Neuropsychological Profiles of Children With Type 1 Diabetes 6 Years After Disease Onset

Article (PDF Available)inDiabetes Care 24(9):1541-6 · October 2001with51 Reads
DOI: 10.2337/diacare.24.9.1541 · Source: PubMed
Abstract
To describe neuropsychological profiles and their relationship to metabolic control in children with type 1 diabetes 6 years after the onset of disease. Children with type 1 diabetes (n = 90), aged 6-17 years, who had previously been assessed soon after diagnosis and 2 years later, were reevaluated 6 years after the onset of disease. Their neuropsychological profiles were compared with those of individuals in a community control group (n = 84), who had been assessed at similar intervals. Relationships between illness variables, such as age at the onset of disease and metabolic control history, and neuropsychological status were also examined. Six years after onset of disease, children with type 1 diabetes performed more poorly than control subjects on measures of intelligence, attention, processing speed, long-term memory, and executive skills. Attention, processing speed, and executive skills were particularly affected in children with onset of disease before 4 years of age, whereas severe hypoglycemia was associated with lower verbal and full-scale intelligence quotient scores. Neuropsychological profiles of children with type 1 diabetes 6 years after the onset of disease are consistent with subtle compromise of anterior and medial temporal brain regions. Severe hypoglycemia, particularly in very young children, is the most plausible explanation for neuropsychological deficits, but the contributory role of chronic hyperglycemia warrants further exploration.
Neuropsychological Profiles of Children
With Type 1 Diabetes 6 Years After
Disease Onset
ELISABETH A. NORTHAM,
PHD
1,2
PETER J. ANDERSON,
BA, GRAD DIP
(APP PSYCH)
1,2
RANI JACOBS,
BSC, GRAD DIP
1,2
MATTHEW HUGHES,
BBUS, GRAD DIP
1,2
GARRY LWARNE,
MBBS, MD
3
GEORGE A. WERTHER,
MBBS, MD
3
OBJECTIVE To describe neuropsychological profiles and their relationship to metabolic
control in children with type 1 diabetes 6 years after the onset of disease.
RESEARCH DESIGN AND METHODS Children with type 1 diabetes (n 90), aged
6–17 years, who had previously been assessed soon after diagnosis and 2 years later, were
reevaluated 6 years after the onset of disease. Their neuropsychological profiles were compared
with those of individuals in a community control group (n 84), who had been assessed at
similar intervals. Relationships between illness variables, such as age at the onset of disease and
metabolic control history, and neuropsychological status were also examined.
RESULTS Six years after onset of disease, children with type 1 diabetes performed more
poorly than control subjects on measures of intelligence, attention, processing speed, long-term
memory, and executive skills. Attention, processing speed, and executive skills were particularly
affected in children with onset of disease before 4 years of age, whereas severe hypoglycemia was
associated with lower verbal and full-scale intelligence quotient scores.
CONCLUSIONS Neuropsychological profiles of children with type 1 diabetes 6 years
after the onset of disease are consistent with subtle compromise of anterior and medial temporal
brain regions. Severe hypoglycemia, particularly in very young children, is the most plausible
explanation for neuropsychological deficits, but the contributory role of chronic hyperglycemia
warrants further exploration.
Diabetes Care 24:1541–1546, 2001
A
constant supply of glucose is criti-
cal for normal cerebral metabolism.
Therefore, it is not surprising that
functional and structural changes within
the central nervous system have been
documented in patients with type 1 dia-
betes (1,2). In adults, neuropsychological
deficits are most evident in those with the
biomedical complications associated with
chronic hyperglycemia (3). Findings from
large-scale prospective studies (4) suggest
that adults are resilient to hypoglycemia-
related effects on neuropsychological
functions, although this point is still de-
bated. In children, early age at onset of
illness and a history of severe hypoglyce-
mia have emerged as the most consistent
risk factors for neuropsychological se-
quelae in children (2,5–9). However, the
specific cognitive skills affected have var-
ied across studies, and the timing, sever-
ity, and frequency of hypoglycemic insult
required to inflict permanent cerebral
dysfunction have yet to be defined.
Ryan and Becker (2) have suggested
that the “early onset” effect is a surrogate
for the impact of hypoglycemia on an im-
mature brain. They point out that very
young children are more likely to experi-
ence serious hypoglycemia because they
lack the ability to perceive and communi-
cate early symptoms and their food intake
and activity levels are unpredictable. In
addition, young children may be more
sensitive than adults to glucose depriva-
tion because of heightened energy re-
quirements related to brain growth and
development. Rovet et al. (6,8) agree that
there may be a critical period of increased
cerebral sensitivity to the effects of type 1
diabetes but have suggested an alterna-
tive, but not mutually exclusive, hypoth-
esis that chronic hyperglycemia may
disrupt myelin formation and neurotrans-
mitter regulation in the developing brain.
