This study examined age-related changes in brain volume and T2 relaxation times across the whole brain using both volumetric and relaxometry magnetic resonance data. We found a negative relationship between age and brain volume and T2 relaxation time loss across large areas of the brain in participants with type 1 diabetes, whereas only minimal changes were evident in the healthy control subjects. These findings were confirmed by regional and voxel-based analyses, which showed greater regional and global age-related reductions in brain volumes and T2 relaxation time in type 1 diabetic participants compared with control subjects. The brain regions most affected in type 1 diabetic participants include the thalamus, lentiform nuclei, insula, and areas in the frontal and temporal lobes. The findings of greater volume and T2 relaxation time decrease with age (and later diabetes onset) are somewhat counterintuitive given conventional wisdom about the greater vulnerability of the very immature CNS and the consistent association between very early onset disease (i.e., younger than 5 to 6 years) and neurocognitive deficits (6
Volume loss and T2 reductions are characteristic of normal ageing, thus our findings could be interpreted as accelerated brain ageing. MRI studies of healthy individuals have shown that brain volume increases during childhood, reaching a maximum in adolescence, thereafter declining in a fairly linear fashion, with acceleration in the rate of decline at ~55 years of age (11
). T2 relaxation time also changes in an age-related manner across the life span. During early development, T2 relaxation time shortens, mainly reflecting the progression of myelination in WM. In addition, a decrease in T2 relaxation time in extrapyramidal structures such as the putamen and caudate nucleus, clearly evident from ~20 years of age, reflects age-dependent accumulation of iron (12
). It is interesting to note that the accelerated T2 reduction observed in the type 1 diabetic participants in this study includes several of these extrapyramidal brain regions, which therefore may indicate a modified rate of iron deposition in these subjects. Indeed, elevated levels of iron have been found in blood plasma in both type 1 and type 2 diabetes (13
), which may be due to modified turnover of erythrocytes (14
). The phenomenon of accelerated brain ageing in diabetes has previously been described by Biessels et al. (15
), but only in older adults, and particularly, but not exclusively, in reference to type 2 diabetes. To our knowledge, this is the first study to raise the possibility of such an effect in a population of youth with type 1 diabetes and a mean age of just 20 years.
Alternatively to a process of premature senescence, our findings might indicate some disruption to the final stages of neurodevelopment, in a process qualitatively different from the neurodegenerative changes postulated by Biessels et al. (15
). Type 1 diabetes, or an aspect of the disease, may affect neurodevelopment such that youth with the disease show less normative age-related increase in brain volume. This is consistent with the findings in a recent study in which the expected rate of increase in total WM volume during early development was not observed in a group of younger (3–10 years old) children with type 1 diabetes (16
). Diabetes-related effects on GM may occur later in neurodevelopment (i.e., during adolescence). Perantie et al. (5
) imaged a sample (mean age of ~12 years) and found no overall differences in GM volume between those with type 1 diabetes and healthy control subjects. In contrast, Musen et al. (17
) conducted voxel-based analyses of a sample of young adults with a mean age ~32 years and reported volume loss in frontal and temporal regions and left thalamus, brain regions that overlap considerably with our own findings (7
). Taken together, these findings suggest that late adolescence-early adulthood may be a critical period in which the GM volumes of youth with type 1 diabetes diverge from those of their healthy peers. This interpretation is consistent with Ryan’s diathesis hypothesis (18
), which posits that early exposure to hyperglycemia increases the vulnerability of the brain to subsequent CNS disruption.
The mechanisms underlying neural changes in our cohort with type 1 diabetes are unclear. Hyperglycemia is linked to excessive activation of the polyol pathway with resulting formation of advanced glycation end products and atrophy, as well as increased oxidative stress associated with cell death (4
). Alternatively, as a consequence of elevated blood glucose levels, the cells may become desensitized to glucose due to saturation of their metabolic activity, endoplasmic reticulum stress, or mitochondrial dysfunction. Glucose has been shown to act as a mitogen in some contexts such as human β-cells (19
). In a different context, hyperglycemia was shown to lead to myocyte cell death (20
) and to reduced cell differentiation in endothelial progenitor cells that is indicative of advanced cell senescence (21
). The effects observed in this study may suggest the existence of a cell-survival failsafe mechanism following sustained hyperglycemia in which glucotoxicity and apoptosis are avoided by desensitization to raised glucose levels such that the propensity for cell division is reduced. In addition, the interaction of age with diabetes demonstrated in this study may reflect diabetes-induced modulation of synaptic plasticity. In groups of young and aged rats exposed to streptozotocin-induced diabetes, the impairment in plasticity was shown to be greater in the older group, implying an interaction between ageing and plasticity-related dysfunction in a model of type 1 diabetes (22
It is important to note that the CNS changes that we demonstrated are subtle and of uncertain functional significance, although we have previously reported lower school completion rates in our cohort (7
). Scans were scrutinized by a neuroradiologist (A.M.), and three participants only had abnormalities that required clinical investigation, two of whom were control participants. Although meta-analyses of both children (6
) and adults (23
) with type 1 diabetes confirm subtle neurocognitive deficits, and there is increasing evidence of structural brain changes [see (24
) for review], the literature is difficult to interpret because of inconsistency across individual reports. Different methodologies and samples heterogeneous for age, age of disease onset, illness duration, and metabolic control history almost certainly contribute to inconsistent findings. We have previously reported that neurocognitive deficits were greater in those with early onset (<5 years) diabetes (7
), yet brain volume and T2 reduction was most evident in our older and later-onset participants. It is difficult to explain the lack of correspondence between structural CNS changes and functional neurocognitive deficits, but this disassociation has been reported before (3
). Lenroot and Giedd (26
) caution that relationships between brain structures and cognition are rarely straightforward even in healthy youth. In our cohort, constant exposure to abnormal glycemic variation may disrupt skill acquisition in the very young child even in the absence of structural CNS change, whereas subtle changes in brain structure may precede global cognitive difficulties in the participants who were older at disease onset.
It is possible that some, or all, of the pathophysiological processes described above have contributed to our findings of age-related brain volume loss and T2 reduction in type 1 diabetic participants. The selectively greater impact on our older participants suggests an interaction between disease effects and neurodevelopmental stage, but serial imaging of a diabetic cohort through childhood to CNS maturity in a controlled design would be necessary to confirm this. Further exploration to clarify age-related changes and the mechanisms underlying brain changes in type 1 diabetes in general are important though, as animal studies have indicated that adjunctive neuroprotective strategies may be possible using either systemic IGF-I (27
) or glucocorticoid receptor antagonists such as mifepristone (28
). These strategies, though promising, are either untried or nascent in the human context.
In the last 15–20 years, standards of care have improved vastly for young people with type 1 diabetes to the point that we rarely see evidence of traditional diabetes complications in pediatric diabetes clinics. The new frontier in diabetes research and care is to facilitate the pre-eminent developmental task of childhood and adolescence: optimal brain development and function.