the assessment. This has been especially problematic in the pediatric research arena where until very recently, most studies of brain function were relatively small in scope and restricted to the administration of a limited number of cognitive tests or the measurement of brain waves. Nevertheless, as the remainder of this section indicates, a pattern of results is beginning to appear in diabetic children which is remarkably similar to that seen in adults with type 1 or type 2 diabetes.

Cognitive Manifestations

Children and adults who develop diabetes within the first 5-7 years of life may show moderate cognitive dysfunction that can affect all cognitive domains, although the specific pattern varies, depending both on the cognitive domain assessed and on the child's age at assessment. Data from a recent meta-analysis of 19 pediatric studies have indicated that effect sizes tend to range between ~ 0.4 and 0.5 for measures of learning, memory, and attention, but are lower for other cognitive domains (47). For the younger child with an early onset of diabetes, decrements are particularly pronounced on visuospatial tasks that require copying complex designs, solving jigsaw puzzles, or using multi-colored blocks to reproduce designs, with girls more likely to earn lower scores than boys (8). By adolescence and early adulthood, gender differences are less apparent and deficits occur on measures of attention, mental efficiency, learning, memory, eye-hand coordination, and "executive functioning" (13, 26, 40, 48-50). Not only do children with an early onset of diabetes often - but not invariably - score lower than healthy comparison subjects, but a subset earn scores that fall into the "clinically impaired" range defined as scores that are more than 2 standard deviations beyond the mean value for nondiabetic comparison subjects (49). According to one estimate, the prevalence of clinically significant impairment is approximately four times higher in those diagnosed within the first 6 years of life as compared to either those diagnosed after that age or to nondiabetic peers (25 vs. 6%) (49). Nevertheless, it is important to keep in mind that not all early onset diabetic children show cognitive dysfunction, and not all tests within a particular cognitive domain differentiate diabetic from nondiabetic subjects. Why certain tests are more sensitive to diabetes-related variables than others remains unknown and unexamined.

The interpretation of the early onset literature is complicated by the fact that in a number of studies, investigators have stratified their diabetic samples in terms of presence or absence of severe hypoglycemic events rather than earlier or later age at onset (14, 51). As a consequence, cognitive dysfunction has been attributed to severe hypoglycemia, but that may be in error insofar as severe hypoglycemia and onset age tend to be interrelated. Data from both epidemiologic (52) and cross-sectional studies (53) show that children with an early onset of diabetes have a greatly increased risk of severe hypoglycemia when compared to those with a later onset (45 vs. 13%). The use of more intensive therapeutic regimens further increases the risk of severe hypoglycemia (54), particularly in those with an earlier onset of diabetes (55), perhaps because of a heightened sensitivity to insulin in young patients (56).

Children and adolescents with a later onset of diabetes also manifest cognitive dysfunction, particularly on tests requiring sustained attention, visuoperceptual skills, and psychomotor speed (2, 9, 11, 13, 14, 37). The magnitude of these effects tends to be relatively modest, with estimates generally approximating ~ 0.2 or less (47), although there is much variation across different studies. Whether learning and memory skills are also compromised - as they clearly are in children with an earlier onset of diabetes -remains controversial (12). Some studies have reported no evidence of mnes-tic deficits (9) while others sometimes (11, 37, 57) but not invariably (14) find deficits on certain types of memory tests, particularly those having a visuospatial component. The extent to which "higher order" cognitive processes are compromised cannot be determined at the present time because of limited ascertainment. With very few exceptions (13), problem-solving and executive functions have not been evaluated in children with diabetes.

Regardless of age at onset, cognitive abnormalities may appear relatively early in the course of diabetes. This is best demonstrated in the Melbourne RcH study, which remains the largest, longest prospective study of children conducted to date. At study entry, there were no differences on any cognitive measure between a representative sample of 90 newly diagnosed diabetic children and 84 healthy children drawn from the community (22). Two years later, those children diagnosed early in life (defined as <4 years) manifested a marked developmental delay insofar as their scores on Vocabulary and Block Design tests improved less over time, as compared to either children with a later onset of diabetes or healthy controls (58). At the 6-year follow-up visit, diabetic children performed worse than nondiabetic subjects on a broad array tests measuring attention, processing speed, long-term memory, and executive skills. These effects were seen in both the early onset and the later onset subgroups, but their magnitude was greater in those diagnosed before 4 years of age (13). No other study of children or adults has yet measured cognition comprehensively since the time of diagnosis and compared the results with a matched group of nondiabetic subjects assessed serially at the same time periods.