Small and unrepresentative samples,
retrospective collection of metabolic con-
trol history, and cross-sectional designs
that provide no information about cogni-
tive status before exposure to adverse
metabolic events limit the conclusions
that can be drawn from previous studies.
Rovet and Ehrlich (7) followed children
during a 7-year period from diagnosis,
but the sample size was small (n 16).
An increased incidence of hypoglycemic
seizures in very young children has made
it difficult to establish whether early onset
and hypoglycemia act synergistically or
independently to compromise neuropsy-
chological functions. The possible impact
of chronic hyperglycemia on prepubertal
children has never been tested ade-
quately, because most studies have used a
single concurrent measure of HbA
1c
as
the index of hyperglycemia. This provides
no information about metabolic control
history beyond the previous 2–3 months.
This study reports findings of a 6-year
follow-up of a large and representative co-
hort of children with type 1 diabetes who
were assessed serially on neuropsycho-
●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●
From the
1
Department of Psychology, Royal Children’s Hospital, Melbourne; the
2
Murdoch Children’s
Research Institute, Royal Children’s Hospital, Melbourne; and the
3
Department of Endocrinology/Diabetes,
Royal Children’s Hospital, Melbourne, Australia.
Address correspondence and reprint requests to Elisabeth Northam, Department of Psychology, Royal
Children’s Hospital, Parkville, Victoria, 3052, Australia. E-mail: northaml@cryptic.rch.unimelb.edu.au.
Received for publication 27 October 2000 and accepted in revised form 16 May 2001.
Abbreviations: CFT, Complex Figure Test; COWAT, Controlled Oral Word Association Test; IQ, intel-
ligence quotient; RAVLT, Rey Auditory Verbal Learning Test; SES, socioeconomic status; WISC-III, Wechsler
Intelligence Scale for Children—3rd edition.
A table elsewhere in this issue shows conventional and Syste`me International (SI) units and conversion
factors for many substances.
Epidemiology/Health Services/Psychosocial Research
ORIGINAL ARTICLE
DIABETES CARE, VOLUME 24, NUMBER 9, SEPTEMBER 2001 1541
logical measures since onset of illness.
Sample characteristics and neuropsycho-
logical profiles of the clinical and control
subjects at diagnosis and 2 years later
have been described in previous reports
(10–12). Duration of illness and treat-
ment procedures were controlled because
clinical care was provided at a single ter-
tiary center, with all children enrolled at
diagnosis and followed at specified in-
tervals. Metabolic control variables were
recorded prospectively. Neuropsycholog-
ical test selection focused on measures of
attention, processing speed, memory,
new learning, and executive functions,
because it has been shown that the pre-
frontal cortex and medial temporal re-
gions of the brain are particularly affected
by abnormal blood glucose levels (1,2).
Furthermore, measures of attention, pro-
cessing speed, and memory are sensitive
to subtle decrements in cognitive function
(13). The neuropsychological profile of
children with type 1 diabetes did not dif-
fer from that of a community control
group when assessed soon after diagnosis
(10). Two years later, children with type 1
diabetes tended to show more negative
change in measures of general intelligence
and performed more poorly on process-
ing speed and learning (11). Early age of
onset predicted negative change on mea-
sures of intelligence quotient (IQ),
whereas both recurrent severe hypoglyce-
mia and chronic hyperglycemia were as-
sociated with reduced memory and
learning capacity (12). This report de-
scribes neuropsychological profiles after
6 years of exposure to the metabolic per-
turbations associated with type 1 diabetes.
RESEARCH DESIGN AND
METHODS
Sample
The cohort has been fully described in
previous reports (10–12). This is a repre-
sentative sample, because virtually all
children within the metropolitan region
and close environs of Melbourne, Austra-
lia, were treated initially at the Royal Chil-
dren’s Hospital, Melbourne. Exclusion
criteria were premorbid history of central
nervous system disease, trauma, or non–
English-speaking parents. Children at-
tending Royal Children’s Hospital 6 years
after onset of disease (i.e., those younger
than 12 years of age at diagnosis) formed
the study population for the third phase
of the study. Of the eligible subjects, 80
children aged 3–11 years at onset of dis-
ease and 74 control subjects who had
been assessed previously 3 months after
diagnosis (T1) and 2 years later (T2)
agreed to participate in the third phase
(T3). Three eligible subjects and four con-
trol subjects declined to participate. An
additional seven control subjects could
not be traced; therefore, the participation
rate was 96% for the clinical cohort and
87% for the control subjects. Ten children
with diabetes diagnosed before 3 years of
age were also been evaluated serially at T1
and T2, and all agreed to participate in the
T3 assessment. Control subjects for this
subset of children were obtained for the
third stage of the project by contacting the
schools that had provided the original
control sample. Children (n 10) of the
same sex whose birthday most closely
matched that of a child with diabetes were
invited to participate in the third phase of
the study. Socioeconomic status (SES) of
the two groups was similar (children with
type 1 diabetes: n 10, [means SD] 3.4
0.5 SES score; control subjects: n 10,
3.4 1.3; NS). Thus, the final sample for
T3 comprised children with type 1 dia-
betes (n 90) and control subjects
(n 84).
