Both measures of subclinical macroangiopathy were not statistically different between patients and controls. In all participants, a greater cIMT was associated with lower white matter tract integrity and functional connectivity. For cognition, an interaction between cIMT and proliferative retinopathy was noted. In patients without, but not with proliferative retinopathy, cIMT was negatively associated with cognition. Carotid stiffness was not associated with brain parameters in this study.
Subclinical macroangiopathy in T1DM
In this study there was no difference in either cIMT or cD between T1DM patients, irrespective of microvascular complication status, and controls. The difference between all patients and controls trended to be statistically significant. These findings are contrary to previous studies, which did observe increased cIMT in T1DM patients relative to controls [8, 9]. This could have been due to the lower sample size of this study compared to another . Alternatively, HbA1c levels in this study were lower than in the other studies, and levels of albuminuria were also lower in this study. Given the associations between higher HbA1c levels and albuminuria , this may explain the differences between studies.
Our negative findings with respect to cIMT between groups are in line with a recently published study in young adults with uncomplicated T1DM with a mean disease duration of 6 years . In that study circulating levels of soluble endothelial CD146 were increased in patients relative to controls and CD146 better differentiated between patients and controls. This suggests that CD146 may be a more sensitive marker for early cardiovascular disease than cIMT, although this is still speculative. The relationship between circulating CD146 and cerebral parameters, and its additive value to measures of cIMT and cD, is unknown. CD146 nervous system knockout mice displayed altered locomotor activity compared with their wildtype counterparts . Future studies should determine the effect of circulating and central levels of soluble CD146 on cognition and cerebral structure/functioning in human T1DM.
Based on previous observations, including those from the DCCT/EDIC study, that showed that albuminuria was among the predictors of progression in cIMT at 12 years of post-trial follow-up , we hypothesized the existence of an interaction between microangiopathy (mainly proliferative retinopathy in our population) and subclinical macroangiopathy. Accordingly, we expected that the co-existence of macro- and microangiopathy in T1DM patients would have the greatest impact on cognitive function and/or brain correlates. Instead, in our study population, a greater cIMT only influences brain variables in patients without microvascular complications. The results of this study are in line with the findings from the DCCT/EDIC study, that also showed that microvascular complications were a stronger predictor of cognitive decline in T1DM patients than cIMT .
Associations with brain parameters
A novel finding is that increased cIMT is related to lower white matter integrity and functional connectivity, i.e. neuronal communication, in certain brain regions. These findings seem to hold true both for those with and without T1MD. As this association is not disease specific it may well be related to aging, as both increased cIMT and loss of white matter integrity are seen with aging [13, 16, 17]. There were no interaction effects of subclinical macroangiopathy and proliferative retinopathy regarding these brain parameters. This may indicate that increased subclinical atherosclerosis in larger vessels has an effect on communication and structure within brain regions, but that retinal angiopathy has no overruling effect, such as found for cognitive performance. Performance on cognitive functions which were assessed in this study, rely on the integration of brain activity from multiple different brain regions, which all have to function properly . As such it may be speculated that proliferative retinopathy, which seems part of generalized microangiopathy as measured in the brain and finger , has consequences for the functioning of one or more brain regions and possibly also for the integration of activity, and thus for cognitive performance. Hence, the effect of subclinical atherosclerosis is overruled when proliferative retinopathy is present. On the other hand, white matter integrity and functional connectivity assessed here were more localized in specific brain regions. As they do not rely on many different cerebral areas or integration of functionality, the effect of disrupted microvasculature may be less pronounced.
In addition to measures of cognition, brain functioning and white matter integrity, the relationship between subclinical macroangiopathy and parameters of cerebral blood flow would have been of interest. A recently published [15O]H2O positron emission tomography (PET) study showed decreased blood flow in adult patients with asymptomatic T1DM relative to controls . These patients were free of clinically manifest macroangiopathy, but carotid ultrasound was not available. Unfortunately, measurements of cerebral blood flow were not included in the current study.
In this study no effects were found for carotid distensibility. Contrary, a previous case–control study showed that in middle-aged T1DM patients without or with mild microvascular complications (mostly background retinopathy), increased aortic stiffness was related to lower total brain white matter volume and increased prevalence of white matter hyperintensities, i.e. ischemic brain damage [21, 22]. Similarly, in elderly with type 2 diabetes (T2DM), both higher subclinical carotid atherosclerotic macroangiopathy and carotid-femoral pulse wave velocity were related to silent cerebral infarctions and white matter hyperintensities respectively. These associations were independent of confounding factors, including age, sex, lipid profile and blood pressure [10, 23]. The results of the current study, together with the results of the previously published studies support the notion that subclinical macroangiopathy is related to cognitive decrements and structural and functional brain deficits that are commonly observed in patients with either T1DM or T2DM. However, the effect sizes seem to be small to moderate, which may indicate that other factors, such as microvascular complications, may be more prominent in inducing cerebral functional and structural changes in diabetes.
The effects sizes of the observed associations were small to moderate, indicating a relatively moderate contribution of cIMT in T1DM-related cognitive dysfunction. From this study it cannot be determined why T1DM-related cerebral compromise in patients with proliferative retinopathy was not exacerbated by measures of subclinical macroangiopathy. However, based on our findings, one may speculate that early cognitive changes, i.e. before microvascular complications are present, may be in part mediated by increased cIMT, but that once microangiopathy has developed T1DM-related cerebral compromise, the effects of subclinical macrovascular disease is overruled. This differential effect of macro- and microvascular disease on CNS function and structure requires further study.
The cross-sectional nature of this study pertains us to draw causal conclusions. Other limitations may include that fact that our patient with proliferative retinopathy had longer disease duration and earlier disease onset age than their counterparts without complications, both of which could constitute a confounder. Therefore, we corrected for diabetes duration in the analyses in T1DM patients. Additional correction for diabetes onset age is not possible due to co-linearity between the two variables. But removing diabetes duration from the analyses and adding diabetes onset age yielded similar results. This may indicate that our findings are independent of disease duration and diabetes onset age. Furthermore, an early disease onset age (i.e. <7 years of age) has been hypothesised to have more adverse effects on the brain than an onset later in life . In this sample early age of onset had no effect on the associations of subclinical macroangiopathy and cerebral compromise. Here, we measured cIMT and cD of the common carotid artery, as it has been found a prognostic measure of cardiovascular disease [16, 25–27]. However, the internal carotid artery provides the main blood supply to the brain, whereas the common carotid artery also supplies the external carotid artery. Additionally examining the relationship between cIMT and cD of the internal carotid artery and brain parameters would have been of interest. Indeed, the Framingham study found stronger associations between internal carotid IMT and brain parameters than between common carotid IMT and brain measures . Future studies will have to determine this relationship in T1DM patients. Also plaque in the internal carotid artery could not be taken into account in this study. Strength of this study includes the relatively large number of well-characterised T1DM patients, especially regarding neuroradiological measurements, as well as the presence of a control group, and the combination of extensive neuropsychological assessment with neuroradiological measurements.