Electrophysiological Changes slowed neural activity, measured at rest by electroencephalogram (EEG) and in response to sensory stimuli, is common in children with diabetes. On tests of auditory- or visual-evoked potentials (AEP; VEP), children and adolescents with more than a 2-year history of diabetes show significant slowing, as indexed by the increased latencies (59). Not only were these effect sizes large (Cohen's d: 1.0-1.2), but 37% of the sample had latencies considered to be abnormal. In contrast, those children with a briefer duration of diabetes had normal latencies. EEG recordings have also demonstrated abnormalities in diabetic adolescents in very good metabolic control. compared to age-matched healthy control subjects, the diabetic patients showed significant increases in delta and theta (slow wave) activity, significant declines in alpha peak frequency - greatest in frontal brain areas, and declines in alpha, beta, and gamma fast wave activity that are most pronounced in posterior temporal regions (60). changes in central slow wave activity were also correlated with reductions in peripheral nerve conduction velocities. Poor metabolic control and severe hypoglycemia were correlated with one another and were associated with the increase in slow wave activity and the reduction in alpha peak frequency. similar results have been reported in other studies of diabetic children (61) and adults (62, 63).

EEG abnormalities have also been associated with childhood diabetes. One large study noted that 26% of their diabetic subjects had abnormal EEG recordings, as compared to 7% of healthy controls (64). Both earlier age at onset and episodes of severe hypoglycemia were strong predictors of pathology in that study and in several other earlier studies (65-67). Although most commentators have assumed that it was the severe hypoglycemic event that caused those EEG abnormalities, there is now some evidence to suggest the obverse: diabetic children with EEG abnormalities recorded at diagnosis may be more likely to experience a seizure or coma (i.e., a severe hypoglycemic event) when blood glucose levels subsequently fall (68). The assumption made by those authors is that the EEG abnormality reflects brain damage that has a genetic or perinatal origin rather than some metabolic perturbation secondary to the onset of diabetes (69). This intriguing possibility - that seizures occur in some diabetic children during hypoglycemia because of the presence of pre-existing brain dysfunction -requires further study.

Cerebral Blood Flow

Little is known about changes in cerebral blood flow (CBF) in children with diabetes. The single study that used single-photon emission tomography (SPECT) found that children with diabetes had lower levels of cerebral perfusion bilaterally as compared to healthy comparison subjects. Basal ganglia and frontal regions showed the greatest reduction in perfusion, followed by parietal and temporal regions (70). This pattern is very similar to that reported in adults with type 1 diabetes (71). No associations were found between CBF measures and neuropsychological test results, duration of diabetes, and HbAlc values, but the sample was small. Despite the recent success of MRI technologies like continuous arterial spin labeling (CASL) (72) in identifying regional differences in cerebral blood flow, this noninvasive, nonradioactive technique has not yet been utilized in studies of children and adolescents.

Brain Structure Anomalies

A very large neuroimaging literature indicates that adults with either type 1 or type 2 diabetes manifest structural changes in a number of brain regions [for comprehensive critical reviews see (73, 74)], but until very recently, there had been little pediatric research on this topic. In what may be the largest study to date, MRI scans were acquired from 108 diabetic and 51 age-matched nondiabetic children, 7-17 years of age, and voxel-based mor-phometry techniques were used to quantify between-group differences in gray- and white-matter volumes, and to correlate those values with measures of recurrent severe hypoglycemia and chronic hyperglycemia (75).

Although brain volumes were found to be comparable in the two groups, analyses restricted to the diabetic sample showed statistically reliable relationships between metabolic variables and specific brain regions. Compared to those children with no past history of severe hypoglycemia, those who experienced 1 or more episodes of severe hypoglycemia had smaller gray-matter volumes in the left (but not right) temporal-occipital region. This left-sided lateralization is consistent with findings from a study of young adults with type 1 diabetes (76) as well as with several case reports of adults experiencing very severe hypoglycemic episodes (77-79). Chronic hyperglycemia - estimated since diagnosis from serial HbA1c values - was also found to be associated with less cortical volume in right posterior regions (particularly the right cuneus and precuneus). Those regions have also been identified in adults as being sensitive to higher lifetime HbA1c values (76). Less white matter was also associated with chronic hyperglycemia in these diabetic children. Parietal regions were particularly affected, with these relationships stronger in the right, as compared to the left, hemisphere.