Procedure
The T3 assessment included a standard-
ized test of general intelligence and tests
of specific neuropsychological functions.
All subjects completed the same battery
(described in MEASURES), and tests were ad-
ministered in a standardized order. Blood
glucose levels of the children with type 1
diabetes were measured before testing. If
a child had a blood glucose level 4
mmol/l, they were given a fast-acting car-
bohydrate snack, and testing proceeded
after a brief interval. The project was ap-
proved by Royal Children’s Hospital Eth-
ics in Human Research Committee.
Measures
Socioeconomic status was measured us-
ing the Daniel Scale of Occupational Pres-
tige (14). This scale is based on occupation
and provides a six-point rating scale (1
high to 6 low SES).
The Wechsler Intelligence Scale for
Children –Third Edition (WISC-III) (15)
was used to assess general intelligence.
Neuropsychological tests
Attention. Digit Forwards, a test of the
ability to attend to and register sequen-
tially presented auditory/verbal informa-
tion, is adapted from the Digit Span
subtest of the WISC-III (15). Code Trans-
mission (16) measures sustained atten-
tion for auditory information. The child is
asked to identify a target stimulus pre-
sented at 2-s intervals via audiotape over
12 min. Scores are obtained for targets
identified correctly, omitted targets, and
nontarget responses. Sky Search (16) as-
sesses the child’s ability to identify a visual
target against background distraction.
The Digit Forwards raw score, targets cor-
rectly identified and targets omitted on
Code Transmission, and targets correctly
identified on Sky Search were used to
measure focused and sustained attention
for verbal information, attentional lapses,
and selective attention for visual informa-
tion, respectively.
Processing speed. Symbol Search, a
subtest of the WISC-III (15), requires
rapid visual scanning, perceptual analy-
sis, and motor response. Sky Motor (16)
assesses simple motor speed. The Contin-
gency Naming Test (17) is a cross-modal
task requiring speeded visual input/
verbal output under conditions of in-
creasing complexity. It measures mental
flexibility and self-monitoring skills as
well as processing speed. Symbol Search
scale score, Sky Motor time score, and the
time taken to complete four trials of the
Contingency Naming Test were used to
assess processing speed.
Immediate memory. Story Memory and
Design Memory (18) measure immediate
recall of prose and visuo-graphic informa-
tion, respectively. The Rey Auditory Ver-
bal Learning Test (RAVLT) (19) assesses
the ability to acquire new verbal informa-
tion. A 15-item word list is presented over
five trials to establish a learning curve.
The child is later asked, without fore-
warning, to recall the list (spontaneous
recall) and to identify words from the list
embedded within a short prose passage
(cued recall). Visual Learning (18) as-
sesses the ability to acquire new visual in-
formation presented over four trials.
Graphic designs are presented in a partic-
ular location on a board, and the child is
asked to remember which spatial location
is associated with each design. Raw scores
for the initial trials of the RAVLT and Vi-
sual Learning as well as Design Memory
and Story Memory total raw scores were
Neuropsychological profiles in type 1 diabetes
1542 DIABETES CARE, VOLUME 24, NUMBER 9, SEPTEMBER 2001
used to assess immediate recall in both
the verbal and visual modalities.
New learning. The total scores, summed
over five trials of the RAVLT and over four
trials of Visual Learning were used to
assess acquisition of new information
with repeated exposure.
Long-term memory. The delayed recall
trials (spontaneous and cued) of the
RAVLT, the Complex Figure Test recall
score (19) (described in EXECUTIVE FUNC-
TIONS), and the Visual Learning and Story
Memory delayed recall scores were used
to assess long-term memory.
Executive functions. The Controlled
Oral Word Association Test (COWAT)
(19) is a measure of verbal fluency/
concept formation and the ability to shift
set and inhibit incorrect responses. The
Complex Figure Test (CFT) (19) is a de-
sign-copying task that measures planning
and organization of complex visuo-
perceptual information and graphomotor
skills. After a time delay, the child is
asked, without forewarning, to copy the
design again from memory. The Tower of
London (19) is a measure of planning and
problem-solving ability, in which the
child is required to reproduce models of
increasing complexity, presented on
stimulus cards, in a specified number of
moves. Making Inferences (20) assesses
the child’s ability to infer meaning from
ambiguous or incomplete complex lin-
guistic information. The total word score
on the COWAT, the copy score of the
CFT, problems correctly solved on the
Tower of London, and the Making Infer-
ences total score were used to assess ex-
ecutive functions.
Self-monitoring. Errors (i.e., repetitions
and incorrect responses) on the COWAT,
self-corrections and errors on the Contin-
gency Naming Test, and intrusions (non-
list words) on the RAVLT were used to
assess self-monitoring.
Metabolic control history
Parents were asked to report episodes of
severe hypoglycemia associated with con-
vulsion or coma occurring at any time
since diagnosis. HbA
1c
was measured at
each 3-month clinic visit using the Bayer
DCA 2000 method (normal reference
range 4.55.7%).
Statistical analyses
Systat for Windows software (version 5;
Systat, Evanston, IL) (21) was used to per-
form statistical analyses.
RESULTS There were no significant
group differences in age (children with
type 1 diabetes: 12.1 2.9; control sub-
jects: 12.1 2.8; NS), sex distribution
(children with type 1 diabetes: 45 girls, 45
boys; control subjects: 44 girls, 40 boys;
NS), or SES (children with type 1 diabe-
tes: 3.8 1.2; control subjects: 4.0 1.5;
NS) at T3. Examination of the baseline
data of T3 participants revealed no signif-
icant group difference on full-scale IQ at
T1 (children with type 1 diabetes: 107.7
16.5; control subjects: 109.6 13.4; NS).
General intelligence
Analysis of variance was used to examine
group differences and effects of age of on-
set on verbal, performance, and full-scale
IQ (Table 1). Preliminary analyses
showed that effects related to age of onset
were most apparent if the group was di-
chotomized into children with onset of
disease before 4 years of age and those
with onset of disease at 4 years or older. In
each analysis of variance, the dependent
variable was the IQ score, and the inde-
pendent variables were group (type 1 di-
abetes, control), and age of onset (early
onset younger than 4 years, later onset 4
years and older). SES was entered as a
covariate. There were significant main ef-
fects on verbal (F 8.07, P 0.01) and
full-scale IQ (F 5.33, P 0.05); chil-
dren with type 1 diabetes obtained lower
scores. Group differences on Performance
IQ were not significant. Examination of
group by interaction of age of onset with
measures of general intelligence revealed
no significant findings.
Neuropsychological functions
Multivariate analysis of covariance was
used to determine group main effects and
group by age of onset interactions on the
neuropsychological composites: atten-
tion, processing speed, immediate mem-
ory, new learning, long-term memory,
executive functions, and self-monitoring
(Table 2). Test age and SES were entered
as covariates.
There was a significant group main
effect (F 2.63, P 0.05) and group age
at onset interaction (F 2.85, P 0.05)
on attention. Results of post hoc tests
showed that children with type 1 diabe-
tes, particularly those with onset of dis-
ease before 4 years of age, identified fewer
Table 1—Significant group differences on measures of general intelligence 6 years after onset of diabetes
Measure
Type 1 diabetes Control subjects Significance
n Score n Score Group Group age at onset
Verbal IQ
All 90 97.4 (1.5) 84 103.2 (1.5) P 0.01 NS
Onset 4 years 24 98.4 (2.5) 27 106.6 (2.4) P 0.01 NS
Onset 4 years 66 96.2 (1.5) 57 99.7 (1.7) P 0.01 NS
Performance IQ
All 89 103.6 (1.8) 83 106.8 (1.8) NS NS
Onset 4 years 24 103.2 (3.1) 27 107.2 (2.9) NS NS
Onset 4 years 65 104.1 (1.9) 56 106.4 (2.0) NS NS
Full-scale IQ
All 89 100.2 (1.6) 83 105.3 (1.5) P 0.05 NS
Onset 4 years 24 100.5 (2.7) 27 107.3 (2.6) P 0.05 NS
Onset 4 years 65 99.9 (1.6) 56 103.2 (1.8) P 0.05 NS
Data are adjusted least-square means (SE).
Northam and Associates
DIABETES CARE, VOLUME 24, NUMBER 9, SEPTEMBER 2001 1543
correct targets on Code Transmission.
There was a significant group main effect
(F 4.81, P 0.01) and a group age at
onset trend (P 0.06) on processing
speed. Results of post hoc tests showed
significantly slower times for children
with early onset type 1 diabetes. There
were no significant main or interaction ef-
fects on immediate memory or new learn-
ing. A significant group effect (F 3.58,
P 0.01) was found on long-term mem-
ory, but the group age at onset interaction
was not significant. Significant main (F
4.57, P 0.01) and group age at onset
interaction effects (F 2.60, P 0.05)
were found on executive functions. Re-
sults of post hoc tests showed that chil-
dren with early onset type 1 diabetes
performed more poorly than children
with later-onset type 1 diabetes or control
subjects. There was a significant group
main effect (F 4.00, P 0.01) but no
group age at onset interaction on self-
monitoring.
Repeated-measures analyses revealed
no significant group differences on neu-
ropsychological measures common to
both T1 and T3 assessments (CFT,
RAVLT, and COWAT) using data from
the subset of children who had been old
enough to complete them at study entry
(i.e., those aged 7 years and older at T1:
children with type 1 diabetes, n 40;
control subjects, n 38).