One needs to be cautious about over-interpreting these data, primarily because there was no evidence that as a group, diabetic children have significantly less brain volume than their carefully matched nondiabetic peers. Nevertheless, the fact that within-group analyses revealed limited, but statistically reliable, relationships between certain brain regions and metabolic variables in these children which are analogous to what has been reported in diabetic adults who were studied with a similar neuroimaging paradigm (76) supports the view that the brain is compromised by diabetes. Moreover, measurable structural changes seem to occur relatively early in the course of the disease since these diabetic children had diabetes for 6.7 years, on average. Whether these modest structural anomalies impact cognitive function remains unknown: no relationships between neuroimaging data and neu-ropsychological test performance have yet been reported in children with diabetes.

A second study, restricted to 62 younger children who developed diabetes early in life (before 6 years of age), noted a very high rate (29%) of clinically significant structural changes in the central nervous system (80) which were evident relatively soon after diagnosis (mean diabetes duration ~ 7 years). The most common anomaly was mesial temporal sclerosis, a condition that ordinarily occurs in less than 1% of the normal pediatric population (81) and is usually associated with temporal lobe epilepsy. Not only was the prevalence of this abnormality greatly elevated, occurring in 16% of the early onset sample, but it was unrelated to a past history of severe hypoglycemia. On the other hand, gray-matter volumes were smaller in the subgroup of children who experienced severe hypoglycemia (seizure or coma) as compared to those with no such history (724 vs. 764 cm3; d = 0.5), regardless of whether hypoglycemia occurred before or after 6 years of age. Reductions in white-matter volume were also reported in this study, but that was dependent on the timing of the hypoglycemic event: children who experienced their first hypoglycemic seizure before 6 years of age had less white matter than those who experienced severe hypoglycemia after that age (490 vs. 531 cm3; d = 0.6); the latter group did not differ from those with no events. Because of marked differences in methodology, these volumetric data are not entirely comparable to those reported by either Perantie et al. in children (75) or by Musen et al. in adults (76). Nevertheless, they provide additional support for the view that the child's brain is sensitive to chronically elevated blood glucose levels - as evidenced by the appearance of mesial temporal sclerosis -and to severe hypoglycemic events.

Brain Metabolites

Indirect evidence of neural damage has also come from studies using MRI spectroscopy to measure brain metabolites. Diabetic children in very poor control (mean HbAlc = 11.9%) showed marked reductions in ^-acetyl-aspartate (NAA) - a marker of neuronal death and dysfunction - in two brain areas: pons and posterior parietal white matter (82). Reductions in choline-containing compounds were also evident in the pons, consistent with the view that the integrity of phospholipid cell membranes, including myelin, may be compromised significantly because of diabetes. Similar reductions in NAA have also been noted in diabetic adults in poor metabolic control (83), in hyperglycemic rats (84), and in diabetic children following an episode of moderately severe hypoglycemia (85). In that latter study, NAA was reduced in frontal and temporal brain regions, as well as in the basal ganglia shortly after the hypoglycemic event. However, those effects were transient; when the children were subsequently re-evaluated 6 months later, the NAA values began to approach normality. Thus, the possibility exists - although remains untested - that the changes in brain metabolites found in poorly controlled diabetic children may not actually reflect permanent neuronal damage but may merely be a consequence of acute hyperglycemia and be reversible following improved metabolic control.

Neurocognitive Phenotypes for the Child with Diabetes: The Search Continues

Despite an increasing interest in brain function in children with diabetes, the research described in this chapter provides, at best, an incomplete picture of neurocognitive status. We do know that children with diabetes earn somewhat lower scores in school, have lower IQ scores, perform more poorly on visuoperceptual and attentional tasks, and are somewhat slower on a variety of mental efficiency tests as compared to their nondiabetic peers. The magnitude of these effects is quite small, unless the child developed diabetes early in life; then, a subset of those children may show moderately severe impairment. Other cognitive domains (e.g., learning, memory, problem-solving, language skills) are also compromised to some extent in children with an earlier age at onset, but there is less consensus as to whether they are affected in children with a later onset of diabetes.

consistent with the mental slowing is the neural slowing noted on a variety of electrophysiological measures obtained either while the child is quietly resting or in response to sensory stimuli. one would assume that a robust relationship would exist between these cognitive and electrophysio-logical measures but remarkably this has not been studied in children. Other measures of brain function and structure also reveal some extremely modest effects in a very limited number of brain regions. Those findings are sufficient for a "proof-of-concept" demonstration - that is, that the brain is indeed affected to some extent in children with diabetes. At the present time, however, this body of research is insufficient to provide an accurate, comprehensive, and integrated delineation of those neurocognitive characteristics.

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