Relationship between metabolic
control variables and
neuropsychological status
Mean concurrent HbA
1c
for the children
with type 1 diabetes was 8.5 1.2%
(clinic average 8.8 1.5%). Mean blood
glucose level before testing was 14.5
6.2 mmol/l. A total of 25 children had
experienced at least one seizure associ-
ated with hypoglycemia. The percentage
of children with a positive seizure history
was similar across the early onset (25%)
and later-onset (27%) groups. A measure
Table 2—Significant group differences on neuropsychological clusters 6 years after onset of diabetes
Measure Type 1 diabetes Control subjects
Group (P)
Group
onset age
(P)All 4 years 4 years All 4 years 4 years
n 90 24 66 84 27 57
Attention 0.05 0.05
Code correct 35.3 (0.6) 34.1 (1.3) 36.5 (0.6) 37.3 (0.6) 37.1 (0.6) 37.5 (0.7) 0.01 NS
Code omissions 2.4 (0.5) 2.6 (1.0) 2.2 (0.5) 1.4 (0.5) 1.5 (0.9) 1.2 (0.6) NS NS
Digits forward 8.2 (0.3) 8.9 (0.5) 7.5 (0.3) 8.5 (0.2) 8.9 (0.5) 8.1 (0.3) NS NS
Sky targets 18.5 (0.3) 18.6 (0.5) 18.4 (0.3) 18.3 (0.2) 18.6 (0.5) 18.0 (0.3) NS NS
Processing speed 0.01 NS
CNT total time 193.6 (5.9) 221.6 (12.1) 165.6 (6.1) 166.5 (5.6) 180.4 (11.3) 152.7 (6.8) 0.01 0.06
Sky time 100.8 (4.1) 114.0 (8.9) 87.5 (4.6) 95.9 (4.1) 100.1 (8.4) 91.6 (5.1) NS NS
Symbol search 10.4 (0.4) 10.2 (0.9) 10.7 (0.5) 11.9 (0.4) 12.7 (0.8) 11.1 (0.5) 0.01 0.06
Immediate memory NS NS
RAVLT1 5.4 (0.2) 5.0 (0.4) 5.9 (0.2) 5.9 (0.2) 5.8 (0.4) 6.0 (0.3) 0.06 NS
Story recall 25.7 (1.2) 22.4 (2.4) 29.0 (1.2) 26.5 (1.1) 25.0 (2.2) 28.0 (1.3) NS NS
Visual learning 1 5.8 (0.3) 6.0 (0.6) 5.5 (0.3) 5.3 (0.3) 5.5 (0.6) 5.0 (0.3) NS NS
Design memory 30.9 (1.1) 30.1 (2.2) 31.6 (1.2) 31.2 (2.2) 31.0 (2.0) 31.3 (1.2) NS NS
New learning NS NS
RAVLT—5 trials 49.1 (1.1) 47.3 (2.1) 50.9 (1.1) 50.6 (1.0) 48.6 (2.0) 52.5 (1.2) NS NS
Visual learning 29.9 (1.2) 31.1 (2.5) 28.9 (1.3) 28.1 (1.2) 28.9 (2.3) 27.4 (1.4) NS NS
Long-term memory 0.01 NS
RAVLT—spontaneous 11.4 (0.4) 11.7 (0.7) 11.1 (0.4) 11.4 (0.3) 11.6 (0.7) 11.2 (0.4) NS NS
RAVLT—cued 13.0 (0.2) 12.3 (0.4) 13.7 (0.2) 13.6 (0.2) 13.2 (0.4) 13.9 (0.2) 0.05 NS
Visual learning 8.9 (0.4) 9.3 (0.8) 8.6 (0.4) 8.3 (0.4) 8.1 (0.8) 8.5 (0.5) NS NS
Rey figure recall 17.4 (0.8) 16.8 (1.7) 18.0 (0.9) 20.1 (0.8) 21.0 (1.6) 19.2 (0.9) 0.01 NS
Story recall 23.3 (1.3) 19.2 (2.6) 27.4 (1.3) 23.9 (1.2) 21.9 (2.4) 25.8 (1.4) NS NS
Executive skills 0.01 0.05
Rey figure copy 27.6 (0.7) 26.8 (1.3) 28.4 (0.7) 30.7 (0.7) 31.7 (1.4) 29.7 (0.8) 0.01 0.05
COWAT total words 25.9 (1.0) 26.8 (2.1) 24.9 (1.0) 26.5 (1.8) 26.2 (2.1) 26.8 (1.2) NS NS
Making inferences 8.7 (0.2) 8.0 (0.5) 9.5 (0.2) 9.4 (0.2) 9.3 (0.5) 9.5 (0.3) 0.05 0.05
TOL completed trials 11.3 (0.1) 11.4 (0.2) 11.3 (0.1) 11.7 (0.1) 11.8 (0.2) 11.7 (0.1) 0.01 NS
Self-monitoring 0.01 NS
COWAT errors 1.6 (0.2) 1.5 (0.4) 1.8 (0.2) 1.1 (0.2) 0.6 (0.4) 1.6 (0.3) 0.05 NS
Code no-targets 2.4 (0.6) 3.4 (1.2) 1.4 (0.7) 0.4 (0.6) 0.1 (1.2) 0.8 (0.7) 0.01 0.08
CNT12 err&sc 1.3 (0.2) 1.2 (0.4) 1.4 (0.2) 1.4 (0.2) 1.4 (0.3) 1.3 (0.2) NS NS
CNT34 err&sc 11.8 (1.1) 14.7 (2.3) 8.9 (1.2) 7.6 (1.1) 8.0 (2.1) 7.1 (1.3) 0.01 NS
RAVLT intrusions 1.5 (0.2) 2.1 (0.4) 0.9 (0.2) 1.0 (0.2) 1.4 (0.4) 0.5 (0.3) 0.08 NS
Data are least-square adjusted means (SE). CNT, Contingency Naming Test. TOL, Tower of London.
Neuropsychological profiles in type 1 diabetes
1544 DIABETES CARE, VOLUME 24, NUMBER 9, SEPTEMBER 2001
of chronic hyperglycemia was formed by
calculating the percentage of time from
diagnosis that the child had recorded
poor control (defined as HbA
1c
9.5%).
Stepwise multiple regression analyses
were conducted to examine the relation-
ship between metabolic control variables
and neuropsychological functioning on
measures for which significant group
(type 1 diabetes, control) differences had
been found. For age-standardized mea-
sures, SES was entered first, with seizure
history (yes or no), and percentage of total
HbA
1c
measurements 9.5% entered on
the second step. Age at time of testing was
also entered on the first step for unstand-
ardized measures. SES and seizure history
were significant predictors of verbal IQ
(r
2
0.201, P 0.01) and full-scale IQ
(r
2
0.126, P 0.05); seizure history
accounted for 6 and 3% of the variance,
respectively. Children with a positive sei-
zure history obtained lower scores. The
regression analyses for IQ measures were
repeated, entering the T1 score as an ad-
ditional predictor variable, with similar
findings. There was a trend (P 0.1) for
seizures to be associated with reduced
self-monitoring (more errors on COWAT
and trials 3 and 4 of the Contingency
Naming Test).
CONCLUSIONS Six years after
onset of disease, children with type 1 di-
abetes performed more poorly than con-
trol subjects on measures of intelligence,
attention, processing speed, long-term
memory, executive functions, and self-
monitoring. Clinical and control groups
had not differed on a measure of full-scale
IQ at T1. Attention, processing speed,
and executive functions were particularly
affected by onset of illness before 4 years
of age, whereas history of seizures was as-
sociated with lower scores on measures of
verbal and full-scale IQ and a tendency to
make more errors on complex tasks.
There were no significant relationships
between chronically elevated blood glu-
cose levels and neuropsychological deficit
test scores, using the definition of hyper-
glycemia devised for this study.
In the current study, verbal IQ
seemed to be more sensitive to illness ef-
fects than performance IQ, consistent
with previous reports of subtle language
deficits in children with type 1 diabetes,
which become more apparent as duration
of illness increased (6,9,22–24). The cur-
rent findings are also consistent with
those of Rovet and Ehrlich (7), who found
that 7 years after onset of disease, verbal
IQ had declined significantly, particularly
in those children with early onset of dis-
ease and/or history of seizures. The expla-
nation for the verbal deficits noted in
children with type 1 diabetes remains
speculative. Reduced stores of over-
learned verbal knowledge may reflect a
semantic memory deficit, secondary to
hypoglycemia-related hippocampal dam-
age in a developing brain. Alternatively,
vigilance and sustained attention are par-
ticularly sensitive to transiently lowered
blood glucose levels (2), and these skills
are critical for effective classroom learn-
ing. Children prone to recurrent hypogly-
cemia may learn less optimally over time,
leading to cumulative deficits in verbal
knowledge, even when cerebral struc-
tures are not permanently damaged.
Deficits in attention (6,7,22), execu-
tive skills (22), and processing speed
(5,8) have been reported in previous
studies of children with type 1 diabetes,
consistent with the current findings. Def-
icits in attention and processing speed
may be linked to the longer evoked po-
tential latencies in children with type 1
diabetes (25). Hershey et al. (5) and Rovet
and Ehrlich (7) identified long-term vi-
sual memory impairments in children
with a history of seizures, whereas in the
current study, the deficit was generalized
rather than confined to the subgroup with
a known history of significant hypoglyce-
mia. Performance on immediate rote
memory tasks was unaffected across all
studies. Hagen et al. (22) suggest that def-
icits in higher-level organization and
strategy, aspects of executive function, ex-
plain poorer performance on complex
memory and learning tasks in children
with type 1 diabetes. If this is true, one
would expect deficits to be less evident on
rote recall tasks and more apparent on
long-term recall tasks, in which success
depends on well-organized encoding and
storage of information.
In the current study, hypoglycemia
exerted specific effects on verbal and full-
scale IQ. There was also a tendency for
children with history of seizures to make
more errors on timed, complex tasks un-
der conditions of stimulus overload, for
example, when required to make rapid
decisions about competing response
choices. The association between history
of seizures and language deficits has been
found before (6,7,22) and forms an intrigu-
ing contrast to studies in adult patients
(26), which report greater sensitivity of
performance IQ to hypoglycemia. Con-
sidering findings from both pediatric and
adult studies, it seems that seizures may
disrupt the development of language
skills but not their maintenance. This in-
terpretation is consistent with the devel-
opmental literature, which suggests that
well-consolidated skills are more resilient
to the effects of subtle brain insults than
skills that are evolving or are yet to emerge
(13).
In the current study, attention, pro-
cessing speed, and executive skills were
particularly affected in children diag-
nosed before 4 years of age. Relationships
between early disease onset and deficits in
processing speed (9,22,27), memory
(9,22,24), and executive skills (5,22)
have been found before. Attention seems
to be particularly vulnerable to early onset
of disease; deficits have been reported in a
number of studies (6,7,9,22,24,27), and
it is possible that attentional deficits con-
tribute to poor performance on memory,
processing speed, and executive tasks.
Traditionally, the effect of early onset
of diabetes has been attributed to the
impact of severe hypoglycemia on a de-
veloping brain. In many previous studies
(8,22,24), children with early onset of
disease had experienced more seizures
than children with later onset, although
information about the age at which sei-
zures actually occurred has not been
provided. This makes it difficult to distin-
guish effects of early onset of disease from
effects related to hypoglycemic seizures.
In their recent report, Rovet and Alvarez
(6) note that although seizures were more
common in the early onset subgroup,
most children experienced their first sei-
zure after 6 years of age. In the current
study, only one of the children with early
onset of disease had experienced a seizure
before 4 years of age, and the proportion
of children with history of seizures in
early and later-onset groups was similar.
However, in both studies, children with
early onset of disease exhibited specific
deficits. These findings suggest that early
onset is a risk factor for neuropsycholog-
ical sequelae independent of hypoglyce-
mic seizures, although it is still possible
that deficits reflect the impact of severe
hypoglycemia short of seizures. This inter-
pretation is consistent with recent reports
(28) showing high rates of nocturnal hypo-
Northam and Associates
DIABETES CARE, VOLUME 24, NUMBER 9, SEPTEMBER 2001 1545
glycemia in children with diabetes, with
small children at greatest risk.
It is important to note a number of
limitations of the current study. Develop-
mental factors limit the overall prospec-
tive design of the study. Longitudinal data
were available only for IQ measures and a
subset of the neuropsychological mea-
sures in children aged 7 years at diag-
nosis. Despite careful definition and
prospective recording of metabolic con-
trol variables, true ascertainment of hy-
perglycemia and hypoglycemia remains
problematic. The strengths of the current
investigation lie in the controlled design,
the large and representative sample, and
the high participation rate during the 6
years of the study. Children with type 1
diabetes and control subjects were
matched on IQ at study entry. Six years
later, children with type 1 diabetes exhib-
ited subtle deficits in intelligence and spe-
cific neuropsychological functions, which
were most evident in those with early on-
set of disease or history of hypoglycemic
seizures. Early onset was established as a
risk factor for neuropsychological se-
quelae independent of hypoglycemic sei-
zures.
The impact of repeated episodes of
severe, often unrecognized, hypoglyce-
mia in the very young child (even when
seizures are not occurring) is the most
plausible explanation for neuropsycho-
logical dysfunction in children with type
1 diabetes. However, the alternative pos-
sibility, that chronically elevated blood
glucose levels may impede myelination
and alter neurotransmitter regulation, a
process that could also have maximum
impact on the small child during a stage of
active brain development, warrants fur-
ther exploration. These alternative hy-
potheses are not mutually exclusive and
are of more than theoretical interest in the
dilemma they pose for those engaged in
the clinical management of small children
with diabetes. Future studies should use
new techniques in neuroimaging and in
the continuous monitoring of blood glu-
cose levels to delineate further etiological
factors in neuropsychological dysfunc-
tion in children with type 1 diabetes.
Acknowledgments This study was sup-
ported by the National Health and Medical Re-
search Council, Australia.
We thank the children and families who so
willingly gave their time to participate in this
research.
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Neuropsychological profiles in type 1 diabetes
1546 DIABETES CARE, VOLUME 24, NUMBER 9, SEPTEMBER 2001
    • "In fact, a previous study from our group on the same cohort suggests that T1D is associated with decreased gray matter volume (GMV), and a decrease in GMV-IQ correlations, in the same regions where increased GMV is associated with higher IQ in healthy controls [Marzelli et al., 2014]. This finding suggests that children with T1D have atypical trajectories of gray matter development in regions contributing to IQ. Accordingly, longer path length in the T1D network observed here is consistent with previous neuropsychological studies that report reduced cognitive function in individuals with T1D [Northam et al., 2001] (see [Northam et al., 2006; Tonoli et al., 2014] for a review). The longer path length might also influence other cognitive abilities, specifically processing speed. "
    [Show abstract] [Hide abstract] ABSTRACT: Type 1 diabetes mellitus (T1D), one of the most frequent chronic diseases in children, is associated with glucose dysregulation that contributes to an increased risk for neurocognitive deficits. While there is a bulk of evidence regarding neurocognitive deficits in adults with T1D, little is known about how early-onset T1D affects neural networks in young children. Recent data demonstrated widespread alterations in regional gray matter and white matter associated with T1D in young children. These widespread neuroanatomical changes might impact the organization of large-scale brain networks. In the present study, we applied graph-theoretical analysis to test whether the organization of structural covariance networks in the brain for a cohort of young children with T1D (N = 141) is altered compared to healthy controls (HC; N = 69). While the networks in both groups followed a small world organization-an architecture that is simultaneously highly segregated and integrated-the T1D network showed significantly longer path length compared with HC, suggesting reduced global integration of brain networks in young children with T1D. In addition, network robustness analysis revealed that the T1D network model showed more vulnerability to neural insult compared with HC. These results suggest that early-onset T1D negatively impacts the global organization of structural covariance networks and influences the trajectory of brain development in childhood. This is the first study to examine structural covariance networks in young children with T1D. Improving glycemic control for young children with T1D might help prevent alterations in brain networks in this population. Hum Brain Mapp, 2016. © 2016 Wiley Periodicals, Inc.
    Article · Jun 2016
    • "One of the DM complications is neuropathy which is resulted from nerve regeneration capacity fault (Edwards et al. 2008; Yasuda et al. 2003). Cognitive disorders including general intelligence, speed of information processing, and learning are the most important central DM difficulties (Northam et al. 2001 ). Several factors are involved in central neuropathy pathogenesis of DM (Patil et al. 2006). "
    [Show abstract] [Hide abstract] ABSTRACT: Long-term hyperglycemia associates with memory defects via hippocampal cells damaging. The aim of the present study was to examine the effect of 1 month of i.p. injections of AG on passive avoidance learning (PAL) and hippocampal apoptosis in rat. Eighty male rats were divided into 10 groups: control, nondiabetics and STZ-induced diabetics treated with AG (50, 100, 200, and 400 mg/kg, i.p.). PAL and the Bcl-2 family gene expressions were determined. Diabetes resulted in memory and Bcl-2 family gene expression deficits. AG (50 and 100 mg/kg) significantly improved the learning and Bcl-2, Bcl-xl, Bax, and Bak impairment in diabetic rats. However, negative effects were indicated by higher doses of the drug (200 and 400 mg/kg). Present study suggests that 1 month of i.p. injections of lower doses of AG, may improve the impaired cognitive tasks in STZ-induced diabetic rats possibly by modulating Bcl-2 family gene expressions.
    Article · Nov 2015
    • "In this sense, tight regulation of insulin levels seems to be mandatory to regulate central function. Central nervous system insulin receptors are highly expressed in regions associated to learning and memory, such as the cortex and the hippocampus and previous studies have reported that cognition impairment detected in type 1 diabetic children, might be related to hypoinsulinemia (Northam et al., 2001; Schoenle et al., 2002). Also, AD brains present lower insulin levels and higher insulin receptors density when compared to control patients (for review see (El Khoury et al., 2014)). "
    [Show abstract] [Hide abstract] ABSTRACT: Aging remains the main risk factor to suffer Alzheimer's disease (AD), though epidemiological studies also support that type 2 diabetes (T2D) is a major contributor. In order to explore the close relationship between both pathologies we have developed an animal model presenting both AD and T2D, by crossing APP/PS1 mice (AD model) with db/db mice (T2D model). We traced metabolic and cognitive evolution before T2D or AD pathology is present (4 weeks of age), when T2D has debuted but no senile plaques are present (14 weeks of age) and when both pathologies are well established (26 weeks of age). APP/PS1xdb/db mice showed an age-dependent synergistic effect between T2D and AD. Significant brain atrophy and tau pathology were detected in the cortex by 14 weeks, that spread to the hippocampus by 26 weeks of age. Severe cognitive impairment was also detected as soon as at 14 weeks of age. Interestingly, in APP/PS1xdb/db mice we observed a shift in Aβ soluble/insoluble levels, and whereas more toxic soluble species were favoured, senile plaques (SP) were reduced. An overall increase of microglia activation was observed in APP/PS1xdb/db mice. We also found exacerbated hemorrhagic burden in APP/PS1xdbd/db mice, suggesting that blood brain barrier alterations may be responsible for the early pathological features observed. Moreover, metabolic parameters can predict many of these alterations, supporting a role for T2D in AD pathology. This new model provides a relevant tool to further explore the relationship between T2D, AD and vascular implications, offering the possibility to assess therapeutic approaches, that by improving T2D metabolic control could delay or prevent AD pathology. Copyright © 2015 Elsevier Ltd. All rights reserved.
    Full-text · Article · Jul 2015
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